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US20200399714A1 - Cancer-related biological materials in microvesicles - Google Patents

Cancer-related biological materials in microvesicles Download PDF

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US20200399714A1
US20200399714A1 US17/014,540 US202017014540A US2020399714A1 US 20200399714 A1 US20200399714 A1 US 20200399714A1 US 202017014540 A US202017014540 A US 202017014540A US 2020399714 A1 US2020399714 A1 US 2020399714A1
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microvesicles
rna
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cells
dna
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Johan Karl Olov Skog
Leonora Balaj
Mikkel Noerholm
Xandra Breakefield
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General Hospital Corp
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    • C12Q1/6876Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
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Definitions

  • the present invention relates to the fields of biomarker analysis, diagnosis, prognosis, patient monitoring, therapy selection, risk assessment, and novel therapeutic agents for human or other animal subjects, particularly the profiling of biological materials from a microvesicle fraction of a biological sample, and novel therapies related to microvesicles.
  • Cancer-related changes include specific mutations in gene sequences (Cortez and Calin, 2009; Diehl et al., 2008; Network, 2008; Parsons et al., 2008), up- and down-regulation of mRNA and miRNA expression (Cortez and Calin, 2009; Itadani et al., 2008; Novakova et al., 2009), mRNA splicing variations, changes in DNA methylation patterns (Cadieux et al., 2006; Kristensen and Hansen, 2009), amplification and deletion of genomic regions (Cowell and Lo, 2009), and aberrant expression of repeated DNA sequences (Ting et al., 2011).
  • Various molecular diagnostic tests such as mutational analysis, methylation status of genomic DNA, and gene expression analysis may detect these changes.
  • tissue sample from a cancer patient because, frequently, fresh tissue samples are difficult or impossible to obtain, and archival tissue samples are often less relevant to the current status of the patient's disease.
  • a less invasive approach using a more easily accessible biological sample, e.g., a blood sample has wide ranging implications in terms of patient welfare, the ability to conduct longitudinal disease monitoring, and the ability to obtain expression profiles even when tissue cells are not easily accessible, e.g., in ovarian or brain cancer patients.
  • PBMC peripheral blood mononuclear cells
  • CTC circulating tumor cells
  • microvesicles can bud/bleb off the plasma membrane of cells, much like retrovirus particles (Booth et al., 2006), be released by fusion of endosomal-derived multivesicular bodies with the plasma membrane (Lakkaraju and Rodriguez-Boulan, 2008), or be formed as apoptotic bodies during programmed cell death (Halicka et al., 2000).
  • defective retrovirus particles derived from human endogenous retroviral (HERV) elements may be found within microvesicle populations (Voisset et al., 2008).
  • Microvesicles from various cell sources have been studied with respect to protein and lipid content (Iero et al., 2008; Thery et al., 2002; Wieckowski and Whiteside, 2006). They have also been observed to contain cellular RNAs and mitochondria DNA (Baj-Krzyworzeka et al., 2006; Guescini et al.; Skog et al., 2008; Valadi et al., 2007) and may facilitate the transfer of genetic information between cells and/or act as a “release hatch” for DNA, RNA, and/or proteins that the cell is trying to eliminate.
  • mRNA and miRNA in microvesicles are observed to be functional following uptake by recipient cells (Burghoff et al., 2008; Deregibus et al., 2007; Ratajczak et al., 2006; Skog et al., 2008; Valadi et al., 2007; Yuan et al., 2009) and it has also been shown that apoptotic bodies can mediate horizontal gene transfer between cells (Bergsmedh et al., 2001).
  • the present invention is directed to microvesicular nucleic acid profiles of microvesicle fractions obtained from a biological sample from a subject, methods for aiding in diagnosis, prognosis, patient monitoring, treatment selection, and risk assessment based on detecting the presence or absence of a genetic aberration in a nucleic acid profile, or changes in a polypeptide profile of a microvesicle fraction obtained from a biological sample from a patient, and therapeutic agents and methods of cancer treatment or prevention.
  • the present invention is based on the discovery of various types of cancer-related biological materials within microvesicles.
  • the biological materials within microvesicles from a biological sample may be characterized and measured, and the results this analysis may be used to aid in biomarker discovery, as well as in diagnosis, prognosis, monitoring, treatment selection, or risk assessment for a disease or other medical condition.
  • the biological materials are nucleic acids and the invention is a method for assaying a biological sample comprising the steps of: a) obtaining or using a microvesicle fraction from a biological sample from a subject; b) extracting nucleic acid from the fraction; and c) detecting the presence or absence of a biomarker in the extracted nucleic acid.
  • the biomarker is a genetic aberration that is associated with the diagnosis, prognosis, or determination of the status or stage of a disease or other medical condition in the subject.
  • the biomarker is a genetic aberration that is associated with a disease or other medical condition or with responsiveness to a specific therapy for the disease or other medical condition in the subject.
  • the biomarker is a genetic aberration that is associated with the subject's risk of developing a disease or other medical condition.
  • the genetic aberration is in or corresponds to a c-myc gene, a transposable element, a retrotransposon element, a satellite correlated gene, a repeated DNA element, a non-coding RNA other than miRNA, or a fragment of any of the foregoing.
  • the genetic aberration is in or corresponds to a transposable element listed in Table 4 or Table 5, or a fragment thereof.
  • the genetic aberration is in or corresponds to retrotransposon elements including LINE, SINE or HERV, or a fragment thereof.
  • the genetic aberration is in or corresponds to a retrotransposon element that is Line1 (L1), ALU, HERV-H, HERV-K, HERV-K6, HERV-W or HERV-C, or a fragment thereof.
  • the genetic aberration is in or corresponds to a satellite-correlated gene listed in Table 6, or a fragment thereof, a repeated DNA element listed in Table 8, or a fragment thereof; or a non-coding RNA listed in Table 9 (other than miRNA) or a fragment thereof.
  • the non-coding RNA for example, can be 7SL RNA.
  • the genetic aberration is in or corresponds to a cancer gene listed in Table 2 or 3, or a fragment thereof.
  • the biological material is protein or polypeptide and the invention is a method for assaying a biological sample from a subject comprising the steps of: a) obtaining or using a microvesicle fraction from a biological sample from a subject b) measuring a protein or polypeptide activity in the fraction; and c) determining whether the protein or polypeptide activity is higher or lower than a normal or average activity for the same protein or polypeptide.
  • an elevated or lowered activity is associated with a diagnosis, prognosis, status or stage of a disease or other medical condition in the subject.
  • an elevated or lowered activity is associated with a disease or other medical condition or with the subject's responsiveness to a specific therapy for the disease or other medical condition.
  • an elevated or lowered activity is associated with the subject's risk of developing a disease or other medical condition.
  • the polypeptide is an enzyme.
  • the polypeptide can be a reverse transcriptase and the method is to determine whether the reverse transcriptase activity is higher than a normal or average activity for reverse transcriptase.
  • the methods may further comprise a step of enriching the microvesicle fraction for microvesicles originating from a specific cell type.
  • the enrichment may be achieved, for example, by affinity purification with antibody-coated magnetic beads.
  • the biological sample from a subject can be a bodily fluid, e.g., blood, serum, plasma, or urine.
  • the subject can be a human subject.
  • the disease or other medical condition may be brain cancer such as medulloblastoma and glioblastoma, or melanoma.
  • the presence or absence of a biomarker in the extracted nucleic acid can be determined by various techniques, e.g., microarray analysis, PCR, quantitative PCR, Digital Gene Expression, or direct sequencing.
  • the present invention is a kit for genetic analysis of a microvesicle fraction obtained from a body fluid sample from a subject, comprising, in a suitable container, one or more reagents capable of hybridizing to or amplifying a nucleic acid corresponding to one or more of the genetic aberrations referenced above.
  • the present invention is an oligonucleotide microarray for genetic analysis of a microvesicle preparation from a body fluid sample from a subject, wherein the oligonucleotides on the array are designed to hybridize to one or more nucleic acids corresponding to one or more of the genetic aberrations referenced above.
  • the present invention is a profile of microvesicular nucleic acid derived from a bodily fluid sample from a subject.
  • the profile may be a genetic aberration in or corresponding to: a) cancer gene listed in Table 2 or 3, or a fragment thereof; b) a transposable element from the subject's genome, preferably an element listed in Table 4 or 5, or a fragment of any of the foregoing; c) a retrotransposon element from the subject's genome, preferably LINE, SINE or HERV, more preferably LINE1 (L1), ALU, HERV-H, HERV-K, HERV-K6, HERV-W or HERV-C, or a fragment of any of the foregoing; d) a satellite correlated gene from the subject's genome, preferably a satellite correlated gene listed in Table 6, or a fragment of any of the foregoing; e) an element of repeated DNA from the subject's genome, preferably an element listed in Table 8, or
  • the genetic aberration can be a species of nucleic acid, the level of expression of a nucleic acid, a nucleic acid variant; or a combination of any of the foregoing.
  • the genetic aberration may be an RNA expression profile.
  • the genetic aberration may be a fragment of a nucleic acid, and in some instances, the fragment contains more than 10 nucleotides.
  • the present invention is a method of identifying a potential new nucleic acid biomarker associated with a disease or other medical condition, status or stage of disease or other medical condition, a subject's risk of developing a disease or other medical condition, or a subject's responsiveness to a specific therapy for a disease or other medical condition.
  • the method comprises the steps of: a) obtaining or using a microvesicle fraction from a biological sample from a subject; b) extracting nucleic acid from the fraction; c) preparing a profile according to any of the above-described profiles; and d) comparing the profile of step c) to a control or reference profile and selecting one or more potential new biomarkers based on one or more differences between the profile of step c) and the control or reference profile.
  • the present invention is a method of treating a subject having a form of cancer in which cancer cells secrete microvesicles.
  • the method comprises administering to the subject a therapeutically effective amount of a composition including an inhibitor of microvesicle secretion; an inhibitor of a reverse transcriptase; a microvesicle neutralizer that neutralizes the pro-tumor progression activity of tumor microvesicles; or any combination of the forgoing.
  • the inhibitor of microvesicle secretion is an inhibitor of RAB GTPase which may be Rab 27a, Rab 27b or Rab 35.
  • the inhibitor of a reverse transcriptase is a nucleoside analog selected from the group comprising 3′-azido2′,3′-dideoxythymidine (AZT); 2′,3′-dideoxyinosine (ddI), 2′,3′-didehyro-3′-deoxythymidine (d4T); nevirapine and efavirenz.
  • the inhibitor of a reverse transcriptase is RNAi targeting the reverse transcriptase gene.
  • the microvesicle neutralizer is a biological agent that binds microvesicles and destroys the integrity of the microvesicles.
  • the present invention is a pharmaceutical composition
  • a pharmaceutical carrier a) an inhibitor of microvesicle secretion, particularly an inhibitor of RAB GTPase, and more particularly Rab 27a, Rab 27b or Rab 35); b) an inhibitor of reverse transcriptase, particularly a nucleoside analog, more particularly 3′-azido2′,3′-dideoxythymidine (AZT); 2′,3′-dideoxyinosine (ddI), 2′,3′-didehyro-3′-deoxythymidine (d4T); nevirapine, or efavirenz, or an RNAi targeting the reverse transcriptase gene; c) a microvesicle neutralizer that neutralizes the pro-tumor progression activity of tumor microvesicles, particularly a biological agent that binds microvesicles and destroys the integrity of the microvesicles; or d) a combination of any of the foregoing.
  • FIG. 1 shows a graph depicting the quantification, size distribution and RNA yield of microvesicles purified from the medulloblastoma cell line D384.
  • Each bar represents the number of particles of a certain size that are present in the media and are released by one cell over 48 hours (hrs). The sum refers to the total number of particles released by one cell over 48 hrs.
  • FIG. 2 shows a graph depicting the quantification, size distribution and RNA yield of microvesicles purified from the medulloblastoma cell line D425 in the same manner as in FIG. 1 .
  • FIG. 3 shows a graph depicting the quantification, size distribution and RNA yield of microvesicles purified from the medulloblastoma cell line D458 in the same manner as in FIG. 1 .
  • FIG. 4 shows a graph depicting the quantification, size distribution and RNA yield of microvesicles purified from the melanoma cell line Yumel 0106 in the same manner as in FIG. 1 .
  • FIG. 5 shows a graph depicting the quantification, size distribution and RNA yield of microvesicles purified from the glioblastoma cell line 20/3 in the same manner as in FIG. 1 .
  • FIG. 6 shows a graph depicting the quantification, size distribution and RNA yield of microvesicles purified from the glioblastoma cell line 11/5 in the same manner as in FIG. 1 .
  • FIG. 7 shows a graph depicting the quantification, size distribution and RNA yield of microvesicles purified from the normal fibroblast cell line HF19 in the same manner as in FIG. 1 .
  • FIG. 8 shows a graph depicting the quantification, size distribution and RNA yield of microvesicles purified from the normal fibroblast cell line HF27 in the same manner as in FIG. 1 .
  • FIG. 9 shows a graph depicting the c-Myc gene yields in terms of genomic DNA extracted from cells of the following cell lines: one normal human fibroblast line (HF19), one GBM line (11/5), one atypical teratoid rhabdoid tumor (AT/RT) line (NS224) and three medulloblastoma (MB) lines (D425, D458 and D384). Quantitative PCR was used to obtain c-Myc Ct values, which were normalized to GAPDH Ct values in the same preparation. The X-axis lists the names of the cell lines tested.
  • FIG. 10 shows a graph depicting the c-Myc gene yields in terms of RNA extracted from microvesicles secreted by cells of the same cell lines and in the same manner as in FIG. 9 . Quantitative Reverse Transcription PCR was used to obtain c-Myc RNA Ct values.
  • FIG. 11 shows a graph depicting the c-Myc gene yields in terms of DNA extracted from microvesicles secreted by cells of the same cell lines and in the same manner as in FIG. 9 . Quantitative PCR was used to obtain c-Myc DNA Ct values.
  • FIG. 12 shows a graph depicting the c-Myc gene yields in terms of RNA extracted from xenograft subcutaneous tumor cells.
  • the subcutaneous tumors were generated by xenografting medulloblastoma cells (MBT; D425 cell line) or epidermoid carcinoma (ECT; A431 cell line) cells in nude mice.
  • the X-axis refers to the different tumor-bearing mice characterized by the type of tumor cell and the tumor mass weight at sacrifice.
  • MBT tumor mass weights are as follows: MBT 1: 3.4 g; MBT 2: 1.7 g; MBT 3: 2.4 g; MBT 4: 2.9 g; and MBT 5: 1.7 g.
  • ECT tumor mass weights are as follows: ECT1 1.7 g; ECT 2: 2.3 g; ECT 3: 3.1 g; ECT 4: 1.9 g; and ECT 5: 2.2 g.
  • Ct values were normalized to GAPDH.
  • the Y-axis refers to the Ct values generated by quantitative reverse transcription PCR of the extracted RNA in each sample. For each RNA extract, two replicate qPCR were performed.
  • FIG. 13 shows a gel picture depicting the c-Myc gene yields in terms of RNA extracted from serum microvesicles from mice that bear subcutaneous tumors.
  • the subcutaneous tumors were generated by xenografting medulloblastoma cells (MBT; D425 cell line) in nude mice.
  • C-Myc product was amplified by reverse transcription PCR method using human c-Myc specific primers and the RNA extracted from serum microvesicles as templates.
  • the amplified c-Myc product should be 89 bp in length.
  • the amplified c-Myc products were resolved by electrophoresis in a 2% agarose gel and visualized with ethidium bromide staining.
  • the arrow points to the position where an 89 bp product appears on the agarose gel.
  • the lanes are referenced as follows: MW: DNA size marker; 1: MBT tumor mass weight of 3.4 g; 2: MBT tumor mass weight of 1.7 g; 3: MBT tumor mass weight of 2.4 g; 4: MBT tumor mass weight of 2.9 g; 5: MBT tumor mass weight of 1.7 g; NC: negative control where no RNA/cDNA was used.
  • FIG. 14 shows a gel picture depicting the c-Myc gene yields in terms of RNA extracted from serum microvesicles from mice that bear subcutaneous tumors in the same manner as in FIG. 13 except that the subcutaneous tumors were generated by xenografting epidermoid carcinoma (ECT; A431 cell line) in nude mice.
  • the lanes are referenced as follows: MW: DNA size marker; 1: ECT tumor mass weight of 1.7 g; 2: ECT tumor mass weight of 2.3 g; 3: ECT tumor mass weight of 3.1 g; 4: ECT tumor mass weight of 1.9 g; 5: ECT tumor mass weight of 2.2 g; NC: negative control where no RNA/cDNA was used.
  • FIG. 15 shows a MA plot depicting relative levels of all represented RNA sequences (using 44,000 RNA probes on the Agilent microarray chip) in cells and microvesicles derived from the cells. The levels of transposon and retrotransposon sequences were compared to the rest of the RNA transcriptome in cells and microvesicles.
  • ExoRNA and cellular RNA were isolated from GBM 20/3 cells and analyzed on an Agilent two-color 44 k array.
  • Y-axis (M) log 2 Exo ⁇ log 2 Cell
  • X-axis (A) 0.5 ⁇ (log 2 Exo+log 2 Cell).
  • FIG. 16 shows a MA plot similar to the plot in FIG. 15 except that the present plot only depicts relative levels of the following four HERV family sequences: HERV-H, HERV-K6, HERV-W and HERV-C, all of which are enriched in microvesicles more than 16-fold as compared to the host cells, i.e., M>4.
  • FIG. 17 shows a MA plot similar to the plot in FIG. 15 except that the present plot only depicts relative levels of DNA transposons.
  • FIG. 18 shows a MA plot similar to the plot in FIG. 15 except that the present plot only depicts relative levels of L1 sequences.
  • FIG. 19 shows a MA plot similar to the plot in FIG. 15 except that the present plot only depicts relative levels of HERV sequences with HERV-H, HERV-C, HERV-K6 and HERV-W being more than 16 fold enriched.
  • FIG. 20 shows a MA plot similar to the plot in FIG. 15 except that the present plot only depicts relative levels of Alu sequences.
  • FIGS. 21A, 21B and 21C show MA plots depicting relative expression levels of L1 ( FIG. 21A ), ALU ( FIG. 21B ) and HERV-K ( FIG. 21C ) RNA in cells and microvesicles derived from the cells.
  • qRT-PCR was carried out for retrotransposon elements in cell RNA and exoRNA from three medulloblastoma (D425, D384 and D458), one GBM (11/5), one melanoma (0106) and one human fibroblast (HF19) line.
  • the RNA expression levels were measured and normalized to GAPDH.
  • HERV-K RNA was not detectable in exoRNA from normal human fibroblasts (HF19), so it was given a Ct value of 36 (below detection limit).
  • FIG. 22 shows a chart depicting the expression levels of HERV-K at different time points in HUVEC cells.
  • the HUVEC cells were exposed to medulloblastoma D384 microvesicles and their expression level of HERV-K RNA was analyzed by qRT-PCR over 72 hrs following exposure. MOCK is non-exposed cells.
  • HERV-K was normalized to GAPDH. P values were calculated using the two-tailed t-test, comparing levels to MOCK infected cells.
  • FIGS. 23A, 23B and 23C show MA plots depicting relative levels of L1 ( FIG. 23A ), ALU ( FIG. 23B ) and HERV-K ( FIG. 23C ) DNA in cells and microvesicles derived from the cells.
  • q-PCR was carried out for retrotransposon elements with cell genomic DNA and microvesicle DNA from three medulloblastoma (D425, D384 and D458), one GBM (11/5), one melanoma (0106) and one human fibroblast (HF19) line.
  • FIG. 24 shows a chart depicting the Reverse Transcriptase (RT) activity in microvesicles secreted by three medulloblastoma (D425, D384 and D458), one GBM (11/5), one melanoma (0106) and one human fibroblast (HF19) line.
  • the RT activity was measured in the microvesicles using the EnzChek RT Assay Kit (Invitrogen) and normalized to protein content.
  • FIGS. 25A, 25B, 25C and 25D show charts depicting Bioanalyzer profiles of exoRNA and exoDNA from tumor or normal cell.
  • FIG. 25A depicts the profile of exoRNA from GBM 11/5 cells. Both 18S and 28S rRNA peaks are detectable (arrowheads).
  • FIG. 25B depicts the profile of exoDNA GBM 11/5 cells. Sizes ranged from 25 to 1000 nucleotides with a peak at 200 nt.
  • FIG. 25C depicts the profile of ExoRNA from human fibroblasts HF19, which was extracted and analyzed as in FIG. 25A . The RNA yield was too low to yield distinct 18S and 28S rRNA peaks. After concentration, these peaks were visible (data not shown).
  • FIG. 25D depicts the profile of ExoDNA from human fibroblasts HF19, which was not readily detectable on the Bioanalyzer even after it was concentrated 30 times. Bioanalyzer profiles were generated using the RNA Pico Chip (
  • FIGS. 26A and 26B show charts depicting the Bioanalyzer profiles of exoDNA from microvesicles isolated from medulloblastoma D384 cells.
  • FIG. 26A depicts the profile of exoDNA purified from externally DNase-treated microvesicles using the Agilent DNA 7500 bioanalyzer chip (Agilent Technologies Inc., Santa Clara, Calif. Cat. Number 5067-1506) that detects dsDNA.
  • FIG. 26B depicts the profile of exoDNA after a second-strand synthesis treatment. Here the same sample as in (A) was subjected to second strand synthesis with Superscript Double-Stranded cDNA synthesis kit (Invitrogen) according to manufacturer's recommendation.
  • FIG. 27 is an agarose gel picture depicting electrophoresis of GAPDH (112 bp) PCR products using templates from different samples.
  • the different samples were exoDNA samples extracted from microvesicles isolated from three medulloblastoma cell lines (D425, D384 and D556) and genomic DNA extracted from L2132 normal fibroblasts as a control double stranded DNA, all four of which were mock treated or treated with S1 nuclease enzyme which degrades single-stranded nucleic acids.
  • FIG. 28 depicts representative bioanalyzer profiles of exoDNA extracted from medulloblastoma cell line D384 before and after S nuclease treatment.
  • FIGS. 29A and 29B show charts depicting quantitative PCR results of c-Myc and POU5F1B, respectively, using as templates genomic DNA from cells or exoDNA extracted from microvesicles isolated from cells.
  • FIG. 29A depicts the results for c-Myc gene.
  • FIG. 29B depicts the results for POU5F1B, which gene sequence (AF268618) is found 319 kb upstream of the c-Myc gene in the genome, but still within the commonly amplified region in tumor cells.
  • the cell lines are medulloblastoma cell lines D458 and D384, glioblastomas (11/5), and fibroblasts HF19.
  • FIG. 30 illustrates the c-Myc copy number analysis results in tumor cell lines using an Affymetrix 250K SNP array.
  • the c-Myc genomic region was analyzed in medulloblastoma lines, D425, D458 and D384, as well as rhabdoid tumor line, NS224.
  • FIGS. 31A and 31B show charts depicting the qPCR results of the n-Myc gene in cells lines medulloblastoma D425, D458 and D384, rhabdoid tumor, GBM, and normal fibroblasts using genomic DNA FIG. 31A or exoDNA FIG. 31B extracted from microvesicles isolated from the cells as templates.
  • FIG. 32 shows a chart depicting the amount of exoDNA extracted from microvesicles isolated from medulloblastoma D384 cell culture media.
  • D384 cells were seeded in 6-well plates and treated with increasing dosages of L-mimosine (200, 400 and 600 ⁇ M) or mock treated.
  • Microvesicles were isolated from the medium after 48 hrs and ssDNA was extracted using the Qiagen PCR purification kit. Single-stranded DNA yields were quantified using the Bioanalyzer and the yields were compared to mock treated cells (normalized to 1.0).
  • FIG. 33 depicts the results of quantitative RT-PCR analysis of the expression levels of 7SL RNA, EGFR and GAPDH in microvesicles isolated from serum samples obtained from a GBM patient or a normal individual.
  • the X-axis is the number of PCR cycles.
  • the Y-axis is the fluorescent intensity (delta Rn) measured by the ABI7500 machine.
  • FIG. 34 depicts a series of signaling pathways related to cell proliferation, growth and/or survival.
  • cell-derived vesicles are heterogeneous in size with diameters ranging from about 10 nm to about 1 ⁇ m.
  • “exosomes” have diameters of approximately 30 to 100 nm, with shedding microvesicles and apoptotic bodies often described as larger (Orozco and Lewis, 2010).
  • Exosomes, shedding microvesicles, microparticles, nanovesicles, apoptotic bodies, nanoparticles and membrane vesicles co-isolate using various techniques and will, therefore, collectively be referred to throughout this specification as “microvesicles” unless otherwise expressly denoted.
  • the present invention is based on the discovery that cancer-related biological materials such as transposable elements, oncogenes, and reverse transcriptase (RT) can be detected in microvesicles.
  • cancer-related biological materials such as transposable elements, oncogenes, and reverse transcriptase (RT) can be detected in microvesicles.
  • the biological materials in microvesicles can be genetic materials, protein materials, lipid materials, or any combination of genetic, protein and lipid materials.
  • Genetic materials include nucleic acids, which can be DNA and its variations, e.g., double-stranded DNA (“dsDNA”), single-stranded DNA (“ssDNA”), genomic DNA, cDNA; RNA and its variations, e.g., mRNA, rRNA, tRNA, microRNA, siRNA, piwi-RNA, coding RNA, non-coding RNA, transposons, satellite repeats, minisatellite repeats, microsatellite repeats, Interspersed repeats such as short interspersed nuclear elements (SINES), e.g. but not limited to Alus, and long interspersed nuclear elements (LINES), e.g. but not limited to LINE-1, human endogenous retroviruses (HERVs), e.g. but not limited to HERV-K; or any combination of any of the above DNA and RNA species.
  • SINES short interspersed nuclear elements
  • LINES long interspersed nuclear elements
  • HERVs human endogenous retroviruse
  • Protein materials can be any polypeptides and polypeptide variants recognized in the art.
  • polypeptide as disclosed in this application refers to both a polypeptide without modifications and a polypeptide variant with modifications.
  • Polypeptides are composed of a chain of amino acids encoded by genetic materials as is well known in the art.
  • a reverse transcriptase is a polypeptide that can function as an enzyme to transcribe RNA into DNA.
  • Polypeptide variants can include, e.g.
  • Lipid materials include fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, fatty acids, glycerolipids, glycerophospholipids, sphingolipids, sterol lipids, prenol lipids, saccharolipids, and polyketides.
  • Microvesicles may be isolated from tissue, cells or other biological samples from a subject.
  • the biological sample may be a bodily fluid from the subject, preferably collected from a peripheral location.
  • Bodily fluids include but are not limited to blood, plasma, serum, urine, sputum, spinal fluid, pleural fluid, nipple aspirates, lymph fluid, fluid of the respiratory, intestinal, and genitourinary tracts, tear fluid, saliva, breast milk, fluid from the lymphatic system, semen, cerebrospinal fluid, intra-organ system fluid, ascitic fluid, tumor cyst fluid, amniotic fluid and combinations thereof.
  • the preferred bodily fluid for use as the biological sample is urine.
  • the preferred bodily fluid is serum.
  • subject is intended to include all animals shown to or expected to harbor nucleic acid-containing microvesicles.
  • the subject is a mammal, e.g., a human or nonhuman primate, a dog, cat, horse, cow, other farm animal, or rodent (e.g. a mouse, rat, guinea pig, etc.).
  • rodent e.g. a mouse, rat, guinea pig, etc.
  • the subject is an avian, amphibian or fish.
  • subject “individual” and “patient” are used interchangeably herein.
  • a profile refers to a set of data or a collection of characteristics or features, which can be determined through the quantitative or qualitative analysis of one or more biological materials, particularly biological materials contained in microvesicles isolated from a subject. The biological materials, extraction of the biological materials, and various types of analysis of the biological materials are described herein.
  • a control or reference profile is a profile obtained from the literature, from an independent subject or subjects, or from the same subject at a different time point.
  • the present invention includes a profile of one or more nucleic acids extracted from microvesicles.
  • the nucleic acids include both RNA and DNA.
  • a nucleic acid profile may be an RNA profile, a DNA profile, or may include profiles of both RNA and DNA.
  • the present invention includes a profile of one or more protein or polypeptide species extracted from microvesicles, particularly, a level of protein activity.
  • the RNA can be coding RNA, e.g., messenger RNA.
  • the RNA can also be non-coding RNA (ncRNA), e.g., ribosomal RNA (rRNA), transfer RNA (tRNA), microRNA, and other non-coding transcripts that may originate from genomic DNA. See Table 9 for more examples of non-coding RNA.
  • Non-coding RNA transcripts may include transcripts from satellite repeats or from transposons, which may be Class I retrotransposons or Class II DNA transposons.
  • the DNA can be single-stranded DNA, e.g., cDNA, which is reverse transcribed from RNA. Reverse transcription is usually mediated by reverse transcriptase encoded by a reverse transcriptase gene in a cell.
  • the DNA can also be single stranded DNA generated during DNA replication. Genomic DNA replicates in the nucleus while the cell is dividing. Some of the replicated DNA may come off its template, be exported out of the nucleus, and packaged into microvesicles. The DNA can further be fragments of double-stranded DNA.
  • the DNA can be non-coding DNA (ncDNA).
  • ncDNA non-coding DNA
  • the human genome contains only about 20,000 protein-coding genes, representing less than 2% of the genome. The ratio of non-coding to protein-coding DNA sequences increases as a function of developmental complexity (Mattick, 2004). Prokaryotes have less than 25% ncDNA, simple eukaryotes have between 25-50%, more complex multicellular organisms like plants and animals have more than 50% ncDNA, with humans having about 98.5% ncDNA (Mattick, 2004)
  • ncRNAs Some of the ncDNA from the genome is transcribed into ncRNA. NcRNAs have been implicated in many important processes in the cell, e.g., enzymes (ribozymes), binding specifically to proteins (aptamers), and regulating gene activity at both the transcriptional and post-transcriptional levels. Examples of ncRNA classes and examples of their functions are shown in Table 9.
  • Ribonuclease P is a ribozyme which is involved in maturation of tRNA by cleaving the precursor tRNA, and nuclear RNaseP can also act as a transcription factor (Jarrous and Reiner, 2007).
  • RNase P Ribonuclease P
  • nuclear RNaseP can also act as a transcription factor
  • bifunctional RNAs have also been described that function both as mRNA and as regulatory ncRNAs (Dinger et al., 2008) or have two different ncRNA functions (Ender et al., 2008).
  • RNA transcript expressed by the inactive X-chromosome, which is used to silence the extra X-chromosome in females (Ng et al., 2007). This RNA transcript binds to and inactivates the same X chromosome from which it is produced.
  • HOX antisense intergenic RNA (HOTAIR) (Rinn et al., 2007). This RNA is expressed from chromosome 12, but controls gene expression on chromosome 2, affecting the skin phenotype on different parts of the body surface (Rinn et al., 2007) and also being involved in cancer metastasis (Gupta et al., 2010).
  • PCA3 a biomarker for prostate cancer (Day et al., 2011).
  • PCA3 can be readily measured in the RNA from urine microvesicles which can be extracted using a rapid filtration concentrator method (Miranda et al., 2010; Nilsson et al., 2009).
  • PCGEM1 Another biomarker for prostate cancer is PCGEM1, which is an ncRNA transcript over-expressed in prostate cancer (Srikantan et al., 2000).
  • ncRNA is NEAT2/MALAT1, which has been found to be upregulated during metastasis of non-small cell lung cancer, and was correlated with poor patient survival (Ji et al., 2003).
  • Microvesicles contain a substantial array of the cellular gene expression profile from the cells from which they originate (their parent cells) at any given time. That is, substantially all the RNAs expressed in the parent cell are present within the microvesicle, although the quantitative levels of these RNAs may differ in the microvesicle compared to the parent cell. Substantially all the genes from the parent cell can, therefore, be tracked in the microvesicle fraction.
  • microvesicles contain DNA from the parent cell, which corresponds to diagnostically relevant aspects of the subject's genome. Therefore, a nucleic acid profile from microvesicles may be associated with a disease or other medical condition.
  • the disease is a neurological disease or other medical condition, e.g., Alzheimer's disease.
  • the nucleic acid profile for Alzheimer's disease may be a profile of early-onset familial Alzheimer's disease, associated genes including, but not limited to, amyloid beta (A4) precursor protein gene, presenilin 1 and presenilin 2.
  • A4 amyloid beta
  • the disease is a cancer.
  • the microvesicular nucleic acid profile for cancer may, e.g., include nucleic acids of one or more cancer-related genes (e.g., known or suspected oncogenes or tumor suppressor genes; or genes whose expression levels correlate with the expression levels of nearby satellites).
  • the determination of a cancer nucleic acid profile, including such cancer related genes, can aid in understanding the status of the cancer cells.
  • the oncogenes or tumor suppressor genes are one or more of those listed in Tables 2 and 3.
  • the cancer-related genes are one or more of those genes whose expression levels correlate with the expression levels of nearby satellites, such as but not limited to the satellite correlated genes listed in Table 6.
  • the cancer-related gene is c-myc.
  • the copy number of c-myc oncogene is usually increased in tumor cells, e.g., medullablastoma cells.
  • the detection of increased c-myc gene copy number in microvesicles indicates an increased c-myc copy number in tumor cells that secret the microvesicles.
  • the cancer-related gene is one or more members in the signaling pathways depicted in FIG. 34 .
  • These signaling pathways control the growth, proliferation and/or survival of cells (Alessi et al., 2009; Dowling et al.; Hanahan and Weinberg, 2000; Sarbassov et al., 2006).
  • These pathways are sometimes cross-linked to each other, and thus enable extracellular signals to elicit multiple biological effects.
  • the growth promoting Ras protein interacts with the survival promoting PI3K and thus growth signals can concurrently evoke survival signals in the cell (Hanahan and Weinberg, 2000).
  • the member is from the RAS/RAF/MEK/MAPK pathway related to melanoma, brain and lung cancers.
  • the MAP kinase is a convergence point for diverse receptor-initiated signaling events at the plasma membrane.
  • the RAS/RAF/MEK/MAPK pathway regulates cell proliferation, differentiation, migration and invasion (Hanahan and Weinberg, 2000).
  • extracellular signal-regulated kinases (ERKs) become activated upon integrin ligation and, thereby, regulate cell migration (Klemke et al., 1997).
  • the member is from the PI3K/PTEN/AKT pathway related to prostate, bladder and kidney cancers.
  • the PI3K/PTEN/AKT pathway is responsible for regulating cell survival (Cheng et al., 2008).
  • Genetic variations in AKT1, AKY2, PIK3CA, PTEN, and FRAP1 are associated with clinical outcomes in patients who receive chemoradiotherapy (Hildebrandt et al., 2009). Therefore, the determination of genetic variations in members of the pathway may help evaluating cancer treatment efficacy.
  • microvesicular nucleic acid profile of the present invention may also reflect the nucleic acid profile of DNA repeats and/or transposable elements in cells from which the microvesicles originate.
  • DNA repeats include one or more repeated DNA elements that are composed of arrays of tandemly repeated DNA with the repeat unit being a simple or moderately complex sequence.
  • the array of tandemly repeated DNA can be of varying size, thereby giving rise to categories of megasatellite, satellite, minisatellite and microsatellite repeats. See Table 7.
  • Repeated DNA of this type is not transcribed and accounts for the bulk of the heterochromatic regions of the genome, being notably found in the vicinity of the centromeres (i.e., pericentromeric heterochromatin).
  • the base composition, and therefore density, of such DNA regions is dictated by the base composition of constituent short repeat units and may diverge from the overall base composition of other cellular DNA.
  • the nucleic acid profiles of the present invention comprising satellite repeats may include profiles of satellite repeat DNA and/or profiles of transcripts that are transcribed from satellite repeats.
  • DNA repeats may serve as biomarkers of cancer cells.
  • some satellite repeats like HSATII are over-expressed in many types of cancers including pancreatic, lung, kidney, ovarian and prostate cancers (Ting et al., 2011).
  • the RNA expression level of such satellite repeats correlates with cancer disease status.
  • DNA repeats encompassed within the scope of the present invention can be one or more of those recited in Table 8.
  • the DNA repeats may be HSATII, ALR, (CATTC) n , or a combination of the HSATII, ALR, and (CATTC) n .
  • Transposable elements encompassed within the scope of the present invention may be one or more DNA transposons and/or retrotransposons.
  • the retrotransposon can be one or more of those recited in Tables 3 and 4.
  • the retrotransposon can be one or more LINEs, Alus, HERVs or a combination of the LINEs, Alus and HERVs.
  • Transposable elements can serve as biomarkers of cancer cells. These repetitive elements constitute almost 50% of the human genome and include: half a million LINE-1 (L1) elements, of which about 100 are transcriptionally active and encode proteins involved in retrotransposition, including reverse transcriptase (RT) and integrase; a million Alu elements, which depend on L1 functions for integration; and thousands of provirus HERV sequences, some of which contain near-to-full length coding sequences (Goodier and Kazazian, 2008; Voisset et al., 2008).
  • L1 LINE-1
  • RT reverse transcriptase
  • Alu elements which depend on L1 functions for integration
  • provirus HERV sequences some of which contain near-to-full length coding sequences (Goodier and Kazazian, 2008; Voisset et al., 2008).
  • retrotransposon genes and/or endogenous reverse transcriptase are sometimes associated with cancer.
  • human LINE-1 p40 protein is often expressed at a higher level in breast cancer than in normal mammary gland (Asch et al., 1996).
  • the microvesicular nucleic acid profiles of retrotransposable elements are suitable for use in aiding the diagnosis, prognosis, and/or monitoring of medical conditions such as cancer, as well as for use in aiding in treatment selection for therapies whose efficacy is affected by the subject's genetic make-up.
  • the microvesicular profile(s) of retrotransposable element(s) are determined by analyzing the content of microvesicles originating from brain cancer, e.g., medullablastoma, glioblastoma, lymphoma, and breast cancer cells.
  • the profile comprises one or more RNA expression levels of L1, Alu and HERV elements.
  • the profile comprises one or more DNA levels of L1 and HERV elements.
  • the profile comprises a profile of the HERV-K element.
  • the profile may comprise the expression of the HERV-K element in microvesicles isolated from plasma from a subject.
  • the expression of the HERV-K element may be assessed by determining the expression of any gene that the HERV-K element may encode, e.g., the group-specific antigen gene (gag), the protease gene (prt), the polymerase gene (pol), and the envelope gene (env) (Lower et al., 1996).
  • the present invention may comprise a profile of the expression of the gag gene in microvesicles.
  • the gag gene is from the HERV-K element and the profile of gag expression reflects the profile of HERV-K expression.
  • the expression of the gag gene can be measured by methods known in the art, e.g., quantitative reverse transcription PCR analysis.
  • the present invention may comprise a profile of the expression of the env gene in microvesicles.
  • the env gene is from the HERV-K element and the profile of env expression reflects the profile of HERV-K expression.
  • the expression of env gene can be measured by methods known in the art, e.g., quantitative reverse transcription PCR analysis.
  • the nucleic acid profiles of the present invention may also comprise the copy number of one or more nucleic acids, the fusion of several nucleic acids, the mutations of one or more nucleic acids, the alternative splicing of one or more nucleic acids, the methylation of one or more nucleic acids, and the single nucleotide polymorphism of one or more nucleic acids.
  • the nucleic acids may correspond to genes, repeats, transposable elements, or other non-coding parts of the genomes of various organisms, including human beings.
  • the present invention encompasses all forms of cancer and pre-cancerous conditions.
  • the present invention encompasses cancer and pre-cancer cells in brain, esophagus, lung, liver, stomach, ovary, testicle, kidney, skin, colon, blood, prostate, breast, uterus, and spleen.
  • the profile of nucleic acids can be obtained through analyzing nucleic acids obtained from isolated microvesicles according to standard protocols in the art.
  • the nucleic acid is DNA.
  • the analysis of the DNA may be performed by one or more various methods known in the art, including microarray analysis for determining the nucleic acid species in the extract, Quantitative PCR for measuring the expression levels of genes, DNA sequencing for detecting mutations in genes, and bisulfite methylation assays for detecting methylation patterns of genes.
  • data analysis may be performed by any of a variety of methods know in the art, e.g., Clustering Analysis, Principle Component Analysis, Linear Discriminant Analysis, Receiver Operating Characteristic Curve Analysis, Binary Analysis, Cox Proportional Hazards Analysis, Support Vector Machines and Recursive Feature Elimination (SVM-RFE), Classification to Nearest Centroid, Evidence-based Analysis, or a combination thereof.
  • Clustering Analysis Principle Component Analysis
  • Linear Discriminant Analysis Linear Discriminant Analysis
  • Receiver Operating Characteristic Curve Analysis Binary Analysis
  • Cox Proportional Hazards Analysis Support Vector Machines and Recursive Feature Elimination (SVM-RFE)
  • SVM-RFE Support Vector Machines and Recursive Feature Elimination
  • the nucleic acid extracted and analyzed from the microvesicles is RNA.
  • the RNA may be subject to Digital Gene Expression (DGE) analysis (Lipson et al., 2009).
  • DGE Digital Gene Expression
  • the RNA may be digested and converted into single stranded cDNA which may then be subject to sequencing analysis on a DNA sequencing machine, e.g., the HeliScopeTM Single Molecule Sequencer from Helicos BioSciences as described in a publication by Ting et al. (Ting et al., 2011).
  • the RNA is preferably reverse-transcribed into complementary DNA (cDNA) before further amplification.
  • cDNA complementary DNA
  • reverse transcription may be performed alone or in combination with an amplification step.
  • a method combining reverse transcription and amplification steps is reverse transcription polymerase chain reaction (RT-PCR), which may be further modified to be quantitative, e.g., quantitative RT-PCR as described in U.S. Pat. No. 5,639,606, which is incorporated herein by reference for this teaching.
  • Another example of the method comprises two separate steps: a first step of reverse transcription to convert RNA into cDNA and a second step of quantifying the amount of cDNA using quantitative PCR.
  • Nucleic acid amplification methods include, without limitation, polymerase chain reaction (PCR) (U.S. Pat. No. 5,219,727) and its variants such as in situ polymerase chain reaction (U.S. Pat. No. 5,538,871), quantitative polymerase chain reaction (U.S. Pat. No. 5,219,727), nested polymerase chain reaction (U.S. Pat. No.
  • PCR polymerase chain reaction
  • U.S. Pat. No. 5,219,727 in situ polymerase chain reaction
  • quantitative polymerase chain reaction U.S. Pat. No. 5,219,727
  • nested polymerase chain reaction U.S. Pat. No.
  • nucleic acid amplification is not performed. Instead, the extracted nucleic acids are analyzed directly, e.g., through next-generation sequencing.
  • the analysis of nucleic acids present in the isolated microvesicles can be quantitative, qualitative, or both quantitative and qualitative.
  • amounts (expression levels), either relative or absolute, of specific nucleic acids of interest within the isolated microvesicles are measured with methods known in the art (some of which are described below).
  • species of specific nucleic acids of interest within the isolated particles, whether wild type or variants, are identified with methods known in the art.
  • the present invention further encompasses methods of creating and using the microvesicular nucleic acid profiles described herein.
  • a method for creating a microvesicular profile comprises the steps of isolating microvesicles from a biological sample (e.g., from a body fluid) obtained from a subject or obtaining a microvesicle fraction isolated from a biological sample obtained from a subject, extracting nucleic acids from the isolated microvesicles or microvesicle fraction (or obtaining such as extraction), and determining the profile of the nucleic acids in the extract.
  • a biological sample e.g., from a body fluid
  • extracting nucleic acids from the isolated microvesicles or microvesicle fraction or obtaining such as extraction
  • microvesicular profiles of the present invention may be used in methods of aiding diagnosis, prognosis, monitoring, therapy selection, or risk assessment of a disease or other medical condition for a subject as described herein and in the claims.
  • the one or more nucleic acid(s) may be one or more genes listed in Table 2 (cancer genes), Table 3 (cancer-related somatic mutations) and Table 6 (satellite-correlated genes).
  • the one or more nucleic acid(s) may be a fragment of a c-myc gene, for example, a fragment of c-myc gene containing more than 10 nucleotides. The fragment may contain incrementally longer sequences of 15, 20, 25, 30, 35, 40, 45, 50, 55, 60 nucleotides, up to the full length of the gene.
  • the one or more nucleic acids may be one or more sequences listed in Table 4 (GBM transposable elements), Table 5 (human transposable elements) and Table 8 (repeated DNA).
  • the one or more nucleic acids may be L1, Alu, HERV, fragments thereof, or any combination of any of the foregoing.
  • the fragment may contain incrementally longer sequences of 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60 nucleotides up to the full length of each gene sequence.
  • the invention comprises microvesicular profiles and methods based on microvesicular polypeptide species, polypeptide activities, or both the species and activities of polypeptides.
  • the polypeptide may be any polypeptide in microvesicles.
  • the polypeptide is a reverse transcriptase.
  • the activity of the reverse transcriptase (RT) can be measured by standard protocols known in the art.
  • the RT activity can be measured by the EnzChek RT Assay Kit (Invitrogen).
  • the human endogenous retrovirus K (HERV-K) reverse transcriptase may serve as a breast cancer prognostic marker (Golan et al., 2008).
  • HERV-K human endogenous retrovirus K reverse transcriptase reverse transcriptase
  • one particular embodiment of the present invention encompasses profiles and related methods based on detecting the activity of HERV-K reverse transcriptase in microvesicles.
  • the present invention also includes a kit for genetic analysis of a microvesicle preparation from a biological sample (e.g., a bodily fluid sample) from a subject.
  • the kit in a suitable container may include one or more reagents capable of hybridizing to or amplifying one or more nucleic acids extracted from microvesicles.
  • the nucleic acids correspond to one or more of those genes listed in Tables 2, 3, 4, 5, 6 and/or 8.
  • the nucleic acids correspond to one or more RNA transcripts of one or more genes listed in Tables 2, 3, 4, 5, 6 and/or 8.
  • the nucleic acid is DNA corresponding to one or more of the genes listed in Tables 2, 3, 4, 5, 6 and/or 8.
  • the present invention further includes an oligonucleotide microarray for genetic analysis of a microvesicle preparation from a body fluid sample from a subject, wherein the various oligonucleotides on the array are designed to hybridize exclusively to nucleic acids corresponding to one or more genes listed in Tables 2, 3, 4, 5, 6 and/or 8.
  • the arrays can be made by standard methods known in the art. For example, SurePrint Technology (Agilent Technologies Corp.) may be used to make as many as 8 arrays on a single slide.
  • the present invention also includes a method of aiding the discovery of one or more biomarkers for a disease or other medical condition.
  • the method may comprise, e.g., the steps of isolating microvesicles from subjects having a disease or other medical condition of interest and also from subjects who do not have the disease or other medical condition of interest; measuring the level of one or more target biological materials extracted from the isolated microvesicles from each of the subjects; comparing the measured levels of the one or more target biological materials from each of the subjects; and determining whether there is a statistically significant difference in the measured levels.
  • the step of determination of a statistically significant difference in the measured levels identifies the one or more target biological materials as potential biomarkers for the disease or other medical condition.
  • the method may be carried out with pre-isolated microvesicle fractions.
  • the one or more biomarkers and nucleic acids in each of the various embodiments of the invention described herein can be one or a collection of genetic aberrations.
  • genetic aberration is used herein to refer to the nucleic acid amounts as well as nucleic acid variants within the nucleic acid-containing particles.
  • genetic aberrations include, without limitation, over-expression of a gene (e.g., an oncogene) or a panel of genes, under-expression of a gene (e.g., a tumor suppressor gene such as p53 or RB) or a panel of genes, alternative production of splice variants of a gene or a panel of genes, gene copy number variants (CNV) (e.g., DNA double minutes) (Hahn, 1993), nucleic acid modifications (e.g., methylation, acetylation and phosphorylations), single nucleotide polymorphisms (SNPs) (e.g., polymorphisms in Alu elements), chromosomal rearrangements (e.g., inversions, deletions and duplications), and mutations (insertions, deletions, duplications, missense, nonsense, synonymous or any other nucleotide changes) of a gene or a panel of genes, which mutations, in many cases, ultimately affect CNV
  • Genetic aberrations can be found in many types of nucleic acids. The determination of such genetic aberrations can be performed by a variety of techniques known to the skilled practitioner. For example, expression levels of nucleic acids, alternative splicing variants, chromosome rearrangement and gene copy numbers can be determined by microarray analysis (see, e.g., U.S. Pat. Nos. 6,913,879, 7,364,848, 7,378,245, 6,893,837 and 6,004,755) and quantitative PCR. Particularly, copy number changes may be detected with the Illumina Infinium II whole genome genotyping assay or Agilent Human Genome CGH Microarray (Steemers et al., 2006).
  • Nucleic acid modifications can be assayed by methods described in, e.g., U.S. Pat. No. 7,186,512 and patent publication WO/2003/023065. Particularly, methylation profiles may be determined by Illumina DNA Methylation OMA003 Cancer Panel.
  • SNPs and mutations can be detected by hybridization with allele-specific probes, enzymatic mutation detection, chemical cleavage of mismatched heteroduplex (Cotton et al., 1988), ribonuclease cleavage of mismatched bases (Myers et al., 1985), mass spectrometry (U.S. Pat. Nos.
  • SSCP single strand conformation polymorphism
  • DGGE denaturing gradient gel electrophoresis
  • TGGE temperature gradient gel electrophoresis
  • RFLP restriction fragment length polymorphisms
  • OPA oligonucleotide ligation assay
  • ASPCR allele-specific PCR
  • Nucleic acid sequencing is to determine the base pair sequences of nucleic acids.
  • Two traditional techniques for sequencing DNA are the Sanger dideoxy termination method (Sanger et al., 1977) and the Maxam-Gilbert chemical degradation method (Maxam and Gilbert, 1977). Both methods deliver four samples with each sample containing a family of DNA strands in which all strands terminate in the same nucleotide.
  • Gel electrophoresis, or more recently capillary array electrophoresis is used to resolve the different length strands and to determine the nucleotide sequence, either by differentially tagging the strands of each sample before electrophoresis to indicate the terminal nucleotide, or by running the samples in different lanes of the gel or in different capillaries.
  • Gene expression levels may be determined by the serial analysis of gene expression (SAGE) technique (Velculescu et al., 1995), quantitative PCR, quantitative reverse transcription PCR, microarray analysis, and next generation DNA sequencing as known in the art.
  • SAGE serial analysis of gene expression
  • biomarkers may be associated with the presence or absence of a disease or other medical condition in a subject. Therefore, detection of the presence or absence of such biomarkers in nucleic acids extracted from isolated microvesicles, according to the methods disclosed herein, may aid diagnosis of the disease or other medical condition in the subject.
  • detection of the presence or absence of the TMPRSS2-ERG fusion gene, PCA-3, or both TMPRSS2-ERG and PCA-3 in nucleic acids extracted from microvesicles isolated from a patient's urine sample may aid in the diagnosis of prostate cancer in the patient.
  • biomarkers may be associated with disease or medical status monitoring in a subject. Therefore, the detection of the presence or absence of such biomarkers in a nucleic acid extraction from isolated microvesicles, according to the methods disclosed herein, may aid in monitoring the progress or reoccurrence of a disease or other medical condition in a subject.
  • MMP matrix metalloproteinase
  • biomarkers have also been found to influence the effectiveness of treatment in a particular patient. Therefore, the detection of the presence or absence of such biomarkers in a nucleic acid extraction from isolated microvesicles, according to the methods disclosed herein, may aid in evaluating the efficacy of a given treatment in a given patient.
  • biomarkers e.g., mutations in a variety of genes, affect the effectiveness of specific medicines used in chemotherapy for treating brain tumors.
  • the identification of these and other biomarkers in nucleic acids extracted from isolated particles from a biological sample from a patient can guide the skilled practitioner in the selection of treatment for the patient.
  • all of the methods mentioned above may further comprise the step of enriching the isolated microvesicles for microvesicles originating from a specific cell type.
  • the cell can be a cancer or pre-cancer cell.
  • Another aspect of the present invention is a method of treating a subject suffering from a form of cancer in which the cancer cells secret microvesicles.
  • the method comprises administering to the subject a therapeutically effective amount of a composition comprising: an inhibitor of microvesicle secretion; an inhibitor of a reverse transcriptase; another microvesicle neutralizer that neutralizes the pro-tumor progression activity of tumor microvesicles; or any combination of the inhibitors/neutralizers.
  • the inhibitor of microvesicle secretion is an inhibitor of the Rab GTPase pathway (Ostrowski et al.).
  • the Rab GTPases are Rab 27a and Rab 27b.
  • the inhibition of the Rab 27a and Rab 27b can be effectuated by silencing the Slp4 gene (also known as SYTL4, synaptotagmin-like 4) and the Slac2b gene (also known as EXPH5, exophilin5), respectively.
  • Slp4 gene also known as SYTL4, synaptotagmin-like 4
  • Slac2b gene also known as EXPH5, exophilin5
  • Gene silencing techniques are well known in the art.
  • One example of such a gene silencing technique is an RNA interference technique that selectively silences genes by delivering shRNA with viral vectors (Sliva and Schnierle).
  • the Rab GTPase is Rab35.
  • the inactivation of Rab35 decreases microvesicle secretion. Therefore, silencing Rab35 may decrease the secretion of microvesicles by cells. Inactivation of Rab35 may be achieved by administering TBC1D10B (TBC1 domain family, member 10B) polypeptide (Sliva and Schnierle).
  • RT inhibitors may be any one of 3′-azido2′,3′-dideoxythymidine (AZT), 2′,3′-dideoxyinosine (ddI), 2′,3′-didehyro-3′-deoxythymidine (d4T), nevirapine and efavirenz.
  • a microvesicle neutralizer may be used to block the effects of microvesicles.
  • such neutralizer may bind to microvesicles and destroy the integrity of microvesicles so that the biological materials in microvesicles are not transferred to other intact cells.
  • the present invention may be as defined in any one of the following numbered paragraphs.
  • microvesicles produced by tumor cells from glioblastoma GBM
  • GBM glioblastoma
  • medulloblastoma a common and malignant tumor in children with frequent amplification of c-Myc
  • AT/RT atypical teratoid rhabdoid tumor
  • melanoma a peripheral tumor which can metastasize to the brain
  • GBM cell lines 20/3 and 11/5 were generated in our laboratory from tumor specimens kindly provided by Dr. Bob Carter (Massachusetts General Hospital), and diagnosed as GBM by a neuropathologist at Massachusetts General Hospital (Skog et al., 2008).
  • Glioblastoma cells were cultured in Dulbecco modified essential medium (DMEM; Invitrogen, Carlsbad, Calif.) containing 10% fetal bovine serum (FBS; JRH Biosciences, Carlsbad, Calif.), and penicillin and streptomycin (10 IU/ml and 10 ⁇ g/ml, respectively; Cellgro, Herndon, Va.).
  • DMEM Dulbecco modified essential medium
  • FBS fetal bovine serum
  • penicillin and streptomycin 10 IU/ml and 10 ⁇ g/ml, respectively; Cellgro, Herndon, Va.
  • medulloblastoma cell lines D458, D384 and D425, as well as rhabdoid AT/RT tumor cell line, NS224, were provided by Drs. Y.-J. Cho and S. L. Pomeroy (Children's Hospital, Boston, Mass.). All medulloblastoma cell lines were cultured in suspension in DMEM containing 10% FBS, 1 ⁇ GutaMAX (Invitrogen) and penicillin/streptomycin. Rhabdoid tumor cell line NS224 was cultured in suspension in DMEM/F12 containing B27 supplement, 20 ng/ml EGF, 20 ng/ml FGF and penicillin/streptomycin.
  • Melanoma cell line, Yumel 0106 was kindly provided by Dr. R. Halaban (Yale New Haven Hospital, New Haven, Conn.) and cultured in OptiMEM (Invitrogen) containing 10% FBS and penicillin/streptomycin.
  • Epidermoid carcinoma cell line, A431 was kindly provided by Huilin Shao (Massachusetts General Hospital) and cultured in DMEM containing 10% FBS and penicillin/streptomycin.
  • Normal human fibroblast lines, HF19 and HF27 were derived from human skin biopsies in the Breakefield laboratory; L2131 was derived in Dr. Christine Klein's laboratory (Univ. Lubeck, Lubeck, Germany) and cultured in DMEM supplemented with 10% FBS, 10 mM HEPES (Invitrogen) and penicillin/streptomycin. All cells were grown in media with 5% exosome-depleted fetal bovine serum (dFBS) (Skog et al., 2008). All cell lines were used over a few passages, as microvesicle yield tended to change over extended passages.
  • dFBS exosome-depleted fetal bovine serum
  • Nanosight LM10 nanoparticle tracking analysis To characterize the size distribution and amount of microvesicles released from tumor cells and normal fibroblasts in culture using Nanosight LM10 nanoparticle tracking analysis (NTA), we isolated microvesicles from the culture media of three medulloblastoma cell lines (D384, D425 and D458), one melanoma (Yumel 0106), two GBMs (20/3 and 11/5) and two normal fibroblasts (HF19 and HF27). The media was first spun at 500 ⁇ g for 10 min. The supernatant was removed and spun again at 16,500 ⁇ g, filtered through a 0.22 ⁇ m filter and used for Nanosight analysis.
  • NTA Nanosight LM10 nanoparticle tracking analysis
  • the nanosight LM10 nanoparticle characterization system (NanoSight Ltd, UK) equipped with a blue laser (405 nm) illumination was used for real-time characterization of the vesicles. The result is presented as the average ⁇ SEM of three independent experiments.
  • medulloblastoma cells released more microvesicles/cell than the other cells types analyzed.
  • the amount of microvesicles released by each cell type was: 13,400-25,300/cell/48 hrs for medulloblastomas ( FIGS. 1-3 ), 12,600/cell/48 hrs for the melanoma ( FIG. 4 ), 7,000-13,000/cell/48 hrs for the GBM cells ( FIGS. 5-6 ), and 3,800-6,200/cell/48 hrs for the normal human fibroblasts ( FIG. 7-8 ).
  • Normal human fibroblasts were of low passage and grew with similar rates as the tumor lines in culture, but were of larger size and hence greater surface area per cell.
  • RNA in the microvesicles released in the culture media from these cells we collected each conditioned medium after culturing for 48 hr and isolated microvesicles by differential centrifugation and filtration through a 0.22 ⁇ m filter followed by ultracentrifugation at 110,000 ⁇ g as detailed in WO 2009/100029.
  • microvesicle pellets generated from 39 ml conditioned medium produced from 0.5 ⁇ 10 6 -3.5 ⁇ 10 6 cells over 48 hours were resuspended in 50 ⁇ L PBS and incubated at 37° C. for 30 min with DNAse I (DNA-FreeTM kit, Ambion) and Exonuclease III (Fermentas, Glen Burnie, Md.), according to the manufacturer's instructions. After treatment, the enzymes were inactivated (using the kit's inactivation reagent and heat inactivation, respectively) and samples processed for RNA extraction.
  • DNAse I DNA-FreeTM kit, Ambion
  • Exonuclease III Fermentas, Glen Burnie, Md.
  • Microvesicles were lysed in 300 ⁇ l MirVana lysis buffer (Ambion, Austin, Tex.) followed by extraction with an equal amount of acid-phenol:chloroform. After centrifugation at 10,000 ⁇ g for 5 min, the upper aqueous phase was removed and further processed to extract RNA using the mirVana RNA isolation kit (Ambion), according to the manufacturer's instructions. RNA extracts were then treated with DNAse (DNA-free kit, Ambion) to exclude DNA carryover. RNA was quantified using a Nanodrop ND-1000 (Thermo Fisher Scientific, Waltham, Mass.) and the quantity and size ranges were evaluated using a 2100 Bioanalyzer (Agilent, Santa Clara, Calif.).
  • RNA 6000 Pico Chip kit detects mainly single strand nucleic acids, but can also detect double strand DNA when present in large amounts. As shown in FIGS.
  • the amount of RNA in microvesicles (exoRNA) from medulloblastoma cells was 120- to 310-fold higher than the amount of exoRNA from normal fibroblasts; the amount of exoRNA from glioblastoma cells was 2.8- to 6.5-fold higher than from normal fibroblasts; and the amount from exoRNA from melanoma cells was similar to that from normal fibroblasts even though melanoma cells shed more than twice as many microvesicles.
  • exoRNA microvesicles
  • RNA and DNA in microvesicles we isolated microvesicles from culture media of medulloblastoma cell line D384, glioblastoma cell line 11/5 and fibroblast cell line H19 as detailed in Example 1. Isolated microvesicles were treated extensively with DNase prior to nucleic acid extraction to reduce the chance of external DNA contamination. Isolated microvesicles may also be treated with RNase prior to nucleic acid extraction although such treatment did not affect the RNA yield from microvesicles probably due to the absence of any significant amounts of external RNA.
  • microvesicle pellets generated from 39 ml conditioned medium produced from 0.5 ⁇ 10 6 -3.5 ⁇ 10 6 cells over 48 hr were resuspended in 50 ⁇ L PBS and incubated at 37° C. for 30 min with DNAse I (DNA-FreeTM kit, Ambion) and Exonuclease III (Fermentas, Glen Burnie, Md.), according to manufacturer's instructions. After treatment, the enzymes were inactivated (using the kit's inactivation reagent and heat inactivation, respectively) and samples processed for DNA extraction.
  • DNAse I DNA-FreeTM kit, Ambion
  • Exonuclease III Fermentas, Glen Burnie, Md.
  • Microvesicles were lysed in 300 ⁇ l MirVana lysis buffer (Ambion, Austin, Tex.) followed by extraction with an equal amount of acid-phenol:chloroform. After centrifugation at 10,000 ⁇ g for 5 min, the upper aqueous phase was removed and further processed to extract DNA using the Qiagen PCR purification kit according to manufacturer's instructions. DNA extracts were then treated with RNase (e.g., RNase A, Fermentas, Glen Burnie, Md.) to exclude RNA carryover.
  • RNase e.g., RNase A, Fermentas, Glen Burnie, Md.
  • RNA 6000 Pico Chip kit detects mainly single stranded (“ss”) nucleic acids, but can also detect double-stranded DNA (dsDNA) when present in large amounts, while the DNA 7500 LabChip kit only detects dsDNA.
  • S1 nuclease 200 U/ml; Fermentas
  • Fermentas Fermentas
  • Genomic cell DNA was isolated from cells with the Flexigene DNA kit (Qiagen, Valencia, Calif.), according to manufacturers' recommendation.
  • RNA profile varied among cell types and culture conditions, but in general, RNA with intact 18S and 28S ribosomal peaks were isolated from microvesicles.
  • the DNA profile also varied among cell types. ExoDNA was much more abundant in microvesicles secreted by glioblastoma tumor cells ( FIG. 25B ) as compared to normal fibroblast cells ( FIG. 25D ).
  • exoDNA was primarily single stranded.
  • exoDNA from medulloblastoma tumor cells D384
  • a dsDNA detection chip no DNA was detected ( FIG. 26A ).
  • this same exoDNA was subjected to second strand synthesis, this same chip detected abundant dsDNA ( FIG. 26B ).
  • exoDNA extracted from microvesicles secreted by GBM cells GBM 20/3.
  • S1 exonuclease assays we isolated exoDNA from three medulloblastoma cell lines (D435, D384, D556) and gDNA from one normal human fibroblast cell line (L2132). Samples were incubated with S nuclease (200 U/ml) at 37° C. for 30 minutes or MOCK treated. PCR for the house-keeping gene GAPDH was then performed on treated and MOCK treated samples. S1 exonuclease specifically digests single stranded nucleic acids. As shown in FIG.
  • Example 3 c-Myc Oncogene Amplification in Cultured Medulloblastoma Tumor Cells can be Detected in Both exoRNA and exoDNA
  • c-Myc oncogene amplification using either exoRNA or exoDNA from medulloblastoma tumor cells.
  • exoRNA and exoDNA were extracted from culture media of three medulloblastoma cell lines (D458, D425 and D384), one atypical teratoid/rhabdoid (AT/RT) tumor cell line NS224, one glioblastoma cell line (11/5), and one normal fibroblast cell line H19 using the same method as detailed in Example 1, respectively.
  • the genomic DNA from each of the same cell lines was extracted according to standard protocols in the art, which can be found in books such as Molecular Cloning: A Laboratory Manual (3-Volume Set) Ed. Joseph Sambrook, David W. Russel, and Joe Sambrook, Cold Spring Harbor Laboratory, 3rd edition (Jan. 15, 2001), ISBN: 0879695773.
  • the extracted nucleic acids were then used in PCR analysis to measure the level of amplifications.
  • PCR analysis of exoRNA total exoRNA (50 ng) was converted into cDNA with the Sensiscript RT Kit (Qiagen) using random primers, according to the manufacturer's instructions, and a 1:20 fraction (corresponding to 2.5 ng reverse transcribed RNA) was used for quantitative PCR (qPCR).
  • qPCR quantitative PCR
  • Amplification conditions consisted of: (1) 1 cycle of 50° C., 2 min; (2) 1 cycle of 95° C., 10 min; (3) 40 cycles of 95° C., 15 sec; and 60° C., 1 min, and (4) a dissociation stage consisting of 1 cycle of 95° C., 15 sec; 60° C., 20 sec; and 95° C., 15 sec on the 7000 ABI Prism PCR system (Applied Biosystems).
  • Cycle threshold (“Ct”) values were analyzed in auto mode and manually inspected for accuracy. The Ct values of both RNA and DNA levels were normalized to the housekeeping gene GAPDH in each sample. Primer dimers were excluded by evaluation of dissociation curve and agarose gel electrophoresis.
  • n-Myc primers 1) Forward TCTACCCGGACGAAGATGAC (SEQ ID NO: 1), Reverse AGCTCGTTCTCAAGCAGCAT (SEQ ID NO: 2) (primers within exon 2); c-Myc primer: Forward TCAAGAGGCGAACACACAAC (SEQ ID NO: 3), Reverse TAACTACCTTGGGGGCCTTT (SEQ ID NO: 4) (both primers in exon 3); c-Myc primer: Forward CCTACCCTCTCAACGACAGC (SEQ ID NO: 5), Reverse CTCTGACCTTTTGCCAGGAG (SEQ ID NO: 6) (spanning intron 2).
  • c-Myc human specific primers Forward CAACCCTTGCCGCATCCAC (SEQ ID NO: 7), Reverse AGTCGCGTCCTTGCTCGG (SEQ ID NO: 8) (both primers in exon 1).
  • POU5F1B primers Forward ATCCTGGGGGTTCTATTTGG (SEQ ID NO: 9), Reverse CTCCAGGTTGCCTCTCACTC (SEQ ID NO: 10); and GAPDH primers: Forward CTCTGCTCCTCCTGTTCGAC (SEQ ID NO: 11) (exon 8), Reverse ACGACCAAATCCGTTGACTC (SEQ ID NO: 12) (exon 9).
  • c-Myc amplification was measured at the genomic level (gDNA) by qPCR ( FIG. 9 ). All three medulloblastoma cell lines had significant amplifications of c-Myc sequences (16-34-fold) compared to fibroblasts and other tumor cell types. RNA and DNA were extracted from microvesicles shed by these cell lines and quantitated by RT-PCR and PCR respectively, using primers in exon 3 with values for c-Myc sequences normalized to glyceraldehyde 3-phosphate dehydrogenase (GAPDH), a housekeeping gene constitutively expressed in cells and found in exoRNA 14 and here in exoDNA.
  • GPDH glyceraldehyde 3-phosphate dehydrogenase
  • Microvesicles from all medulloblastoma cell lines showed elevated levels of c-Myc sequences, both for exoRNA (8-45-fold) and exoDNA (10-25 fold), compared to microvesicles from fibroblasts and tumor cells with diploid c-Myc copy numbers ( FIGS. 10-11 ). Also, using primers that span a full intron, we successfully detected a 1.6 kb fragment corresponding to the unspliced c-Myc genomic DNA (verified by sequencing) in exoDNA from all three medulloblastoma cell lines, but not in any of the other cell lines.
  • n-Myc sequences in cellular genomic DNA (gDNA) or exoRNA were also measured by qPCR and qRT-PCR and none of the other tumor types showed genomic amplification of n-Myc sequences or elevated levels of n-Myc exoRNA ( FIGS. 31A and B).
  • c-Myc DNA quantitated for gDNA and exoDNA/RNA in these medulloblastoma lines were also compared to levels estimated by 250K single nucleotide polymorphism (SNP) analysis.
  • SNP single nucleotide polymorphism
  • genomic DNA was extracted from medulloblastoma cell pellets using the Puregene DNA Extraction Kit (Gentra Systems, Minneapolis, Minn.), according to the manufacturer's instructions.
  • To obtain signal intensities and genotype calls genomic DNA samples were digested, labeled and hybridized to Affymetrix 250K StyI SNP arrays, according to the manufacturer's protocol (Affymetrix, Santa Clara, Calif.).
  • c-Myc amplified human medulloblastoma cells
  • epidermoid carcinoma tumor cells non-amplified
  • c-Myc amplified human medulloblastoma cells
  • non-amplified epidermoid carcinoma tumor cells
  • RNA extraction Approximately 1 ml of blood was obtained from each mouse and allowed to clot at room temperature for 15 min and then centrifuged at 1300 ⁇ g for 10 min. The serum was then filtered through a 0.22 ⁇ m filter and stored at ⁇ 80° C. Samples were thawed and centrifuged for 1 hr at 100,000 ⁇ g to obtain microvesicles for RNA extraction, as described above.
  • microvesicles were isolated from serum samples in tumor-bearing mice and exoRNA was extracted from the isolated microvesicles.
  • Human c-Myc was detected in exoRNAs from 2/5 (40%) of the medulloblastoma-bearing mice ( FIG. 13 ) and from 0/5 (0%) of the epidermoid carcinoma-bearing mice ( FIG. 14 ).
  • microarray results have been deposited with a Geo accession number GSE13470.
  • the results indicate the presence of higher transcription levels of a number of retrotransposon sequences in exoRNA extracts as compared to cellular RNA extracts.
  • the microarray data was represented on a MA plot as the cumulative abundance (in microvesicles and cells) of specific RNAs (X-axis) and the relative ratio of these RNAs in microvesicles versus cells (Y-axis).
  • the Y-axis scale was log 2 , so RNAs above 4 or below ⁇ 4 on the Y-axis have at least a 16-fold different level in the microvesicles vs. cells.
  • M value above 4 There were many RNA species that were at least 16 fold more abundant in microvesicles than in cells
  • M value below ⁇ 4 There were many RNA species that were at least ⁇ 16 fold less abundant in microvesicles than in cells.
  • RNA from DNA transposons was similar in content in cells and microvesicles with the M values spreading between ⁇ 4 and 4.
  • RNA from retrotransposons e.g. HERV, Alu and L1
  • HERV-H was the most abundant and microvesicle-enriched in these GBM cells, followed by HERV-C, HERV-K6 and HERV-W. Therefore, some retrotransposon RNAs, e.g., HERV RNA, may be selectively packaged or enriched, in tumor microvesicles.
  • L1 and HERV-K retrotransposons, as well as Alu elements have been implicated in tumor progression, we further assayed their levels in cellular RNA and exoRNA from tumor and normal cells by qRT-PCR (again with the caveat that the primers used only detect a subset of these sequences). See FIGS. 21A-C .
  • the expression levels were normalized to that of the GAPDH mRNA.
  • L1 and Alu sequences were abundant in both cells and microvesicles (high values on the X-axis) and enriched in most of the microvesicles compared to the cells (M>0). The levels of retrotransposon sequences tended to be higher in exoRNA vs.
  • HERV-K RNA was not detectable in exoRNA from normal human fibroblasts (HF19), with a Ct value of 36 (below detection limit). This difference between levels of HERV-K RNA in microvesicles from fibroblasts and tumor cells is shown in the MA plot ( FIG. 21C ).
  • the expression levels of the 7SL RNA, EGFR and GAPDH were determined using qRT-PCR following a procedure as detailed in Example 3.
  • the primers used for the qRT-PCR are as follows: 7SL-RNA: Forward primer 5′ CAAAACTCCCGTGCTGATCA 3′ (SEQ IDNO: 13), Reverse primer 5′ GGCTGGAGTGCAGTGGCTAT 3′ (SEQ ID NO: 14), Probe (FAM labeled MGB probe), 5′ TGGGATCGCGCCTGT 3′ (SEQ ID NO: 15); EGFR: Forward primer 5′ TATGTCCTCATTGCCCTCAACA 3′ (SEQ IDNO: 16), Reverse primer 5′ CTGATGATCTGCAGGTTTTCCA 3′ (SEQ ID NO: 17), Probe (FAM labeled MGB probe), 5′ AAGGAATTCGCTCCACTG 3′ (SEQ ID NO: 18); GAPDH, huGAPDH ID 4326317E from the vendor Applied Biosystems Inc.
  • the expression levels of the 7SL RNA in microvesicles from GBM serum samples were about 200 times higher than the levels from normal serum samples.
  • the expression levels of EGFR in microvesicles from GBM serum samples were about 2 times higher than the levels from normal serum samples.
  • the expression levels of GAPDH in microvesicles from GBM serum samples were roughly the same as the levels in normal serum samples.
  • one aspect of the present invention is directed to the profile of 7SL RNA in microvesicles isolated from a subject, e.g., a human being.
  • the profile of 7SL RNA may be the expression profile of the 7SL RNA.
  • the profile of 7SL RNA may be correlated with the medical condition of the subject wherefrom the microvesicles are isolated.
  • Another aspect of the present invention is directed to a method of aiding the diagnosis, prognosis or selection of treatment therapy of a medical condition by determining the profile of the 7SL RNA.
  • the determination of the profile of 7SL RNA may be the determination of the expression profile of the 7SL RNA. Since the profile of 7SL RNA may be correlated with the medical condition of the subject wherefrom the microvesicles are isolated, the determination of the profile in microvesicles may therefore aid the diagnosis, prognosis or selection of treatment therapy for the subject.
  • human umbilical vein endothelial cells were exposed to microvesicles from medulloblastoma cells and levels of HERV-K RNA were measured in HUVEC cells over time.
  • Human umbilical vein endothelial cells (HUVEC) cells kindly provided by Dr. Jonathan Song (Massachusetts General Hospital), were cultured in gelatin—coated flasks in endothelial basal medium (Lonza, Walkersville, Md.) supplemented with hEGF, hydrocortisone, GA-1000 and FBS (Singlequots from Lonza). All cell lines were used over a few passages, as microvesicle yield tended to change over extended passages.
  • HUVEC cells were seeded in 12-well plates at a density of 1.5 ⁇ 10 5 cells/well.
  • Microvesicles were isolated from 1.2 ⁇ 10 7 D384 cells over a 48 hour period and added to each well in a total volume of 400 ⁇ l DMEM.
  • Mock treated cells were incubated in 400 ⁇ l exosome-free DMEM.
  • the cells were incubated for 2 hrs at 37° C. and were then replenished with 1.5 ml DMEM (with 5% dFBS).
  • Cells were collected at different time points after the microvesicle exposure and cell RNA was extracted for qRT-PCR analysis. The result is presented as the average ⁇ SEM of three independent experiments.
  • HERV-K RNA expression was increased in HUVEC cells at 2, 6, 12, 24, 48 and 72 hours after microvesicle exposure.
  • the increased HERV-K RNA expression in HUVEC cells indicated that the microvesicles contained active HERV-K genes and such genes were transferred to the HUVEC cells.
  • ExoDNA was also analyzed at the retrotransposon level with qPCR.
  • ExoDNAs were extracted from microvesicles as detailed in Example 2.
  • gDNA were extracted from cells as detailed in Example 3.
  • the primers used for qPCR are as follows: GAPDH primers: Forward CTCTGCTCCTCCTGTTCGAC (SEQ ID NO: 19) (exon 8), Reverse ACGACCAAATCCGTTGACTC (SEQ ID NO: 20) (exon 9); L1 primers: Forward TAAGGGCAGCCAGAGAGAAA (SEQ ID NO: 21), Reverse GCCTGGTGGTGACAAAATCT (SEQ ID NO: 22); HERV-K6 primers: Forward GGAGAGAAGCTGTCCTGTGG (SEQ ID NO: 23), Reverse TGACTGGACTTGCACGTAGG (SEQ ID NO: 24); Alu primers: Forward CATGTGGGTTAGCCTGGTCT (SEQ ID NO: 25), Reverse TTCCCACATTGCGTCATTTA (S
  • the exoDNA levels were compared to nuclear gDNA isolated from the cells in MA plots.
  • the levels of exoDNA in microvesicles and gDNA in corresponding cells were normalized to levels of GAPDH.
  • the exoDNA (presumably originating from the cytoplasmic compartment) and gDNA (isolated from the nuclear compartment of the cells) showed clearly different patterns (M ⁇ 0).
  • L1 was slightly enriched in all medulloblastomas ( FIG. 23A ).
  • HERV-K DNA was enriched in two of the medulloblastomas (D425 and D384) ( FIG. 23C ).
  • Alu was not enriched in any of the medulloblastoma tested ( FIG. 23B ).
  • RT activity endogenous Reverse Transcription activity in exosomes.
  • RIPA buffer 50 mM Tris-HCl (pH 8); 150 mM NaCl, 2.5% sodium dodecyl sulfate, 2.5% deoxycholic acid, 2.5% Nonidet P-40] for 20 min at 4° C. Exosomal debris was removed by centrifugation at 14,000 ⁇ g for 15 min. Proteins were quantified by Bradford assay and diluted 1:6 for each RT reaction.
  • the RT assay was performed using the EnzCheck RT assay kit (Invitrogen) on a 25 ⁇ L reaction, as described by the manufacturer. Fluorescence signal of the samples was measured before and after the RT incubation. The difference between the two values indicates newly synthesized DNA. Serial dilutions of SuperScriptTM III First Strand (Invitrogen) were used as standards. The result is presented as the average ⁇ SEM of three independent experiments.
  • RT activities in the 0106, GBM11/5, GBM 20/3 and HF19 cells are significantly less than those in D384, D425 and D458 cells.
  • This decreased RT activities correlate well with the reduced levels of L1 and HERV-K exoDNA in 0106, GBM11/5, GBM 20/3 and HF19 cells (as shown by the negative values on the MA plots in FIGS. 23A and C).
  • Such correlation suggests that a fraction of exoDNA may be cDNA.
  • exoDNA might also include fragments of genomic DNA.
  • L-mimosine to inhibit DNA replication and examined whether the inhibition affected the yield of exoDNA. If the exoDNA yield is decreased after inhibition, it is very likely that exoDNA may contain fragments of genomic DNA.
  • D384 cells were plated on 6-well plates (2 ⁇ 10 6 cells/well) and treated with increasing amounts (200, 400 and 600 ⁇ M) of L-mimosine (Sigma-Aldrich, St. Louis, Mo.) which is an inhibitor of DNA replication.
  • L-mimosine Sigma-Aldrich, St. Louis, Mo.
  • the drug was added at one time point and 48 hrs after, the media was collected and processed for the isolation of microvesicles.
  • Cell viability was assessed by cell count using the Countess Automated Cell Counter (Invitogen). SsDNA yields are normalized to one.
  • the exoDNA yield in microvesicles was decreased by about 50% following inhibition of DNA replication with L-mimosine. Therefore, some of the exoDNA may also be fragments of genomic DNA generated during DNA replication and mitosis.
  • Chromo- Tumour Tumour Locuslink Protein some types types Cancer Symbol ID ID* band (somatic) (germline) syndrome ABL1 25 P00519 9q34.1 CML, ALL — — ABL2 27 P42684 1q24-q25 AML — — AF15Q14 57082 NP_065113 15q14 AML — — AF1Q 10962 Q13015 1q21 ALL — — AF3p21 51517 Q9NZQ3 3p21 ALL — — AF5q31 27125 NP_055238 5q31 ALL — — AKT2 208 P31751 19q13.1- Ovarian, — — q13.2 pancreatic ALK 238 Q9UM73 2p23 ALCL — — ALO17 57714 XP_290769 17q25.3 ALCL — — APC 324 P25054 5q21 Colorectal, Colorectal, Colorectal,
  • ⁇ D (large deletion) covers the abnormalities that result in allele loss/loss of heterozygosity at many recessive cancer genes.
  • ⁇ O (other) in the ‘mutation type’ column refers primarily to small in-frame deletions/insertions as found in KIT/PDGFRA, and larger duplications/insertions as found in FLT3 and EGFR. Note that where an inversion/large deletion has been shown to result in a fusions protein, these have been listed under translocations.
  • the Wellcome Trust Sanger Institute web version of the cancer-gene set can be found at http://www.sanger.ac.uk/genetics/CPG/Census/.
  • A amplification; AEL, acute eosinophilic leukaemia; AL, acute leukaemia; ALCL, anaplastic large-cell lymphoma; ALL, acute lymphocytic leukaemia; AML, acute myelogenous leukaemia; APL, acute promyelocytic leukaemia; B-ALL, B-cell acute lymphocytic leukaemia; B-CLL, B-cell lymphocytic leukaemia; B-NHL, B-cell non-Hodgkin's lymphoma; CLL, chronic lymphatic leukaemia; CML, chronic myeloid leukaemia; CMML, chronic myelomonocytic leukaemia; CNS, central nervous system; D, large deletion; DFSP, dermatofibrosarcoma protuberans; DLBCL, diffuse large B-cell lymphoma; Dom, dominant; E, epithelial; F, frameshift; GIST, gastrointestinal stromal tumour; J
  • transposable elements in GBM microvesicles GenBank Name Accession No. Homo sapiens transposon-derived Buster1 [NM_021211] transposase-like protein gene (LOC58486) Human endogenous retrovirus H [U88896] protease/integrase-derived ORF1, ORF2, and putative envelope protein mRNA, complete cds Human endogenous retrovirus type C oncovirus [M74509] sequence Human endogenous retroviral H protease/ [U88898] integrase-derived ORF1 mRNA, complete cds, and putative envelope protein mRNA, partial cds.
  • CBL Homo sapiens Cas-Br-M (murine) ecotropic
  • CBL retroviral transforming sequence
  • K Homo sapiens endogenous retroviral sequence K
  • EMVK6 Homo sapiens endogenous retroviral family W
  • EBVWE1 Homo sapiens Cas-Br-M (murine) ecotropic
  • CBLB retroviral transforming sequence b
  • CBLB Homo sapiens mRNA containing human [AF026246] endogenous retrovirus H and human endogenous retrovirus E sequences Homo sapiens cDNA FLJ11804 fis, clone [AK021866] HEMBA1006272, moderately similar to RETROVIRUS-RELATED PROTEASE (EC 3.4.23.—).
  • Non-coding RNA Abbreviation Example of function Reference Transfer RNA tRNA Translation (Aitken et al., 2010) Ribosomal RNA rRNA Translation (Aitken et al., 2010) Signal recognition 7SL RNA or Translocation of proteins across the (Gribaldo and particle RNA SRP RNA Endoplasmatic Reticulum Brochier- Armanet, 2006) Small nuclear RNA snRNA Splicing (Valadkhan, 2010) Small nucleolar RNA snoRNA Guides chemical modifications of (Kiss, 2002) other RNAs (like methylation and pseudouridylation).
  • Short Interspersed SINE The most common SINE is the Alu (Mariner et al., repetitive elements element ( ⁇ 10% of the genome). Alu 2008) is upregulated in response to stress and binds RNA polymerase II to suppress transcription.
  • microRNA miRNA Post-transcriptional gene silencing Bartel, 2009
  • Small interfering RNA siRNA Post-transcriptional gene silencing Elbashir et al., 2001
  • Piwi-interacting RNA piRNA Transciptional gene silencing (Taft et al., 2010) defense against retrotransposons Ribonuclease P RNase P Ribozyme involved in tRNA (Guerrier-Takada maturation et al., 1983) Ribonuclease MRP RNase MRP Ribozyme involved in rRNA (Li et al., 2002) maturation as well as mitochondrial DNA replication Y RNA Y RNA RNA processing, DNA replication (Lerner et al., 1981)

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Abstract

Disclosed herein are methods for assaying a biological sample from a subject by analyzing components of microvesicle fractions in aid of risk, diagnosis, prognosis or monitoring of, or directing treatment of the subject for, a disease or other medical condition in the subject. Also disclosed are methods of treatment and identifying biomarkers using a microvesicle fraction of a subject. Kits, pharmaceutical compositions, and profiles related to the methods are also disclosed.

Description

    CROSS REFERENCE TO RELATED APPLICATIONS
  • This application is a Divisional Application of U.S. application Ser. No. 15/012,111 filed Feb. 1, 2016, which is a Continuation Application of U.S. application Ser. No. 13/819,539 filed Oct. 17, 2013 which is a 35 U.S.C. § 371 National Phase Entry Application of International Application No. PCT/US2011/050041 filed Aug. 31, 2011, which designates the U.S., and which claims the benefit of 35 U.S.C. § 119(e) to U.S. Provisional Application Ser. No. 61/378,860 filed Aug. 31, 2010; 61/421,421 filed Dec. 9, 2010; 61/437,547 filed Jan. 28, 2011; 61-438,199 filed Jan. 31, 2011; and 61/493,261 filed Jun. 3, 2011, the contents of each of which are incorporated herein by reference in their entirety.
  • GOVERNMENT SUPPORT
  • This invention was made with Government support under grants CA86355, CA69246, CA141226, and CA141150 awarded by National Cancer Institute. The Government has certain rights in the invention.
  • SEQUENCE LISTING
  • The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Jan. 29, 2016, is named Sequence_Listing_030258-069537-C and is 5,407 bytes in size.
  • FIELD OF INVENTION
  • The present invention relates to the fields of biomarker analysis, diagnosis, prognosis, patient monitoring, therapy selection, risk assessment, and novel therapeutic agents for human or other animal subjects, particularly the profiling of biological materials from a microvesicle fraction of a biological sample, and novel therapies related to microvesicles.
  • BACKGROUND OF THE INVENTION
  • Increasing knowledge of the genetic and epigenetic changes occurring in cancer cells provides an opportunity to detect, characterize, and monitor tumors by analysing tumor-related nucleic acid sequences and profiles. Cancer-related changes include specific mutations in gene sequences (Cortez and Calin, 2009; Diehl et al., 2008; Network, 2008; Parsons et al., 2008), up- and down-regulation of mRNA and miRNA expression (Cortez and Calin, 2009; Itadani et al., 2008; Novakova et al., 2009), mRNA splicing variations, changes in DNA methylation patterns (Cadieux et al., 2006; Kristensen and Hansen, 2009), amplification and deletion of genomic regions (Cowell and Lo, 2009), and aberrant expression of repeated DNA sequences (Ting et al., 2011). Various molecular diagnostic tests such as mutational analysis, methylation status of genomic DNA, and gene expression analysis may detect these changes.
  • Research uncovering the molecular mechanisms underlying cancer improves our understanding of how to select and design optimal treatment regimes for a patient's disease based on the molecular makeup of his or her particular cancer. Over the past few years, this has led to a significant increase in the development of therapies specifically targeting gene mutations involved in disease progression. In parallel, the use of molecular diagnostic testing for cancer diagnosis, prognosis and treatment selection has expanded, driven by the need for more cost efficient applications of expensive therapies. Current molecular diagnostics has so far almost exclusively relied on assaying cancer cells from tissue biopsy by needle aspiration or surgical resection.
  • However, the ability to perform these tests using a blood sample is sometimes more desirable than using a tissue sample from a cancer patient because, frequently, fresh tissue samples are difficult or impossible to obtain, and archival tissue samples are often less relevant to the current status of the patient's disease. A less invasive approach using a more easily accessible biological sample, e.g., a blood sample, has wide ranging implications in terms of patient welfare, the ability to conduct longitudinal disease monitoring, and the ability to obtain expression profiles even when tissue cells are not easily accessible, e.g., in ovarian or brain cancer patients.
  • Currently, gene expression profiling of blood samples involves the analysis of RNA extracted from peripheral blood mononuclear cells (PBMC) (Hakonarson et al., 2005) or circulating tumor cells (CTC) (Cristofanilli and Mendelsohn, 2006).
  • Many types of cancer cells release an abundance of small membrane-bound vesicles, which have been observed on their surface in culture (Skog et al., 2008). These microvesicles are generated and released through several processes and vary in size (from about 30 nm to about 1 μm in diameter) and content (Simons and Raposo, 2009). Microvesicles can bud/bleb off the plasma membrane of cells, much like retrovirus particles (Booth et al., 2006), be released by fusion of endosomal-derived multivesicular bodies with the plasma membrane (Lakkaraju and Rodriguez-Boulan, 2008), or be formed as apoptotic bodies during programmed cell death (Halicka et al., 2000). In addition, defective (i.e., non-infectious without helper-virus) retrovirus particles derived from human endogenous retroviral (HERV) elements may be found within microvesicle populations (Voisset et al., 2008).
  • Microvesicles from various cell sources have been studied with respect to protein and lipid content (Iero et al., 2008; Thery et al., 2002; Wieckowski and Whiteside, 2006). They have also been observed to contain cellular RNAs and mitochondria DNA (Baj-Krzyworzeka et al., 2006; Guescini et al.; Skog et al., 2008; Valadi et al., 2007) and may facilitate the transfer of genetic information between cells and/or act as a “release hatch” for DNA, RNA, and/or proteins that the cell is trying to eliminate. Both mRNA and miRNA in microvesicles are observed to be functional following uptake by recipient cells (Burghoff et al., 2008; Deregibus et al., 2007; Ratajczak et al., 2006; Skog et al., 2008; Valadi et al., 2007; Yuan et al., 2009) and it has also been shown that apoptotic bodies can mediate horizontal gene transfer between cells (Bergsmedh et al., 2001).
  • Knowing the expression profile, mutational profile, or both expression and mutational profiles of individual cancer is helpful for personalized medicine as many drugs target specific pathways affected by the genetic status of the tumors. Detection of genetic biomarkers in blood samples from tumor patients is challenging due to the need for high sensitivity against a background of normal cellular nucleic acids found circulating in blood. Microvesicles released by tumor cells into the circulation can provide a window into the genetic status of individual tumors (Skog et al., 2008).
  • The present invention is directed to microvesicular nucleic acid profiles of microvesicle fractions obtained from a biological sample from a subject, methods for aiding in diagnosis, prognosis, patient monitoring, treatment selection, and risk assessment based on detecting the presence or absence of a genetic aberration in a nucleic acid profile, or changes in a polypeptide profile of a microvesicle fraction obtained from a biological sample from a patient, and therapeutic agents and methods of cancer treatment or prevention.
  • SUMMARY OF THE INVENTION
  • The present invention is based on the discovery of various types of cancer-related biological materials within microvesicles. The biological materials within microvesicles from a biological sample may be characterized and measured, and the results this analysis may be used to aid in biomarker discovery, as well as in diagnosis, prognosis, monitoring, treatment selection, or risk assessment for a disease or other medical condition.
  • In one aspect, the biological materials are nucleic acids and the invention is a method for assaying a biological sample comprising the steps of: a) obtaining or using a microvesicle fraction from a biological sample from a subject; b) extracting nucleic acid from the fraction; and c) detecting the presence or absence of a biomarker in the extracted nucleic acid. In a method for aiding in the diagnosis, prognosis or monitoring of a subject, the biomarker is a genetic aberration that is associated with the diagnosis, prognosis, or determination of the status or stage of a disease or other medical condition in the subject. In a method for aiding in treatment selection for a subject in need of or potentially in need of therapeutic treatment, the biomarker is a genetic aberration that is associated with a disease or other medical condition or with responsiveness to a specific therapy for the disease or other medical condition in the subject. In a method for aiding in a determination of a subject's risk of developing a disease or other medical condition, the biomarker is a genetic aberration that is associated with the subject's risk of developing a disease or other medical condition.
  • In some embodiments of the above methods, the genetic aberration is in or corresponds to a c-myc gene, a transposable element, a retrotransposon element, a satellite correlated gene, a repeated DNA element, a non-coding RNA other than miRNA, or a fragment of any of the foregoing.
  • In other embodiments of the above methods, the genetic aberration is in or corresponds to a transposable element listed in Table 4 or Table 5, or a fragment thereof. For one example, the genetic aberration is in or corresponds to retrotransposon elements including LINE, SINE or HERV, or a fragment thereof. For another example, the genetic aberration is in or corresponds to a retrotransposon element that is Line1 (L1), ALU, HERV-H, HERV-K, HERV-K6, HERV-W or HERV-C, or a fragment thereof.
  • In further embodiments of the above methods, the genetic aberration is in or corresponds to a satellite-correlated gene listed in Table 6, or a fragment thereof, a repeated DNA element listed in Table 8, or a fragment thereof; or a non-coding RNA listed in Table 9 (other than miRNA) or a fragment thereof. The non-coding RNA, for example, can be 7SL RNA.
  • In yet further embodiments of the above methods, the genetic aberration is in or corresponds to a cancer gene listed in Table 2 or 3, or a fragment thereof.
  • In another aspect, the biological material is protein or polypeptide and the invention is a method for assaying a biological sample from a subject comprising the steps of: a) obtaining or using a microvesicle fraction from a biological sample from a subject b) measuring a protein or polypeptide activity in the fraction; and c) determining whether the protein or polypeptide activity is higher or lower than a normal or average activity for the same protein or polypeptide. In a method for aiding in the diagnosis, prognosis or monitoring of a subject, an elevated or lowered activity is associated with a diagnosis, prognosis, status or stage of a disease or other medical condition in the subject. In a method for aiding in directing treatment of a subject, an elevated or lowered activity is associated with a disease or other medical condition or with the subject's responsiveness to a specific therapy for the disease or other medical condition. In a method in aid of a determination of a subject's risk of developing a disease or other medical condition, an elevated or lowered activity is associated with the subject's risk of developing a disease or other medical condition. In some embodiments of the foregoing methods, the polypeptide is an enzyme. For example, the polypeptide can be a reverse transcriptase and the method is to determine whether the reverse transcriptase activity is higher than a normal or average activity for reverse transcriptase.
  • In the present invention, the methods may further comprise a step of enriching the microvesicle fraction for microvesicles originating from a specific cell type. The enrichment may be achieved, for example, by affinity purification with antibody-coated magnetic beads.
  • In the present invention, the biological sample from a subject can be a bodily fluid, e.g., blood, serum, plasma, or urine. The subject can be a human subject. When the subject is a human, the disease or other medical condition may be brain cancer such as medulloblastoma and glioblastoma, or melanoma.
  • In the present invention, the presence or absence of a biomarker in the extracted nucleic acid can be determined by various techniques, e.g., microarray analysis, PCR, quantitative PCR, Digital Gene Expression, or direct sequencing.
  • In yet another aspect, the present invention is a kit for genetic analysis of a microvesicle fraction obtained from a body fluid sample from a subject, comprising, in a suitable container, one or more reagents capable of hybridizing to or amplifying a nucleic acid corresponding to one or more of the genetic aberrations referenced above.
  • In yet another aspect, the present invention is an oligonucleotide microarray for genetic analysis of a microvesicle preparation from a body fluid sample from a subject, wherein the oligonucleotides on the array are designed to hybridize to one or more nucleic acids corresponding to one or more of the genetic aberrations referenced above.
  • In yet another aspect, the present invention is a profile of microvesicular nucleic acid derived from a bodily fluid sample from a subject. The profile may be a genetic aberration in or corresponding to: a) cancer gene listed in Table 2 or 3, or a fragment thereof; b) a transposable element from the subject's genome, preferably an element listed in Table 4 or 5, or a fragment of any of the foregoing; c) a retrotransposon element from the subject's genome, preferably LINE, SINE or HERV, more preferably LINE1 (L1), ALU, HERV-H, HERV-K, HERV-K6, HERV-W or HERV-C, or a fragment of any of the foregoing; d) a satellite correlated gene from the subject's genome, preferably a satellite correlated gene listed in Table 6, or a fragment of any of the foregoing; e) an element of repeated DNA from the subject's genome, preferably an element listed in Table 8, or a fragment of any of the foregoing; or f) a non-coding RNA other than miRNA, preferably a species listed in Table 9, or a fragment of any of the foregoing. In one embodiment, the profile is a genetic aberration in the cancer gene c-myc. In another embodiment, the profile is a genetic aberration in the non-coding 7SL RNA.
  • In all of the foregoing nucleic acid-related embodiments of the invention, the genetic aberration can be a species of nucleic acid, the level of expression of a nucleic acid, a nucleic acid variant; or a combination of any of the foregoing. For example, the genetic aberration may be an RNA expression profile. For another example, the genetic aberration may be a fragment of a nucleic acid, and in some instances, the fragment contains more than 10 nucleotides.
  • In yet another aspect, the present invention is a method of identifying a potential new nucleic acid biomarker associated with a disease or other medical condition, status or stage of disease or other medical condition, a subject's risk of developing a disease or other medical condition, or a subject's responsiveness to a specific therapy for a disease or other medical condition. The method comprises the steps of: a) obtaining or using a microvesicle fraction from a biological sample from a subject; b) extracting nucleic acid from the fraction; c) preparing a profile according to any of the above-described profiles; and d) comparing the profile of step c) to a control or reference profile and selecting one or more potential new biomarkers based on one or more differences between the profile of step c) and the control or reference profile.
  • In yet anther aspect, the present invention is a method of treating a subject having a form of cancer in which cancer cells secrete microvesicles. The method comprises administering to the subject a therapeutically effective amount of a composition including an inhibitor of microvesicle secretion; an inhibitor of a reverse transcriptase; a microvesicle neutralizer that neutralizes the pro-tumor progression activity of tumor microvesicles; or any combination of the forgoing. In some embodiments, the inhibitor of microvesicle secretion is an inhibitor of RAB GTPase which may be Rab 27a, Rab 27b or Rab 35. In other embodiments, the inhibitor of a reverse transcriptase is a nucleoside analog selected from the group comprising 3′-azido2′,3′-dideoxythymidine (AZT); 2′,3′-dideoxyinosine (ddI), 2′,3′-didehyro-3′-deoxythymidine (d4T); nevirapine and efavirenz. In further embodiments, the inhibitor of a reverse transcriptase is RNAi targeting the reverse transcriptase gene. In still further embodiments, the microvesicle neutralizer is a biological agent that binds microvesicles and destroys the integrity of the microvesicles.
  • In yet another aspect, the present invention is a pharmaceutical composition comprising, in a suitable pharmaceutical carrier: a) an inhibitor of microvesicle secretion, particularly an inhibitor of RAB GTPase, and more particularly Rab 27a, Rab 27b or Rab 35); b) an inhibitor of reverse transcriptase, particularly a nucleoside analog, more particularly 3′-azido2′,3′-dideoxythymidine (AZT); 2′,3′-dideoxyinosine (ddI), 2′,3′-didehyro-3′-deoxythymidine (d4T); nevirapine, or efavirenz, or an RNAi targeting the reverse transcriptase gene; c) a microvesicle neutralizer that neutralizes the pro-tumor progression activity of tumor microvesicles, particularly a biological agent that binds microvesicles and destroys the integrity of the microvesicles; or d) a combination of any of the foregoing.
  • BRIEF DESCRIPTION OF THE DRAWINGS
  • FIG. 1 shows a graph depicting the quantification, size distribution and RNA yield of microvesicles purified from the medulloblastoma cell line D384. Each bar represents the number of particles of a certain size that are present in the media and are released by one cell over 48 hours (hrs). The sum refers to the total number of particles released by one cell over 48 hrs. ExoRNA refers to the total RNA yield in microvesicles from 1×106 cells over 48 hrs. The result is presented as the mean SEM (n=3).
  • FIG. 2 shows a graph depicting the quantification, size distribution and RNA yield of microvesicles purified from the medulloblastoma cell line D425 in the same manner as in FIG. 1.
  • FIG. 3 shows a graph depicting the quantification, size distribution and RNA yield of microvesicles purified from the medulloblastoma cell line D458 in the same manner as in FIG. 1.
  • FIG. 4 shows a graph depicting the quantification, size distribution and RNA yield of microvesicles purified from the melanoma cell line Yumel 0106 in the same manner as in FIG. 1.
  • FIG. 5 shows a graph depicting the quantification, size distribution and RNA yield of microvesicles purified from the glioblastoma cell line 20/3 in the same manner as in FIG. 1.
  • FIG. 6 shows a graph depicting the quantification, size distribution and RNA yield of microvesicles purified from the glioblastoma cell line 11/5 in the same manner as in FIG. 1.
  • FIG. 7 shows a graph depicting the quantification, size distribution and RNA yield of microvesicles purified from the normal fibroblast cell line HF19 in the same manner as in FIG. 1.
  • FIG. 8 shows a graph depicting the quantification, size distribution and RNA yield of microvesicles purified from the normal fibroblast cell line HF27 in the same manner as in FIG. 1.
  • FIG. 9 shows a graph depicting the c-Myc gene yields in terms of genomic DNA extracted from cells of the following cell lines: one normal human fibroblast line (HF19), one GBM line (11/5), one atypical teratoid rhabdoid tumor (AT/RT) line (NS224) and three medulloblastoma (MB) lines (D425, D458 and D384). Quantitative PCR was used to obtain c-Myc Ct values, which were normalized to GAPDH Ct values in the same preparation. The X-axis lists the names of the cell lines tested. The Y-axis is the fold change, represented as the ratio of the Ct value for each cell line to the Ct value for the normal fibroblast cell line HF19. In all cases, the Ct values are expressed as mean SEM (n=3) and analyzed by a two-tailed t-test.
  • FIG. 10 shows a graph depicting the c-Myc gene yields in terms of RNA extracted from microvesicles secreted by cells of the same cell lines and in the same manner as in FIG. 9. Quantitative Reverse Transcription PCR was used to obtain c-Myc RNA Ct values.
  • FIG. 11 shows a graph depicting the c-Myc gene yields in terms of DNA extracted from microvesicles secreted by cells of the same cell lines and in the same manner as in FIG. 9. Quantitative PCR was used to obtain c-Myc DNA Ct values.
  • FIG. 12 shows a graph depicting the c-Myc gene yields in terms of RNA extracted from xenograft subcutaneous tumor cells. The subcutaneous tumors were generated by xenografting medulloblastoma cells (MBT; D425 cell line) or epidermoid carcinoma (ECT; A431 cell line) cells in nude mice. The X-axis refers to the different tumor-bearing mice characterized by the type of tumor cell and the tumor mass weight at sacrifice. MBT tumor mass weights are as follows: MBT 1: 3.4 g; MBT 2: 1.7 g; MBT 3: 2.4 g; MBT 4: 2.9 g; and MBT 5: 1.7 g. ECT tumor mass weights are as follows: ECT1 1.7 g; ECT 2: 2.3 g; ECT 3: 3.1 g; ECT 4: 1.9 g; and ECT 5: 2.2 g. Ct values were normalized to GAPDH. The Y-axis refers to the Ct values generated by quantitative reverse transcription PCR of the extracted RNA in each sample. For each RNA extract, two replicate qPCR were performed.
  • FIG. 13 shows a gel picture depicting the c-Myc gene yields in terms of RNA extracted from serum microvesicles from mice that bear subcutaneous tumors. The subcutaneous tumors were generated by xenografting medulloblastoma cells (MBT; D425 cell line) in nude mice. C-Myc product was amplified by reverse transcription PCR method using human c-Myc specific primers and the RNA extracted from serum microvesicles as templates. The amplified c-Myc product should be 89 bp in length. The amplified c-Myc products were resolved by electrophoresis in a 2% agarose gel and visualized with ethidium bromide staining. The arrow points to the position where an 89 bp product appears on the agarose gel. The lanes are referenced as follows: MW: DNA size marker; 1: MBT tumor mass weight of 3.4 g; 2: MBT tumor mass weight of 1.7 g; 3: MBT tumor mass weight of 2.4 g; 4: MBT tumor mass weight of 2.9 g; 5: MBT tumor mass weight of 1.7 g; NC: negative control where no RNA/cDNA was used.
  • FIG. 14 shows a gel picture depicting the c-Myc gene yields in terms of RNA extracted from serum microvesicles from mice that bear subcutaneous tumors in the same manner as in FIG. 13 except that the subcutaneous tumors were generated by xenografting epidermoid carcinoma (ECT; A431 cell line) in nude mice. The lanes are referenced as follows: MW: DNA size marker; 1: ECT tumor mass weight of 1.7 g; 2: ECT tumor mass weight of 2.3 g; 3: ECT tumor mass weight of 3.1 g; 4: ECT tumor mass weight of 1.9 g; 5: ECT tumor mass weight of 2.2 g; NC: negative control where no RNA/cDNA was used.
  • FIG. 15 shows a MA plot depicting relative levels of all represented RNA sequences (using 44,000 RNA probes on the Agilent microarray chip) in cells and microvesicles derived from the cells. The levels of transposon and retrotransposon sequences were compared to the rest of the RNA transcriptome in cells and microvesicles. ExoRNA and cellular RNA were isolated from GBM 20/3 cells and analyzed on an Agilent two-color 44 k array. Y-axis (M)=log2Exo−log2Cell, X-axis (A)=0.5×(log2Exo+log2Cell).
  • FIG. 16 shows a MA plot similar to the plot in FIG. 15 except that the present plot only depicts relative levels of the following four HERV family sequences: HERV-H, HERV-K6, HERV-W and HERV-C, all of which are enriched in microvesicles more than 16-fold as compared to the host cells, i.e., M>4.
  • FIG. 17 shows a MA plot similar to the plot in FIG. 15 except that the present plot only depicts relative levels of DNA transposons.
  • FIG. 18 shows a MA plot similar to the plot in FIG. 15 except that the present plot only depicts relative levels of L1 sequences.
  • FIG. 19 shows a MA plot similar to the plot in FIG. 15 except that the present plot only depicts relative levels of HERV sequences with HERV-H, HERV-C, HERV-K6 and HERV-W being more than 16 fold enriched.
  • FIG. 20 shows a MA plot similar to the plot in FIG. 15 except that the present plot only depicts relative levels of Alu sequences.
  • FIGS. 21A, 21B and 21C show MA plots depicting relative expression levels of L1 (FIG. 21A), ALU (FIG. 21B) and HERV-K (FIG. 21C) RNA in cells and microvesicles derived from the cells. qRT-PCR was carried out for retrotransposon elements in cell RNA and exoRNA from three medulloblastoma (D425, D384 and D458), one GBM (11/5), one melanoma (0106) and one human fibroblast (HF19) line. The RNA expression levels were measured and normalized to GAPDH. HERV-K RNA was not detectable in exoRNA from normal human fibroblasts (HF19), so it was given a Ct value of 36 (below detection limit).
  • FIG. 22 shows a chart depicting the expression levels of HERV-K at different time points in HUVEC cells. The HUVEC cells were exposed to medulloblastoma D384 microvesicles and their expression level of HERV-K RNA was analyzed by qRT-PCR over 72 hrs following exposure. MOCK is non-exposed cells. HERV-K was normalized to GAPDH. P values were calculated using the two-tailed t-test, comparing levels to MOCK infected cells.
  • FIGS. 23A, 23B and 23C show MA plots depicting relative levels of L1 (FIG. 23A), ALU (FIG. 23B) and HERV-K (FIG. 23C) DNA in cells and microvesicles derived from the cells. q-PCR was carried out for retrotransposon elements with cell genomic DNA and microvesicle DNA from three medulloblastoma (D425, D384 and D458), one GBM (11/5), one melanoma (0106) and one human fibroblast (HF19) line. The DNA levels were measured and normalized to GAPDH. Results are expressed as average±SEM (n=3).
  • FIG. 24 shows a chart depicting the Reverse Transcriptase (RT) activity in microvesicles secreted by three medulloblastoma (D425, D384 and D458), one GBM (11/5), one melanoma (0106) and one human fibroblast (HF19) line. The RT activity was measured in the microvesicles using the EnzChek RT Assay Kit (Invitrogen) and normalized to protein content. The RT activity is measured as RT units calculated based on the standard curve generated using SuperScript III (Invitrogen). Results are expressed as average±SEM (n=3).
  • FIGS. 25A, 25B, 25C and 25D show charts depicting Bioanalyzer profiles of exoRNA and exoDNA from tumor or normal cell. FIG. 25A depicts the profile of exoRNA from GBM 11/5 cells. Both 18S and 28S rRNA peaks are detectable (arrowheads). FIG. 25B depicts the profile of exoDNA GBM 11/5 cells. Sizes ranged from 25 to 1000 nucleotides with a peak at 200 nt. FIG. 25C depicts the profile of ExoRNA from human fibroblasts HF19, which was extracted and analyzed as in FIG. 25A. The RNA yield was too low to yield distinct 18S and 28S rRNA peaks. After concentration, these peaks were visible (data not shown). FIG. 25D depicts the profile of ExoDNA from human fibroblasts HF19, which was not readily detectable on the Bioanalyzer even after it was concentrated 30 times. Bioanalyzer profiles were generated using the RNA Pico Chip (Agilent).
  • FIGS. 26A and 26B show charts depicting the Bioanalyzer profiles of exoDNA from microvesicles isolated from medulloblastoma D384 cells. FIG. 26A depicts the profile of exoDNA purified from externally DNase-treated microvesicles using the Agilent DNA 7500 bioanalyzer chip (Agilent Technologies Inc., Santa Clara, Calif. Cat. Number 5067-1506) that detects dsDNA. FIG. 26B depicts the profile of exoDNA after a second-strand synthesis treatment. Here the same sample as in (A) was subjected to second strand synthesis with Superscript Double-Stranded cDNA synthesis kit (Invitrogen) according to manufacturer's recommendation.
  • FIG. 27 is an agarose gel picture depicting electrophoresis of GAPDH (112 bp) PCR products using templates from different samples. The different samples were exoDNA samples extracted from microvesicles isolated from three medulloblastoma cell lines (D425, D384 and D556) and genomic DNA extracted from L2132 normal fibroblasts as a control double stranded DNA, all four of which were mock treated or treated with S1 nuclease enzyme which degrades single-stranded nucleic acids.
  • FIG. 28 depicts representative bioanalyzer profiles of exoDNA extracted from medulloblastoma cell line D384 before and after S nuclease treatment.
  • FIGS. 29A and 29B show charts depicting quantitative PCR results of c-Myc and POU5F1B, respectively, using as templates genomic DNA from cells or exoDNA extracted from microvesicles isolated from cells. FIG. 29A depicts the results for c-Myc gene. FIG. 29B depicts the results for POU5F1B, which gene sequence (AF268618) is found 319 kb upstream of the c-Myc gene in the genome, but still within the commonly amplified region in tumor cells. The cell lines are medulloblastoma cell lines D458 and D384, glioblastomas (11/5), and fibroblasts HF19.
  • FIG. 30 illustrates the c-Myc copy number analysis results in tumor cell lines using an Affymetrix 250K SNP array. The c-Myc genomic region was analyzed in medulloblastoma lines, D425, D458 and D384, as well as rhabdoid tumor line, NS224.
  • FIGS. 31A and 31B show charts depicting the qPCR results of the n-Myc gene in cells lines medulloblastoma D425, D458 and D384, rhabdoid tumor, GBM, and normal fibroblasts using genomic DNA FIG. 31A or exoDNA FIG. 31B extracted from microvesicles isolated from the cells as templates.
  • FIG. 32 shows a chart depicting the amount of exoDNA extracted from microvesicles isolated from medulloblastoma D384 cell culture media. D384 cells were seeded in 6-well plates and treated with increasing dosages of L-mimosine (200, 400 and 600 μM) or mock treated. Microvesicles were isolated from the medium after 48 hrs and ssDNA was extracted using the Qiagen PCR purification kit. Single-stranded DNA yields were quantified using the Bioanalyzer and the yields were compared to mock treated cells (normalized to 1.0).
  • FIG. 33 depicts the results of quantitative RT-PCR analysis of the expression levels of 7SL RNA, EGFR and GAPDH in microvesicles isolated from serum samples obtained from a GBM patient or a normal individual. The X-axis is the number of PCR cycles. The Y-axis is the fluorescent intensity (delta Rn) measured by the ABI7500 machine.
  • FIG. 34 depicts a series of signaling pathways related to cell proliferation, growth and/or survival.
  • DETAILED DESCRIPTION OF THE INVENTION
  • As described above, cell-derived vesicles are heterogeneous in size with diameters ranging from about 10 nm to about 1 μm. For example, “exosomes” have diameters of approximately 30 to 100 nm, with shedding microvesicles and apoptotic bodies often described as larger (Orozco and Lewis, 2010). Exosomes, shedding microvesicles, microparticles, nanovesicles, apoptotic bodies, nanoparticles and membrane vesicles co-isolate using various techniques and will, therefore, collectively be referred to throughout this specification as “microvesicles” unless otherwise expressly denoted.
  • The present invention is based on the discovery that cancer-related biological materials such as transposable elements, oncogenes, and reverse transcriptase (RT) can be detected in microvesicles.
  • The biological materials in microvesicles can be genetic materials, protein materials, lipid materials, or any combination of genetic, protein and lipid materials.
  • Genetic materials include nucleic acids, which can be DNA and its variations, e.g., double-stranded DNA (“dsDNA”), single-stranded DNA (“ssDNA”), genomic DNA, cDNA; RNA and its variations, e.g., mRNA, rRNA, tRNA, microRNA, siRNA, piwi-RNA, coding RNA, non-coding RNA, transposons, satellite repeats, minisatellite repeats, microsatellite repeats, Interspersed repeats such as short interspersed nuclear elements (SINES), e.g. but not limited to Alus, and long interspersed nuclear elements (LINES), e.g. but not limited to LINE-1, human endogenous retroviruses (HERVs), e.g. but not limited to HERV-K; or any combination of any of the above DNA and RNA species.
  • Protein materials can be any polypeptides and polypeptide variants recognized in the art. For convenience, “polypeptide” as disclosed in this application refers to both a polypeptide without modifications and a polypeptide variant with modifications. Polypeptides are composed of a chain of amino acids encoded by genetic materials as is well known in the art. For example, a reverse transcriptase is a polypeptide that can function as an enzyme to transcribe RNA into DNA. Polypeptide variants can include, e.g. polypeptides modified by acylation, ubiquitination, SUMOYlation, alkylation, amidation, glycosylation, hydroxylation, carboxylation, phosphorylations, oxidation, sulfation, selenoylation, nitrosylation, or glutathionylation.
  • Lipid materials include fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, fatty acids, glycerolipids, glycerophospholipids, sphingolipids, sterol lipids, prenol lipids, saccharolipids, and polyketides.
  • Microvesicles may be isolated from tissue, cells or other biological samples from a subject. For example, the biological sample may be a bodily fluid from the subject, preferably collected from a peripheral location. Bodily fluids include but are not limited to blood, plasma, serum, urine, sputum, spinal fluid, pleural fluid, nipple aspirates, lymph fluid, fluid of the respiratory, intestinal, and genitourinary tracts, tear fluid, saliva, breast milk, fluid from the lymphatic system, semen, cerebrospinal fluid, intra-organ system fluid, ascitic fluid, tumor cyst fluid, amniotic fluid and combinations thereof. In some embodiments, the preferred bodily fluid for use as the biological sample is urine. In other embodiments, the preferred bodily fluid is serum.
  • The term “subject” is intended to include all animals shown to or expected to harbor nucleic acid-containing microvesicles. In particular embodiments, the subject is a mammal, e.g., a human or nonhuman primate, a dog, cat, horse, cow, other farm animal, or rodent (e.g. a mouse, rat, guinea pig, etc.). In one embodiment, the subject is an avian, amphibian or fish. The terms “subject,” “individual” and “patient” are used interchangeably herein.
  • Methods for isolating microvesicles from a biological sample and extracting biological materials from the isolated microvesicles are described in this application as well as in scientific publications and patent applications, e.g. (Chen et al., 2010; Miranda et al., 2010; Skog et al., 2008). See also WO 2009/100029, WO 2011/009104, WO 2011/031892 and WO 2011/031877. These publications are incorporated herein by reference for their disclosure pertaining to isolation and extraction methods and techniques.
  • A profile, as used herein, refers to a set of data or a collection of characteristics or features, which can be determined through the quantitative or qualitative analysis of one or more biological materials, particularly biological materials contained in microvesicles isolated from a subject. The biological materials, extraction of the biological materials, and various types of analysis of the biological materials are described herein. A control or reference profile is a profile obtained from the literature, from an independent subject or subjects, or from the same subject at a different time point.
  • In one aspect, the present invention includes a profile of one or more nucleic acids extracted from microvesicles. The nucleic acids include both RNA and DNA. A nucleic acid profile may be an RNA profile, a DNA profile, or may include profiles of both RNA and DNA. In other aspects, the present invention includes a profile of one or more protein or polypeptide species extracted from microvesicles, particularly, a level of protein activity.
  • In all of the various aspects of the invention described herein in relation to RNA, the RNA can be coding RNA, e.g., messenger RNA. The RNA can also be non-coding RNA (ncRNA), e.g., ribosomal RNA (rRNA), transfer RNA (tRNA), microRNA, and other non-coding transcripts that may originate from genomic DNA. See Table 9 for more examples of non-coding RNA. Non-coding RNA transcripts may include transcripts from satellite repeats or from transposons, which may be Class I retrotransposons or Class II DNA transposons.
  • In all of the various aspects of the invention described herein in relation to DNA, the DNA can be single-stranded DNA, e.g., cDNA, which is reverse transcribed from RNA. Reverse transcription is usually mediated by reverse transcriptase encoded by a reverse transcriptase gene in a cell. The DNA can also be single stranded DNA generated during DNA replication. Genomic DNA replicates in the nucleus while the cell is dividing. Some of the replicated DNA may come off its template, be exported out of the nucleus, and packaged into microvesicles. The DNA can further be fragments of double-stranded DNA.
  • In addition, the DNA can be non-coding DNA (ncDNA). The human genome contains only about 20,000 protein-coding genes, representing less than 2% of the genome. The ratio of non-coding to protein-coding DNA sequences increases as a function of developmental complexity (Mattick, 2004). Prokaryotes have less than 25% ncDNA, simple eukaryotes have between 25-50%, more complex multicellular organisms like plants and animals have more than 50% ncDNA, with humans having about 98.5% ncDNA (Mattick, 2004)
  • Some of the ncDNA from the genome is transcribed into ncRNA. NcRNAs have been implicated in many important processes in the cell, e.g., enzymes (ribozymes), binding specifically to proteins (aptamers), and regulating gene activity at both the transcriptional and post-transcriptional levels. Examples of ncRNA classes and examples of their functions are shown in Table 9.
  • Many of the ncRNA species have multiple functions. For example, Ribonuclease P (RNase P) is a ribozyme which is involved in maturation of tRNA by cleaving the precursor tRNA, and nuclear RNaseP can also act as a transcription factor (Jarrous and Reiner, 2007). In addition, bifunctional RNAs have also been described that function both as mRNA and as regulatory ncRNAs (Dinger et al., 2008) or have two different ncRNA functions (Ender et al., 2008).
  • One example of the many long ncRNAs is the X-inactive specific transcript (Xist) expressed by the inactive X-chromosome, which is used to silence the extra X-chromosome in females (Ng et al., 2007). This RNA transcript binds to and inactivates the same X chromosome from which it is produced.
  • Another example is the HOX antisense intergenic RNA (HOTAIR) (Rinn et al., 2007). This RNA is expressed from chromosome 12, but controls gene expression on chromosome 2, affecting the skin phenotype on different parts of the body surface (Rinn et al., 2007) and also being involved in cancer metastasis (Gupta et al., 2010).
  • Yet another example of ncRNA is PCA3, a biomarker for prostate cancer (Day et al., 2011). PCA3 can be readily measured in the RNA from urine microvesicles which can be extracted using a rapid filtration concentrator method (Miranda et al., 2010; Nilsson et al., 2009). Another biomarker for prostate cancer is PCGEM1, which is an ncRNA transcript over-expressed in prostate cancer (Srikantan et al., 2000).
  • Yet another example of ncRNA is NEAT2/MALAT1, which has been found to be upregulated during metastasis of non-small cell lung cancer, and was correlated with poor patient survival (Ji et al., 2003).
  • Microvesicles contain a substantial array of the cellular gene expression profile from the cells from which they originate (their parent cells) at any given time. That is, substantially all the RNAs expressed in the parent cell are present within the microvesicle, although the quantitative levels of these RNAs may differ in the microvesicle compared to the parent cell. Substantially all the genes from the parent cell can, therefore, be tracked in the microvesicle fraction. In addition, microvesicles contain DNA from the parent cell, which corresponds to diagnostically relevant aspects of the subject's genome. Therefore, a nucleic acid profile from microvesicles may be associated with a disease or other medical condition.
  • In one embodiment, the disease is a neurological disease or other medical condition, e.g., Alzheimer's disease. The nucleic acid profile for Alzheimer's disease may be a profile of early-onset familial Alzheimer's disease, associated genes including, but not limited to, amyloid beta (A4) precursor protein gene, presenilin 1 and presenilin 2.
  • In another embodiment, the disease is a cancer. The microvesicular nucleic acid profile for cancer may, e.g., include nucleic acids of one or more cancer-related genes (e.g., known or suspected oncogenes or tumor suppressor genes; or genes whose expression levels correlate with the expression levels of nearby satellites). The determination of a cancer nucleic acid profile, including such cancer related genes, can aid in understanding the status of the cancer cells. In one embodiment, the oncogenes or tumor suppressor genes are one or more of those listed in Tables 2 and 3. In another embodiment, the cancer-related genes are one or more of those genes whose expression levels correlate with the expression levels of nearby satellites, such as but not limited to the satellite correlated genes listed in Table 6.
  • In some instances, the cancer-related gene is c-myc. The copy number of c-myc oncogene is usually increased in tumor cells, e.g., medullablastoma cells. The detection of increased c-myc gene copy number in microvesicles indicates an increased c-myc copy number in tumor cells that secret the microvesicles.
  • In other instances, the cancer-related gene is one or more members in the signaling pathways depicted in FIG. 34. These signaling pathways control the growth, proliferation and/or survival of cells (Alessi et al., 2009; Dowling et al.; Hanahan and Weinberg, 2000; Sarbassov et al., 2006). These pathways are sometimes cross-linked to each other, and thus enable extracellular signals to elicit multiple biological effects. For example, the growth promoting Ras protein interacts with the survival promoting PI3K and thus growth signals can concurrently evoke survival signals in the cell (Hanahan and Weinberg, 2000).
  • For one example, the member is from the RAS/RAF/MEK/MAPK pathway related to melanoma, brain and lung cancers. The MAP kinase is a convergence point for diverse receptor-initiated signaling events at the plasma membrane. The RAS/RAF/MEK/MAPK pathway regulates cell proliferation, differentiation, migration and invasion (Hanahan and Weinberg, 2000). In addition, extracellular signal-regulated kinases (ERKs) become activated upon integrin ligation and, thereby, regulate cell migration (Klemke et al., 1997).
  • For another sample, the member is from the PI3K/PTEN/AKT pathway related to prostate, bladder and kidney cancers. The PI3K/PTEN/AKT pathway is responsible for regulating cell survival (Cheng et al., 2008). Genetic variations in AKT1, AKY2, PIK3CA, PTEN, and FRAP1 are associated with clinical outcomes in patients who receive chemoradiotherapy (Hildebrandt et al., 2009). Therefore, the determination of genetic variations in members of the pathway may help evaluating cancer treatment efficacy.
  • The microvesicular nucleic acid profile of the present invention may also reflect the nucleic acid profile of DNA repeats and/or transposable elements in cells from which the microvesicles originate.
  • DNA repeats include one or more repeated DNA elements that are composed of arrays of tandemly repeated DNA with the repeat unit being a simple or moderately complex sequence. The array of tandemly repeated DNA can be of varying size, thereby giving rise to categories of megasatellite, satellite, minisatellite and microsatellite repeats. See Table 7. Repeated DNA of this type is not transcribed and accounts for the bulk of the heterochromatic regions of the genome, being notably found in the vicinity of the centromeres (i.e., pericentromeric heterochromatin). The base composition, and therefore density, of such DNA regions is dictated by the base composition of constituent short repeat units and may diverge from the overall base composition of other cellular DNA. The nucleic acid profiles of the present invention comprising satellite repeats may include profiles of satellite repeat DNA and/or profiles of transcripts that are transcribed from satellite repeats.
  • DNA repeats may serve as biomarkers of cancer cells. For example, some satellite repeats like HSATII are over-expressed in many types of cancers including pancreatic, lung, kidney, ovarian and prostate cancers (Ting et al., 2011). The RNA expression level of such satellite repeats correlates with cancer disease status. DNA repeats encompassed within the scope of the present invention can be one or more of those recited in Table 8. In some embodiments, the DNA repeats may be HSATII, ALR, (CATTC)n, or a combination of the HSATII, ALR, and (CATTC)n.
  • Transposable elements encompassed within the scope of the present invention may be one or more DNA transposons and/or retrotransposons. The retrotransposon can be one or more of those recited in Tables 3 and 4. In other embodiments, the retrotransposon can be one or more LINEs, Alus, HERVs or a combination of the LINEs, Alus and HERVs.
  • Transposable elements can serve as biomarkers of cancer cells. These repetitive elements constitute almost 50% of the human genome and include: half a million LINE-1 (L1) elements, of which about 100 are transcriptionally active and encode proteins involved in retrotransposition, including reverse transcriptase (RT) and integrase; a million Alu elements, which depend on L1 functions for integration; and thousands of provirus HERV sequences, some of which contain near-to-full length coding sequences (Goodier and Kazazian, 2008; Voisset et al., 2008). Without being bound by theory, increased expression of retrotransposon elements in cancer appears to result in part from overall hypomethylation of the genome, which is also associated with genomic instability (Daskalos et al., 2009; Estecio et al., 2007) and tumor progression (Cho et al., 2007; Roman-Gomez et al., 2008).
  • Increased transcription of retrotransposon elements in the human genome has been noted in a number of cancer cell types. For example, increased expression of L1 and HERV, as well as formation of retrovirus-like particles, has been reported in tumor tissue from breast cancer, melanoma, germ cell carcinoma and prostate cancer. See U.S. Pat. No. 7,776,523 and Bratthauer et al., 1994; Golan et al., 2008; Ruprecht et al., 2008. Retrotransposon RNA and proteins, as well as antibodies against HERV proteins and virus-like particles, have also been found in blood of some cancer patients (Contreras-Galindo et al., 2008; Kleiman et al., 2004; Ruprecht et al., 2008; Wang-Johanning et al., 2008).
  • High level expression of retrotransposon genes and/or endogenous reverse transcriptase are sometimes associated with cancer. For example, human LINE-1 p40 protein is often expressed at a higher level in breast cancer than in normal mammary gland (Asch et al., 1996). Thus, the microvesicular nucleic acid profiles of retrotransposable elements are suitable for use in aiding the diagnosis, prognosis, and/or monitoring of medical conditions such as cancer, as well as for use in aiding in treatment selection for therapies whose efficacy is affected by the subject's genetic make-up.
  • In one embodiment of the present invention, the microvesicular profile(s) of retrotransposable element(s) are determined by analyzing the content of microvesicles originating from brain cancer, e.g., medullablastoma, glioblastoma, lymphoma, and breast cancer cells. In one instance, the profile comprises one or more RNA expression levels of L1, Alu and HERV elements. In another instance, the profile comprises one or more DNA levels of L1 and HERV elements.
  • In one embodiment, the profile comprises a profile of the HERV-K element. For example, the profile may comprise the expression of the HERV-K element in microvesicles isolated from plasma from a subject. The expression of the HERV-K element may be assessed by determining the expression of any gene that the HERV-K element may encode, e.g., the group-specific antigen gene (gag), the protease gene (prt), the polymerase gene (pol), and the envelope gene (env) (Lower et al., 1996).
  • In one instance, the present invention may comprise a profile of the expression of the gag gene in microvesicles. The gag gene is from the HERV-K element and the profile of gag expression reflects the profile of HERV-K expression. The expression of the gag gene can be measured by methods known in the art, e.g., quantitative reverse transcription PCR analysis.
  • In another instance, the present invention may comprise a profile of the expression of the env gene in microvesicles. The env gene is from the HERV-K element and the profile of env expression reflects the profile of HERV-K expression. The expression of env gene can be measured by methods known in the art, e.g., quantitative reverse transcription PCR analysis.
  • In addition to the mRNA expression levels of one or more nucleic acids, the nucleic acid profiles of the present invention may also comprise the copy number of one or more nucleic acids, the fusion of several nucleic acids, the mutations of one or more nucleic acids, the alternative splicing of one or more nucleic acids, the methylation of one or more nucleic acids, and the single nucleotide polymorphism of one or more nucleic acids. The nucleic acids may correspond to genes, repeats, transposable elements, or other non-coding parts of the genomes of various organisms, including human beings.
  • The present invention encompasses all forms of cancer and pre-cancerous conditions. For example, without limitation, the present invention encompasses cancer and pre-cancer cells in brain, esophagus, lung, liver, stomach, ovary, testicle, kidney, skin, colon, blood, prostate, breast, uterus, and spleen.
  • The profile of nucleic acids can be obtained through analyzing nucleic acids obtained from isolated microvesicles according to standard protocols in the art.
  • In one embodiment, the nucleic acid is DNA. The analysis of the DNA may be performed by one or more various methods known in the art, including microarray analysis for determining the nucleic acid species in the extract, Quantitative PCR for measuring the expression levels of genes, DNA sequencing for detecting mutations in genes, and bisulfite methylation assays for detecting methylation patterns of genes.
  • In some embodiments of the present invention, data analysis may be performed by any of a variety of methods know in the art, e.g., Clustering Analysis, Principle Component Analysis, Linear Discriminant Analysis, Receiver Operating Characteristic Curve Analysis, Binary Analysis, Cox Proportional Hazards Analysis, Support Vector Machines and Recursive Feature Elimination (SVM-RFE), Classification to Nearest Centroid, Evidence-based Analysis, or a combination thereof.
  • In another embodiment, the nucleic acid extracted and analyzed from the microvesicles is RNA. In some instance, the RNA may be subject to Digital Gene Expression (DGE) analysis (Lipson et al., 2009). In this method, the RNA may be digested and converted into single stranded cDNA which may then be subject to sequencing analysis on a DNA sequencing machine, e.g., the HeliScope™ Single Molecule Sequencer from Helicos BioSciences as described in a publication by Ting et al. (Ting et al., 2011).
  • In other instances, the RNA is preferably reverse-transcribed into complementary DNA (cDNA) before further amplification. Such reverse transcription may be performed alone or in combination with an amplification step. One example of a method combining reverse transcription and amplification steps is reverse transcription polymerase chain reaction (RT-PCR), which may be further modified to be quantitative, e.g., quantitative RT-PCR as described in U.S. Pat. No. 5,639,606, which is incorporated herein by reference for this teaching. Another example of the method comprises two separate steps: a first step of reverse transcription to convert RNA into cDNA and a second step of quantifying the amount of cDNA using quantitative PCR.
  • Nucleic acid amplification methods include, without limitation, polymerase chain reaction (PCR) (U.S. Pat. No. 5,219,727) and its variants such as in situ polymerase chain reaction (U.S. Pat. No. 5,538,871), quantitative polymerase chain reaction (U.S. Pat. No. 5,219,727), nested polymerase chain reaction (U.S. Pat. No. 5,556,773), self-sustained sequence replication and its variants (Guatelli et al., 1990), transcriptional amplification system and its variants (Kwoh et al., 1989), Qb Replicase and its variants (Miele et al., 1983), cold-PCR (Li et al., 2008), BEAMing (Li et al., 2006) or any other nucleic acid amplification methods, followed by the detection of the amplified molecules using techniques well known to those of skill in the art. Especially useful are those detection schemes designed for the detection of nucleic acid molecules if such molecules are present in very low numbers. The foregoing references are incorporated herein for their teachings of these methods. In other embodiment, the step of nucleic acid amplification is not performed. Instead, the extracted nucleic acids are analyzed directly, e.g., through next-generation sequencing.
  • The analysis of nucleic acids present in the isolated microvesicles can be quantitative, qualitative, or both quantitative and qualitative. For quantitative analysis, the amounts (expression levels), either relative or absolute, of specific nucleic acids of interest within the isolated microvesicles are measured with methods known in the art (some of which are described below). For qualitative analysis, the species of specific nucleic acids of interest within the isolated particles, whether wild type or variants, are identified with methods known in the art.
  • The present invention further encompasses methods of creating and using the microvesicular nucleic acid profiles described herein. In one embodiment of a method for creating a microvesicular profile, the method comprises the steps of isolating microvesicles from a biological sample (e.g., from a body fluid) obtained from a subject or obtaining a microvesicle fraction isolated from a biological sample obtained from a subject, extracting nucleic acids from the isolated microvesicles or microvesicle fraction (or obtaining such as extraction), and determining the profile of the nucleic acids in the extract.
  • The microvesicular profiles of the present invention may be used in methods of aiding diagnosis, prognosis, monitoring, therapy selection, or risk assessment of a disease or other medical condition for a subject as described herein and in the claims.
  • In some embodiments of the present invention, the one or more nucleic acid(s) may be one or more genes listed in Table 2 (cancer genes), Table 3 (cancer-related somatic mutations) and Table 6 (satellite-correlated genes). In one embodiment, the one or more nucleic acid(s) may be a fragment of a c-myc gene, for example, a fragment of c-myc gene containing more than 10 nucleotides. The fragment may contain incrementally longer sequences of 15, 20, 25, 30, 35, 40, 45, 50, 55, 60 nucleotides, up to the full length of the gene.
  • In other embodiments, the one or more nucleic acids may be one or more sequences listed in Table 4 (GBM transposable elements), Table 5 (human transposable elements) and Table 8 (repeated DNA). In one embodiment, the one or more nucleic acids may be L1, Alu, HERV, fragments thereof, or any combination of any of the foregoing. The fragment may contain incrementally longer sequences of 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60 nucleotides up to the full length of each gene sequence.
  • In one embodiment, the invention comprises microvesicular profiles and methods based on microvesicular polypeptide species, polypeptide activities, or both the species and activities of polypeptides. The polypeptide may be any polypeptide in microvesicles. In some embodiments, the polypeptide is a reverse transcriptase. The activity of the reverse transcriptase (RT) can be measured by standard protocols known in the art. For example, the RT activity can be measured by the EnzChek RT Assay Kit (Invitrogen).
  • The human endogenous retrovirus K (HERV-K) reverse transcriptase may serve as a breast cancer prognostic marker (Golan et al., 2008). As such, one particular embodiment of the present invention encompasses profiles and related methods based on detecting the activity of HERV-K reverse transcriptase in microvesicles.
  • The present invention also includes a kit for genetic analysis of a microvesicle preparation from a biological sample (e.g., a bodily fluid sample) from a subject. The kit in a suitable container may include one or more reagents capable of hybridizing to or amplifying one or more nucleic acids extracted from microvesicles. In some embodiments, the nucleic acids correspond to one or more of those genes listed in Tables 2, 3, 4, 5, 6 and/or 8. In some further embodiments, the nucleic acids correspond to one or more RNA transcripts of one or more genes listed in Tables 2, 3, 4, 5, 6 and/or 8. In other further embodiments, the nucleic acid is DNA corresponding to one or more of the genes listed in Tables 2, 3, 4, 5, 6 and/or 8.
  • The present invention further includes an oligonucleotide microarray for genetic analysis of a microvesicle preparation from a body fluid sample from a subject, wherein the various oligonucleotides on the array are designed to hybridize exclusively to nucleic acids corresponding to one or more genes listed in Tables 2, 3, 4, 5, 6 and/or 8. The arrays can be made by standard methods known in the art. For example, SurePrint Technology (Agilent Technologies Corp.) may be used to make as many as 8 arrays on a single slide.
  • The present invention also includes a method of aiding the discovery of one or more biomarkers for a disease or other medical condition. The method may comprise, e.g., the steps of isolating microvesicles from subjects having a disease or other medical condition of interest and also from subjects who do not have the disease or other medical condition of interest; measuring the level of one or more target biological materials extracted from the isolated microvesicles from each of the subjects; comparing the measured levels of the one or more target biological materials from each of the subjects; and determining whether there is a statistically significant difference in the measured levels. The step of determination of a statistically significant difference in the measured levels identifies the one or more target biological materials as potential biomarkers for the disease or other medical condition. As an alternative to isolating microvesicles, the method may be carried out with pre-isolated microvesicle fractions.
  • The one or more biomarkers and nucleic acids in each of the various embodiments of the invention described herein can be one or a collection of genetic aberrations. The term “genetic aberration” is used herein to refer to the nucleic acid amounts as well as nucleic acid variants within the nucleic acid-containing particles. Specifically, genetic aberrations include, without limitation, over-expression of a gene (e.g., an oncogene) or a panel of genes, under-expression of a gene (e.g., a tumor suppressor gene such as p53 or RB) or a panel of genes, alternative production of splice variants of a gene or a panel of genes, gene copy number variants (CNV) (e.g., DNA double minutes) (Hahn, 1993), nucleic acid modifications (e.g., methylation, acetylation and phosphorylations), single nucleotide polymorphisms (SNPs) (e.g., polymorphisms in Alu elements), chromosomal rearrangements (e.g., inversions, deletions and duplications), and mutations (insertions, deletions, duplications, missense, nonsense, synonymous or any other nucleotide changes) of a gene or a panel of genes, which mutations, in many cases, ultimately affect the activity and function of the gene products, lead to alternative transcriptional splice variants and/or changes of gene expression level, or combinations of any of the foregoing.
  • Genetic aberrations can be found in many types of nucleic acids. The determination of such genetic aberrations can be performed by a variety of techniques known to the skilled practitioner. For example, expression levels of nucleic acids, alternative splicing variants, chromosome rearrangement and gene copy numbers can be determined by microarray analysis (see, e.g., U.S. Pat. Nos. 6,913,879, 7,364,848, 7,378,245, 6,893,837 and 6,004,755) and quantitative PCR. Particularly, copy number changes may be detected with the Illumina Infinium II whole genome genotyping assay or Agilent Human Genome CGH Microarray (Steemers et al., 2006).
  • Nucleic acid modifications can be assayed by methods described in, e.g., U.S. Pat. No. 7,186,512 and patent publication WO/2003/023065. Particularly, methylation profiles may be determined by Illumina DNA Methylation OMA003 Cancer Panel.
  • SNPs and mutations can be detected by hybridization with allele-specific probes, enzymatic mutation detection, chemical cleavage of mismatched heteroduplex (Cotton et al., 1988), ribonuclease cleavage of mismatched bases (Myers et al., 1985), mass spectrometry (U.S. Pat. Nos. 6,994,960, 7,074,563, and 7,198,893), single strand conformation polymorphism (SSCP) (Orita et al., 1989), denaturing gradient gel electrophoresis (DGGE)(Fischer and Lerman, 1979a; Fischer and Lerman, 1979b), temperature gradient gel electrophoresis (TGGE) (Fischer and Lerman, 1979a; Fischer and Lerman, 1979b), restriction fragment length polymorphisms (RFLP) (Kan and Dozy, 1978a; Kan and Dozy, 1978b), oligonucleotide ligation assay (OLA), allele-specific PCR (ASPCR) (U.S. Pat. No. 5,639,611), ligation chain reaction (LCR) and its variants (Abravaya et al., 1995; Landegren et al., 1988; Nakazawa et al., 1994), flow-cytometric heteroduplex analysis (WO/2006/113590), nucleic acid sequencing, and combinations/modifications thereof.
  • Nucleic acid sequencing is to determine the base pair sequences of nucleic acids. Two traditional techniques for sequencing DNA are the Sanger dideoxy termination method (Sanger et al., 1977) and the Maxam-Gilbert chemical degradation method (Maxam and Gilbert, 1977). Both methods deliver four samples with each sample containing a family of DNA strands in which all strands terminate in the same nucleotide. Gel electrophoresis, or more recently capillary array electrophoresis is used to resolve the different length strands and to determine the nucleotide sequence, either by differentially tagging the strands of each sample before electrophoresis to indicate the terminal nucleotide, or by running the samples in different lanes of the gel or in different capillaries. Related methods using dyes or fluorescent labels associated with the terminal nucleotide have been developed, where sequence determination is also made by gel electrophoresis and automated fluorescent detectors. For example, the Sanger-extension method has recently been modified for use in an automated micro-sequencing system which requires only sub-microliter volumes of reagents and dye-labelled dideoxyribonucleotide triphosphates. U.S. Pat. No. 5,846,727.
  • More recently, high throughput DNA sequencing methods of various types have been developed and used to delineate nuclei acis sequences. These new methods are applied in sequencing machines including the 454 GenomeSequencer FLX instrument (Roche Applied Science), the Illumina (Solexa) Genome Analyzer, the Applied Biosystems ABI SOLiD system, the Helicos single-molecule sequencing device (HeliScope), and the Ion semiconductor sequencing by Ion Torrent Systems Inc. See also US patent application publications No. 20110111401 and No. 20110098193. It is understood that as the sequencing technology evolves, the analysis of nucleic acids obtained in the invention may be performed using any new sequencing method as one skilled in the art sees appropriate.
  • Gene expression levels may be determined by the serial analysis of gene expression (SAGE) technique (Velculescu et al., 1995), quantitative PCR, quantitative reverse transcription PCR, microarray analysis, and next generation DNA sequencing as known in the art.
  • In general, the methods for analyzing genetic aberrations are reported in numerous publications, not limited to those cited herein, and are available to skilled practitioners. The appropriate method of analysis will depend upon the specific goals of the analysis, the condition/history of the patient, and the specific cancer(s), diseases or other medical conditions to be detected, monitored or treated. The forgoing references are incorporated herein for their teaching of these methods.
  • Many biomarkers may be associated with the presence or absence of a disease or other medical condition in a subject. Therefore, detection of the presence or absence of such biomarkers in nucleic acids extracted from isolated microvesicles, according to the methods disclosed herein, may aid diagnosis of the disease or other medical condition in the subject.
  • For example, as described in WO 2009/100029, detection of the presence or absence of the EGFRvIII mutation in nucleic acids extracted from microvesicles isolated from a patient serum sample aided in the diagnosis and/or monitoring of glioblastoma in the patient. This is so because the expression of the EGFRvIII mutation is specific to some tumors and defines a clinically distinct subtype of glioma (Pelloski et al., 2007).
  • For another example, as described in WO 2009/100029, detection of the presence or absence of the TMPRSS2-ERG fusion gene, PCA-3, or both TMPRSS2-ERG and PCA-3 in nucleic acids extracted from microvesicles isolated from a patient's urine sample may aid in the diagnosis of prostate cancer in the patient.
  • Further, many biomarkers may be associated with disease or medical status monitoring in a subject. Therefore, the detection of the presence or absence of such biomarkers in a nucleic acid extraction from isolated microvesicles, according to the methods disclosed herein, may aid in monitoring the progress or reoccurrence of a disease or other medical condition in a subject.
  • For example, as described in WO 2009/100029, the determination of matrix metalloproteinase (MMP) levels in nucleic acids extracted from microvesicles isolated from an organ transplantation patient may be used to monitor the post-transplantation condition, as a significant increase in the expression level of MMP-2 after kidney transplantation may indicate the onset and/or deterioration of post-transplantation complications. Similarly, a significantly elevated level of MMP-9 after lung transplantation, suggests the onset and/or deterioration of bronchiolitis obliterans syndrome.
  • Many biomarkers have also been found to influence the effectiveness of treatment in a particular patient. Therefore, the detection of the presence or absence of such biomarkers in a nucleic acid extraction from isolated microvesicles, according to the methods disclosed herein, may aid in evaluating the efficacy of a given treatment in a given patient. For example, as disclosed in Table 1 in the publication by Furnari et al. (Furnari et al., 2007), biomarkers, e.g., mutations in a variety of genes, affect the effectiveness of specific medicines used in chemotherapy for treating brain tumors. The identification of these and other biomarkers in nucleic acids extracted from isolated particles from a biological sample from a patient can guide the skilled practitioner in the selection of treatment for the patient.
  • Without limitation, all of the methods mentioned above may further comprise the step of enriching the isolated microvesicles for microvesicles originating from a specific cell type. For example, the cell can be a cancer or pre-cancer cell.
  • Another aspect of the present invention is a method of treating a subject suffering from a form of cancer in which the cancer cells secret microvesicles. The method comprises administering to the subject a therapeutically effective amount of a composition comprising: an inhibitor of microvesicle secretion; an inhibitor of a reverse transcriptase; another microvesicle neutralizer that neutralizes the pro-tumor progression activity of tumor microvesicles; or any combination of the inhibitors/neutralizers.
  • In one embodiment, the inhibitor of microvesicle secretion is an inhibitor of the Rab GTPase pathway (Ostrowski et al.).
  • In some instances, the Rab GTPases are Rab 27a and Rab 27b. The inhibition of the Rab 27a and Rab 27b can be effectuated by silencing the Slp4 gene (also known as SYTL4, synaptotagmin-like 4) and the Slac2b gene (also known as EXPH5, exophilin5), respectively. Gene silencing techniques are well known in the art. One example of such a gene silencing technique is an RNA interference technique that selectively silences genes by delivering shRNA with viral vectors (Sliva and Schnierle).
  • In other instances, the Rab GTPase is Rab35. The inactivation of Rab35 decreases microvesicle secretion. Therefore, silencing Rab35 may decrease the secretion of microvesicles by cells. Inactivation of Rab35 may be achieved by administering TBC1D10B (TBC1 domain family, member 10B) polypeptide (Sliva and Schnierle).
  • In another embodiment, instead of, or in addition to, inhibiting microvesicle secretion, the reverse transcriptase activity is inhibited by administration of an RT inhibitor. RT inhibitors may be any one of 3′-azido2′,3′-dideoxythymidine (AZT), 2′,3′-dideoxyinosine (ddI), 2′,3′-didehyro-3′-deoxythymidine (d4T), nevirapine and efavirenz.
  • Further, a microvesicle neutralizer may be used to block the effects of microvesicles. For example, such neutralizer may bind to microvesicles and destroy the integrity of microvesicles so that the biological materials in microvesicles are not transferred to other intact cells.
  • It should be understood that this invention is not limited to the particular methodologies, protocols and reagents, described herein, which may vary. The terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention, which is defined solely by the claims.
  • The contents of earlier filed provisional applications U.S. Ser. No. 61/378,860, filed Aug. 31, 2010, U.S. Ser. No. 61/421,421, filed Dec. 9, 2010, U.S. Ser. No. 61/437,547, filed Jan. 28, 2011, U.S. Ser. No. 61/438,199, filed Jan. 31, 2011, and 61/493,261 filed Jun. 3, 2011 are herein incorporated by reference in their entirety.
  • All patents, patent applications, and publications cited herein are expressly incorporated herein by reference for the purpose of describing and disclosing, for example, the methodologies and techniques described in such publications that might be used in connection with the present invention. These publications are provided solely for their disclosure prior to the filing date of the present application. Nothing in this regard should be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention or for any other reason. All statements as to the date or representation as to the contents of these documents is based on the information available to the applicants and does not constitute any admission as to the correctness of the dates or contents of these documents.
  • The present invention may be as defined in any one of the following numbered paragraphs.
    • 1. A method for assaying a biological sample from a subject in aid of diagnosis, prognosis or monitoring of a disease or other medical condition in the subject, comprising the steps of:
      • a. obtaining or using a microvesicle fraction from a biological sample from a subject;
      • b. extracting nucleic acid from the fraction; and
      • c. detecting the presence or absence of a biomarker in the extracted nucleic acid; wherein the biomarker is a genetic aberration associated with diagnosis, prognosis, status or stage of a disease or other medical condition, and wherein the genetic aberration is in or corresponds to:
        • i. a c-myc gene;
        • ii. a transposable element;
        • iii. a retrotransposon element;
        • iv. a satellite correlated gene;
        • v. a repeated DNA element;
        • vi. non-coding RNA other than miRNA; or
        • vii. a fragment of any of the foregoing.
    • 2. The method of paragraph 1, wherein the genetic aberration is in or corresponds to a transposable element listed in Table 4 or Table 5, or a fragment thereof.
    • 3. The method of paragraph 1, wherein the genetic aberration is in or corresponds to a retrotransposon element that is LINE, SINE or HERV, or a fragment thereof.
    • 4. The method of paragraph 3, wherein the genetic aberration is in or corresponds to a retrotransposon element that is Line1 (L1), ALU, HERV-H, HERV-K, HERV-K6, HERV-W or HERV-C, or a fragment thereof.
    • 5. The method of paragraph 1, wherein the genetic aberration is in or corresponds to a satellite correlated gene listed in Table 6, or a fragment thereof.
    • 6. The method of paragraph 1, wherein the genetic aberration is in or corresponds to a repeated DNA element listed in Table 8, or a fragment thereof.
    • 7. The method of paragraph 1, wherein the genetic aberration is in or corresponds to a non-coding RNA listed in Table 9 (or a fragment thereof), other than miRNA.
    • 8. The method of paragraph 7, wherein the non-coding RNA is 7SL.
    • 9. A method for assaying a biological sample from a subject in aid of directing treatment of the subject for a disease or other medical condition, comprising the steps of:
      • a. obtaining or using a microvesicle fraction from a biological sample from a subject;
      • b. extracting nucleic acid from the fraction; and
      • c. detecting the presence or absence of a biomarker in the extracted nucleic acid; wherein the biomarker is a genetic aberration associated with a disease or other medical condition or with responsiveness to a specific therapy for the disease or other medical condition, and wherein the genetic aberration is in or corresponds to:
        • i. a c-myc gene;
        • ii. a transposable element;
        • iii. a retrotransposon element;
        • iv. a satellite correlated gene;
        • v. a repeated DNA element;
        • vi. non-coding RNA other than miRNA; or
        • vii. a fragment of any of the foregoing.
    • 10. The method of paragraph 9, wherein the genetic aberration is in or corresponds to a transposable element listed in Table 4 or Table 5, or a fragment thereof.
    • 11. The method of paragraph 9, wherein the genetic aberration is in or corresponds to a retrotransposon element that is LINE, SINE or HERV, or a fragment thereof.
    • 12. The method of paragraph 11, wherein the genetic aberration is in or corresponds to a retrotransposon element that is Line (L1), ALU, HERV-H, HERV-K, HERV-K6, HERV-W or HERV-C, or a fragment thereof.
    • 13. The method of paragraph 9, wherein the genetic aberration is in or corresponds to a satellite correlated gene listed in Table 6, or a fragment thereof.
    • 14. The method of paragraph 9, wherein the genetic aberration is in or corresponds to a repeated DNA element listed in Table 8, or a fragment thereof.
    • 15. The method of paragraph 9, wherein the genetic aberration is in or corresponds to a non-coding RNA listed in Table 9 (or a fragment thereof), other than miRNA.
    • 16. The method of paragraph 15, wherein the non-coding RNA is 7SL.
    • 17. A method for assaying a biological sample from a subject in aid of a determination of the subject's risk of developing a disease or other medical condition, comprising the steps of:
      • a. obtaining or using a microvesicle fraction from a biological sample from a subject;
      • b. extracting nucleic acid from the fraction; and
      • c. detecting the presence or absence of a biomarker in the extracted nucleic acid, wherein the biomarker is a genetic aberration associated with a determination of the subject's risk of developing a disease or other medical condition, and wherein the genetic aberration is in or corresponds to:
        • i. a c-myc gene;
        • ii. a transposable element;
        • iii. a retrotransposon element;
        • iv. a satellite correlated gene;
        • v. a repeated DNA element;
        • vi. non-coding RNA other than miRNA; or
        • vii. a fragment of any of the foregoing.
    • 18. The method of paragraph 17, wherein the genetic aberration is in or corresponds to a transposable element listed in Table 4 or Table 5, or a fragment thereof.
    • 19. The method of paragraph 17, wherein the genetic aberration is in or corresponds to a retrotransposon element that is LINE, SINE or HERV, or a fragment thereof.
    • 20. The method of paragraph 19, wherein the genetic aberration is in or corresponds to a retrotransposon element that is Line (L1), ALU, HERV-H, HERV-K, HERV-K6, HERV-W or HERV-C, or a fragment thereof.
    • 21. The method of paragraph 17, wherein the genetic aberration is in or corresponds to a satellite correlated gene listed in Table 6, or a fragment thereof.
    • 22. The method of paragraph 17, wherein the genetic aberration is in or corresponds to a repeated DNA element listed in Table 8, or a fragment thereof.
    • 23. The method of paragraph 17, wherein the genetic aberration is in or corresponds to a non-coding RNA listed in Table 9 (or a fragment thereof), other than miRNA.
    • 24. The method of paragraph 23, wherein the non-coding RNA is 7SL.
    • 25. A method for assaying a biological sample from a subject in aid of diagnosis, prognosis or monitoring of a disease or other medical condition in the subject, comprising the steps of:
      • a. obtaining or using a microvesicle fraction from a biological sample from a subject;
      • b. extracting nucleic acid from the fraction; and
      • c. detecting the presence or absence of a biomarker in the extracted nucleic acid; wherein the biomarker is a genetic aberration associated with diagnosis, prognosis, status or stage of a disease or other medical condition, and wherein the genetic aberration is in or corresponds to a cancer gene listed in Table 2 or 3, or a fragment thereof.
    • 26. A method for assaying a biological sample from a subject in aid of directing treatment of the subject for a disease or other medical condition, comprising the steps of:
      • a. obtaining or using a microvesicle fraction from a biological sample from a subject;
      • b. extracting nucleic acid from the fraction; and
      • c. detecting the presence or absence of a biomarker in the extracted nucleic acid; wherein the biomarker is a genetic aberration associated with a disease or other medical condition or with responsiveness to a specific therapy for the disease or other medical condition, and wherein the genetic aberration is in or corresponds to a cancer gene listed in Table 2 or 3, or a fragment thereof
    • 27. A method for assaying a biological sample from a subject in aid of a determination of the subject's risk of developing a disease or other medical condition, comprising the steps of:
      • a. obtaining or using a microvesicle fraction from a biological sample from a subject;
      • b. extracting nucleic acid from the fraction; and
      • c. detecting the presence or absence of a biomarker in the extracted nucleic acid; wherein the biomarker is a genetic aberration associated with a determination of the subject's risk of developing a disease or other medical condition, and wherein the genetic aberration is in or corresponds to a cancer gene listed in Table 2 or 3, or a fragment thereof.
    • 28. A method for assaying a biological sample from a subject in aid of diagnosis, prognosis or monitoring of a disease or other medical condition in the subject, comprising the steps of:
      • a. obtaining or using a microvesicle fraction from a biological sample from a subject;
      • b. measuring a polypeptide activity in the fraction; and
      • c. determining whether the polypeptide activity is higher or lower than a normal or average activity for the polypeptide;
      • wherein an elevated or lowered activity is associated with diagnosis, prognosis, status or stage of a disease or other medical condition.
    • 29. The method of paragraph 28, wherein the polypeptide is an enzyme.
    • 30. The method of paragraph 29, wherein the enzyme is reverse transcriptase.
    • 31. The method of paragraph 30, wherein step (c) involves determining whether the reverse transcriptase activity is higher than a normal or average activity for reverse transcriptase.
    • 32. A method for assaying a biological sample from a subject in aid of directing treatment of the subject for a disease or other medical condition, comprising the steps of:
      • a. obtaining or using a microvesicle fraction from a biological sample from a subject;
      • b. measuring a polypeptide activity in the fraction; and
      • c. determining whether the polypeptide activity is higher or lower than a normal or average activity for the same polypeptide; wherein an elevated or lowered activity is associated with a disease or other medical condition or with responsiveness to a specific therapy for the disease or other medical condition.
    • 33. The method of paragraph 32, wherein the polypeptide is an enzyme.
    • 34. The method of paragraph 33, wherein the enzyme is reverse transcriptase.
    • 35. The method of paragraph 34, wherein step (c) involves determining whether the reverse transcriptase activity is higher than a normal or average activity for reverse transcriptase.
    • 36. A method for assaying a biological sample from a subject in aid of a determination of the subject's risk of developing a disease or other medical condition, comprising the steps of:
      • a. obtaining or using a microvesicle fraction from a biological sample from a subject;
      • b. measuring a polypeptide activity in the fraction; and
      • c. determining whether the polypeptide activity is higher or lower than a normal or average activity for the same polypeptide; wherein an elevated or lowered activity is associated with a subject's risk of developing a disease or other medical condition.
    • 37. The method of paragraph 36, wherein the polypeptide is an enzyme.
    • 38. The method of paragraph 37, wherein the enzyme is reverse transcriptase.
    • 39. The method of paragraph 38, wherein step (c) involves determining whether the reverse transcriptase activity is higher than a normal or average activity for reverse transcriptase.
    • 40. The method of any of paragraphs 1-27, wherein the genetic aberration is:
      • a. a species of nucleic acid;
      • b. the level of expression of a nucleic acid;
      • c. a nucleic acid variant; or
      • d. a combination of any of the foregoing.
    • 41. The method of any of paragraphs 1-27, wherein the nucleic acid is RNA and the genetic aberration is an expression profile.
    • 42. The method of any of paragraphs 1-27, wherein the fragment contains more than 10 nucleotides.
    • 43. The method of any of paragraphs 1-39, wherein the biological sample is a bodily fluid.
    • 44. The method of paragraph 43, wherein the bodily fluid is blood, serum, plasma, or urine.
    • 45. The method of any of paragraphs 1-39, wherein the subject is a human subject.
    • 46. The method of paragraph 45, wherein the disease or other medical condition is brain cancer.
    • 47. The method of paragraph 46, wherein the brain cancer is medulloblastoma or glioblastoma.
    • 48. The method of paragraph 45, wherein the disease or other medical condition is melanoma.
    • 49. The method of any of paragraphs 1-27, wherein the step of detecting the presence or absence of a biomarker in the extracted nucleic acid comprises microarray analysis, PCR, quantitative PCR, Digital Gene Expression, or direct sequencing.
    • 50. The method of any of paragraphs 1-39, further comprising the step of enriching the microvesicle fraction for microvesicles originating from a specific cell type.
    • 51. A kit for genetic analysis of a microvesicle fraction obtained from a body fluid sample from a subject, comprising, in a suitable container, one or more reagents capable of hybridizing to or amplifying a nucleic acid corresponding to one or more of the genetic aberrations referenced in any of paragraphs 1-27.
    • 52. An oligonucleotide microarray for genetic analysis of a microvesicle preparation from a body fluid sample from a subject, wherein the oligonucleotides on the array are designed to hybridize to one or more nucleic acids corresponding to one or more of the genetic aberrations referenced in any of paragraphs 1-27.
    • 53. A profile of microvesicular nucleic acid derived from a bodily fluid sample from a subject, wherein the profile comprises a genetic aberration in or corresponding to a cancer gene listed in Table 2 or 3, or a fragment thereof.
    • 54. The profile of paragraph 53, wherein the cancer gene is a c-myc gene.
    • 55. A profile of microvesicular nucleic acid derived from a bodily fluid sample from a subject, wherein the profile comprises a genetic aberration in or corresponding to transposable element from the subject's genome, preferably an element listed in Table 4 or 5, or a fragment of any of the foregoing.
    • 56. A profile of microvesicular nucleic acid derived from a bodily fluid sample from a subject, wherein the profile comprises a genetic aberration in or corresponding to a retrotransposon element from the subject's genome, preferably LINE, SINE or HERV, more preferably LINE1 (L1), ALU, HERV-H, HERV-K, HERV-K6, HERV-W or HERV-C, or a fragment of any of the foregoing.
    • 57. A profile of microvesicular nucleic acid derived from a bodily fluid sample from a subject, wherein the profile comprises a genetic aberration in or corresponding to a satellite correlated gene from the subject's genome, preferably a satellite correlated gene listed in Table 6, or a fragment of any of the foregoing.
    • 58. A profile of microvesicular nucleic acid derived from a bodily fluid sample from a subject, wherein the profile comprises a genetic aberration in or corresponding to an element of repeated DNA from the subject's genome, preferably an element listed in Table 8, or a fragment of any of the foregoing.
    • 59. A profile of microvesicular nucleic acid derived from a bodily fluid sample from a subject, wherein the profile comprises a genetic aberration in or corresponding to non-coding RNA other than miRNA, preferably a species listed in Table 9, or a fragment of any of the foregoing.
    • 60. The profile of paragraph 59, wherein the non-coding RNA is 7SL.
    • 61. The profile of any of paragraphs 53-60, wherein the genetic aberration is:
      • a. a species of nucleic acid;
      • b. the level of expression of a nucleic acid;
      • c. a nucleic acid variant; or
      • d. a combination of any of the foregoing.
    • 62. A method of identifying a potential new nucleic acid biomarker associated with a disease or other medical condition, status or stage of disease or other medical condition, a subject's risk of developing a disease or other medical condition, or a subject's responsiveness to a specific therapy for a disease or other medical condition, comprising the steps of:
      • (a) obtaining or using a microvesicle fraction from a biological sample from a subject;
      • (b) extracting nucleic acid from the fraction;
      • (c) preparing a profile according to any of paragraphs 53-60; and
      • (d) comparing the profile of step (c) to a control or reference profile and selecting one or more potential new biomarkers based on one or more differences between the profile of step (c) and the control or reference profile.
    • 63. A method of treating a subject having a form of cancer in which cancer cells secrete microvesicles, the method comprising administering to the subject a therapeutically effective amount of a composition comprising:
      • a. an inhibitor of microvesicle secretion;
      • b. an inhibitor of a reverse transcriptase;
      • c. a microvesicle neutralizer that neutralizes the pro-tumor progression activity of tumor microvesicles; or
      • d. any combination of the forgoing.
    • 64. The method of paragraph 63, wherein the inhibitor of microvesicle secretion is an inhibitor of RAB GTPase.
    • 65. The method of paragraph 64, where in the Rab GTPase is Rab 27a, Rab 27b or Rab 35.
    • 66. The method of paragraph 63, wherein the inhibitor of a reverse transcriptase is a nucleoside analog selected from the group comprising 3′-azido2′,3′-dideoxythymidine (AZT), 2′,3′-dideoxyinosine (ddI), 2′,3′-didehyro-3′-deoxythymidine (d4T), nevirapine and efavirenz.
    • 67. The method of paragraph 63, wherein the inhibitor of a reverse transcriptase is RNAi targeting the reverse transcriptase gene.
    • 68. The method of paragraph 63, wherein the microvesicle neutralizer is a biological agent that binds microvesicles and destroys the integrity of the microvesicles.
    • 69. A pharmaceutical composition comprising, in a suitable pharmaceutical carrier: (a) an inhibitor of microvesicle secretion, particularly an inhibitor of RAB GTPase, and more particularly Rab 27a, Rab 27b or Rab 35); (b) an inhibitor of reverse transcriptase, particularly a nucleoside analog, more particularly 3′-azido2′,3′-dideoxythymidine (AZT), 2′,3′-dideoxyinosine (ddI), 2′,3′-didehyro-3′-deoxythymidine (d4T), nevirapine, or efavirenz, or an RNAi targeting the reverse transcriptase gene; (c) a microvesicle neutralizer that neutralizes the pro-tumor progression activity of tumor microvesicles, particularly a biological agent that binds microvesicles and destroys the integrity of the microvesicles; or (d) a combination of any of the foregoing.
      1.
  • The invention is further illustrated by the following examples, which should not be construed as further limiting. Examples of the disclosed subject matter are set forth below. Other features, objects, and advantages of the disclosed subject matter will be apparent from the detailed description, figures, examples and claims. Methods and materials substantially similar or equivalent to those described herein can be used in the practice or testing of the presently disclosed subject matter. Exemplary methods and materials are now described as follows.
  • EXAMPLES Example 1 Cultured Cells Release an Abundance of Microvesicles
  • We found that cultured tumor cells as well as normal cells release microvesicles. Here, we analyzed microvesicles produced by tumor cells from glioblastoma (GBM), a common and malignant brain tumor in adults; medulloblastoma, a common and malignant tumor in children with frequent amplification of c-Myc (Bigner et al., 1990); atypical teratoid rhabdoid tumor (AT/RT), a high-grade malignant tumor in children (Tez et al., 2008); and malignant melanoma, a peripheral tumor which can metastasize to the brain (Jemal et al., 2008). We analyzed microvesicles produced by epidermoid carcinoma cells as a control for the study. Increased expression of EGFR, but not c-Myc gene, was found in epidermoid carcinoma cells (Giard et al., 1973).
  • We cultured glioblastoma, medulloblastoma, melanoma and normal human fibroblast cells and monitored the release of microvesicles from each cell type. Specifically, primary GBM cell lines 20/3 and 11/5 were generated in our laboratory from tumor specimens kindly provided by Dr. Bob Carter (Massachusetts General Hospital), and diagnosed as GBM by a neuropathologist at Massachusetts General Hospital (Skog et al., 2008). Glioblastoma cells were cultured in Dulbecco modified essential medium (DMEM; Invitrogen, Carlsbad, Calif.) containing 10% fetal bovine serum (FBS; JRH Biosciences, Carlsbad, Calif.), and penicillin and streptomycin (10 IU/ml and 10 μg/ml, respectively; Cellgro, Herndon, Va.).
  • Primary medulloblastoma cell lines D458, D384 and D425, as well as rhabdoid AT/RT tumor cell line, NS224, were provided by Drs. Y.-J. Cho and S. L. Pomeroy (Children's Hospital, Boston, Mass.). All medulloblastoma cell lines were cultured in suspension in DMEM containing 10% FBS, 1×GutaMAX (Invitrogen) and penicillin/streptomycin. Rhabdoid tumor cell line NS224 was cultured in suspension in DMEM/F12 containing B27 supplement, 20 ng/ml EGF, 20 ng/ml FGF and penicillin/streptomycin.
  • Melanoma cell line, Yumel 0106, was kindly provided by Dr. R. Halaban (Yale New Haven Hospital, New Haven, Conn.) and cultured in OptiMEM (Invitrogen) containing 10% FBS and penicillin/streptomycin. Epidermoid carcinoma cell line, A431 (ATCC) was kindly provided by Huilin Shao (Massachusetts General Hospital) and cultured in DMEM containing 10% FBS and penicillin/streptomycin.
  • Normal human fibroblast lines, HF19 and HF27 were derived from human skin biopsies in the Breakefield laboratory; L2131 was derived in Dr. Christine Klein's laboratory (Univ. Lubeck, Lubeck, Germany) and cultured in DMEM supplemented with 10% FBS, 10 mM HEPES (Invitrogen) and penicillin/streptomycin. All cells were grown in media with 5% exosome-depleted fetal bovine serum (dFBS) (Skog et al., 2008). All cell lines were used over a few passages, as microvesicle yield tended to change over extended passages.
  • To characterize the size distribution and amount of microvesicles released from tumor cells and normal fibroblasts in culture using Nanosight LM10 nanoparticle tracking analysis (NTA), we isolated microvesicles from the culture media of three medulloblastoma cell lines (D384, D425 and D458), one melanoma (Yumel 0106), two GBMs (20/3 and 11/5) and two normal fibroblasts (HF19 and HF27). The media was first spun at 500×g for 10 min. The supernatant was removed and spun again at 16,500×g, filtered through a 0.22 μm filter and used for Nanosight analysis. The nanosight LM10 nanoparticle characterization system (NanoSight Ltd, UK) equipped with a blue laser (405 nm) illumination was used for real-time characterization of the vesicles. The result is presented as the average±SEM of three independent experiments.
  • We found that medulloblastoma cells released more microvesicles/cell than the other cells types analyzed. The amount of microvesicles released by each cell type was: 13,400-25,300/cell/48 hrs for medulloblastomas (FIGS. 1-3), 12,600/cell/48 hrs for the melanoma (FIG. 4), 7,000-13,000/cell/48 hrs for the GBM cells (FIGS. 5-6), and 3,800-6,200/cell/48 hrs for the normal human fibroblasts (FIG. 7-8). Normal human fibroblasts were of low passage and grew with similar rates as the tumor lines in culture, but were of larger size and hence greater surface area per cell.
  • To measure the amount of RNA in the microvesicles released in the culture media from these cells, we collected each conditioned medium after culturing for 48 hr and isolated microvesicles by differential centrifugation and filtration through a 0.22 μm filter followed by ultracentrifugation at 110,000×g as detailed in WO 2009/100029.
  • For purposes of RNA extraction from microvesicles, microvesicle pellets generated from 39 ml conditioned medium produced from 0.5×106-3.5×106 cells over 48 hours were resuspended in 50 μL PBS and incubated at 37° C. for 30 min with DNAse I (DNA-Free™ kit, Ambion) and Exonuclease III (Fermentas, Glen Burnie, Md.), according to the manufacturer's instructions. After treatment, the enzymes were inactivated (using the kit's inactivation reagent and heat inactivation, respectively) and samples processed for RNA extraction.
  • Microvesicles were lysed in 300 μl MirVana lysis buffer (Ambion, Austin, Tex.) followed by extraction with an equal amount of acid-phenol:chloroform. After centrifugation at 10,000×g for 5 min, the upper aqueous phase was removed and further processed to extract RNA using the mirVana RNA isolation kit (Ambion), according to the manufacturer's instructions. RNA extracts were then treated with DNAse (DNA-free kit, Ambion) to exclude DNA carryover. RNA was quantified using a Nanodrop ND-1000 (Thermo Fisher Scientific, Waltham, Mass.) and the quantity and size ranges were evaluated using a 2100 Bioanalyzer (Agilent, Santa Clara, Calif.).
  • ExoRNA in microvesicles was measured using a 2100 Bioanalyzer (Agilent) with RNA 6000 Pico Chip for RNA. The Bioanalyzer RNA 6000 Pico Chip kit detects mainly single strand nucleic acids, but can also detect double strand DNA when present in large amounts. As shown in FIGS. 1-8, the amount of RNA in microvesicles (exoRNA) from medulloblastoma cells was 120- to 310-fold higher than the amount of exoRNA from normal fibroblasts; the amount of exoRNA from glioblastoma cells was 2.8- to 6.5-fold higher than from normal fibroblasts; and the amount from exoRNA from melanoma cells was similar to that from normal fibroblasts even though melanoma cells shed more than twice as many microvesicles. Thus, medulloblastoma tumor cells, in particular, release abundant microvesicles with a high content of exoRNA.
  • Example 2 Characterization of RNA and DNA in Microvesicles
  • To characterize the RNA and DNA in microvesicles, we isolated microvesicles from culture media of medulloblastoma cell line D384, glioblastoma cell line 11/5 and fibroblast cell line H19 as detailed in Example 1. Isolated microvesicles were treated extensively with DNase prior to nucleic acid extraction to reduce the chance of external DNA contamination. Isolated microvesicles may also be treated with RNase prior to nucleic acid extraction although such treatment did not affect the RNA yield from microvesicles probably due to the absence of any significant amounts of external RNA.
  • ExoRNA was extracted from isolated microvesicles as detailed in Example 1.
  • For exoDNA extraction, microvesicle pellets generated from 39 ml conditioned medium produced from 0.5×106-3.5×106 cells over 48 hr were resuspended in 50 μL PBS and incubated at 37° C. for 30 min with DNAse I (DNA-Free™ kit, Ambion) and Exonuclease III (Fermentas, Glen Burnie, Md.), according to manufacturer's instructions. After treatment, the enzymes were inactivated (using the kit's inactivation reagent and heat inactivation, respectively) and samples processed for DNA extraction.
  • Microvesicles were lysed in 300 μl MirVana lysis buffer (Ambion, Austin, Tex.) followed by extraction with an equal amount of acid-phenol:chloroform. After centrifugation at 10,000×g for 5 min, the upper aqueous phase was removed and further processed to extract DNA using the Qiagen PCR purification kit according to manufacturer's instructions. DNA extracts were then treated with RNase (e.g., RNase A, Fermentas, Glen Burnie, Md.) to exclude RNA carryover. DNA were quantified using a Nanodrop ND-1000 (Thermo Fisher Scientific, Waltham, Mass.) and the quantity and size ranges were evaluated using a 2100 Bioanalyzer (Agilent, Santa Clara, Calif.). ExoDNA in microvesicles was measured using a 2100 Bioanalyzer (Agilent) with RNA 6000 Pico Chip and/or DNA 7500 LabChip kits. The Bioanalyzer RNA 6000 Pico Chip kit detects mainly single stranded (“ss”) nucleic acids, but can also detect double-stranded DNA (dsDNA) when present in large amounts, while the DNA 7500 LabChip kit only detects dsDNA. S1 nuclease (200 U/ml; Fermentas) was also used to digest single stranded nucleic acid at 37° C. for 30 min. Genomic cell DNA was isolated from cells with the Flexigene DNA kit (Qiagen, Valencia, Calif.), according to manufacturers' recommendation.
  • As shown in FIGS. 25A and 25C, the RNA profile varied among cell types and culture conditions, but in general, RNA with intact 18S and 28S ribosomal peaks were isolated from microvesicles.
  • The DNA profile also varied among cell types. ExoDNA was much more abundant in microvesicles secreted by glioblastoma tumor cells (FIG. 25B) as compared to normal fibroblast cells (FIG. 25D).
  • We also found that exoDNA was primarily single stranded. When exoDNA from medulloblastoma tumor cells (D384) was analyzed using a dsDNA detection chip, no DNA was detected (FIG. 26A). However, when this same exoDNA was subjected to second strand synthesis, this same chip detected abundant dsDNA (FIG. 26B). Similar results were obtained with exoDNA extracted from microvesicles secreted by GBM cells (GBM 20/3).
  • That exoDNA was primarily single stranded DNA was also supported by our S1 exonuclease assays and PicoGreen assays. In the S1 exonuclease assays, we isolated exoDNA from three medulloblastoma cell lines (D435, D384, D556) and gDNA from one normal human fibroblast cell line (L2132). Samples were incubated with S nuclease (200 U/ml) at 37° C. for 30 minutes or MOCK treated. PCR for the house-keeping gene GAPDH was then performed on treated and MOCK treated samples. S1 exonuclease specifically digests single stranded nucleic acids. As shown in FIG. 27, without S treatment, the bands for exoDNAs extracted from microvesicles secreted by medulloblastoma cell lines (D425m, D384 and D556) were observed on the gel. In contrast, after S treatment, the bands for exoDNAs extracted from microvesicles secreted by medulloblastoma cell lines (D425m, D384 and D556) did not show up. As a control, the band for the genomic DNA extracted from fibroblast cell line L2132 still showed up after S1 exonuclease digestion. Therefore, exoDNA was sensitive to S exonuclease digestion, suggesting that exoDNA is likely to be single stranded DNA.
  • Further, quantitative analysis of exoDNA using PicoGreen® (Thermo Scientific, Waltham, Mass.), which is a sensitive dsDNA binding fluorescent dye, showed an 18-fold lower amount of nucleic acids in comparison with the amount detected using the Bioanalyzer RNA chip. Since the Bioanalyzer RNA chip detection method can detect only single stranded nucleic acids, the exoDNA extract contained mainly single stranded nucleic acids.
  • Example 3 c-Myc Oncogene Amplification in Cultured Medulloblastoma Tumor Cells can be Detected in Both exoRNA and exoDNA
  • We detected c-Myc oncogene amplification using either exoRNA or exoDNA from medulloblastoma tumor cells. To measure the amount of c-Myc amplification, we extracted exoRNA and exoDNA, from culture media of three medulloblastoma cell lines (D458, D425 and D384), one atypical teratoid/rhabdoid (AT/RT) tumor cell line NS224, one glioblastoma cell line (11/5), and one normal fibroblast cell line H19 using the same method as detailed in Example 1, respectively. The genomic DNA from each of the same cell lines was extracted according to standard protocols in the art, which can be found in books such as Molecular Cloning: A Laboratory Manual (3-Volume Set) Ed. Joseph Sambrook, David W. Russel, and Joe Sambrook, Cold Spring Harbor Laboratory, 3rd edition (Jan. 15, 2001), ISBN: 0879695773. The extracted nucleic acids were then used in PCR analysis to measure the level of amplifications.
  • For PCR analysis of exoRNA, total exoRNA (50 ng) was converted into cDNA with the Sensiscript RT Kit (Qiagen) using random primers, according to the manufacturer's instructions, and a 1:20 fraction (corresponding to 2.5 ng reverse transcribed RNA) was used for quantitative PCR (qPCR). For PCR analysis of the gDNA and exoDNA, qPCR was carried out using 10 ng DNA as a template. All reactions were performed in a 25 μl reaction using Power SYBR® Green PCR Master Mix (Applied Biosystems, Foster City, Calif.) and 160 nM of each primer. Amplification conditions consisted of: (1) 1 cycle of 50° C., 2 min; (2) 1 cycle of 95° C., 10 min; (3) 40 cycles of 95° C., 15 sec; and 60° C., 1 min, and (4) a dissociation stage consisting of 1 cycle of 95° C., 15 sec; 60° C., 20 sec; and 95° C., 15 sec on the 7000 ABI Prism PCR system (Applied Biosystems). Cycle threshold (“Ct”) values were analyzed in auto mode and manually inspected for accuracy. The Ct values of both RNA and DNA levels were normalized to the housekeeping gene GAPDH in each sample. Primer dimers were excluded by evaluation of dissociation curve and agarose gel electrophoresis.
  • Sequences of the primers used were as follows n-Myc primers: 1) Forward TCTACCCGGACGAAGATGAC (SEQ ID NO: 1), Reverse AGCTCGTTCTCAAGCAGCAT (SEQ ID NO: 2) (primers within exon 2); c-Myc primer: Forward TCAAGAGGCGAACACACAAC (SEQ ID NO: 3), Reverse TAACTACCTTGGGGGCCTTT (SEQ ID NO: 4) (both primers in exon 3); c-Myc primer: Forward CCTACCCTCTCAACGACAGC (SEQ ID NO: 5), Reverse CTCTGACCTTTTGCCAGGAG (SEQ ID NO: 6) (spanning intron 2). c-Myc human specific primers: Forward CAACCCTTGCCGCATCCAC (SEQ ID NO: 7), Reverse AGTCGCGTCCTTGCTCGG (SEQ ID NO: 8) (both primers in exon 1). POU5F1B primers: Forward ATCCTGGGGGTTCTATTTGG (SEQ ID NO: 9), Reverse CTCCAGGTTGCCTCTCACTC (SEQ ID NO: 10); and GAPDH primers: Forward CTCTGCTCCTCCTGTTCGAC (SEQ ID NO: 11) (exon 8), Reverse ACGACCAAATCCGTTGACTC (SEQ ID NO: 12) (exon 9).
  • Levels of c-Myc amplification were measured at the genomic level (gDNA) by qPCR (FIG. 9). All three medulloblastoma cell lines had significant amplifications of c-Myc sequences (16-34-fold) compared to fibroblasts and other tumor cell types. RNA and DNA were extracted from microvesicles shed by these cell lines and quantitated by RT-PCR and PCR respectively, using primers in exon 3 with values for c-Myc sequences normalized to glyceraldehyde 3-phosphate dehydrogenase (GAPDH), a housekeeping gene constitutively expressed in cells and found in exoRNA14 and here in exoDNA. Microvesicles from all medulloblastoma cell lines showed elevated levels of c-Myc sequences, both for exoRNA (8-45-fold) and exoDNA (10-25 fold), compared to microvesicles from fibroblasts and tumor cells with diploid c-Myc copy numbers (FIGS. 10-11). Also, using primers that span a full intron, we successfully detected a 1.6 kb fragment corresponding to the unspliced c-Myc genomic DNA (verified by sequencing) in exoDNA from all three medulloblastoma cell lines, but not in any of the other cell lines.
  • Furthermore, to establish that this genomic fragment of c-Myc in microvesicles was derived from a genomic amplicon, we verified the presence of elevated levels of a flanking gene, POU5F1B gene (Storlazzi et al., 2006) at levels matching those of c-Myc (FIG. 29B). POU5F1B PCR product was also verified by sequencing.
  • Levels of n-Myc sequences in cellular genomic DNA (gDNA) or exoRNA were also measured by qPCR and qRT-PCR and none of the other tumor types showed genomic amplification of n-Myc sequences or elevated levels of n-Myc exoRNA (FIGS. 31A and B).
  • The levels of c-Myc DNA quantitated for gDNA and exoDNA/RNA in these medulloblastoma lines were also compared to levels estimated by 250K single nucleotide polymorphism (SNP) analysis. For gene copy number estimation by the SNP array analysis, genomic DNA was extracted from medulloblastoma cell pellets using the Puregene DNA Extraction Kit (Gentra Systems, Minneapolis, Minn.), according to the manufacturer's instructions. To obtain signal intensities and genotype calls, genomic DNA samples were digested, labeled and hybridized to Affymetrix 250K StyI SNP arrays, according to the manufacturer's protocol (Affymetrix, Santa Clara, Calif.). Signal intensities were normalized using rank invariant set normalization, and copy numbers for altered genomic regions were inferred using the GLAD (Gain and Loss of DNA) algorithm available in the Genepattern software package (www.genepattern.org). C-Myc and n-Myc copy numbers were inferred by analyzing the smoothed copy number data at genomic regions ch8q24.12 and ch2p24, respectively.
  • The results are shown in Table 1 and in FIG. 30 in are presentative heat map. Increased levels of c-Myc exoDNA corresponded well to the genomic copy number estimated by 250 k SNP and qPCR in medulloblastoma lines, as compared to normal diploid levels in other cell lines, with correspondingly elevated c-Myc exoRNA in medulloblastoma microvesicles.
  • TABLE 1
    Assessment of c-Myc gene amplification levels in different cell types.
    c-Myc genomic c-Myc amount c-Myc amount
    Method copy number exoRNAa exoDNAb
    D425 FISH >25   8 ± 2.0  13 ± 0.2
    250 k SNP c 15
    qPCR   8 ± 3.6
    D384 250 k SNP 25 42 ± 22  25 ± 3.7
    qPCR  12 ± 4.7
    D458 250 k SNP 17 45 ± 11  10 ± 0.6
    qPCR  17 ± 3.0
    NS224 250 k SNP 2 0.8 ± 0.3 4.2 ± 0.1
    qPCR 2
    GBM11/5 qPCR 2 2.8 ± 1.4 0.4 ± 0.1
    HF19 qPCR 2 1 1
    a2.5 ng reverse transcribed exoRNA and 10 ng of exoDNA were used as template for qPCR. All values were normalized to GAPDH mRNA.
    bFISH = Fluorescence in situ hybridization of metaphase chromosome spread.63
    cSee representative heat map shown in FIG. 30.
  • Example 4 c-Myc Oncogene Amplification in Xenografted Medulloblastoma Tumor Cells In Vivo can be Detected with Both ExoRNA and ExoDNA
  • To assess the potential diagnostic utility of using exoRNA to detect c-Myc amplification in tumors, human medulloblastoma cells (c-Myc amplified) and epidermoid carcinoma tumor cells (non-amplified) were grown as xenograft tumors in nude mice. In the xenograft experiments, two groups of five adult immunodeficient mice (nu/nu NCI) were each injected subcutaneously in both flanks with 5×106 medulloblastoma cells (line D425) or epidermoid carcinoma cells (line A431). Tumors were allowed to grow for three weeks; the mice were then sacrificed and blood was drawn by cardiac puncture. Approximately 1 ml of blood was obtained from each mouse and allowed to clot at room temperature for 15 min and then centrifuged at 1300×g for 10 min. The serum was then filtered through a 0.22 μm filter and stored at −80° C. Samples were thawed and centrifuged for 1 hr at 100,000×g to obtain microvesicles for RNA extraction, as described above.
  • As shown in FIG. 12, microvesicles were isolated from serum samples in tumor-bearing mice and exoRNA was extracted from the isolated microvesicles. Human c-Myc was detected in exoRNAs from 2/5 (40%) of the medulloblastoma-bearing mice (FIG. 13) and from 0/5 (0%) of the epidermoid carcinoma-bearing mice (FIG. 14).
  • Example 5 Retrotransposon Elements are Enriched in Tumor Microvesicles
  • We analyzed the RNA species in cellular RNA and exoRNA preparations from a low passage GBM line by microarray analysis using a whole genome array (Agilent Technologies). Briefly, RNA was extracted from microvesicles, as described above. RNA (0.5 μg) was used for linear T7-based amplification and Cy-3/Cy-5 labeling (Agilent Low RNA Input Linear Amp Kit, Agilent Technologies) following the manufacturer's protocol. The microarray experiments were performed by Miltenyi Biotec (Auburn, Calif.) using the Agilent whole human genome microarray, 4×44K (44,000 probes), two-color array. The array was performed on two different RNA preparations from primary GBM cells and their microvesicles.
  • The microarray results have been deposited with a Geo accession number GSE13470. The results indicate the presence of higher transcription levels of a number of retrotransposon sequences in exoRNA extracts as compared to cellular RNA extracts.
  • From the two-color Agilent array data, we generated MA plots as previously described (Storey and Tibshirani, 2003). The intensities of the expression levels for each transcript were obtained from the array data for both exoRNA extracts from microvesicles and cellular RNA extracts from cells. The intensity of exoRNA is here designated “Microvesicle.” The intensity of cellular RNA is here designated “Cell”. The log ratio of the intensities of microvesicle/cell is plotted on the Y-axis (M=log2Microvesicle−log2Cell) and the mean log expression of the two on the X-axis (A=0.5×(log2Microvesicle+log2Cell)).
  • As shown in FIG. 15, the microarray data was represented on a MA plot as the cumulative abundance (in microvesicles and cells) of specific RNAs (X-axis) and the relative ratio of these RNAs in microvesicles versus cells (Y-axis). The Y-axis scale was log2, so RNAs above 4 or below −4 on the Y-axis have at least a 16-fold different level in the microvesicles vs. cells. There were many RNA species that were at least 16 fold more abundant in microvesicles than in cells (M value above 4). Similarly, there were also many RNA species that were at least 16 fold less abundant in microvesicles than in cells (M value below −4).
  • As shown in FIG. 17, RNA from DNA transposons was similar in content in cells and microvesicles with the M values spreading between −4 and 4. In contrast, as shown in FIGS. 18-20, RNA from retrotransposons, e.g. HERV, Alu and L1, was frequently higher in microvesicles than in cells. This was particularly notable for the HERV sequences. As shown in FIG. 16, HERV-H was the most abundant and microvesicle-enriched in these GBM cells, followed by HERV-C, HERV-K6 and HERV-W. Therefore, some retrotransposon RNAs, e.g., HERV RNA, may be selectively packaged or enriched, in tumor microvesicles.
  • Since only a selected subset of transposon/retrotransposon probes are represented on the Agilent arrays, other retrotransposons that are not represented on the Agilent arrays may be enriched in microvesicles from tumor cells as well.
  • Since L1 and HERV-K retrotransposons, as well as Alu elements (Goodier and Kazazian, 2008), have been implicated in tumor progression, we further assayed their levels in cellular RNA and exoRNA from tumor and normal cells by qRT-PCR (again with the caveat that the primers used only detect a subset of these sequences). See FIGS. 21A-C. The expression levels were normalized to that of the GAPDH mRNA. L1 and Alu sequences were abundant in both cells and microvesicles (high values on the X-axis) and enriched in most of the microvesicles compared to the cells (M>0). The levels of retrotransposon sequences tended to be higher in exoRNA vs. cellular RNA, with HERV-K being relatively high in some tumors. Interestingly, HERV-K RNA was not detectable in exoRNA from normal human fibroblasts (HF19), with a Ct value of 36 (below detection limit). This difference between levels of HERV-K RNA in microvesicles from fibroblasts and tumor cells is shown in the MA plot (FIG. 21C).
  • Example 6 the Non-Coding 7SL RNA in Microvesicles as Biomarkers for Cancer Cells
  • We found that the expression profiles of the non-coding 7SL RNA in microvesicles from plasma may serve as biomarkers for glioblastoma. We obtained de-identified blood samples from a GBM patient and healthy control from the biobank at Massachusetts General Hospital. We took the serum for each blood sample and isolated microvesicles from the serum using the method as described in Example 1. RNA was extracted from the isolated microvesicles for further analysis. The expression levels of the 7SL RNA, EGFR and GAPDH were determined using qRT-PCR following a procedure as detailed in Example 3. The primers used for the qRT-PCR are as follows: 7SL-RNA: Forward primer 5′ CAAAACTCCCGTGCTGATCA 3′ (SEQ IDNO: 13), Reverse primer 5′ GGCTGGAGTGCAGTGGCTAT 3′ (SEQ ID NO: 14), Probe (FAM labeled MGB probe), 5′ TGGGATCGCGCCTGT 3′ (SEQ ID NO: 15); EGFR: Forward primer 5′ TATGTCCTCATTGCCCTCAACA 3′ (SEQ IDNO: 16), Reverse primer 5′ CTGATGATCTGCAGGTTTTCCA 3′ (SEQ ID NO: 17), Probe (FAM labeled MGB probe), 5′ AAGGAATTCGCTCCACTG 3′ (SEQ ID NO: 18); GAPDH, huGAPDH ID 4326317E from the vendor Applied Biosystems Inc.
  • The results show that the expression profile of the 7SL RNA in microvesicles correlates with the disease status of the subject from which the microvesicles were isolated (FIG. 34). The expression levels of the 7SL RNA in microvesicles from GBM serum samples were about 200 times higher than the levels from normal serum samples. In contrast, the expression levels of EGFR in microvesicles from GBM serum samples were about 2 times higher than the levels from normal serum samples. Further, the expression levels of GAPDH in microvesicles from GBM serum samples were roughly the same as the levels in normal serum samples.
  • As such, one aspect of the present invention is directed to the profile of 7SL RNA in microvesicles isolated from a subject, e.g., a human being. The profile of 7SL RNA may be the expression profile of the 7SL RNA. The profile of 7SL RNA may be correlated with the medical condition of the subject wherefrom the microvesicles are isolated.
  • Another aspect of the present invention is directed to a method of aiding the diagnosis, prognosis or selection of treatment therapy of a medical condition by determining the profile of the 7SL RNA. The determination of the profile of 7SL RNA may be the determination of the expression profile of the 7SL RNA. Since the profile of 7SL RNA may be correlated with the medical condition of the subject wherefrom the microvesicles are isolated, the determination of the profile in microvesicles may therefore aid the diagnosis, prognosis or selection of treatment therapy for the subject.
  • Example 7 Retrotransposon Elements in Tumor Microvesicles are Transferrable
  • To determine whether microvesicles could transfer HERV-K RNA to normal cells, human umbilical vein endothelial cells (HUVEC) were exposed to microvesicles from medulloblastoma cells and levels of HERV-K RNA were measured in HUVEC cells over time. Human umbilical vein endothelial cells (HUVEC) cells, kindly provided by Dr. Jonathan Song (Massachusetts General Hospital), were cultured in gelatin—coated flasks in endothelial basal medium (Lonza, Walkersville, Md.) supplemented with hEGF, hydrocortisone, GA-1000 and FBS (Singlequots from Lonza). All cell lines were used over a few passages, as microvesicle yield tended to change over extended passages.
  • Specifically, HUVEC cells were seeded in 12-well plates at a density of 1.5×105 cells/well. Microvesicles were isolated from 1.2×107 D384 cells over a 48 hour period and added to each well in a total volume of 400 μl DMEM. Mock treated cells were incubated in 400 μl exosome-free DMEM. The cells were incubated for 2 hrs at 37° C. and were then replenished with 1.5 ml DMEM (with 5% dFBS). Cells were collected at different time points after the microvesicle exposure and cell RNA was extracted for qRT-PCR analysis. The result is presented as the average±SEM of three independent experiments.
  • As shown in FIG. 22, HERV-K RNA expression was increased in HUVEC cells at 2, 6, 12, 24, 48 and 72 hours after microvesicle exposure. The increased HERV-K RNA expression in HUVEC cells indicated that the microvesicles contained active HERV-K genes and such genes were transferred to the HUVEC cells.
  • Example 8 Retrotransposon Elements in the Form of ExoDNA were Enriched in Tumor Microvesicles with Elevated RT Activities
  • ExoDNA was also analyzed at the retrotransposon level with qPCR. ExoDNAs were extracted from microvesicles as detailed in Example 2. gDNA were extracted from cells as detailed in Example 3. The primers used for qPCR are as follows: GAPDH primers: Forward CTCTGCTCCTCCTGTTCGAC (SEQ ID NO: 19) (exon 8), Reverse ACGACCAAATCCGTTGACTC (SEQ ID NO: 20) (exon 9); L1 primers: Forward TAAGGGCAGCCAGAGAGAAA (SEQ ID NO: 21), Reverse GCCTGGTGGTGACAAAATCT (SEQ ID NO: 22); HERV-K6 primers: Forward GGAGAGAAGCTGTCCTGTGG (SEQ ID NO: 23), Reverse TGACTGGACTTGCACGTAGG (SEQ ID NO: 24); Alu primers: Forward CATGTGGGTTAGCCTGGTCT (SEQ ID NO: 25), Reverse TTCCCACATTGCGTCATTTA (SEQ ID NO: 26).
  • The exoDNA levels were compared to nuclear gDNA isolated from the cells in MA plots. The levels of exoDNA in microvesicles and gDNA in corresponding cells were normalized to levels of GAPDH. The exoDNA (presumably originating from the cytoplasmic compartment) and gDNA (isolated from the nuclear compartment of the cells) showed clearly different patterns (M≠0). L1 was slightly enriched in all medulloblastomas (FIG. 23A). HERV-K DNA was enriched in two of the medulloblastomas (D425 and D384) (FIG. 23C). In contrast, Alu was not enriched in any of the medulloblastoma tested (FIG. 23B).
  • We further found that the enrichment of the transposable elements at the exoDNA level in the medulloblastoma cell lines corresponded to high levels of endogenous Reverse Transcription (RT) activity in exosomes. To measure RT activities, microvesicles were lysed in RIPA buffer [50 mM Tris-HCl (pH 8); 150 mM NaCl, 2.5% sodium dodecyl sulfate, 2.5% deoxycholic acid, 2.5% Nonidet P-40] for 20 min at 4° C. Exosomal debris was removed by centrifugation at 14,000×g for 15 min. Proteins were quantified by Bradford assay and diluted 1:6 for each RT reaction. The RT assay was performed using the EnzCheck RT assay kit (Invitrogen) on a 25 μL reaction, as described by the manufacturer. Fluorescence signal of the samples was measured before and after the RT incubation. The difference between the two values indicates newly synthesized DNA. Serial dilutions of SuperScript™ III First Strand (Invitrogen) were used as standards. The result is presented as the average±SEM of three independent experiments.
  • As shown in FIG. 24, RT activities in the 0106, GBM11/5, GBM 20/3 and HF19 cells are significantly less than those in D384, D425 and D458 cells. This decreased RT activities correlate well with the reduced levels of L1 and HERV-K exoDNA in 0106, GBM11/5, GBM 20/3 and HF19 cells (as shown by the negative values on the MA plots in FIGS. 23A and C). Such correlation suggests that a fraction of exoDNA may be cDNA.
  • In addition, we found that exoDNA might also include fragments of genomic DNA. We used L-mimosine to inhibit DNA replication and examined whether the inhibition affected the yield of exoDNA. If the exoDNA yield is decreased after inhibition, it is very likely that exoDNA may contain fragments of genomic DNA.
  • Specifically, D384 cells were plated on 6-well plates (2×106 cells/well) and treated with increasing amounts (200, 400 and 600 μM) of L-mimosine (Sigma-Aldrich, St. Louis, Mo.) which is an inhibitor of DNA replication. The drug was added at one time point and 48 hrs after, the media was collected and processed for the isolation of microvesicles. Cell viability was assessed by cell count using the Countess Automated Cell Counter (Invitogen). SsDNA yields are normalized to one.
  • As shown in FIG. 32, the exoDNA yield in microvesicles was decreased by about 50% following inhibition of DNA replication with L-mimosine. Therefore, some of the exoDNA may also be fragments of genomic DNA generated during DNA replication and mitosis.
  • While the present invention has been disclosed with reference to certain embodiments, numerous modifications, alterations, and changes to the described embodiments are possible without departing from the sphere and scope of the present invention, as defined in the appended claims. Accordingly, it is intended that the present invention not be limited to the described embodiments, but that it has the full scope defined by the language of the following claims, and equivalents thereof.
  • TABLE 2
    Cancer genes.
    Chromo- Tumour Tumour
    Locuslink Protein some types types Cancer
    Symbol ID ID* band (somatic) (germline) syndrome
    ABL1 25 P00519 9q34.1 CML, ALL
    ABL2 27 P42684 1q24-q25 AML
    AF15Q14 57082 NP_065113 15q14 AML
    AF1Q 10962 Q13015 1q21 ALL
    AF3p21 51517 Q9NZQ3 3p21 ALL
    AF5q31 27125 NP_055238 5q31 ALL
    AKT2 208 P31751 19q13.1- Ovarian,
    q13.2 pancreatic
    ALK 238 Q9UM73 2p23 ALCL
    ALO17 57714 XP_290769 17q25.3 ALCL
    APC 324 P25054 5q21 Colorectal, Colorectal, Adenomatous
    pancreatic, pancreatic, polyposis
    desmoid, desmoid, coli;
    hepatoblastoma, hepatoblastoma, Turcot
    glioma, glioma, syndrome
    other CNS other CNS
    ARHGEF12 23365 NP_056128 11q23.3 AML
    ARHH 399 Q15669 4p13 NHL
    ARNT 405 P27540 1q21 AML
    ASPSCR1 79058 NP_076988 17q25 Alveolar soft
    part sarcoma
    ATF1 466 P18846 12q13 Malignant
    melanoma of
    soft parts,
    angiomatoid
    fibrous
    histiocytoma
    ATIC 471 P31939 2q35 ALCL
    ATM 472 Q13315 11q22.3 T-PLL Leukaemia, Ataxia
    lymphoma, telangiectasia
    medulloblastoma,
    glioma
    BCL10 8915 O95999 1p22 MALT
    BCL11A 53335 NP_060484 2p13 B-CLL
    BCL11B 64919 NP_612808 14q32.1 T-ALL
    BCL2 596 P10415 18q21.3 NHL, CLL
    BCL3 602 P20749 19q13 CLL
    BCL5 603 I52586 17q22 CLL
    BCL6 604 P41182 3q27 NHL, CLL
    BCL7A 605 NP_066273 12q24.1 B-NHL
    BCL9 607 O00512 1q21 B-ALL
    BCR 613 P11274 22q11.21 CML, ALL
    BHD 201163 NP_659434 17p11.2 Renal, Brit-
    fibrofolliculomas, Hogg-
    trichodiscomas Dube
    syndrome
    BIRC3 330 Q13489 11q22- MALT
    q23
    BLM 641 P54132 15q26.1 Leukaemia, Bloom
    lymphoma, Syndrome
    skin
    squamous
    cell, other
    cancers
    BMPR1A 657 P36894 10q22.3 Gastrointestinal Juvenile
    polyps polyposis
    BRAF 673 P15056 7q34 Melanoma,
    colorectal,
    papillary
    thyroid,
    borderline
    ovarian,
    NSCLC,
    cholangiocarcinoma
    BRCA1 672 P38398 17q21 Ovarian Breast Hereditary
    ovarian breast/ovarian
    BRCA2 675 P51587 13q12 Breast, Breast, Hereditary
    ovarian, ovarian, breast/
    pancreatic pancreatic,
    leukaemia
    (FANCB,
    FANCD1)
    BRD4 23476 O60885 19p13.1 Lethal
    midline
    carcinoma of
    young people
    BTG1 694 P31607 12q22 BCLL
    CBFA2T1 862 Q06455 8q22 AML
    CBFA2T3 863 NP_005178 16q24 AML
    CBFB 865 Q13951 16q22 AML
    CBL 867 P22681 11q23.3 AML
    CCND1 595 P24385 11q13 CLL, B-ALL,
    breast
    CDH1 999 P12830 16q22.1 Lobular Gastric Familial
    breast, gastric gastric
    carcinoma
    CDK4 1019 P11802 12q14 Melanoma Familial
    malignant
    melanoma
    CDKN2A- 1029 NP_478102 9p21 Melanoma Melanoma Familial
    p14ARF multipule other pancreatic malignant
    melanoma
    CDKN2A- 1029 P42771 9p21 Melanoma Melanoma Familial
    p16INK4A multipule other pancreatic malignant
    melanoma
    CDX2 1045 Q99626 13q12.3 AML
    CEBPA 1050 NP_004355 11p15.5 AML, MDS
    CEP1 11064 NP_008949 9q33 MPD/NHL
    CHIC2 26511 NP_036242 4q11-q12 AML
    CHN1 1123 P15882 2q31- Extraskeletal
    q32.1 myxoid
    chondrosarcoma
    CLTC 1213 Q00610 17q11- ALCL
    qter
    COL1A1 1277 P02452 17q21.31- Dermatofibrosarcoma
    q22 protuberans
    COPEB 1316 Q99612 10p15 Prostatic,
    glioma
    COX6C 1345 P09669 8q22-q23 Uterine
    leiomyoma
    CREBBP 1387 Q92793 16p13.3 AL, AML
    CTNNB1 1499 P35222 3p22- Colorectal,
    p21.3 ovarian,
    hepatoblastoma,
    others
    CYLD 1540 NP_056062 16q12- Cylindroma Cylindroma Familial
    q13 cylindromatosis
    D10S170 8030 NP_005427 10q21 Papillary
    thyroid,
    CML
    DDB2 1643 Q92466 11p12 Skin basal Xenoderma
    cell, skin pigmentosum
    squamous E
    cell,
    melanoma
    DDIT3 1649 P35638 12q13.1- Liposarcoma
    q13.2
    DDX10 1662 Q13206 11q22- AML§
    q23
    DEK 7913 P35659 6p23 AML
    EGFR 1956 P00533 7p12.3- Glioma
    p12.1
    EIF4A2 1974 Q14240 3q27.3 NHL
    ELKS 23085 NP_055879 12p13.3 Papillary
    thyroid
    ELL 8178 P55199 19p13.1 AL
    EP300 2033 Q09472 22q13 Colorectal,
    breast,
    pancreatic,
    AML
    EPS15 2060 P42566 1p32 ALL
    ERBB2 2064 P04626 17q21.1 Breast,
    ovarian, other
    tumour types
    ERCC2 2068 P18074 19q13.2- Skin basal Xenoderma
    q13.3 cell, skin pigmentosum
    squamous D
    cell,
    melanoma
    ERCC3 2071 P19447 2q21 Skin basal Xenoderma
    cell, skin pigmentosum
    squamous B
    cell,
    melanoma
    ERCC4 2072 Q92889 16p13.3- Skin basal Xenoderma
    cell, skin pigmentosum
    squamous F
    cell,
    melanoma
    ERCC5 2073 P28715 13q33 Skin basal Xenoderma
    cell, skin pigmentosum
    squamous G
    cell,
    melanoma
    ERG 2078 P11308 21q22.3 Ewing's
    sarcoma
    ETV1 2115 P50549 7p22 Ewing's
    sarcoma
    ETV4 2118 P43268 17q21 Ewing's
    sarcoma
    ETV6 2120 P41212 12p13 Congenital
    fibrosarcoma,
    multiple
    leukaemia
    and
    lymphoma,
    secretory
    breast
    EVI1 2122 Q03112 3q26 AML, CML
    EWSR1 2130 NP_005234 22q12 Ewing's
    sarcoma,
    desmoplastic
    small round
    cell, ALL
    EXT1 2131 NP_000118 8q24.11- Exostoses, Multiple
    q24.13 osteosarcoma exostoses
    type 1
    EXT2 2132 Q93063 11p12- Exostoses, Multiple
    p11 osteosarcoma exostoses
    type 2
    FACL6 23305 NP_056071 5q31 AML, AEL
    FANCA 2175 NP_000126 16q24.3 AML, Fanconi
    leukaemia anaemia A
    FANCC 2176 Q00597 9q22.3 AML, Fanconi
    leukaemia anaemia C
    FANCD2 2177 NP_149075 3p26 AML, Fanconi
    leukaemia anaemia D2
    FANCE 2178 NP_068741 6p21- AML, Fanconi
    p22 leukaemia anaemia E
    FANCF 2188 Q9NPI8 11p15 AML, Fanconi
    leukaemia anaemia F
    FANCG 2189 O15287 9p13 AML, Fanconi
    leukaemia anaemia G
    FEV 54738 NP_059991 2q36 Ewing's
    sarcoma
    FGFR1 2260 P11362 8p11.2- MPD/NHL
    p11.1
    FGFR1OP 11116 NP_008976 6q27 MPD/NHL
    FGFR2 2263 P21802 10q26 Gastric
    FGFR3 2261 P22607 4p16.3 Bladder, MM
    FH 2271 P07954 1q42.1 Leiomyomatosis, Hereditary
    renal leiomyomatosis
    and
    renal-cell
    cancer
    FIP1L1 81608 NP_112179 4q12 Idiopathic
    hypereosinophilic
    syndrome
    FLI1 2313 Q01543 11q24 Ewing's
    sarcoma
    FLT3 2322 P36888 13q12 AML, ALL
    FLT4 2324 P35916 5q35.3 Angiosarcoma
    FNBP1 23048 XP_052666 9q23 AML
    FOXO1A 2308 Q12778 13q14.1 Alveolar
    rhabdomyosarcomas
    FOXO3A 2309 O43524 6q21 AL
    FSTL3 10272 O95633 19p13 B-CLL
    FUS 2521 P35637 16p11.2 Liposarcoma
    GAS7 8522 O60861 17p AML§
    GATA1 2623 P15976 Xp11.23 Megakaryoblastic
    leukaemia
    of
    Down
    syndrome
    GMPS 8833 P49915 3q24 AML
    GNAS 2778 P04895 20q13.2 Pituitary
    adenoma
    GOLGA5 9950 NP_005104 14q Papillary
    thyroid
    GPC3 2719 P51654 Xq26.1 Wilms' Simpson-
    tumour Golabi-
    Behmel O
    syndrome
    GPHN 10243 Q9NQX3 14q24 AL
    GRAF 23092 NP_055886 5q31 AML, MDS
    HEI10 57820 NP_067001 14q11.1 Uterine
    leiomyoma
    HIP1 3092 O00291 7q11.23 CMML
    HIST1H4I 8294 NP_003486 6p21.3 NHL
    HLF 3131 Q16534 17q22 ALL
    HMGA2 8091 P52926 12q15 Lipoma
    HOXA11 3207 P31270 7p15- CML
    p14.2
    HOXA13 3209 P31271 7p15- AML
    p14.2
    HOXA9 3205 P31269 7p15- AML§
    p14.2
    HOXC13 3229 P31276 12q13.3 AML
    HOXD11 3237 P31277 2q31-q32 AML
    HOXD13 3239 P35453 2q31-q32 AML§
    HRAS 3265 P01112 11p15.5 Infrequent
    sarcomas,
    rare other
    types
    HRPT2 3279 NP_013522 1q21-q31 Parathyroid Parathyroid Hyperpara-
    adenoma adenoma, thyroidism
    multiple jaw
    ossifying jaw tumour
    fibroma syndrome
    HSPCA 3320 P07900 1q21.2- NHL
    q22
    HSPCB 3326 P08238 6p12 NHL
    IGHα 3492 14q32.33 MM,
    Burkitt's
    lymphoma,
    NHL, CLL,
    B-ALL,
    MALT
    IGKα 50802 2p12 Burkitt's
    lymphoma
    IGLα 3535 22q11.1- Burkitt's
    q11.2 lymphoma
    IL21R 50615 Q9HBE5 16p11 NHL
    IRF4 3662 Q15306 6p25-p23 MM
    IRTA1 83417 NP_112572 1q21 B-NHL
    JAK2 3717 O60674 9p24 ALL, AML
    KIT 3815 P10721 4q12 GIST, AML, GIST, Familial
    TGCT epithelioma gastrointestinal
    stromal
    KRAS2 3845 NP_004976 12p12.1 Pancreatic,
    colorectal,
    lung, thyroid,
    AML, others
    LAF4 3899 P51826 2q11.2- ALL
    q12
    LASP1 3927 Q14847 17q11- AML
    q21.3
    LCK 3932 NP_005347 1p35- T-ALL
    p34.3
    LCP1 3936 P13796 13q14.1- NHL
    q14.3
    LCX 80312 XP_167612 10q21 AML
    LHFP 10186 NP_005771 13q12 Lipoma
    LMO1 4004 P25800 11p15 T-ALL
    LMO2 4005 P25791 11p13 T-ALL
    LPP 4026 NP_005569 3q28 Lipoma,
    leukaemia
    LYL1 4066 P12980 19p13.2- T-ALL
    p13.1
    MADH4 4089 Q13485 18q21.1 Colorectal, Gastrointestinal Juvenile
    pancreatic, polyps polyposis
    small
    intestine
    MALT1 10892 Q9UDY8 18q21 MALT
    MAML2 84441 XP_045716 11q22- Salivary-
    q23 gland
    mucoepidermoid
    MAP2K4 6416 P45985 17p11.2 Pancreatic,
    breast,
    colorectal
    MDS1 4197 Q13465 3q26 MDS, AML
    MECT1 94159 AAK93832.1 19p13 Salivary-
    gland
    mucoepidermoid
    MEN1 4221 O00255 11q13 Parathyroid Parathyroid Multiple
    adenoma, endocrine
    pituitary neoplasia
    adenoma, type 1
    pancreatic
    islet cell,
    carcinoid
    MET 4233 P08581 7q31 Papillary Papillary Familial
    renal, head- renal papillary
    neck renal
    squamous
    cell
    MHC2TA 4261 P33076 16p13 NHL
    MLF1 4291 P58340 3q25.1 AHL
    MLH1 4292 P40692 3p21.3 Colorectal, Colorectal, Hereditary
    endometrial, endometrial, non-
    ovarian, CNS ovarian, CNS polyposis
    colorectal,
    Turcot
    syndrome
    MLL 4297 Q03164 11q23 AML, ALL
    MLLT1 4298 Q03111 19p13.3 AL
    MLLT10 8028 P55197 10p12 AL
    MLLT2 4299 P51825 4q21 AL
    MLLT3 4300 P42568 9p22 ALL
    MLLT4 4301 P55196 6q27 AL
    MLLT6 4302 P55198 17q21 AL
    MLLT7 4303 NP_005929 Xq13.1 AL
    MN1 4330 Q10571 22q13 AML,
    meningioma
    MSF 10801 NP_006631 17q25 AML§
    MSH2 4436 P43246 2p22-p21 Colorectal, Colorectal, Hereditary
    endometrial, endometrial, non-
    ovarian ovarian polyposis
    colorectal
    MSH6 2956 P52701 2p16 Colorectal Colorectal, Hereditary
    endometrial, non-
    ovarian polyposis
    colorectal
    MSN 4478 P26038 Xq11.2- ALCL
    q12
    MUTYH 4595 NP_036354 1p34.3- Colorectal Adenomatous
    1p32.1 polypsis
    coli
    MYC 4609 P01106 8q24.12- Burkitt's
    q24.13 lymphoma,
    amplified in
    other cancers,
    B-CLL
    MYCL1 4610 P12524 1p34.3 Small cell
    lung
    MYCN 4613 P04198 2p24.1 Neuroblastoma
    MYH11 4629 P35749 16p13.13- AML
    p13.12
    MYH9 4627 P35579 22q13.1 ALCL
    MYST4 23522 NP_036462 10q22 AML
    NACA 4666 NP_005585 12q23- NHL
    q24.1
    NBS1 4683 NP_002476 8q21 NHL, glioma, Nijmegen
    medulloblastoma, breakage
    rhabdomyosarcoma syndrome
    NCOA2 10499 Q15596 8q13.1 AML
    NCOA4 8031 Q13772 10q11.2 Papillary
    thyroid
    NF1 4763 P21359 17q12 Neurofibroma, Neurofibroma, Neurofibromatosis
    glioma glioma type 1
    NF2 4771 P35240 22q12.2 Meningioma, Meningioma, Neurofibromatosis
    acoustic acoustic type 2
    neuroma neuroma
    NOTCH1 4851 P46531 9q34.3 T-ALL
    NPM1 4869 P06748 5q35 NHL, APL,
    AML
    NR4A3 8013 Q92570 9q22 Extraskeletal
    myxoid
    chondrosarcoma
    NRAS 4893 P01111 1p13.2 Melanoma,
    MM, AML,
    thyroid
    NSD1 64324 NP_071900 5q35 AML
    NTRK1 4914 P04629 1q21- Papillary
    q22 thyroid
    NTRK3 4916 Q16288 15q25 Congenital
    fibrosarcoma,
    secretory
    breast
    NUMA1 4926 NP_006176 11q13 APL
    NUP214 8021 P35658 9q34.1 AML
    NUP98 4928 P52948 11p15 AML
    NUT 256646 XP_171724 15q13 Lethal
    midline
    carcinoma of
    young people
    OLIG2 10215 Q13516 21q22.11 T-ALL
    PAX3 5077 P23760 2q35 Alveolar
    rhabdomyosarcoma
    PAX5 5079 Q02548 9p13 NHL
    PAX7 5081 P23759 1p36.2- Alveolar
    p36.12 rhabdomyosarcoma
    PAX8 7849 Q06710 2q12- Follicular
    q14 thyroid
    PBX1 5087 NP_002576 1q23 Pre-B-ALL
    PCM1 5108 NP_006188 8p22- Papillary
    p21.3 thyroid
    PDGFB 5155 P01127 22q12.3- DFSP
    q13.1
    PDGFRA 5156 P16234 4q11- GIST
    q13
    PDGFRB 5159 NP_002600 5q31- MPD, AML,
    q32 CMML,
    CML
    PICALM 8301 Q13492 11q14 T-ALL, AML
    PIM1 5292 P11309 6p21.2 NHL
    PML 5371 P29590 15q22 APL
    PMS1 5378 P54277 2q31- Colorectal, Hereditary
    q33 endometrial, non-
    ovarian polyposis
    colorectal
    cancer
    PMS2 5395 P54278 7p22 Colorectal, Hereditary
    endometrial, non-
    ovarian, polyposis
    medulloblastoma, colorectal
    glioma cancer,
    Turcot
    syndrome
    PMX1 5396 P54821 1q24 AML
    PNUTL1 5413 NP_002679 22q11.2 AML
    POU2AF1 5450 Q16633 11q23.1 NHL
    PPARG 5468 P37231 3p25 Follicular
    thyroid
    PRCC 5546 Q92733 1q21.1 Papillary
    renal
    PRKAR1A 5573 P10644 17q23- Papillary Myxoma, Carney
    q24 thyroid endocrine, complex
    papillary
    thyroid
    PRO1073 29005 Q9UHZ2 11q31.1 Renal-cell
    carcinoma
    (childhood
    epitheloid)
    PSIP2 11168 NP_150091 9p22.2 AML
    PTCH 5727 Q13635 9q22.3 Skin basal Skin basal Nevoid
    cell, cell, basal-cell
    medulloblastoma medulloblastoma carsinoma
    syndrome
    PTEN 5728 O00633 10q23.3 Glioma, Harmartoma, Cowden
    prostatic, glioma, syndrome,
    endometrial prostatic, Bannayan-
    endometrial Riley-
    Ruvalcaba
    syndrome
    PTPN11 5781 Q06124 12q24.1 JMML,
    AML, MDS
    RAB5EP 9135 NP_004694 17p13 CMML
    RAD51L1 5890 NP_002868 14q23- Limpoma,
    q24.2 uterine
    leiomyoma
    RAPIGDS1 5910 P52306 4q21- T-ALL
    q25
    RARA 5914 P10276 17q12 APL
    RB1 5925 P06400 13q14 Retinoblastoma, Retinoblastoma, Familial
    sarcoma, sarcoma, retinoblastoma
    breast, small- breast, small-
    cell lung cell lung
    RECQL4 9401 O94761 8q24.3 Osteosarcoma, Rothmund-
    skin basal and Thompson
    squamous cell syndrome
    REL 5966 Q04864 2p13- Hodgkin
    p12 Lymphoma
    RET 5979 P07949 10q11.2 Medullary Medullary Multilpe
    thyroid, thyroid, endocrine
    papillary papillary 2A/2B
    thyroid, thyroid,
    pheochromocytoma pheochromo-
    cytomaneoplasia
    RPL22 6146 P35268 3q26 AML, CML
    RUNX1 861 Q01196 21q22.3 AML, pre-B-ALL
    RUNXBP2 799 NP_006757 8p11 AML
    SBDS 51119 Q9Y3A5 7q11 AML, MDS Schwachman-
    Diamond
    syndrome
    SDHB 6390 P21912 1p36.1- Paraganglioma, Familial
    p35 pheochromocytoma paraganglioma
    SDHC 6391 O75609 1q21 Paraganglioma, Familial
    pheochromocytoma paraganglioma
    SDHD 6392 O14521 11q23 Paraganglioma, Familial
    pheochromocytoma paraganglioma
    SEPT6 23157 NP_055944 Xq24 AML
    SET 6418 Q01105 9q34 AML
    SFPQ 6421 P23246 1p34.3 Papillary
    renal cell
    SH3GL1 6455 Q99961 19p13.3 AL
    SMARCB1 6598 Q12824 22q11 Malignant Malignant Rhabdoid
    rhabdoid rhabdoid predispositioon
    SMO 6608 Q99835 7q31-q32 Skin basal
    cell
    SS18 6760 Q15532 18q11.2 Synovial
    sarcoma
    SS18L1 26039 O75177 20q13.3 Synovial
    sarcoma
    SSH3BP1 10006 NP_005461 10p11.2 AML
    SSX1 6756 Q16384 Xp11.23- Synovial
    p11.22 sarcoma
    SSX2 6757 Q16385 Xp11.23- Synovial
    p11.22 sarcoma
    SSX4 6759 Q60224 Xp11.23 Synovial
    sarcoma
    STK11 6794 Q15831 19p13.3 NSCLC Jejunal Peutz-
    harmartoma, Jeghers
    ovarian, syndrome
    testicular,
    pancreatic
    STL 7955 NOPROTEIN 6q23 B-ALL
    SUFU 51684 NP_057253 10q24.32 Medulloblastoma Medulloblastoma Medulloblastoma
    predisposition
    TAF15 8148 Q92804 17q11.1- Extraskeletal
    q11.2 myxoid
    chondrosarcomas,
    ALL
    TAL1 6886 P17542 1p32 Lymphoblastic
    leukaemia/
    biphasic
    TAL2 6887 Q16559 9q31 T-ALL
    TCF1 6927 P20823 12q24.2 Hepatic Hepatic Familial
    adenoma, adenoma, hepatic
    hepatocellular hepatocellular adenoma
    carcinoma carcinoma
    TCF12 6938 Q99081 15q21 Extraskeletal
    myxoid
    chondrosarcoma
    TCF3 6929 P15923 19p13.3 pre-B-ALL
    TCL1A 8115 NP_068801 14q32.1 T-CLL
    TEC 7006 P42680 4p12 Extraskeletal
    myxoid
    chondrosarcoma
    TFE3 7030 P19532 Xp11.22 Papillary
    renal,
    alveolar soft
    part sarcoma
    TFEB 7942 P19484 6p21 Renal
    (childhood
    epithelioid)
    TFG 10342 NP_006061 3q11- Papillary
    q12 thyroid,
    ALCL
    TFPT 29844 NP_037474 19q13 Pre-B-ALL
    TFRC 7037 P02786 3q29 NHL
    TIF1 8805 O15164 7q32- APL
    q34
    TLX1 3195 P31314 10q24 T-ALL
    TLX3 30012 O43711 5q35.1 T-ALL
    TNFRSF6 355 P25445 10q24.1 TGCT, nasal
    NK/T
    lymphoma,
    skin
    squamous-
    cell
    carcinoma
    (burn-scar
    related)
    TOP1 7150 P11387 20q12- AML§
    q13.1
    TP53 7157 P04637 17p13 Breast, Breast, Li-
    colorectal, sarcoma, Fraumeni
    lung, adrenocortical syndrome
    sarcoma, carcinoma,
    adrenocortical, glioma,
    glioma, multiple other
    multiple other types
    types
    TPM3 7170 P06753 1q22- Papillary
    q23 thyroid,
    ALCL
    TPM4 7171 P07226 19p13.1 ALCL
    TPR 7175 P12270 1q25 Papillary
    thyroid
    TRAα 6955 14q11.2 T-ALL
    TRBα 6957 7q35 T-ALL
    TRDα 6964 14q11 T-cell
    leukaemia
    TRIM33 51592 Q9UPN9 1p13 Papillary
    thyroid
    TRIP11 9321 NP_004230 14q31- AML
    q32
    TSC1 7248 Q92574 9q34 Hamartoma, Tuberous
    renal cell sclerosis 1
    TSC2 7249 P49815 16p13.3 Hamartoma, Tuberous
    renal cell sclerosis 2
    TSHR 7253 P16473 14q31 Toxic thyroid Thyroid
    adenoma adenoma
    VHL 7428 P40337 3p25 Renal, Renal, von
    hemangioma, hemangioma, Hippel-
    pheochromocytoma pheochromocytoma Lindau
    syndrome
    WAS 7454 P42768 Xp11.23- Lymphoma Wiskott-
    p11.22 Aldrich
    syndrome
    WHSC1L1 54904 NP_060248 8p12 AML
    WRN 7486 Q14191 8p12- Osteosarcoma, Werner
    p11.2 meningioma, syndrome
    others
    WT1 7490 NP_000369 11p13 Wilms', Wilms' Denys-
    desmoplastic Drash
    small round syndrome,
    cell Frasier
    syndrome,
    Familial
    Wilms'
    tumor
    XPA 7507 P23025 9q22.3 Skin basal Xeroderma
    cell, skin pigmentosum A
    squamous
    cell,
    melanoma
    XPC 7508 Q01831 3p25 Skin basal Xeroderma
    cell, skin pigmentosum C
    squamous
    cell,
    melanoma
    ZNF145 7704 Q05516 11q23.1 APL
    ZNF198 7750 Q9UBW7 13q11- MPD/NHL
    q12
    ZNF278 23598 NP_055138 22q12- Ewing's
    q14 sarcoma
    ZNF384 171017 NP_597733 12p13 ALL
    ZNFN1A1 10320 NP_006051 7p12 ALL,
    DLBCL
    Cancer
    Tissue molecular Mutation Translocation
    Symbol type genetics type partner
    ABL1 L Dom T BCR,
    ETV6
    ABL2 L Dom T ETV6
    AF15Q14 L Dom T MLL
    AF1Q L Dom T MLL
    AF3p21 L Dom T MLL
    AF5q31 L Dom T MLL
    AKT2 E Dom A
    ALK L Dom T NPM1,
    TPM3,
    TFG,
    TPM4,
    ATIC,
    CLTC,
    MSN,
    ALO17
    ALO17 L Dom T ALK
    APC E, M, O Rec D, Mis,
    N, F, S
    ARHGEF12 L Dom T MLL
    ARHH L Dom T BCL6
    ARNT L Dom T ETV6
    ASPSCR1 M Dom T TFE3
    ATF1 E, M Dom T EWSR1
    ATIC L Dom T ALK
    ATM L, O Rec D, Mis, N,
    F, S
    BCL10 L Dom T IGHa
    BCL11A L Dom T IGHa
    BCL11B L Dom T TLX3
    BCL2 L Dom T IGHa
    BCL3 L Dom T IGHa
    BCL5 L Dom T MYC
    BCL6 L Dom T, Mis IG loci,
    ZNFN1A1,
    LCP1,
    PIM1,
    TFRC,
    MHC2TA,
    NACA,
    HSPCB,
    HSPCA,
    HIST1H4I,
    IL21R,
    POU2AF1,
    ARHH,
    EIF4A2
    BCL7A L Dom T MYC
    BCL9 L Dom T IGHa,
    IGLa
    BCR L Dom T ABL1,
    FGFR1
    BHD E, M Rec? Mis, N, F
    BIRC3 L Dom T MALT1
    BLM L, E Rec Mis, N, F
    BMPR1A E Rec Mis, N, F
    BRAF E Dom M
    BRCA1 E Rec D, Mis, N,
    F, S
    BRCA2 L, E Rec D, Mis, N, —F, S
    ovarian
    BRD4 E Dom T NUT
    BTG1 L Dom T MYC
    CBFA2T1 L Dom T MLL,
    RUNX1
    CBFA2T3 L Dom T RUNX1
    CBFB L Dom T MYH11
    CBL L Dom T MLL
    CCND1 L, E Dom T IGHa,
    FSTL3
    CDH1 E Rec Mis, N, F,
    S
    CDK4 E Dom Mis
    CDKN2A- L, E, M, Rec D, S
    p14ARF O
    CDKN2A- L, E, M, Rec D, Mis, N,
    p16INK4A O F, S
    CDX2 L Dom T ETV6
    CEBPA L Dom Mis, N, F
    CEP1 L Dom T FGFR1
    CHIC2 L Dom T ETV6
    CHN1 M Dom T TAF15
    CLTC L Dom T ALK
    COL1A1 M Dom T PDGFB
    COPEB E, O Rec Mis, N
    COX6C M Dom T HMGA2
    CREBBP L Dom T MLL,
    MORF,
    RUNXBP2
    CTNNB1 E, M, O Dom H, Mis
    CYLD E Rec Mis, N, F,
    S
    D10S170 E Dom T RET,
    PDGFRB
    DDB2 E Rec M, N
    DDIT3 M Dom T FUS
    DDX10 L Dom T NUP98
    DEK L Dom T NUP214
    EGFR O Dom A, O
    EIF4A2 L Dom T BCL6
    ELKS E Dom T RET
    ELL L Dom T MLL
    EP300 L ,E Rec T MLL,
    RUNXBP2
    EPS15 L Dom T MLL
    ERBB2 E Dom A
    ERCC2 E Rec M, N, F, S
    ERCC3 E Rec M, S
    ERCC4 E Rec M, N, F
    ERCC5 E Rec M, N, F
    ERG M Dom T EWSR1
    ETV1 M Dom T EWSR1
    ETV4 M Dom T EWSR1
    ETV6 L, E, M Dom T NTRK3,
    RUNX1,
    PDGFRB,
    ABL1,
    MN1,
    ABL2,
    FACL6,
    CHIC2,
    ARNT,
    JAK2,
    EVI1,
    CDX2,
    STL
    EVI1 L Dom T RUNX1,
    ETV6
    EWSR1 L, M Dom T FRI1,
    ERG,
    ZNF278,
    NR4A3,
    TEC,
    FEV,
    ATF1,
    ETV1,
    ETV4,
    WT1,
    ZNF384
    EXT1 M Rec Mis, N, F,
    S
    EXT2 M Rec Mis, N, F,
    S
    FACL6 L Dom T ETV6
    FANCA L Rec D, Mis, N,
    F, S
    FANCC L Rec D, Mis, N,
    F, S
    FANCD2 L Rec D, Mis, N,
    F
    FANCE L Rec N, F, S
    FANCF L Rec N, F
    FANCG L Rec Mis, N, F,
    S
    FEV M Dom T EWSR1
    FGFR1 L Dom T BCR,
    FOP,
    ZNF198,
    CEP1
    FGFR1OP L Dom T FGFR1
    FGFR2 E Dom Mis
    FGFR3 L, E Dom Mis, T IGHα
    FH E, M Rec Mis, N, F
    FIP1L1 L Dom T PDGFRA
    FLI1 M Dom T EWSR1
    FLT3 L Dom Mis, O
    FLT4 M Dom Mis
    FNBP1 L Dom T MLL
    FOXO1A M Dom T PAX3
    FOXO3A L Dom T MLL
    FSTL3 L Dom T CCND1
    FUS M Dom T DDIT3
    GAS7 L Dom T MLL
    GATA1 L Dom Mis, F
    GMPS L Dom T MLL
    GNAS E Dom Mis
    GOLGA5 E Dom T RET
    GPC3 O Rec T, D, Mis,
    N, F, S
    GPHN L Dom T MLL
    GRAF L Dom T, F, S MLL
    HEI10 M Dom T HMGA2
    HIP1 L Dom T PDGFRB
    HIST1H4I L Dom T BCL6
    HLF L Dom T TCF3
    HMGA2 M Dom T LHFP,
    RAD51,
    L1,
    LPP,
    HEI10,
    COX6C
    HOXA11 L Dom T NUP98
    HOXA13 L Dom T NUP98
    HOXA9 L Dom T NUP98
    HOXC13 L Dom T NUP98
    HOXD11 L Dom T NUP98
    HOXD13 L Dom T NUP98
    HRAS L, M Dom Mis
    HRPT2 E, M Rec Mis, N, F
    HSPCA L Dom T BCL6
    HSPCB L Dom T BCL6
    IGHα L Dom T MYC,
    FGFR3,
    PAX5,
    IRTA1,
    IRF4,
    CCND1,
    BCL9,
    BCL6,
    BCL8,
    BCL2,
    BCL3,
    BCL10,
    BCL11A,
    LHX4
    IGKα L Dom T MYC
    IGLα L Dom T BCL9,
    MYC
    IL21R L Dom T BCL6
    IRF4 L Dom T IGHα
    IRTA1 L Dom T IGHα
    JAK2 L Dom T ETV6
    KIT L, M, O Dom Mis, O
    KRAS2 L, E, M, Dom Mis
    O
    LAF4 L Dom T MLL
    LASP1 L Dom T MLL
    LCK L Dom T TRBα
    LCP1 L Dom T BCL6
    LCX L Dom T MLL
    LHFP M Dom T HMGA2
    LMO1 L Dom T TRDα
    LMO2 L Dom T TRDα
    LPP L, M Dom T HMGA2,
    MLL
    LYL1 L Dom T TRBα
    MADH4 E Rec D, Mis, N,
    F
    MALT1 L Dom T BIRC3
    MAML2 E Dom T MECT1
    MAP2K4 E Rec D, Mis, N
    MDS1 L Dom T RUNX1
    MECT1 E Dom T MAML2
    MEN1 E Rec D, Mis, N,
    F, S
    MET E Dom Mis
    MHC2TA L Dom T BCL6
    MLF1 L Dom T NPM1
    MLH1 E, O Rec D, Mis, N,
    F, S
    MLL L Dom T, O MLL,
    MLLT1,
    MLLT2,
    MLLT3,
    MLLT4,
    MLLT7,
    MLLT10,
    MLLT6,
    ELL,
    EPS15,
    AF1Q,
    CREBBP,
    SH3GL1,
    FNBP1,
    PNUTL1,
    MSF,
    GPHN,
    GMPS,
    SSH3BP1,
    ARHGEF12,
    GAS7,
    FOXO3A,
    LAF4,
    LCX,
    SEPT6,
    LPP,
    CBFA2T1,
    GRAF,
    EP300,
    PICALM
    MLLT1 L Dom T MLL
    MLLT10 L Dom T MLL,
    PICALM
    MLLT2 L Dom T MLL
    MLLT3 L Dom T MLL
    MLLT4 L Dom T MLL
    MLLT6 L Dom T MLL
    MLLT7 L Dom T MLL
    MN1 L Dom T ETV6
    MSF L Dom T MLL
    MSH2 E Rec D, Mis, N,
    F, S
    MSH6 E Rec Mis, N, F,
    S
    MSN L Dom T ALK
    MUTYH E Rec Mis, N, F,
    S
    MYC L, E Dom A, T IGKα,
    BCL5,
    BCL7A,
    BTG1,
    TRAα,
    IGHα
    MYCL1 E Dom A
    MYCN O Dom A
    MYH11 L Dom T CBFB
    MYH9 L Dom T ALK
    MYST4 L Dom T CREBBP
    NACA L Dom T BCL6
    NBS1 L, E, M, Rec Mis, N, F
    O
    NCOA2 L Dom T RUNXBP2
    NCOA4 E Dom T RET
    NF1 O Rec D, Mis, N,
    F, S, O
    NF2 O Rec D, Mis, N,
    F, S, O
    NOTCH1 L Dom T TRBα
    NPM1 L Dom T ALK,
    RARA,
    MLF1
    NR4A3 M Dom T EWSR1
    NRAS L, E Dom Mis
    NSD1 L Dom T NUP98
    NTRK1 E Dom T TPM3,
    TPR,
    TFG
    NTRK3 E, M Dom T ETV6
    NUMA1 L Dom T RARA
    NUP214 L Dom T DEK,
    SET
    NUP98 L Dom T HOXA9,
    NSD1,
    WHSC1L1,
    DDX10,
    TOP1,
    HOXD13,
    PMX1,
    HOXA13,
    HOXD11,
    HOXA11,
    RAP1GDS1
    NUT E Dom T BRD4
    OLIG2 L Dom T TRAα
    PAX3 M Dom T FOXO1A
    PAX5 L Dom T IGHα
    PAX7 M Dom T FOXO1A
    PAX8 E Dom T PPARG
    PBX1 L Dom T TCF3
    PCM1 E Dom T RET
    PDGFB M Dom T COL1A1
    PDGFRA M, O Dom Mis, O
    PDGFRB L Dom T ETV6,
    TRIP11,
    HIP1,
    RAB5EP,
    H4
    PICALM L Dom T MLLT10,
    MLL
    PIM1 L Dom T BCL6
    PML L Dom T RARA
    PMS1 E Rec Mis, N
    PMS2 E Rec Mis, N, F
    PMX1 L Dom T NUP98
    PNUTL1 L Dom T MLL
    POU2AF1 L Dom T BCL6
    PPARG E Dom T PAX8
    PRCC E Dom T TFE3
    PRKAR1A E, M Dom, T, Mis, N, RET
    Rec F, S
    PRO1073 E Dom T TFEB
    PSIP2 L Dom T NUP98
    PTCH E, M Rec Mis, N, F,
    S
    PTEN L, E, M, Rec D, Mis, N,
    O F, S
    PTPN11 L Dom Mis
    RAB5EP L Dom T PDGFRB
    RAD51L1 M Dom T HMGA2
    RAPIGDS1 L Dom T NUP98
    RARA L Dom T PML,
    ZNF145,
    TIF1,
    NUMA1,
    NPM1
    RB1 L, E, M, Rec D, Mis, N,
    O F, S
    RECQL4 M Rec N, F, S
    REL L Dom A
    RET E, O Dom T, Mis, N, H4,
    F PRKAR1A,
    NCOA4,
    PCM1,
    GOLGA5,
    TRIM33
    RPL22 L Dom T RUNX1
    RUNX1 L Dom T RPL22,
    MDS1,
    EVI1,
    CBFA2T3,
    CBFA2T1,
    ETV6
    RUNXBP2 L Dom T CREBBP,
    NCOA2,
    EP300
    SBDS L Rec Gene
    conversion
    SDHB O Rec Mis, N, F
    SDHC O Rec Mis, N, F
    SDHD O Rec Mis, N, F,
    S
    SEPT6 L Dom T MLL
    SET L Dom T NUP214
    SFPQ E Dom T TFE3
    SH3GL1 L Dom T MLL
    SMARCB1 M Rec D, N, F, S
    SMO E Dom Mis
    SS18 M Dom T SSX1,
    SSX2
    SS18L1 M Dom T SSX1
    SSH3BP1 L Dom T MLL
    SSX1 M Dom T SS18
    SSX2 M Dom T SS18
    SSX4 M Dom T SS18
    STK11 E, M, O Rec D, Mis, N,
    STL L Dom T ETV6
    SUFU O Rec D, F, S
    TAF15 L, M Dom T TEC,
    CHN1,
    ZNF384
    TAL1 L Dom T TRDα
    TAL2 L Dom T TRBα
    TCF1 E Rec Mis, F
    TCF12 M Dom T TEC
    TCF3 L Dom T PBX1,
    HLF,
    TFPT
    TCL1A L Dom T TRAα
    TEC M Dom T EWSR1,
    TAF15,
    TCF12
    TFE3 E Dom T SFPQ,
    ASPSCR1,
    PRCC
    TFEB E, M Dom T ALPHA
    TFG E, L Dom T NTRK1,
    ALK
    TFPT L Dom T TCF3
    TFRC L Dom T BCL6
    TIF1 L Dom T RARA
    TLX1 L Dom T TRBα,
    TRDα
    TLX3 L Dom T BCL11B
    TNFRSF6 L, E, O Rec Mis
    TOP1 L Dom T NUP98
    TP53 L, E, M, Rec Mis, N, F
    O
    TPM3 E, L Dom T NTRK1,
    ALK
    TPM4 L Dom T ALK
    TPR E Dom T NTRK1
    TRAα L Dom T ATL,
    OLIG2,
    MYC,
    TCL1A
    TRBα L Dom T HOX11,
    LCK,
    NOTCH1,
    TAL2,
    LYL1
    TRDα L Dom T TAL1,
    HOX11,
    TLX1,
    LMO1,
    LMO2
    TRIM33 E Dom T RET
    TRIP11 L Dom T PDGFRB
    TSC1 E, O Rec D, Mis, N,
    F, S
    TSC2 E, O Rec D, Mis, N,
    F, S
    TSHR E Dom Mis
    VHL E, M, O Rec D, Mis, N,
    F, S
    WAS L Rec Mis, N, F,
    S
    WHSC1L1 L Dom T NUP98
    WRN L, E, M, Rec Mis, N, F,
    O S
    WT1 O Rec D, Mis, N, EWSR1
    F, S
    XPA E Rec Mis, N, F,
    S
    XPC E Rec Mis, N, F,
    S
    ZNF145 L Dom T RARA
    ZNF198 L Dom T FGFR1
    ZNF278 M Dom T EWSR1
    ZNF384 L Dom T EWSR1,
    TAF15
    ZNFN1A1 L Dom T BCL6
    *From Swiss-Prot/Refseq.
    D (large deletion) covers the abnormalities that result in allele loss/loss of heterozygosity at many recessive cancer genes.
    §Refers to cases of acute myeloid leukaemia that are associated with treatment.
    O (other) in the ‘mutation type’ column refers primarily to small in-frame deletions/insertions as found in KIT/PDGFRA, and larger duplications/insertions as found in FLT3 and EGFR.
    Note
    that where an inversion/large deletion has been shown to result in a fusions protein, these have been listed under translocations. The Wellcome Trust Sanger Institute web version of the cancer-gene set can be found at http://www.sanger.ac.uk/genetics/CPG/Census/.
    A, amplification;
    AEL, acute eosinophilic leukaemia;
    AL, acute leukaemia;
    ALCL, anaplastic large-cell lymphoma;
    ALL, acute lymphocytic leukaemia;
    AML, acute myelogenous leukaemia;
    APL, acute promyelocytic leukaemia;
    B-ALL, B-cell acute lymphocytic leukaemia;
    B-CLL, B-cell lymphocytic leukaemia;
    B-NHL, B-cell non-Hodgkin's lymphoma;
    CLL, chronic lymphatic leukaemia;
    CML, chronic myeloid leukaemia;
    CMML, chronic myelomonocytic leukaemia;
    CNS, central nervous system;
    D, large deletion;
    DFSP, dermatofibrosarcoma protuberans;
    DLBCL, diffuse large B-cell lymphoma;
    Dom, dominant;
    E, epithelial;
    F, frameshift;
    GIST, gastrointestinal stromal tumour;
    JMML, juvenile myelomonocytic leukaemia;
    L, leukaemia/lymphoma;
    M, mesenchymal;
    MALT, mucosa-associated lymphoid tissue;
    MDS, myelodysplastic syndrome;
    MM, multiple myeloma;
    Mis, missense;
    N, nonsense;
    NHL, non-Hodgkin's lymphoma;
    NK/T, natural killer T cell;
    NSCLC, non-small-cell lung cancer;
    O, other;
    pre-B-ALL, pre-B-cell acute lymphoblastic leukaemia;
    Rec, recessive;
    S, splice site;
    T, translocation;
    T-ALL, T-cell acute lymphoblastic leukaemia;
    T-CLL, T-cell chronic lymphocytic leukaemia;
    TGCT, testicular germ-cell tumour;
    T-PLL, T-cell prolymphocytic leukaemia.
  • TABLE 3
    List of genes which contain cancer-related somatic mutations. The list was adapted
    from Sanger Center's COSMIC database(Bamford et al., 2004; Forbes et al., 2008; Forbes et al.;
    Forbes et al.; Friedberg; Pleasance et al.). The gene names are uniquely assigned by HUGO Gene
    Nomenclature Committee (http://www.genenames.org/index.html, accessed Jan. 31, 2011).
    HGNC Gene HGNC Gene HGNC Gene HGNC Gene HGNC Gene
    Name Name Name Name Name
    39340 A1BG A1CF A2BP1 A2LD1
    A2M A2ML1 A2RRG4_ A3GALT2 A4D198_
    HUMAN HUMAN
    A4D226_HUMAN A4GALT A4GNT AAAS AACS
    AADAC AADACL2 AADACL3 AADACL4 AADAT
    AAGAB AAK1 AAMP AANAT AARS
    AARS2 AARSD1 AASDH AASDHPPT AASS
    AATF AATK AB019437_1 ABAT ABBA-1
    ABCA1 ABCA10 ABCA12 ABCA13 ABCA2
    ABCA3 ABCA4 ABCA5 ABCA6 ABCA7
    ABCA8 ABCA9 ABCB1 ABCB10 ABCB11
    ABCB4 ABCB5 ABCB6 ABCB7 ABCB8
    ABCB9 ABCC1 ABCC10 ABCC11 ABCC12
    ABCC2 ABCC3 ABCC4 ABCC5 ABCC6
    ABCC8 ABCC9 ABCD1 ABCD2 ABCD3
    ABCD4 ABCE1 ABCF1 ABCF2 ABCF3
    ABCG1 ABCG2 ABCG4 ABCG5 ABCG8
    ABHD1 ABHD10 ABHD11 ABHD12 ABHD12B
    ABHD13 ABHD14A ABHD14B ABHD15 ABHD2
    ABHD3 ABHD4 ABHD5 ABHD6 ABHD8
    ABI1 ABI2 ABI3 ABI3BP ABL1
    ABL2 ABLIM1 ABLIM3 ABO ABP1
    ABR ABRA ABT1 ABTB1 ABTB2
    AC002472.13 AC007731_16 AC008537_5-2 AC008969.1 AC010872_2
    AC012100.1 AC013469_8-2 AC021593.2 AC022098.2 AC023469_1
    AC027369_8 AC068473.1 AC079612.1 AC092070_2 AC093393.1
    AC097374_3 AC099524.1 AC103710_2 AC112491_4 AC114273.2
    AC120042.2 AC127391_4 AC142381_2 AC142381_2_ ACAA1
    ENST00000356559
    ACAA2 ACACA ACACB ACAD10 ACAD11
    ACAD8 ACAD9 ACADL ACADM ACADS
    ACADSB ACADVL ACAN ACAP1 ACAP2
    ACAP3 ACAT1 ACAT2 ACBD3 ACBD4
    ACBD5 ACBD6 ACBD7 ACCN1 ACCN2
    ACCN3 ACCN4 ACCN5 ACCS ACCSL
    ACD ACE ACE2 ACER1 ACER2
    ACER3 ACHE ACIN1 ACLY ACMSD
    ACN9 ACO1 ACO2 ACOT1 ACOT11
    ACOT12 ACOT13 ACOT2 ACOT4 ACOT6
    ACOT7 ACOT8 ACOT9 ACOX1 ACOX2
    ACOX3 ACOXL ACP1 ACP2 ACP5
    ACP6 ACPL2 ACPP ACPT ACR
    ACRBP ACRC ACRV1 ACSBG1 ACSBG2
    ACSF2 ACSF3 ACSL1 ACSL3 ACSL4
    ACSL5 ACSL6 ACSM1 ACSM2A ACSM2B
    ACSM3 ACSM5 ACSS1 ACSS2 ACSS3
    ACTA1 ACTA2 ACTB ACTBL2 ACTC1
    ACTG1 ACTG2 ACTL6A ACTL6B ACTL7A
    ACTL7B ACTL8 ACTL9 ACTN1 ACTN2
    ACTN3 ACTN4 ACTR10 ACTR1A ACTR1B
    ACTR2 ACTR3 ACTR3B ACTR5 ACTR6
    ACTR8 ACTRT1 ACTRT2 ACVR1 ACVR1B
    ACVR1C ACVR2A ACVR2B ACVRL1 ACY1
    ACY3 ACYP1 ACYP2 ADA ADAD1
    ADAD2 ADAL ADAM10 ADAM11 ADAM12
    ADAM15 ADAM17 ADAM18 ADAM19 ADAM2
    ADAM20 ADAM21 ADAM22 ADAM22_ ADAM23
    ENST00000315984
    ADAM28 ADAM29 ADAM30 ADAM32 ADAM33
    ADAM7 ADAM8 ADAM9 ADAMDEC1 ADAMTS1
    ADAMTS10 ADAMTS12 ADAMTS13 ADAMTS14 ADAMTS15
    ADAMTS16 ADAMTS16_ ADAMTS17 ADAMTS18 ADAMTS19
    ENST00000274181
    ADAMTS2 ADAMTS20 ADAMTS3 ADAMTS4 ADAMTS5
    ADAMTS6 ADAMTS6_ ADAMTS7 ADAMTS8 ADAMTS9
    ENST00000381055
    ADAMTSL1 ADAMTSU_ ADAMTSL2 ADAMTSL3 ADAMTSL4
    ENST00000380548
    ADAMTSL5 ADAP1 ADAP2 ADAR ADARB1
    ADARB2 ADAT1 ADAT2 ADAT3 ADC
    ADCK1 ADCK2 ADCK4 ADCK5 ADCY1
    ADCY10 ADCY2 ADCY3 ADCY4 ADCY5
    ADCY6 ADCY7 ADCY8 ADCY9 ADCYAP1
    ADCYAP1R1 ADD1 ADD2 ADD3 ADH1A
    ADH1B ADH4 ADH5 ADH6 ADH7
    ADHFE1 ADI1 ADIPOQ ADIPOR1 ADIPOR2
    ADK ADM ADM2 ADNP ADNP2
    ADO ADORA1 ADORA2A ADORA2B ADORA3
    ADPGK ADPRH ADPRHL1 ADPRHL2 ADRA1A
    ADRA1B ADRA1D ADRA2A ADRA2B ADRA2C
    ADRB1 ADRB2 ADRB3 ADRBK1 ADRBK2
    ADRM1 ADSL ADSS ADSSL1 AEBP1
    AEN AES AFAP1 AFAP1L1 AFAP1L2
    AFF1 AFF2 AFF3 AFF4 AFG3L2
    AFM AFMID AFP AFTPH AGA
    AGAP1 AGAP2 AGAP3 AGAP4 AGAP5
    AGAP7 AGAP8 AGBL2 AGBL4 AGBL5
    AGC1 AGER AGFG1 AGFG2 AGGF1
    AGK AGL AGMAT AGPAT1 AGPAT2
    AGPAT3 AGPAT4 AGPAT5 AGPAT6 AGPAT9
    AGPHD1 AGPS AGR2 AGR3 AGRN
    AGRP AGT AGTPBP1 AGTR1 AGTR2
    AGTRAP AGXT AGXT2 AGXT2L1 AGXT2L2
    AHCTF1 AHCTF1P AHCY AHCYL1 AHCYL2
    AHDC1 AHI1 AHNAK AHNAK2 AHR
    AHRR AHSA1 AHSA2 AHSG AHSP
    AICDA AIDA AIF1 AIF1L AIF1_
    ENST0000076051
    AIFM1 AIFM2 AIFM3 AIG1 AIM1
    AIM1L AIM2 AIMP1 AIMP2 AIP
    AIPL1 AIRE AJAP1 AK1 AK2
    AK3 AK3L1 AK5 AK7 AKAP1
    AKAP10 AKAP11 AKAP12 AKAP13 AKAP14
    AKAP2 AKAP3 AKAP4 AKAP5 AKAP6
    AKAP7 AKAP8 AKAP9 AKAP9_ AKD1
    NM_005751
    AKIRIN1 AKIRIN2 AKNA AKNAD1 AKR1A1
    AKR1B1 AKR1B10 AKR1B1P8 AKR1C1 AKR1C2
    AKR1C3 AKR1C4 AKR1CL1 AKR1D1 AKR1E2
    AKR7A2 AKR7A3 AKR7L AKT1 AKT1S1
    AKT2 AKT3 AKTIP AL121675_ AL122001_
    36-2 32
    AL161645_14 AL512274_9 ALAD ALAS1 ALAS2
    ALB ALCAM ALDH16A1 ALDH18A1 ALDH1A1
    ALDH1A2 ALDH1A3 ALDH1B1 ALDH1L1 ALDH1L2
    ALDH2 ALDH3A1 ALDH3A2 ALDH3B2 ALDH4A1
    ALDH5A1 ALDH6A1 ALDH7A1 ALDH8A1 ALDH9A1
    ALDOA ALDOB ALDOC ALG1 ALG10
    ALG10B ALG11 ALG12 ALG13 ALG14
    ALG1L ALG2 ALG5 ALG6 ALG8
    ALG9 ALK ALKBH1 ALKBH2 ALKBH3
    ALKBH4 ALKBH5 ALKBH6 ALKBH7 ALKBH8
    ALLC ALMS1 ALOX12 ALOX12B ALOX12P2
    ALOX15 ALOX15B ALOX5 ALOX5AP ALOXE3
    ALPI ALPK1 ALPK2 ALPK2_ ALPK3
    ENST00000361673
    ALPL ALPP ALPPL2 ALS2 ALS2CL
    ALS2CR11 ALS2CR12 ALS2CR8 ALX1 ALX3
    ALX4 AMAC1 AMAC1L2 AMACR AMBN
    AMBP AMBRA1 AMD1 AMDHD1 AMDHD2
    AMELX AMELY AMFR AMH AMHR2
    AMICA1 AMIGO1 AMIGO2 AMIGO3 AMMECR1
    AMMECR1L AMN AMOT AMOTL1 AMOTL2
    AMPD1 AMPD2 AMPD2_ AMPD3 AMPH
    ENST00000393689
    AMT AMTN AMY1A AMY1B AMY1C
    AMY2A AMY2B AMZ1 AMZ2 ANAPC1
    ANAPC10 ANAPC11 ANAPC13 ANAPC2 ANAPC4
    ANAPC5 ANAPC7 ANG ANGELI ANGEL2
    ANGPT1 ANGPT2 ANGPT4 ANGPTL1 ANGPTL2
    ANGPTL3 ANGPTL4 ANGPTL5 ANGPTL6 ANGPTL7
    ANK1 ANK2 ANK3 ANKAR ANKDD1A
    ANKFN1 ANKFY1 ANKH ANKHD1 ANKHD1-
    EIF4EBP3
    ANKK1 ANKLE2 ANKMY1 ANKMY2 ANKRA2
    ANKRD1 ANKRD10 ANKRD11 ANKRD12 ANKRD13A
    ANKRD13B ANKRD13C ANKRD13D ANKRD16 ANKRD17
    ANKRD18A ANKRD2 ANKRD20A1 ANKRD20A2 ANKRD20A3
    ANKRD20A4 ANKRD20A5 ANKRD22 ANKRD23 ANKRD24
    ANKRD26 ANKRD27 ANKRD28 ANKRD29 ANKRD30A
    ANKRD31 ANKRD32 ANKRD33 ANKRD34A ANKRD34B
    ANKRD35 ANKRD37 ANKRD39 ANKRD40 ANKRD42
    ANKRD43 ANKRD44 ANKRD45 ANKRD46 ANKRD49
    ANKRD5 ANKRD50 ANKRD52 ANKRD53 ANKRD54
    ANKRD55 ANKRD56 ANKRD57 ANKRD58 ANKRD6
    ANKRD60 ANKRD7 ANKRD9 ANKS1A ANKS3
    ANKS4B ANKS6 ANKZF1 ANLN ANO10
    ANO2 ANO3 ANO4 ANO5 ANO6
    ANO7 ANO8 ANO9 ANP32B ANP32C
    ANP32D ANP32E ANPEP ANTXR1 ANTXRL
    ANUBL1 ANXA1 ANXA10 ANXA11 ANXA13
    ANXA2 ANXA3 ANXA4 ANXA5 ANXA6
    ANXA7 ANXA8 ANXA8L1 ANXA8L2 ANXA9
    AOAH AOC2 AOC3 AOF2 AOX1
    AP001011.2_ AP001011.3_ AP005901_2 AP1AR AP1B1
    ENST00000261598 ENST00000320876
    AP1G1 AP1G2 AP1M1 AP1M2 AP1S1
    AP1S2 AP1S3 AP2A1 AP2A2 AP2B1
    AP2M1 AP2S1 AP3B1 AP3B2 AP3D1
    AP3M1 AP3M2 AP3S1 AP3S2 AP4B1
    AP4E1 AP4M1 AP4S1 APAF1 APBA1
    APBA2 APBA3 APBB1 APBB1IP APBB2
    APBB3 APC APC2 APCDD1 APCDD1L
    APCS APEH APEX1 APEX2 APH1A
    APH1B API5 APIP APITD1 APLF
    APLN APLNR APLP1 APLP2 APOA1
    APOA1BP APOA2 APOA4 APOA5 APOB
    APOB48R APOBEC1 APOBEC2 APOBEC3A APOBEC3B
    APOBEC3C APOBEC3D APOBEC3F APOBEC3G APOBEC3H
    APOBEC4 APOC1 APOC2 APOC3 APOC4
    APOD APOE APOH APOL1 APOL2
    APOL3 APOL4 APOL5 APOL6 APOLD1
    APOM APOO APOOL APP APPBP2
    APPL1 APPL2 APRT APTX AQP1
    AQP10 AQP11 AQP12A AQP2 AQP3
    AQP4 AQP5 AQP6 AQP7 AQP8
    AQP9 AQR AR ARAF ARAP1
    ARAP2 ARAP3 ARC ARCN1 ARD1B
    AREG ARF1 ARF3 ARF4 ARF5
    ARF6 ARFGAP1 ARFGAP2 ARFGAP3 ARFGEF1
    ARFGEF2 ARFIP1 ARFIP2 ARFRP1 ARG1
    ARG2 ARGFX ARGLU1 ARHGAP1 ARHGAP10
    ARHGAP11A ARHGAP11B ARHGAP12 ARHGAP15 ARHGAP17
    ARHGAP18 ARHGAP19 ARHGAP19_ ARHGAP20 ARHGAP21
    ENST00000358531
    ARHGAP22 ARHGAP23 ARHGAP24 ARHGAP25 ARHGAP26
    ARHGAP27 ARHGAP28 ARHGAP29 ARHGAP30 ARHGAP31
    ARHGAP32 ARHGAP32_ ARHGAP33 ARHGAP36 ARHGAP4
    ENST00000310343
    ARHGAP5 ARHGAP6 ARHGAP8 ARHGAP9 ARHGDIA
    ARHGDIB ARHGDIG ARHGEF1 ARHGEF10 ARHGEF1OL
    ARHGEF10_ ARHGEF11 ARHGEF12 ARHGEF15 ARHGEF16
    ENST00000398564
    ARHGEF17 ARHGEF18 ARHGEF19 ARHGEF2 ARHGEF3
    ARHGEF4 ARHGEF5 ARHGEF5L ARHGEF6 ARHGEF7
    ARHGEF9 ARID1A ARID1B ARID2 ARID3A
    ARID3B ARID3C ARID4A ARID4B ARID4B_
    ENST00000264183
    ARID5A ARID5B ARIH1 ARIH2 ARL1
    ARL10 ARL11 ARL13A ARL13B ARL14
    ARL15 ARL17B ARL2 ARL2BP ARL3
    ARL4A ARL4C ARL4D ARL4P ARL5A
    ARL5B ARL5C ARL6 ARL6IP1 ARL6IP4
    ARL6IP5 ARL6IP6 ARL8A ARL8B ARL9
    ARMC1 ARMC10 ARMC2 ARMC3 ARMC4
    ARMC6 ARMC7 ARMC8 ARMC9 ARMCX1
    ARMCX2 ARMCX3 ARMCX4 ARMCX5 ARMCX6
    ARNT ARNT2 ARNTL ARNTL2 ARPC1A
    ARPC1B ARPC2 ARPC3 ARPC4 ARPC5
    ARPC5L ARPM1 ARPP-21 ARPP19 ARR3
    ARRB1 ARRB2 ARRDC1 ARRDC2 ARRDC3
    ARRDC4 ARSA ARSB ARSD ARSE
    ARSF ARSG ARSH ARSI ARSJ
    ARSK ART1 ART3 ART4 ART5
    ARTN ARV1 ARVCF ARX AS3MT
    ASAH1 ASAH2 ASAH2B ASAM ASAP1
    ASAP2 ASAP3 ASB1 ASB10 ASB11
    ASB12 ASB13 ASB14 ASB15 ASB16
    ASB17 ASB18 ASB2 ASB3 ASB4
    ASB5 ASB6 ASB7 ASB8 ASB9
    ASCC1 ASCC2 ASCC3 ASCL1 ASCL2
    ASCL3 ASCL4 ASF1B ASGR1 ASGR1_
    ENST00000380920
    ASGR2 ASH1L ASH2L ASIP ASL
    ASMT ASMTL ASNA1 ASNS ASNSD1
    ASNS_ ASPA ASPDH ASPH ASPHD1
    ENST00000394309
    ASPHD2 ASPM ASPN ASPRV1 ASPSCR1
    ASRGL1 ASS1 ASTE1 ASTL ASTN1
    ASTN2 ASXL1 ASXL2 ASXL3 ASZ1
    ATAD1 ATAD2 ATAD2B ATAD2B_ ATAD3A
    ENST00000238789
    ATAD3B ATAD3B_ ATAD5 ATCAY ATE1
    ENST00000378741
    ATF1 ATF2 ATF3 ATF4 ATF5
    ATF6 ATF6B ATF7IP ATF7IP2 ATG10
    ATG12 ATG16L1 ATG16L2 ATG2A ATG2B
    ATG3 ATG4A ATG4A_ ATG4C ATG4D
    ENST00000372232
    ATG5 ATG7 ATG9A ATG9B ATHL1
    ATIC ATLI ATL2 ATL3 ATM
    ATMIN ATN1 ATOH1 ATOH7 ATOH8
    ATP10A ATP10B ATP10D ATP11A ATP11B
    ATP11C ATP12A ATP13A1 ATP13A2 ATP13A3
    ATP13A4 ATP13A5 ATP1A1 ATP1A2 ATP1A3
    ATP1A4 ATP1B1 ATP1B2 ATP1B3 ATP1B4
    ATP2A1 ATP2A2 ATP2A3 ATP2B1 ATP2B2
    ATP2B3 ATP2B3_ ATP2B4 ATP2C1 ATP2C2
    ENST00000370186
    ATP4A ATP4B ATP5A1 ATP5B ATP5C1
    ATP5D ATP5E ATP5F1 ATP5G1 ATP5G2
    ATP5G3 ATP5H ATP5I ATP5J ATP5J2
    ATP5L ATP5O ATP5S ATP5SL ATP6AP1
    ATP6AP1L ATP6AP2 ATP6V0A1 ATP6V0A2 ATP6V0A4
    ATP6V0B ATP6V0C ATP6V0D1 ATP6V0D2 ATP6V0E1
    ATP6V0E2L ATP6V1A ATP6V1B1 ATP6V1B2 ATP6V1C1
    ATP6V1C2 ATP6V1D ATP6V1E1 ATP6V1E2 ATP6V1F
    ATP6V1G1 ATP6V1G2 ATP6V1G3 ATP6V1H ATP7A
    ATP7B ATP8A1 ATP8A2 ATP8B1 ATP8B2
    ATP8B4 ATP9A ATP9B ATPAF1 ATPAF2
    ATPBD3 ATPBD4 ATPGD1 ATPIF1 ATR
    ATRIP ATRN ATRNL1 ATRX ATXN1
    ATXN10 ATXN2 ATXN2L ATXN3 ATXN3L
    ATXN7 ATXN7L1 ATXN7L2 ATXN7L3 AUH
    AUP1 AURKA AURKAIP1 AURKB AURKC
    AUTS2 AVEN AVIL AVL9 AVP
    AVPI1 AVPR1A AVPR1B AVPR2 AWAT1
    AWAT2 AXIN1 AXIN2 AXL AZGP1
    AZI1 AZI2 AZIN1 AZU1 B2M
    B3GALNT1 B3GALNT2 B3GALT1 B3GALT2 B3GALT4
    B3GALT5 B3GALT6 B3GALTL B3GAT1 B3GAT2
    B3GAT3 B3GNT1 B3GNT2 B3GNT3 B3GNT4
    B3GNT5 B3GNT6 B3GNT7 B3GNT8 B3GNTL1
    B3Gn-T6 B4GALNT1 B4GALNT2 B4GALNT3 B4GALNT4
    B4GALT1 B4GALT2 B4GALT3 B4GALT4 B4GALT5
    B4GALT6 B4GALT7 B7 B9D1 B9D2
    BAALC BAAT BACE1 BACE2 BACH1
    BACH2 BAD BAG1 BAG2 BAG3
    BAG4 BAG5 BAHD1 BAI1 BAI2
    BAI3 BAIAP2 BAIAP2L1 BAIAP2L2 BAIAP3
    BAK1 BAMBI BANF1 BANF2 BANK1
    BANP BAP1 BARD1 BARHL1 BARHL2
    BARX1 BARX2 BASP1 BAT1 BAT2
    BAT2D1 BAT2D1_ BAT3 BAT4 BAT5
    ENST00000392078
    BATF BATF2 BATF3 BAX BAZ1A
    BAZ1B BAZ2A BAZ2B BBC3 BBOX1
    BBS1 BBS10 BBS12 BBS2 BBS4
    BBS5 BBS7 BBS9 BBX BCAM
    BCAN BCAP29 BCAP31 BCAR1 BCAR3
    BCAS1 BCAS2 BCAS3 BCAS4 BCAS4_
    ENST00000358791
    BCAT1 BCAT2 BCCIP BCDIN3D BCHE
    BCKDHA BCKDHB BCKDK BCL10 BCL11A
    BCL11B BCL2 BCL2A1 BCL2L1 BCL2L10
    BCL2L11 BCL2L12 BCL2L13 BCL2L14 BCL2L15
    BCL2L2 BCL3 BCL6 BCL6B BCL7A
    BCL7B BCL7C BCL9 BCL9L BCLAF1
    BCMO1 BCO2 BCOR BCORL1 BCORL2
    BCR BCS1L BDH1 BDH2 BDKRB1
    BDKRB2 BDNF BDP1 BECN1 BEGAIN
    BEND2 BEND3 BEND4 BEND5 BEND6
    BEND7 BEST1 BEST2 BEST3 BEST4
    BET1 BET1L BEX1 BEX2 BEX4
    BEX5 BFAR BFSP1 BFSP2 BGLAP
    BGN BHLHA15 BHLHB9 BHLHE22 BHLHE23
    BHLHE40 BHLHE41 BHMT BHMT2 BICC1
    BICD1 BICD2 BID BIK BIN1
    BIN2 BIRC2 BIRC3 BIRC5 BIRC6
    BIRC7 BIRC8 BIVM BLCAP BLID
    BLK BLM BLMH BLNK BLOC1S1
    BLOC1S2 BLOC1S3 BLVRA BLVRB BLYM_
    HUMAN
    BLZF1 BMF BMI1 BMP1 BMP10
    BMP15 BMP2 BMP2K BMP2KL BMP2K_
    ENST00000335016
    BMP3 BMP4 BMP5 BMP6 BMP7
    BMP8A BMP8B BMPER BMPR1A BMPR1B
    BMPR2 BMS1 BMX BNC1 BNC2
    BNIP1 BNIP2 BNIP3 BNIP3L BNIPL
    BOC BOD1 BOD1L BOK BOLA1
    BOLA2 BOLA2B BOLA3 BOLL BOP1
    BPGM BPHL BPI BPIL1 BPIL2
    BPIL3 BPNT1 BPTF BPY2B BPY2C
    BRAF BRAP BRCA1 BRCA2 BRCC3
    BRD1 BRD2 BRD2_ BRD3 BRD3_
    ENST00000395289 ENST00000303407
    BRD4 BRD4_ BRD7 BRD8 BRD9
    ENST00000263377
    BRDT BRE BRF1 BRF2 BRI3
    BRI3BP BRIP1 BRIX1 BRMS1 BRMS1L
    BRP44 BRP44L BRPF1 BRPF3 BRS3
    BRSK1 BRSK2 BRWD1 BRWD3 BSCL2
    BSDC1 BSG BSN BSND BSPRY
    BST1 BST2 BSX BTAF1 BTBD1
    BTBD10 BTBD11 BTBD12 BTBD16 BTBD17
    BTBD2 BTBD3 BTBD6 BTBD7 BTBD8
    BTBD9 BTBD9_ BTC BTD BTF3
    ENST00000403056
    BTF3L1 BTF3L3 BTF3L4 BTG1 BTG2
    BTG3 BTG4 BTK BTLA BTN1A1
    BTN2A1 BTN2A2 BTN2A3 BTN3A1 BTN3A2
    BTN3A3 BTNL2 BTNL8 BTNL9 BTRC
    BUB1 BUB1B BUB3 BUD13 BUD31
    BVES BYSL BZRAP1 BZW1 BZW2
    C10orf10 C10orf104 C10orf107 C10orf11 C10orf111
    C10orf113 C10orf113_ C10orf114 C10orf116 C10orf118
    ENST00000377118
    C10orf119 C10orf12 C10orf120 C10orf125 C10orf128
    C10orf129 C10orf131 C10orf137 C10orf18 C10orf2
    C10orf25 C10orf26 C10orf27 C10orf28 C10orf31
    C10orf32 C10orf35 C10orf4 C10orf46 C10orf47
    C10orf53 C10orf54 C10orf57 C10orf58 C10orf6
    C10orf61 C10orf62 C10orf64 C10orf68 C10orf71
    C10orf71_ C10orf72 C10orf76 C10orf78 C10orf79
    ENST00000374144
    C10orf81 C10orf82 C10orf84 C10orf88 C10orf90
    C10orf91 C10orf92 C10orf93 C10orf95 C10orf96
    C10orf99 C11orf1 C11orf10 C11orf16 C11orf17
    C11orf2 C11orf24 C11orf30 C11orf34 C11orf35
    C11orf40 C11orf41 C11orf42 C11orf44 C11orf45
    C11orf46 C11orf47 C11orf48 C11orf49 C11orf51
    C11orf52 C11orf53 C11orf54 C11orf57 C11orf58
    C11orf59 C11orf60 C11orf61 C11orf63 C11orf65
    C11orf66 C11orf67 C11orf68 C11orf70 C11orf73
    C11orf74 C11orf75 C11orf76 C11orf77 C11orf82
    C11orf83 C11orf84 C11orf85 C11orf86 C11orf87
    C11orf88 C11orf9 C11orf92 C12orf10 C12orf11
    C12orf12 C12orf23 C12orf24 C12orf26 C12orf28
    C12orf29 C12orf32 C12orf34 C12orf35 C12orf36
    C12orf37 C12orf39 C12orf4 C12orf40 C12orf42
    C12orf43 C12orf44 C12orf45 C12orf48 C12orf49
    C12orf5 C12orf50 C12orf52 C12orf54 C12orf55
    C12orf56 C12orf57 C12orf59 C12orf60 C12orf61
    C12orf62 C12orf63 C12orf64 C12orf65 C12orf66
    C12orf67 C12orf68 C12orf69 C12orf72 C12orf74
    C12orf76 C13orf1 C13orf15 C13orf16 C13orf23
    C13orf26 C13orf27 C13orf28 C13orf30 C13orf31
    C13orf33 C13orf34 C13orf35 C13orf36 C13orf37
    C13orf39 C13orf40 C14orf1 C14orf100 C14orf101
    C14orf102 C14orf104 C14orf105 C14orf106 C14orf109
    C14orf115 C14orf118 C14orf119 C14orf126 C14orf128
    C14orf129 C14orf135 C14orf138 C14orf142 C14orf143
    C14orf145 C14orf147 C14orf148 C14orf149 C14orf153
    C14orf156 C14orf159 C14orf166 C14orf167 C14orf173
    C14orf174 C14orf177 C14orf178 C14orf179 C14orf180
    C14orf181 C14orf182 C14orf183 C14orf2 C14orf20
    C14orf21 C14orf23 C14orf28 C14orf37 C14orf38
    C14orf39 C14orf4 C14orf43 C14orf45 C14orf48
    C14orf49 C14orf50 C14orf68 C14orf73 C14orf79
    C14orf80 C14orf93 C15orf17 C15orf2 C15orf23
    C15orf24 C15orf26 C15orf27 C15orf29 C15orf32
    C15orf33 C15orf38 C15orf39 C15orf40 C15orf42
    C15orf43 C15orf44 C15orf48 C15orf52 C15orf53
    C15orf54 C15orf55 C15orf56 C15orf57 C15orf58
    C15orf59 C15orf63 C16orf11 C16orf13 C16orf3
    C16orf35 C16orf38 C16orf42 C16orf45 C16orf46
    C16orf48 C16orf5 C16orf53 C16orf54 C16orf55
    C16orf57 C16orf58 C16orf59 C16orf61 C16orf62
    C16orf63 C16orf65 C16orf68 C16orf7 C16orf70
    C16orf71 C16orf72 C16orf73 C16orf75 C16orf78
    C16orf79 C16orf80 C16orf85 C16orf87 C16orf88
    C16orf89 C16orf91 C16orf92 C16orf93 C17orf101
    C17orf102 C17orf103 C17orf28 C17orf37 C17orf38
    C17orf39 C17orf42 C17orf46 C17orf47 C17orf48
    C17orf49 C17orf50 C17orf53 C17orf55 C17orf56
    C17orf57 C17orf58 C17orf59 C17orf60 C17orf61
    C17orf62 C17orf64 C17orf65 C17orf66 C17orf67
    C17orf68 C17orf70 C17orf71 C17orf74 C17orf76
    C17orf77 C17orf79 C17orf80 C17orf81 C17orf82
    C17orf85 C17orf87 C17orf90 C17orf91 C17orf92
    C17orf97 C17orf98 C18orf1 C18orf10 C18orf19
    C18orf21 C18orf22 C18orf25 C18orf26 C18orf32
    C18orf34 C18orf45 C18orf54 C18orf55 C18orf56
    C18orf62 C18orf8 C19orf10 C19orf12 C19orf16
    C19orf18 C19orf2 C19orf20 C19orf21 C19orf22
    C19orf24 C19orf26 C19orf28 C19orf29 C19orf29_
    ENST00000429344
    C19orf33 C19orf35 C19orf36 C19orf39 C19orf40
    C19orf41 C19orf42 C19orf43 C19orf44 C19orf45
    C19orf46 C19orf47 C19orf48 C19orf50 C19orf51
    C19orf52 C19orf53 C19orf56 C19orf57 C19orf59
    C19orf6 C19orf60 C19orf61 C19orf63 C19orf67
    C19orf75 C1D C1GALT1 C1GALT1C1 C1QA
    C1QB C1QBP C1QC C1QL1 C1QL2
    C1QL3 C1QL4 C1QTNF1 C1QTNF2 C1QTNF3
    C1QTNF4 C1QTNF5 C1QTNF6 C1QTNF7 C1QTNF8
    C1QTNF9 C1RL C1S C1orf100 C1orf101
    C1orf103 C1orf105 C1orf106 C1orf107 C1orf109
    C1orf111 C1orf112 C1orf113 C1orf114 C1orf115
    C1orf116 C1orf122 C1orf123 C1orf124 C1orf125
    C1orf127 C1orf128 C1orf129 C1orf130 C1orf131
    C1orf135 C1orf14 C1orf141 C1orf144 C1orf146
    C1orf147 C1orf150 C1orf151 C1orf156 C1orf158
    C1orf161 C1orf162 C1orf163 C1orf164 C1orf167
    C1orf168 C1orf170 C1orf172 C1orf173 C1orf174
    C1orf175 C1orf177 C1orf182 C1orf183 C1orf186
    C1orf187 C1orf189 C1orf190 C1orf192 C1orf194
    C1orf198 C1orf201 C1orf21 C1orf210 C1orf212
    C1orf213 C1orf216 C1orf218 C1orf220 C1orf222
    C1orf227 C1orf229 C1orf25 C1orf26 C1orf31
    C1orf34 C1orf35 C1orf38 C1orf43 C1orf49
    C1orf50 C1orf51 C1orf52 C1orf54 C1orf55
    C1orf56 C1orf57 C1orf58 C1orf59 C1orf61
    C1orf63 C1orf64 C1orf65 C1orf66 C1orf67
    C1orf68 C1orf69 C1orf74 C1orf77 C1orf83
    C1orf84 C1orf85 C1orf86 C1orf87 C1orf88
    C1orf89 C1orf9 C1orf91 C1orf92 C1orf93
    C1orf94 C1orf95 C1orf96 C2 C20orf103
    C20orf106 C20orf107 C20orf108 C20orf11 C20orf111
    C20orf112 C20orf114 C20orf118 C20orf133 C20orf134
    C20orf134_ C20orf135 C20orf141 C20orf144 C20orf151
    ENST00000330271
    C20orf152 C20orf160 C20orf165 C20orf166 C20orf177
    C20orf185 C20orf186 C20orf187 C20orf191 C20orf194
    C20orf195 C20orf196 C20orf197 C20orf20 C20orf200
    C20orf201 C20orf24 C20orf26 C20orf27 C20orf29
    C20orf3 C20orf30 C20orf4 C20orf43 C20orf46
    C20orf54 C20orf62 C200rg C20orf70 C20orf71
    C20orf72 C20orf74 C20orf78 C20orf79 C20orf80
    C20orf85 C20orf94 C20orf95 C200 rf96 C21orf105
    C21orf124 C21orf13 C21orf15 C21orf2 C21orf29
    C21orf33 C21orf34 C21orf45 C21orf56 C21orf57
    C21orf58 C21orf59 C21orf62 C21orf63 C21orf66
    C21orf7 C21orf70 C21orf74 C21orf88 C21orf89
    C21orf9 C21orf91 C22orf13 C22orf15 C22orf23
    C22orf24 C22orf25 C22orf26 C22orf28 C22orf29
    C22orf30 C22orf31 C22orf32 C22orf33 C22orf36
    C22orf39 C22orf40 C22orf42 C22orf43 C22orf9
    C2CD2 C2CD2L C2CD3 C2CD4A C2CD4B
    C2orf15 C2orf16 C2orf18 C2orf24 C2orf27A
    C2orf27B C2orf28 C2orf29 C2orf3 C2orf34
    C2orf39 C2orf40 C2orf42 C2orf43 C2orf44
    C2orf47 C2orf48 C2orf49 C2orf50 C2orf51
    C2orf52 C2orf53 C2orf54 C2orf55 C2orf56
    C2orf57 C2orf60 C2orf61 C2orf62 C2orf63
    C2orf63_ C2orf64 C2orf65 C2orf66 C2orf67
    ENST00000407122
    C2orf68 C2orf69 C2orf7 C2orf70 C2orf71
    C2orf76 C2orf77 C2orf79 C2orf80 C2orf82
    C2orf83 C2orf84 C2orf85 C2orf86 C2orf88
    C3 C3AR1 C3P1 C3orf1 C3orf14
    C3orf15 C3orf17 C3orf18 C3orf19 C3orf20
    C3orf21 C3orf22 C3orf23 C3orf24 C3orf25
    C3orf26 C3orf27 C3orf28 C3orf30 C3orf31
    C3orf32 C3orf33 C3orf34 C3orf35 C3orf36
    C3orf37 C3orf38 C3orf39 C3orf43 C3orf45
    C3orf46 C3orf49 C3orf53 C3orf54 C3orf57
    C3orf58 C3orf59 C3orf62 C3orf63 C3orf64
    C3orf67 C3orf70 C3orf72 C3orf75 C3orf77
    C4A C4B C4BPA C4BPB C4orf14
    C4orf17 C4orf19 C4orf21 C4orf22 C4orf23
    C4orf26 C4orf27 C4orf31 C4orf32 C4orf33
    C4orf34 C4orf35 C4orf36 C4orf37 C4orf39
    C4orf40 C4orf41 C4orf42 C4orf43 C4orf44
    C4orf46 C4orf49 C4orf50 C4orf6 C4orf7
    C5 C5AR1 C5orf13 C5orf15 C5orf22
    C5orf23 C5orf24 C5orf28 C5orf30 C5orf32
    C5orf33 C5orf34 C5orf35 C5orf36 C5orf37
    C5orf38 C5orf39 C5orf4 C5orf40 C5orf41
    C5orf42 C5orf43 C5orf45 C5orf46 C5orf48
    C5orf49 C5orf5 C5orf50 C5orf51 C5orf53
    C5orf54 C5orf56 C6 C6orf1 C6orf10
    C6orf103 C6orf105 C6orf106 C6orf108 C6orf114
    C6orf115 C6orf118 C6orf12 C6orf120 C6orf124
    C6orf125 C6orf129 C6orf130 C6orf134 C6orf136
    C6orf138 C6orf142 C6orf145 C6orf146 C6orf15
    C6orf150 C6orf153 C6orf154 C6orf162 C6orf163_
    ENST00000369574
    C6orf165 C6orf167 C6orf168 C6orf170 C6orf173
    C6orf174 C6orf182 C6orf186 C6orf191 C6orf192
    C6orf195 C6orf201 C6orf203 C6orf204 C6orf211
    C6orf213 C6orf218 C6orf221 C6orf222 C6orf223
    C6orf224 C6orf225 C6orf227 C6orf25 C6orf26
    C6orf27 C6orf35 C6orf47 C6orf48 C6orf49
    C6orf57 C6orf58 C6orf62 C6orf64 C6orf70
    C6orf72 C6orf81 C6orf87 C6orf89 C6orf94
    C6orf97 C6orf98 C7 C7orf11 C7orf16
    C7orf20 C7orf23 C7orf25 C7orf26 C7orf27
    C7orf28A C7orf28B C7orf29 C7orf30 C7orf31
    C7orf33 C7orf34 C7orf36 C7orf41 C7orf42
    C7orf43 C7orf44 C7orf45 C7orf46 C7orf47
    C7orf49 C7orf50 C7orf51 C7orf52 C7orf53
    C7orf54 C7orf55 C7orf58 C7orf59 C7orf60
    C7orf62 C7orf63 C7orf64 C7orf66 C7orf68
    C7orf69 C7orf70 C7orf72_ C8A C8B
    ENST00000297001
    C8G C8orf12 C8orf13 C8orf14 C8orf30A
    C8orf31 C8orf33 C8orf34 C8orf37 C8orf38
    C8orf4 C8orf40 C8orf41 C8orf44 C8orf45
    C8orf46 C8orf47 C8orf55 C8orf58 C8orf59
    C8orf76 C8orf79 C8orf8 C8orf80 C8orf82
    C8orf84 C8orf85 C8orf86 C9 C9orf100
    C9orf102 C9orf103 C9orf106 C9orf11 C9orf114
    C9orf116 C9orf117 C9orf119 C9orf123 C9orf125
    C9orf128 C9orf129 C9orf131 C9orf135 C9orf139
    C9orf140 C9orf142 C9orf144 C9orf150 C9orf152
    C9orf153 C9orf156 C9orf16 C9orf163 C9orf164
    C9orf167 C9orf170 C9orf171 C9orf21 C9orf23
    C9orf24 C9orf25 C9orf3 C9orf30 C9orf37
    C9orf4 C9orf40 C9orf41 C9orf43 C9orf46
    C9orf47 C9orf48 C9orf5 C9orf50 C9orf51
    C9orf56 C9orf6 C9orf62 C9orf64 C9orf66
    C9orf68 C9orf7 C9orf71 C9orf72 C9orf75
    C9orf78 C9orf79 C9orf80 C9orf82 C9orf84
    C9orf85 C9orf86 C9orf89 C9orf9 C9orf91
    C9orf93 C9orf95 C9orf96 C9orf98 C9orf98_
    ENST00000298545
    CA1 CA10 CA11 CA12 CA13
    CA14 CA2 CA3 CA4 CA5A
    CA5B CA5BP CA6 CA7 CA8
    CA9 CAB39 CAB39L CABC1 CABIN1
    CABLES1 CABLES2 CABP1 CABP2 CABP4
    CABP5 CABP7 CABYR CACHD1 CACNA1A
    CACNA1A_ CACNA1B CACNA1C CACNA1D CACNA1E
    ENST00000357018
    CACNA1F CACNA1G CACNA1H CACNA1H_ CACNA1I
    ENST00000358590
    CACNA1S CACNA2D1 CACNA2D2 CACNA2D3 CACNB1
    CACN B2 CACN B3 CACNG1 CACNG2 CACNG3
    CACNG4 CACNG5 CACNG6 CACNG7 CACNG8
    CACYBP CAD CADM1 CADM2 CADM3
    CADM4 CADPS CADPS2 CAGE1 CALB1
    CALB2 CALCA CALCB CALCOCO1 CALCOCO2
    CALCR CALCRL CALD1 CALHM1 CALHM2
    CALM1 CALM2 CALM3 CALML3 CALML4
    CALML5 CALML6 CALN1 CALR CALR3
    CALU CALY CAMK1 CAMK1D CAMK1G
    CAMK2A CAMK2B CAMK2D CAMK2G CAMK2N1
    CAMK2N2 CAMK4 CAMKK1 CAMKK2 CAMKV
    CAMKV_ CAMLG CAMP CAMSAP1 CAMSAP1L1
    ENST00000477224
    CAMTA1 CAMTA2 CANDI CAND2 CANT1
    CANX CAP1 CAP2 CAPG CAPN1
    CAPN10 CAPN11 CAPN12 CAPN13 CAPN2
    CAPN3 CAPN5 CAPN6 CAPN7 CAPN9
    CAPNS1 CAPRIN1 CAPRI N2 CAPS CAPS2
    CAPSL CAPZA1 CAPZA2 CAPZA3 CAPZB
    CARD10 CARD11 CARD14 CARD16 CARD17
    CARD18 CARD6 CARD8 CARD9 CARHSP1
    CARKD CARM1 CARS CARS2 CARTPT
    CASC1 CASC3 CASC4 CASC5 CASD1
    CASK CASKIN1 CASKIN2 CASP1 CASP10
    CASP14 CASP2 CASP3 CASP4 CASP5
    CASP6 CASP7 CASP8 CASP9 CASQ1
    CASQ2 CASR CASS4 CAST CASZ1
    CAT CATSPER1 CATSPER2 CATSPER3 CATSPER4
    CATSPERB CATSPERG CAV1 CAV2 CAV3
    CBARA1 CBFA2T2 CBFA2T3 CBFB CBL
    CBLB CBLC CBLL1 CBLN1 CBLN2
    CBLN3 CBLN4 CBR1 CBR3 CBR4
    CBS CBWD1 CBWD2 CBWD3 CBWD5
    CBWD6 CBX1 CBX2 CBX3 CBX4
    CBX5 CBX6 CBX7 CBX8 CBY1
    CC2D1A CC2D1B CC2D2A CC2D2B CCAR1
    CCBE1 CCBL1 CCBL2 CCBL2_ CCBP2
    ENST00000370491
    CCDC101 CCDC102A CCDC102B CCDC103 CCDC104
    CCDC105 CCDC106 CCDC107 CCDC108 CCDC109A
    CCDC109B CCDC11 CCDC110 CCDC111 CCDC112
    CCDC113 CCDC114 CCDC115 CCDC116 CCDC117
    CCDC12 CCDC120 CCDC121 CCDC122 CCDC123
    CCDC124 CCDC125 CCDC126 CCDC127 CCDC128
    CCDC13 CCDC130 CCDC132 CCDC132_ CCDC134
    ENST00000305866
    CCDC135 CCDC137 CCDC138 CCDC14 CCDC140
    CCDC141 CCDC142 CCDC144B CCDC144NL CCDC146
    CCDC147 CCDC148 CCDC149 CCDC15 CCDC151
    CCDC153 CCDC155 CCDC157 CCDC158 CCDC160
    CCDC18 CCDC19 CCDC21 CCDC22 CCDC23
    CCDC24 CCDC25 CCDC27 CCDC28A CCDC28B
    CCDC29 CCDC3 CCDC30 CCDC33 CCDC34
    CCDC35 CCDC36 CCDC37 CCDC38 CCDC39
    CCDC40 CCDC41 CCDC42 CCDC46 CCDC47
    CCDC48 CCDC50 CCDC51 CCDC52 CCDC54
    CCDC55 CCDC56 CCDC58 CCDC59 CCDC6
    CCDC60 CCDC62 CCDC63 CCDC64 CCDC65
    CCDC66 CCDC67 CCDC68 CCDC69 CCDC7
    CCDC70 CCDC71 CCDC72 CCDC73 CCDC74A
    CCDC74B CCDC76 CCDC77 CCDC78 CCDC8
    CCDC80 CCDC81 CCDC82 CCDC83 CCDC84
    CCDC85A CCDC85B CCDC86 CCDC87 CCDC88A
    CCDC88B CCDC89 CCDC9 CCDC90A CCDC90B
    CCDC91 CCDC92 CCDC93 CCDC94 CCDC96
    CCDC97 CCDC99 CCHCR1 CCIN CCK
    CCKAR CCKBR CCL1 CCL11 CCL13
    CCL14 CCL15 CCL16 CCL17 CCL18
    CCL19 CCL2 CCL20 CCL21 CCL22
    CCL23 CCL24 CCL25 CCL26 CCL27
    CCL28 CCL3 CCL3L1 CCL3L3 CCL4
    CCL4L1 CCL4L2 CCL5 CCL7 CCL8
    CCM2 CCNA1 CCNA2 CCNB1 CCNB1IP1
    CCNB2 CCNB3 CCNB3_ CCNC CCND1
    ENST00000376042
    CCND2 CCND3 CCNDBP1 CCNE1 CCNE2
    CCNF CCNG1 CCNG2 CCNH CCNI
    CCNI2 CCNJ CCNJL CCNL1 CCNL2
    CCNO CCNT1 CCNT2 CCNY CCNYL1
    CCNYL2 CCPG1 CCR1 CCR10 CCR2
    CCR3 CCR4 CCR5 CCR6 CCR7
    CCR8 CCR9 CCRL1 CCRL2 CCRN4L
    CCS CCT2 CCT3 CCT4 CCT5
    CCT6A CCT6B CCT7 CCT8 CCT8L1
    CCT8L2 CD101 CD109 CD14 CD151
    CD160 CD163 CD163L1 CD164 CD164L2
    CD180 CD19 CD1A CD1B CD1C
    CD1D CD1E CD2 CD200 CD200R1
    CD200R1L CD207 CD209 CD22 CD226
    CD244 CD247 CD248 CD27 CD274
    CD276 CD28 CD2AP CD2BP2 CD300A
    CD300C CD300E CD300LB CD300LD CD300LF
    CD300LG CD302 CD320 CD33 CD34
    CD36 CD36_ CD37 CD38 CD3D
    ENST00000433696
    CD3E CD3EAP CD3G CD4 CD40
    CD40LG CD44 CD46 CD47 CD48
    CD5 CD52 CD53 CD55 CD58
    CD59 CD5L CD6 CD63 CD68
    CD69 CD7 CD70 CD72 CD74
    CD79A CD79B CD80 CD81 CD82
    CD83 CD84 CD86 CD8A CD8B
    CD9 CD93 CD96 CD97 CD99
    CD99L2 CDA CDADC1 CDAN1 CDC123
    CDC14A CDC14B CDC16 CDC20 CDC2OB
    CDC23 CDC25A CDC25B CDC25C CDC26
    CDC27 CDC2L2 CDC34 CDC37 CDC37L1
    CDC37P1 CDC40 CDC42 CDC42BPA CDC42BPB
    CDC42BPG CDC42EP1 CDC42EP2 CDC42EP3 CDC42EP4
    CDC42EP5 CDC42SE1 CDC42SE2 CDC45L CDC5L
    CDC6 CDC7 CDC73 CDCA2 CDCA3
    CDCA4 CDCA5 CDCA7 CDCA7L CDCA8
    CDCP1 CDCP2 CDH1 CDH10 CDH11
    CDH12 CDH13 CDH15 CDH16 CDH17
    CDH18 CDH19 CDH2 CDH20 CDH22
    CDH23 CDH24 CDH26 CDH3 CDH4
    CDH5 CDH6 CDH7 CDH8 CDH9
    CDHR1 CDHR5 CDIPT CDK1 CDK10
    CDK11B CDK12 CDK13 CDK14 CDK15
    CDK1_
    CDK16 CDK17 CDK18 CDK19 ENST00000395284
    CDK2 CDK20 CDK2AP1 CDK2AP2 CDK3
    CDK4 CDK5 CDK5R1 CDK5R2 CDK5RAP1
    CDK5RAP2 CDK5RAP3 CDK6 CDK7 CDK8
    CDK9 CDKAL1 CDKL1 CDKL2 CDKL3
    CDKL4 CDKL5 CDKN1A CDKN1B CDKN1C
    CDKN2A CDKN2AIP CDKN2AIPNL CDKN2B CDKN2C
    CDKN2D CDKN2a(p14) CDKN3 CDNF CD01
    CDON CDR1 CDR2 CDRT1 CDRT15
    CDRT4 CDS1 CDS2 CDSN CDT1
    CDV3 CDX1 CDX2 CDX4 CDY1
    CDY1B CDY2A CDY2B CDYL CDYL2
    CEACAM1 CEACAM18 CEACAM18_ CEACAM19 CEACAM20
    ENST00000451626
    CEACAM3 CEACAM4 CEACAM5 CEACAM6 CEACAM7
    CEACAM8 CEBPA CEBPB CEBPE CEBPG
    CEBPZ CECR1 CECR2 CECR5 CECR6
    CEL CELA1 CELA2A CELA2B CELA3A
    CELA3B CELF1 CELF2 CELF3 CELF4
    CELF5 CELF6 CELP CELSR1 CELSR2
    CELSR3 CEMP1 CEND1 CENPA CENPB
    CENPC1 CENPE CENPF CENPH CENPI
    CENPJ CENPK CENPL CENPM CENPN
    CENPO CENPP CENPQ CENPT CENPV
    CEP110 CEP120 CEP135 CEP152 CEP164
    CEP170 CEP170L CEP192 CEP250 CEP290
    CEP55 CEP57 CEP63 CEP68 CEP70
    CEP72 CEP76 CEP78 CEP97 CEPT1
    CER1 CERCAM CERK CERKL CES1
    CES1_ CES2 CES3 CES7 CES8
    ENST00000360526
    CETN1 CETN2 CETN3 CETP CFB
    CFC1 CFC1B CFD CFDP1 CFH
    CFHR1 CFHR2 CFHR3 CFHR4 CFHR5
    CFI CFL1 CFL2 CFLAR CFP
    CFTR CGA CGB CGB1 CGB2
    CGB5 CGB7 CGB8 CGGBP1 CGI-77
    CGN CGNL1 CGREF1 CGRRF1 CH25H
    CHAC1 CHAC2 CHAD CHADL CHAF1A
    CHAF1B CHAT CHCHD1 CHCHD10 CHCHD2
    CHCHD3 CHCHD4 CHCHD5 CHCHD6 CHCHD7
    CHCHD8 CHCHD9 CHD1 CHD1L CHD2
    CHD3 CHD4 CHD5 CHD6 CHD7
    CHD8 CHD9 CHDH CHEK1 CHEK2
    CHERP CHFR CHGA CHGB CHI3L1
    CHI3L2 CHIA CHIC1 CHIC2 CHID1
    CHIT1 CHKA CHKB CHL1 CHM
    CHML CHMP2A CHMP2B CHMP4A CHMP4B
    CHMP4C CHMP5 CHMP6 CHMP7 CHN1
    CHN2 CHODL CHORDC1 CHP CHP2
    CHPF CHPF2 CHPT1 CHRAC1 CHRD
    CHRDL1 CHRDL2 CHRFAM7A CHRM1 CHRM2
    CHRM3 CHRM5 CHRNA1 CHRNA10 CHRNA2
    CHRNA3 CHRNA4 CHRNA5 CHRNA6 CHRNA7
    CHRNA9 CHRNB1 CHRNB2 CHRNB3 CHRNB4
    CHRND CHRNE CHRNG CHST1 CHST10
    CHST11 CHST12 CHST13 CHST14 CHST15
    CHST2 CHST3 CHST4 CHST5 CHST6
    CHST7 CHST8 CHST9 CHSY1 CHSY3
    CHTF18 CHTF8 CHUK CHURC1 CIAO1
    CIAPIN1 CIB1 CIB2 CIB3 CIB4
    CIC CIDEA CIDEB CIDEC CIITA
    CILP CILP2 CINP CIR1 CIRBP
    CIRH1A CISD1 CISD1B CISD2 CISH
    CIT CITED1 CITED2 CITED4 CIZ1
    CKAP2 CKAP2L CKAP4 CKAP5 CKB
    CKLF CKM CKMT1A CKMT1B CKMT2
    CKS1B CKS2 CLASP1 CLASP2 CLC
    CLCA1 CLCA2 CLCA3P CLCA4 CLCC1
    CLCF1 CLCN1 CLCN2 CLCN3 CLCN4
    CLCN5 CLCN6 CLCN7 CLCNKA CLCNKB
    CLDN1 CLDN10 CLDN11 CLDN12 CLDN14
    CLDN15 CLDN16 CLDN17 CLDN18 CLDN19
    CLDN2 CLDN20 CLDN22 CLDN3 CLDN4
    CLDN5 CLDN6 CLDN7 CLDN8 CLDN9
    CLDND1 CLDND2 CLEC10A CLEC11A CLEC12A
    CLEC12B CLEC14A CLEC16A CLEC18A CLEC18B
    CLEC18C CLEC1A CLEC1B CLEC2B CLEC2D
    CLEC3A CLEC3B CLEC4A CLEC4C CLEC4D
    CLEC4E CLEC4F CLEC4G CLEC4M CLEC5A
    CLEC6A CLEC7A CLEC9A CLECL1 CLGN
    CLIC1 CLIC2 CLIC3 CLIC4 CLIC5
    CLIC6 CLIP1 CLIP2 CLIP3 CLIP4
    CLK1 CLK2 CLK3 CLK4 CLLU1
    CLLU1OS CLMN CLN3 CLN5 CLN6
    CLN8 CLNS1A CLOCK CLP1 CLPB
    CLPP CLPS CLPTM1 CLPTM1L CLPX
    CLRN1 CLRN2 CLRN3 CLSPN CLSTN1
    CLSTN2 CLSTN3 CLTA CLTB CLTC
    CLTCL1 CLU CLUAP1 CLUL1 CLVS2
    CLYBL CMA1 CMAS CMBL CMC1
    CMKLR1 CMPK1 CMPK2 CMTM1 CMTM2
    CMTM3 CMTM4 CMTM5 CMTM6 CMTM7
    CMTM8 CMYA5 CNBP CNDP1 CNDP2
    CNFN CNGA1 CNGA2 CNGA3 CNGA4
    CNGB1 CNGB3 CNIH CNIH2 CNIH3
    CNIH4 CNKSR1 CNKSR2 CNKSR3 CNN1
    CNN2 CNN3 CNNM1 CNNM2 CNNM3
    CNNM4 CNO CNOT1 CNOT10 CNOT2
    CNOT3 CNOT4 CNOT6 CNOT6L CNOT7
    CNOT8 CNP CNPY1 CNPY2 CNPY3
    CNPY4 CNR1 CNR2 CNRIP1 CNST
    CNTD1 CNTD2 CNTF CNTFR CNTLN
    CNTN1 CNTN2 CNTN3 CNTN4 CNTN5
    CNTN6 CNTNAP1 CNTNAP2 CNTNAP3 CNTNAP4
    CNTNAP5 CNTROB COASY COBL COBLL1
    COBRA1 COCH COE4_HUMAN COG1 COG2
    COG3 COG4 COG5 COG6 COG7
    COG8 COIL COL10A1 COL11A1 COL11A2
    COL12A1 COL13A1 COL14A1 COL15A1 COL16A1
    COL17A1 COL18A1 COL19A1 COL1A1 COL1A2
    COL20A1 COL22A1 COL23A1 COL24A1 COL25A1
    COL27A1 COL28A1 COL2A1 COL3A1 COL4A1
    COL4A2 COL4A3 COL4A3BP COL4A4 COL4A5
    COL4A6 COL5A1 COL5A2 COL5A3 COL6A1
    COL6A2 COL6A3 COL6A6 COL7A1 COL8A1
    COL8A2 COL9A1 COL9A2 COL9A3 COLEC10
    COLEC11 COLEC12 COLQ COMMD1 COMMD10
    COMMD2 COMMD3 COMMD4 COMMD5 COMMD6
    COMMD7 COMMD8 COMMD9 COMP COMT
    COMTD1 COPA COPB1 COPB2 COPE
    COPG COPS2 COPS3 COPS4 COPS5
    COPS6 COPS7A COPS7B COPS8 COPZ1
    COQ10A COQ10B COQ2 COQ3 COQ4
    COQ5 COQ6 COQ7 COQ9 CORIN
    CORO1A CORO1B CORO1C CORO2A CORO2B
    CORO6 CORO7 CORT COTL1 COX10
    COX11 COX15 COX16 COX17 COX18
    COX19 COX4I1 COX4I2 COX4NB COX5A
    COX5B COX6A1 COX6A2 COX6B1 COX6B1_
    ENST00000392201
    COX6B2 COX6BP3 COX6C COX7A1 COX7A2
    COX7A2L COX7AP2 COX7B COX7B2 COX7C
    COX8A COX8C CP CP110 CPA1
    CPA2 CPA3 CPA4 CPA5 CPA6
    CPAMD8 CPB1 CPB2 CPD CPE
    CPEB1 CPEB2 CPEB3 CPEB4 CPLX2
    CPLX3 CPLX4 CPM CPN1 CPN2
    CPNE1 CPNE2 CPNE3 CPNE4 CPNE5
    CPNE6 CPNE7 CPNE8 CPNE9 CPO
    CPDX CPPED1 CPS1 CPSF1 CPSF2
    CPSF3 CPSF3L CPSF4 CPSF4L CPSF6
    CPSF7 CPT1A CPT1B CPT1C CPT2
    CPVL CPXCR1 CPXM1 CPXM2 CPZ
    CR1 CR1L CR2 CRABP1 CRABP2
    CRADD CRAT CRB1 CRB2 CRB3
    CRBN CRCP CRCT1 CREB1 CREB3
    CREB3L1 CREB3L2 CREB3L3 CREB3L4 CREB5
    CREBBP CREBL2 CREBZF CREG1 CREG2
    CRELD1 CRELD2 CREM CREM_ CRH
    ENST00000395887
    CRHBP CRHR1 CRHR2 CRIM1 CRIP1
    CRIP2 CRIP3 CRIPAK CRIPT CRISP1
    CRISP2 CRISP3 CRISPLD1 CRISPLD2 CRK
    CRKL CRLF1 CRLF2 CRLF3 CRLS1
    CRMP1 CRNKL1 CRNN CROCC CROT
    CRP CRSP3 CRTAC1 CRTAM CRTAP
    CRTC1 CRTC2 CRTC3 CRX CRY1
    CRY2 CRYAA CRYAB CRYBA1 CRYBA2
    CRYBA4 CRYBB1 CRYBB2 CRYBB3 CRYBG3
    CRYGA CRYGB CRYGC CRYGD CRYGN
    CRYGS CRYL1 CRYM CRYZ CRYZL1
    CS CSAD CSAG1 CSAG2 CSAG3
    CSAG4 CSDA CSDC2 CSDE1 CSE1L
    CSF1 CSF1R CSF2 CSF2RA CSF2RB
    CSF3 CSF3R CSGALNACT1 CSGALNACT2 CSH1
    CSH2 CSHL1 CSK CSMD1 CSMD1_
    ENST00000318252
    CSMD2 CSMD3 CSN2 CSN3 CSNK1A1
    CSNK1A1L CSNK1D CSNK1E CSNK1E_ CSNK1G1
    ENST00000403904
    CSNK1G2 CSNK1G3 CSNK2A1 CSNK2A2 CSNK2B
    CSPG4 CSPG5 CSPP1 CSRNP1 CSRNP2
    CSRNP3 CSRP1 CSRP2 CSRP2BP CSRP3
    CST1 CST11 CST2 CST3 CST4
    CST5 CST6 CST7 CST8 CST9
    CST9L CSTA CSTB CSTF1 CSTF2
    CSTF2T CSTF3 CSTL1 CT45-1 CT45A2
    CT45A3 CT45A4 CT45A5 CT45A6 CT47A1
    CT47A10 CT47A11 CT47A2 CT47A3 CT47A4
    CT47A5 CT47A6 CT47A7 CT47A8 CT47A9
    CTAG1A CTAG1B CTAG2 CTAG2_ CTAGE5
    ENST00000247306
    CTBP1 CTBP2 CTBS CTCF CTCFL
    CTD-2267G17_3 CTDP1 CTDSP1 CTDSP2 CTDSPL
    CTDSPL2 CTF1 CTGF CTH CTHRC1
    CTLA4 CTNNA1 CTNNA2 CTNNA2_ CTNNA3
    ENST00000466387
    CTNNAL1 CTNNB1 CTNNBIP1 CTNNBL1 CTNND1
    CTNND2 CTNS CTPS CTPS2 CTR9
    CTRB1 CTRB2 CTRC CTRL CTSA
    CTSB CTSC CTSD CTSE CTSF
    CTSG CTSH CTSK CTSL1 CTSL2
    CTSL3 CTSO CTSS CTSW CTSZ
    CTTN CTTNBP2 CTTNBP2NL CTU2 CTXN1
    CTXN3 CU041_HUMAN CU085_ CUBN CUEDC1
    HUMAN
    CUEDC2 CUL1 CUL2 CUL3 CUL4A
    CUL4B CUL4B_ CUL5 CUL7 CUL9
    ENST00000371322
    CUTA CUTC CUX1 CUX1_ CUX2
    ENST00000292538
    CUZD1 CWC22 CWC27 CWF19L1 CWF19L2
    CWH43 CX3CL1 CX3CR1 CXADR CXCL1
    CXCL10 CXCL11 CXCL12 CXCL13 CXCL14
    CXCL16 CXCL17 CXCL2 CXCL3 CXCL5
    CXCL6 CXCL9 CXCR1 CXCR2 CXCR3
    CXCR4 CXCR5 CXCR6 CXCR7 CXXC1
    CXXC4 CXXC5 CXorf1 CXorf15 CXorf19
    CXorf21 CXorf22 CXorf23 CXorf24 CXorf25
    CXorf26 CXorf27 CXorf28 CXorf29 CXorf30
    CXorf31 CXorf35 CXorf36 CXorf38 CXorf40A
    CXorf40B CXorf41 CXorf42 CXorf48 CXorf56
    CXorf57 CXorf58 CXorf59 CXorf61 CXorf62
    CXorf65 CXorf66 CXorf67 CYB561 CYB561D1
    CYB561D2 CYB5A CYB5B CYB5D1 CYB5D2
    CYB5R1 CYB5R2 CYB5R3 CYB5R4 CYBA
    CYBASC3 CYBB CYBRD1 CYC1 CYCS
    CYCSP52 CYFIP1 CYFIP2 CYGB CYHR1
    CYLC1 CYLC2 CYLD CYP11A1 CYP11B1
    CYP11B2 CYP17A1 CYP19A1 CYP1A1 CYP1A2
    CYP1B1 CYP20A1 CYP21A2 CYP24A1 CYP26A1
    CYP26B1 CYP26C1 CYP27A1 CYP27B1 CYP27C1
    CYP2A13 CYP2A6 CYP2A7 CYP2B6 CYP2B7P1
    CYP2C18 CYP2C19 CYP2C8 CYP2C9 CYP2D6
    CYP2E1 CYP2F1 CYP2J2 CYP2R1 CYP2S1
    CYP2U1 CYP2W1 CYP39A1 CYP3A4 CYP3A43
    CYP3A5 CYP3A7 CYP46A1 CYP4A11 CYP4A22
    CYP4B1 CYP4F11 CYP4F12 CYP4F2 CYP4F22
    CYP4F3 CYP4F8 CYP4V2 CYP4X1 CYP4Z1
    CYP51A1 CYP7A1 CYP7B1 CYP8B1 CYR61
    CYS1 CYSLTR1 CYSLTR2 CYTH1 CYTH2
    CYTH3 CYTH4 CYTIP CYTL1 CYTSA
    CYTSB CYYR1 CYorf15B CaMK1b D2HGDH
    D4S234E DAAM1 DAAM2 DAB1 DAB2
    DAB2IP DACH1 DACH2 DACH2_ DACT1
    ENST00000373131
    DACT2 DAD1 DAG1 DAGLA DAGLB
    DAK DALRD3 DAMS_ DAND5 DAO
    HUMAN
    DAOA DAP DAP3 DAPK1 DAPK2
    DAPK3 DAPL1 DAPP1 DARC DARS
    DARS2 DAXX DAZ2 DAZ3 DAZAP1
    DAZAP2 DAZL DBC1 DBF4 DBF4B
    DBF4B_ DBH DBI DBN1 DBNDD1
    ENST00000315005
    DBNDD2 DBNL DBP DBR1 DBT
    DBX1 DBX2 DCAF10 DCAF12 DCAF12L1
    DCAF12L2 DCAF13 DCAF15 DCAF16 DCAF17
    DCAF4 DCAF4L1 DCAF4L2 DCAF5 DCAF6
    DCAF7 DCAF8 DCAF8L1 DCAF8L2 DCAKD
    DCBLD1 DCBLD2 DCC DCD DCDC1
    DCDC2 DCDC5 DCHS1 DCHS2 DCI
    DCK DCLK1 DCLK2 DCLK3 DCLRE1A
    DCLRE1B DCLRE1C DCLRE1C_ DCN DCP1A
    ENST00000378278
    DCP1B DCP2 DCPS DCST1 DCST2
    DCT DCTD DCTN1 DCTN3 DCTN4
    DCTN5 DCTN6 DCTPP1 DCUN1D1 DCUN1D2
    DCUN1D3 DCUN1D4 DCUN1D5 DCX DCXR
    DDA1 DDAH1 DDAH2 DDB1 DDB2
    DDC DDHD1 DDHD2 DDI1 DDI2
    DDIT3 DDIT4 DDIT4L DDN DDO
    DDOST DDR1 DDR2 DDRGK1 DDT
    DDTL DDX1 DDX10 DDX11 DDX12
    DDX12_ DDX17 DDX18 DDX19A DDX19B
    ENST00000432996
    DDX20 DDX21 DDX23 DDX24 DDX25
    DDX26B DDX27 DDX28 DDX31 DDX39
    DDX3X DDX3Y DDX4 DDX41 DDX42
    DDX43 DDX46 DDX47 DDX49 DDX5
    DDX50 DDX51 DDX52 DDX53 DDX54
    DDX55 DDX56 DDX58 DDX59 DDX6
    DDX60 DDX60L DDX60_ DEAF1 01-Dec
    ENST00000393743
    DECR1 DECR2 DEDD DEDD2 DEF6
    DEF8 DEFA1 DEFA1B DEFA3 DEFA4
    DEFA5 DEFA6 DEFB1 DEFB103A DEFB103B
    DEFB104A DEFB104B DEFB105A DEFB105B DEFB106A
    DEFB106B DEFB107A DEFB107B DEFB108B DEFB110
    DEFB111 DEFB112 DEFB113 DEFB114 DEFB115
    DEFB116 DEFB118 DEFB119 DEFB121 DEFB123
    DEFB124 DEFB125 DEFB126 DEFB127 DEFB128
    DEFB129 DEFB130 DEFB131 DEFB132 DEFB134
    DEFB135 DEFB136 DEFB4A DEGS1 DEGS2
    DEK DEM1 DENND1A DENND1B DENND1C
    DENND2A DENND2C DENND2D DENND3 DENND4A
    DENND4B DENND4C DENND5A DENND5B DEPDC1
    DEPDC1B DEPDC4 DEPDC5 DEPDC6 DEPDC7
    DERL1 DERL2 DERL3 DES DET1
    DEXI DFFA DFFB DFNA5 DFNB31
    DFNB59 DGAT1 DGAT2 DGAT2L6 DGCR14
    DGCR2 DGCR6 DGCR6L DGCR8 DGKA
    DGKB DGKD DGKE DGKG DGKH
    DGKI DGKK DGKQ DGKZ DGUOK
    DHCR24 DHCR7 DHDDS DHDH DHDPSL
    DHFR DHFRL1 DHH DHODH DHPS
    DHRS1 DHRS11 DHRS12 DHRS13 DHRS2
    DHRS3 DHRS4 DHRS4L2 DHRS7 DHRS7B
    DHRS9 DHRSX DHTKD1 DHX15 DHX16
    DHX29 DHX30 DHX32 DHX33 DHX34
    DHX35 DHX36 DHX37 DHX38 DHX40
    DHX57 DHX58 DHX8 DHX9 DIABLO
    DIAPH1 DIAPH2 DIAPH3 DICER1 DIDO1
    DIMT1L DIO1 DIO3 DIP2B DIP2C
    DIRAS1 DIRAS2 DIRAS3 DIRC1 DIRC2
    DI53 DIS3L DI53L2 DISC1 DISP1
    DISP2 DIXDC1 DKC1 DKFZP434P1750 DKFZP564O0823
    DKFZP566M114 DKK1 DKK2 DKK3 DKK4
    DKKL1 DLAT DLC1 DLC1_ DLD
    ENST00000316609
    DLEC1 DLEU2L DLG1 DLG2 DLG3
    DLG4_ DLG5 DLGAP1 DLGAP2 DLGAP2_
    ENST00000293813 ENST00000356067
    DLGAP3 DLGAP4 DLGAP5 DLK1 DLK2
    DLL1 DLL3 DLL4 DLST DLX1
    DLX2 DLX3 DLX4 DLX5 DLX6
    DMAP1 DMBT1 DMBX1 DMC1 DMD
    DMD_ DMGDH DMKN DMP1 DMPK
    ENST00000378687
    DMRT1 DMRT2 DMRT2_ DMRT3 DMRTA1
    ENST00000302441
    DMRTB1 DMRTC1 DMRTC1B DMRTC2 DMTF1
    DMWD DMXL1 DMXL2 DNA2L DNAH1
    DNAH10 DNAH10_same_ DNAH11 DNAH12L DNAH14
    name
    DNAH17 DNAH1_ DNAH2 DNAH3 DNAH5
    ENST00000420323
    DNAH6 DNAH7 DNAH8 DNAH9 DNAI1
    DNAI2 DNAJA1 DNAJA2 DNAJA3 DNAJA4
    DNAJB1 DNAJB11 DNAJB12 DNAJB13 DNAJB14
    DNAJB2 DNAJB4 DNAJB5 DNAJB6 DNAJB7
    DNAJB8 DNAJB9 DNAJC1 DNAJC10 DNAJC11
    DNAJC12 DNAJC13 DNAJC14 DNAJC15 DNAJC16
    DNAJC17 DNAJC18 DNAJC19 DNAJC2 DNAJC21
    DNAJC22 DNAJC24 DNAJC25 DNAJC25- DNAJC27
    GNG10
    DNAJC28 DNAJC3 DNAJC30 DNAJC4 DNAJC5
    DNAJC5B DNAJC5G DNAJC6 DNAJC7 DNAJC8
    DNAJC9 DNAL4 DNALI1 DNAPTP6 DNASE1
    DNASE1L1 DNASE1L2 DNASE1L3 DNASE2 DNASE2B
    DND1 DNER DNHD1_ DNHL1 DNLZ
    ENST00000254579
    DNM1 DNM1L DNM2 DNM3 DNMBP
    DNMT1 DNMT3A DNMT3B DNMT3L DNPEP
    DNTT DNTTIP1 DOC2A DOCK1 DOCK10
    DOCK10_ DOCK11 DOCK2 DOCK3 DOCK3_
    ENST00000373702 ENST00000266037
    DOCK4 DOCKS DOCK6 DOCK7 DOCK8
    DOCK9 DOHH DOK1 DOK2 DOK3
    DOK4 DOK5 DOK6 DOK7 DOLK
    DOLPP1 DOM3Z DONSON DOPEY1 DOPEY2
    DOT1L DPAGT1 DPCR1 DPEP1 DPEP2
    DPEP3 DPF1 DPF2 DPH1 DPH1-
    OVCA2
    DPH2 DPH3 DPH3B DPH5 DPM1
    DPM2 DPM3 DPP10 DPP3 DPP4
    DPP6 DPP7 DPP8 DPP9 DPPA2
    DPPA3 DPPA4 DPPA5 DPRX DPT
    DPY19L1 DPY19L2 DPY19L3 DPY19L4 DPY30
    DPYD DPYS DPYSL2 DPYSL3 DPYSL4
    DPYSL5 DQX1 DR1 DRAM1 DRAM2
    DRAP1 DRD1 DRD2 DRD3 DRD4
    DRD5 DRD5P1 DRG1 DRG2 DRP2
    DSC1 DSC2 DSC3 DSCAM DSCAML1
    DSCC1 DSCR3 DSCR4 DSCR6 DSE
    DSEL DSG1 DSG2 DSG3 DSG4
    DSN1 DSP DSPP DST DSTN
    DSTYK DST_ DST_ DTD1 DTHD1
    ENST00000370754 ENST00000370769
    DTL DTNA DTNB DTNBP1 DTWD1
    DTWD2 DTX1 DTX2 DTX3 DTX3L
    DTX4 DTYMK DULLARD DUOX1 DUOX2
    DUOXA1 DUOXA2 DUPD1 DUS1L DUS2L
    DUS3L DUS4L DUSP1 DUSP10 DUSP11
    DUSP12 DUSP13 DUSP13_ DUSP14 DUSP15
    ENST00000356369
    DUSP16 DUSP18 DUSP19 DUSP2 DUSP21
    DUSP22 DUSP23 DUSP26 DUSP27 DUSP28
    DUSP3 DUSP4 DUSP5 DUSP5P DUSP6
    DUSP7 DUSP8 DUSP9 DUT DUXA
    DVL1 DVL2 DVL3 DYDC1 DYDC2
    DYM DYNC1H1 DYNC1I1 DYNC1I2 DYNC1LI1
    DYNC1LI2 DYNC2H1 DYNC2H1_ DYNC2LI1 DYNLL1
    ENST00000398093
    DYNLL2 DYNLRB1 DYNLRB2 DYNLT1 DYNLT3
    DYRK1A DYRK1B DYRK2 DYRK3 DYRK4
    DYSF DYSFIP1 DYX1C1 DZIP1 DZIP1L
    DZIP3 E2F1 E2F2 E2F3 E2F4
    E2F5 E2F6 E2F7 E2F8 E4F1
    EAF1 EAF2 EAPP EARS2 EBAG9
    EBF1 EBF3 EBI3 EBNA1BP2 EBP
    EBPL ECD ECE1 ECE2 ECEL1
    ECH1 ECHDC1 ECHDC2 ECHDC3 ECHS1
    ECM1 ECM2 ECOP ECSIT ECT2
    ECT2L EDA EDA2R EDAR EDARADD
    EDC3 EDC4 EDDM3A EDDM3B EDEM1
    EDEM2 EDEM3 EDF1 EDG6 EDIL3
    EDN1 EDN2 EDN3 EDNRA EDNRB
    EEA1 EED EEF1A1 EEF1A1P11 EEF1A2
    EEF1B2 EEF1D EEF1E1 EEF2 EEF2K
    EEFSEC EEPD1 EFCAB1 EFCAB2 EFCAB3
    EFCAB4A EFCAB4B EFCAB5 EFCAB6 EFCAB7
    EFEMP1 EFEMP2 EFHA1 EFHA2 EFHB
    EFHC1 EFHC2 EFHD1 EFHD2 EFNA1
    EFNA2 EFNA3 EFNA4 EFNA5 EFNB1
    EFNB2 EFNB3 EFR3A EFS EFTUD1
    EFTUD2 EGF EGFL4 EGFL6 EGFL7
    EGFL8 EGFLAM EGFR EGFR_ EGLN1
    ENST00000344576
    EGLN2 EGLN3 EGR1 EGR2 EGR3
    EGR4 EHBP1 EHBP1L1 EHD1 EHD2
    EHD3 EHD4 EHF EHHADH EHMT1
    EHMT2 EI24 EID1 EID2 EID2B
    EIF1 EIF1AD EIF1AX EIF1AY EIF1B
    EIF2A EIF2AK1 EIF2AK2 EIF2AK3 EIF2AK4
    EIF2A_ EIF2B1 EIF2B2 EIF2B3 EIF2B4
    ENST00000487799
    EIF2B5 EIF2C1 EIF2C2 EIF2C3 EIF2C4
    EIF2S1 EIF2S2 EIF2S3 EIF3A EIF3B
    EIF3C EIF3CL EIF3D EIF3E EIF3EIP
    EIF3F EIF3G EIF3H EIF3I EIF3J
    EIF3K EIF3M EIF3S8 EIF4A1 EIF4A2
    EIF4A3 EIF4B EIF4E EIF4E2 EIF4E3
    EIF4EBP1 EIF4EBP2 EIF4EBP3 EIF4ENIF1 EIF4G1
    EIF4G2 EIF4G3 EIF4H EIF5 EIF5A
    EIF5A2 EIF5B EIF6 ELAC1 ELAC2
    ELANE ELAVL1 ELAVL2 ELAVL3 ELAVL4
    ELF1 ELF2 ELF3 ELF4 ELF5
    ELFN2 ELK1 ELK3 ELK4 ELL
    ELL2 ELL3 ELMO1 ELMO2 ELMO3
    ELMOD2 ELMOD3 ELN ELOF1 ELOVL1
    ELOVL2 ELOVL3 ELOVL4 ELOVL5 ELOVL6
    ELOVL7 ELP2 ELP3 ELP4 ELSPBP1
    ELTD1 EMB EMCN EMD EME1
    EME2 EMID1 EMID2 EMILIN1 EMILIN2
    EMILIN3 EML1 EML2 EML3 EML4
    EML5 EMP1 EMP2 EMP3 EMR1
    EMR2 EMR3 EMR4 EMX1 EMX2
    EN1 EN2 ENAH ENAM ENC1
    ENDOD1 ENDOG ENDOU ENG ENGASE
    ENHO ENKUR ENO1 ENO2 ENO3
    ENO4 ENOPH1 ENOSF1 ENOX1 ENOX2
    ENPEP ENPP1 ENPP2 ENPP3 ENPP4
    ENPP5 ENPP6 ENPP7 ENSA ENSG00000038102
    ENSG00000064489 ENSG00000068650 ENSG00000101152 ENSG00000102445 ENSG00000104880
    ENSG00000106232 ENSG00000107816 ENSG00000115339 ENSG00000117540 ENSG00000118519
    ENSG00000118928 ENSG00000123257 ENSG00000124224 ENSG00000124677 ENSG00000124854
    ENSG00000124915 ENSG00000125631 ENSG00000125822 ENSG00000125881 ENSG00000125964
    ENSG00000126002 ENSG00000126217 ENSG00000128422 ENSG00000128563 ENSG00000129973
    ENSG00000130225 ENSG00000130241 ENSG00000131484 ENSG00000135213 ENSG00000135702
    ENSG00000135749 ENSG00000137021 ENSG00000137746 ENSG00000139239 ENSG00000140209
    ENSG00000142832 ENSG00000142951 ENSG00000143910 ENSG00000144396 ENSG00000145642
    ENSG00000146736 ENSG00000147113 ENSG00000148667 ENSG00000148713 ENSG00000148805
    ENSG00000149618 ENSG00000149658 ENSG00000150980 ENSG00000153081 ENSG00000154732
    ENSG00000156367 ENSG00000156509 ENSG00000157819 ENSG00000157999 ENSG00000158185
    ENSG00000158301 ENSG00000158403 ENSG00000159239 ENSG00000161643 ENSG00000162568
    ENSG00000162621 ENSG00000162644 ENSG00000162734 ENSG00000162767 ENSG00000162872
    ENSG00000163144 ENSG00000163182 ENSG00000163612 ENSG00000164159 ENSG00000164236
    ENSG00000164241 ENSG00000164500 ENSG00000164845 ENSG00000164860 ENSG00000164946
    ENSG00000165114 ENSG00000165124 ENSG00000165429 ENSG00000165851 ENSG00000165935
    ENSG00000166013 ENSG00000166329 ENSG00000166492 ENSG00000166593 ENSG00000166707
    ENSG00000167281 ENSG00000167390 ENSG00000167433 ENSG00000167442 ENSG00000167475
    ENSG00000168038 ENSG00000168113 ENSG00000168561 ENSG00000169664 ENSG00000169697
    ENSG00000170238 ENSG00000170817 ENSG00000170987 ENSG00000171084 ENSG00000171459
    ENSG00000171841 ENSG00000171878 ENSG00000171995 ENSG00000172070 ENSG00000172212
    ENSG00000172261 ENSG00000172764 ENSG00000172786 ENSG00000172823 ENSG00000172895
    ENSG00000172899 ENSG00000172900 ENSG00000172963 ENSG00000173115 ENSG00000173213
    ENSG00000173609 ENSG00000173671 ENSG00000173679 ENSG00000173774 ENSG00000173780
    ENSG00000173820 ENSG00000173863 ENSG00000173961 ENSG00000173968 ENSG00000174028
    ENSG00000174057 ENSG00000174104 ENSG00000174121 ENSG00000174126 ENSG00000174144
    ENSG00000174398 ENSG00000174440 ENSG00000174459 ENSG00000174483 ENSG00000174658
    ENSG00000174681 ENSG00000174880 ENSG00000175117 ENSG00000175143 ENSG00000175267
    ENSG00000175822 ENSG00000175856 ENSG00000176050 ENSG00000176207 ENSG00000176220
    ENSG00000176757 ENSG00000176819 ENSG00000176900 ENSG00000176937 ENSG00000176951
    ENSG00000176960 ENSG00000177111 ENSG00000177634 ENSG00000177835 ENSG00000177858
    ENSG00000177863 ENSG00000178006 ENSG00000178225 ENSG00000178322 ENSG00000178510
    ENSG00000178546 ENSG00000178585 ENSG00000179294 ENSG00000179312 ENSG00000179326
    ENSG00000179360 ENSG00000179574 ENSG00000179702 ENSG00000179755 ENSG00000179824
    ENSG00000179851 ENSG00000180150 ENSG00000180494 ENSG00000180518 ENSG00000180519
    ENSG00000180649 ENSG00000180715 ENSG00000180882 ENSG00000181437 ENSG00000181669
    ENSG00000181882 ENSG00000181922 ENSG00000182053 ENSG00000182065 ENSG00000182150
    ENSG00000182553 ENSG00000182625 ENSG00000182729 ENSG00000182933 ENSG00000182957
    ENSG00000183000 ENSG00000183059 ENSG00000183096 ENSG00000183122 ENSG00000183144
    ENSG00000183190 ENSG00000183239 ENSG00000183317 ENSG00000183355 ENSG00000183397
    ENSG00000183405 ENSG00000183445 ENSG00000183455 ENSG00000183514 ENSG00000183627
    ENSG00000183817 ENSG00000183851 ENSG00000183920 ENSG00000183981 ENSG00000183983
    ENSG00000184008 ENSG00000184064 ENSG00000184100 ENSG00000184263 ENSG00000184352
    ENSG00000184353 ENSG00000184391 ENSG00000184490 ENSG00000184493 ENSG00000184521
    ENSG00000184543 ENSG00000184653 ENSG00000184673 ENSG00000184844 ENSG00000184888
    ENSG00000184902 ENSG00000185034 ENSG00000185055 ENSG00000185082 ENSG00000185095
    ENSG00000185319 ENSG00000185448 ENSG00000185467 ENSG00000185636 ENSG00000185641
    ENSG00000185685 ENSG00000185758 ENSG00000185834 ENSG00000185863 ENSG00000185929
    ENSG00000185945 ENSG00000185956 ENSG00000186218 ENSG00000186259 ENSG00000186381
    ENSG00000186400 ENSG00000186414 ENSG00000186483 ENSG00000186659 ENSG00000186663
    ENSG00000186709 ENSG00000186728 ENSG00000186743 ENSG00000186756 ENSG00000186773
    ENSG00000186787 ENSG00000187042 ENSG00000187072 ENSG00000187080 ENSG00000187522
    ENSG00000187534 ENSG00000187544 ENSG00000187600 ENSG00000187615 ENSG00000187653
    ENSG00000187661 ENSG00000187686 ENSG00000187791 ENSG00000187809 ENSG00000187828
    ENSG00000187851 ENSG00000187900 ENSG00000187938 ENSG00000187963 ENSG00000187988
    ENSG00000187999 ENSG00000188013 ENSG00000188023 ENSG00000188031 ENSG00000188075
    ENSG00000188082 ENSG00000188144 ENSG00000188292 ENSG00000188405 ENSG00000188423
    ENSG00000188438 ENSG00000188447 ENSG00000188463 ENSG00000188469 ENSG00000188604
    ENSG00000188668 ENSG00000188683 ENSG00000188796 ENSG00000188831 ENSG00000188841
    ENSG00000188873 ENSG00000188890 ENSG00000188912 ENSG00000188926 ENSG00000188974
    ENSG00000188985 ENSG00000188989 ENSG00000189118 ENSG00000189119 ENSG00000189128
    ENSG00000189244 ENSG00000189258 ENSG00000189279 ENSG00000189290 ENSG00000189311
    ENSG00000189378 ENSG00000189384 ENSG00000196076 ENSG00000196094 ENSG00000196115
    ENSG00000196121 ENSG00000196183 ENSG00000196230 ENSG00000196285 ENSG00000196292
    ENSG00000196306 ENSG00000196454 ENSG00000196527 ENSG00000196681 ENSG00000196690
    ENSG00000196926 ENSG00000196930 ENSG00000196940 ENSG00000196960 ENSG00000197023
    ENSG00000197049 ENSG00000197149 ENSG00000197185 ENSG00000197218 ENSG00000197246
    ENSG00000197320 ENSG00000197335 ENSG00000197369 ENSG00000197407 ENSG00000197438
    ENSG00000197450 ENSG00000197475 ENSG00000197481 ENSG00000197490 ENSG00000197526
    ENSG00000197575 ENSG00000197585 ENSG00000197608 ENSG00000197630 ENSG00000197680
    ENSG00000197799 ENSG00000197825 ENSG00000197865 ENSG00000197883 ENSG00000198059
    ENSG00000198079 ENSG00000198107 ENSG00000198154 ENSG00000198179 ENSG00000198229
    ENSG00000198273 ENSG00000198322 ENSG00000198326 ENSG00000198475 ENSG00000198544
    ENSG00000198615 ENSG00000198616 ENSG00000198649 ENSG00000198684 ENSG00000198694
    ENSG00000198706 ENSG00000198725 ENSG00000198726 ENSG00000198731 ENSG00000198760
    ENSG00000198778 ENSG00000198789 ENSG00000198801 ENSG00000198810 ENSG00000198902
    ENSG00000198921 ENSG00000198957 ENSG00000198965 ENTHD1 ENTPD1
    ENTPD2 ENTPD3 ENTPD4 ENTPD5 ENTPD6
    ENTPD7 ENTPD8 ENY2 EOMES EP300
    EP400 EPAS1 EPB41 EPB41L1 EPB41L2
    EPB41L3 EPB41L4A EPB41L4B EPB41L5 EPB42
    EPB49 EPC1 EPC2 EPCAM EPDR1
    EPGN EPHA1 EPHA10 EPHA2 EPHA3
    EPHA4 EPHA5 EPHA6 EPHA7 EPHA8
    EPHB1 EPHB1_ EPHB2 EPHB3 EPHB4
    ENST00000398015
    EPHB6 EPHX1 EPHX2 EPHX3 EPHX4
    EPM2A EPN2 EPN3 EPO EPOR
    EPRS EPS15 EPS15L1 EPS8 EPS8L1
    EPS8L2 EPS8L3 EPSTI1 EPX EPYC
    ERAL1 ERAP1 ERAP2 ERAS ERBB2
    ERBB2IP ERBB3 ERBB3_ ERBB4 ERC1
    ENST00000267101
    ERCC1 ERCC2 ERCC3 ERCC4 ERCC5
    ERCC6 ERCC6L ERCC8 EREG ERF
    ERG ERGIC1 ERGIC2 ERGIC3 ERH
    ERI1 ERI2 ERI3 ERICH1 ERLEC1
    ERLIN2 ERMAP ERMN ERMP1 ERN1
    ERN2 ERO1L ERO1LB ERP27 ERP29
    ERP44 ERRFI1 ERVFC1 ERVWE1 ESAM
    ESCO1 ESCO2 ESD ESF1 ESM1
    ESPL1 ESPN ESPNL ESR1 ESR2
    ESRP1 ESRP2 ESRRA ESRRB ESRRG
    ESSPL ESX1 ESYT1 ESYT2 ESYT3
    ETAA1 ETF1 ETFA ETFB ETFDH
    ETHE1 ETNK1 ETNK2 ETS1 ETS2
    ETV1 ETV2 ETV3 ETV3L ETV4
    ETV5 ETV6 ETV7 EVC EVC2
    EVI2A EVI2B EVI5 EVI5L EVL
    EVPL EVX1 EVX2 EWSR1 EXD1
    EXD3 EXDL2 EXO1 EXOC1 EXOC2
    EXOC3 EXOC3L EXOC3L2 EXOC4 EXOC5
    EXOC6 EXOC6B EXOC7 EXOC8 EXOG
    EXOSC1 EXOSC10 EXOSC2 EXOSC3 EXOSC4
    EXOSC5 EXOSC6 EXOSC7 EXOSC8 EXOSC9
    EXPH5 EXT1 EXT2 EXTL1 EXTL2
    EXTL3 EYA1 EYA2 EYA3 EYA4
    EYS EZH1 EZH2 EZH2_ EZR
    ENST00000350995
    F10 F11 F11R F12 F13A1
    F13B F2 F2R F2RL1 F2RL2
    F2RL3 F3 F5 F7 F8
    F8A1 F8A2 F8A3 F8_ F9
    ENST00000360256
    FA2H FA87B_HUMAN FAAH FAAH2 FABP1
    FABP12 FABP2 FABP3 FABP4 FABP5
    FABP6 FABP7 FABP9 FABPE_ FADD
    HUMAN
    FADS1 FADS2 FADS3 FADS6 FAF1
    FAF2 FAH FAHD1 FAHD2A FAHD2B
    FAIM FAIM2 FAIM3 FAM100A FAM100B
    FAM101A FAM102A FAM102B FAM103A1 FAM104B
    FAM105A FAM105B FAM107A FAM107B FAM108A1
    FAM108A3 FAM108B1 FAM109A FAM109B FAM110A
    FAM110B FAM110C FAM111A FAM111B FAM113A
    FAM113B FAM114A1 FAM114A2 FAM115A FAM115C
    FAM116A FAM117A FAM117B FAM118A FAM118B
    FAM119A FAM119B FAM120A FAM120AOS FAM120B
    FAM120C FAM122A FAM122B FAM122C FAM123A
    FAM123B FAM123C FAM124A FAM124B FAM125A
    FAM125B FAM126A FAM126B FAM127A FAM127B
    FAM127C FAM128A FAM128B FAM129A FAM129B
    FAM129C FAM131A FAM131B FAM131C FAM132A
    FAM133A FAM134A FAM134B FAM134C FAM135A
    FAM135B FAM136A FAM13A1 FAM13C FAM149A
    FAM150A FAM151A FAM151B FAM153A FAM153B
    FAM153C FAM154A FAM154B FAM155A FAM155B
    FAM156A FAM156B FAM158A FAM159A FAM160A2
    FAM160B1 FAM161A FAM161B FAM162A FAM162B
    FAM163A FAM163B FAM164A FAM164C FAM165B
    FAM166A FAM167B FAM168A FAM168B FAM169A
    FAM170A FAM171A1 FAM171B FAM172A FAM173A
    FAM173B FAM174A FAM174B FAM175A FAM175B
    FAM176A FAM176B FAM177A1 FAM177B FAM178B
    FAM179A FAM179B FAM180A FAM181A FAM181B
    FAM184A FAM184B FAM186A FAM186B FAM187B
    FAM188A FAM188B FAM189A1 FAM189A2 FAM189B
    FAM18B FAM18B2 FAM190A FAM190B FAM192A
    FAM193A FAM194A FAM194B FAM195A FAM196A
    FAM198A FAM198B FAM199X FAM19A2 FAM19A3
    FAM19A4 FAM19A5 FAM200A FAM20A FAM20B
    FAM21A FAM21C FAM22A FAM22D FAM22F
    FAM22G FAM23A FAM23B FAM24A FAM24B
    FAM26A FAM26D FAM26E FAM26F FAM32A
    FAM33A FAM35A FAM36A FAM38B FAM39B
    FAM3A FAM3B FAM3C FAM3D FAM40A
    FAM4OB FAM43A FAM43B FAM45A FAM45B
    FAM46A FAM46B FAM46C FAM46D FAM47A
    FAM47B FAM47C FAM48A FAM48B1 FAM48B2
    FAM49A FAM49B FAM50A FAM50B FAM53A
    FAM53B FAM53C FAM54A FAM54B FAM55A
    FAM55C FAM55D FAM57A FAM57B FAM58A
    FAM58B FAM59A FAM5B FAM5C FAM60A
    FAM63A FAM63B FAM64A FAM65A FAM65B
    FAM65C FAM69B FAM69C FAM70A FAM7OB
    FAM71A FAM71B FAM71C FAM71E1 FAM71F1
    FAM72A FAM72B FAM73A FAM73B FAM74A3
    FAM75A1 FAM75A2 FAM75A6 FAM75A7 FAM76A
    FAM76B FAM78A FAM78B FAM81A FAM81B
    FAM82A1 FAM82A2 FAM82B FAM83A FAM83B
    FAM83C FAM83D FAM83E FAM83F FAM83G
    FAM83H FAM84A FAM84B FAM86A FAM86C
    FAM87B FAM89A FAM89B FAM8A1 FAM90A1
    FAM90A20 FAM91A1 FAM92B FAM96A FAM98A
    FAM98B FAM98C FAM9A FAM9B FAM9C
    FANCA FANCB FANCC FANCD2 FANCE
    FANCF FANCG FANCI FANCL FANCM
    FANK1 FAP FAR1 FAR2 FARP1
    FARP2 FARS2 FARSA FARSB FAS
    FASLG FASN FASTK FASTKD1 FASTKD2
    FASTKD3 FASTKD5 FAT FAT1 FAT2
    FAT3 FAT4 FAT4_ FATE1 FAU
    ENST00000394329
    FBF1 FBL FBLIM1 FBLN1 FBLN2
    FBLN2_ FBLN5 FBLN7 FBN1 FBN2
    ENST00000492059
    FBN3 FBP1 FBP2 FBRSL1 FBXL12
    FBXL13 FBXL14 FBXL15 FBXL16 FBXL17
    FBXL18 FBXL19 FBXL2 FBXL20 FBXL21
    FBXL21_ FBXL22 FBXL3 FBXL4 FBXL5
    ENST00000297158
    FBXL6 FBXL7 FBXL8 FBXO10 FBXO11
    FBXO15 FBXO16 FBXO17 FBXO18 FBXO2
    FBXO21 FBXO22 FBXO24 FBXO25 FBXO27
    FBXO28 FBXO3 FBXO30 FBXO31 FBXO32
    FBXO33 FBXO34 FBXO36 FBXO38 FBXO39
    FBXO4 FBXO40 FBXO41 FBXO42 FBXO43
    FBXO44 FBXO45 FBXO46 FBXO47 FBXO48
    FBXO5 FBXO6 FBXO7 FBXO8 FBXO9
    FBXW10 FBXW11 FBXW12 FBXW2 FBXW4
    FBXW5 FBXW7 FBXW7_ FBXW8 FBXW9
    NM_018315_2
    FCAMR FCAR FCER1A FCER1G FCER2
    FCF1 FCGBP FCGR1A FCGR1B FCGR2A
    FCGR2B FCGR3A FCGR3B FCGRT FCHO1
    FCHSD1 FCHSD2 FCN1 FCN2 FCN3
    FCRL1 FCRL2 FCRL3 FCRL4 FCRL5
    FCRL6 FCRLA FCRLB FDFT1 FDPS
    FDX1 FDX1L FDXR FECH FEM1A
    FEM1B FEM1C FEN1 FER FER1L6
    FERD3L FERMT1 FERMT2 FERMT3 FES
    FETUB FEV FEZ1 FEZF1 FEZF2
    FFAR1 FFAR2 FFAR3 FGA FGB
    FGD1 FGD2 FGD3 FGD4 FGD5
    FGD6 FGF1 FGF10 FGF11 FGF12
    FGF13 FGF14 FGF16 FGF17 FGF18
    FGF19 FGF2 FGF20 FGF21 FGF22
    FGF23 FGF3 FGF4 FGF5 FGF6
    FGF7 FGF7P2 FGF8 FGF9 FGFBP1
    FGFBP2 FGFBP3 FGFR1 FGFR1OP FGFR1OP2
    FGFR1_ FGFR2 FGFR3 FGFR4 FGFR4_
    ENST00000425967 ENST00000292408
    FGFRL1 FGG FGGY FGL1 FGL2
    FGR FH FHAD1 FHDC1 FHIT
    FHL1 FHL2 FHL3 FHL5 FHOD1
    FHOD3 FIBCD1 FIBIN FIBP FICD
    FIG4 FIGF FIGN FIGNL1 FILIP1
    FILIP1L FIP1L1 FIS1 FITM1 FITM2
    FIZ1 FKBP10 FKBP11 FKBP14 FKBP1A
    FKBP1B FKBP1C FKBP2 FKBP3 FKBP4
    FKBP5 FKBP6 FKBP7 FKBP8 FKBP9
    FKBP9L FKBPL FKRP FKTN FLAD1
    FLCN FLG FLG2 FLI1 FLII
    FLJ10357 FLJ10404 FLJ10490 FLJ13236 FLJ13855
    FLJ14075 FLJ14627 FLJ14775 FLJ16165 FLJ16171
    FLJ16331 FLJ16360 FLJ16369 FLJ16542 FLJ20184
    FLJ20273 FLJ20366 FLJ20584 FLJ23356 FLJ23584
    FLJ25006 FLJ25917 FLJ31132 FLJ34521 FLJ35880
    FLJ38348 FLJ38451 FLJ38576 FLJ39257 FLJ39369
    FLJ41131 FLJ41603 FLJ42177 FLJ42418 FLJ42957
    FLJ43374 FLJ43806 FLJ43980 FLJ44048 FLJ44060
    FLJ44216 FLJ44635 FLJ44817 FLJ44874 FLJ45224
    FLJ45422 FLJ45455 FLJ45831 FLJ45910 FLJ45983
    FLJ46321 FLJ90650 FLNA FLNB FLNC
    FLOT1 FLOT2 FLRT1 FLRT2 FLRT3
    FLT1 FLT3 FLT3LG FLT4 FLT4_
    ENST00000261937
    FLVCR1 FLVCR2 FLYWCH1 FLYWCH2 FMN2
    FMNL1 FMNL2 FMNL3 FMO1 FMO2
    FMO3 FMO4 FMO5 FMO6P FMOD
    FMR1 FMR1NB FN1 FN3K FN3KRP
    FNBP1L FNBP1_ FNBP4 FNDC1 FNDC3A
    ENST00000372416
    FNDC3B FNDC4 FNDC5 FNDC7 FNDC8
    FNIP1 FNIP2 FNTA FNTB FOLH1
    FOLH1B FOLR1 FOLR2 FOS FOSB
    FOSL1 FOSL2 FOXA1 FOXA2 FOXA3
    FOXB1 FOXB2 FOXC1 FOXC2 FOXD2
    FOXD3 FOXD4 FOXD4L1 FOXD4L2 FOXD4L3
    FOXD4L4 FOXD4L6 FOXE1 FOXE3 FOXF1
    FOXF2 FOXG1 FOXH1 FOXI1 FOXI2
    FOXI3 FOXJ1 FOXJ2 FOXJ3 FOXK1
    FOXK2 FOXL1 FOXL2 FOXM1 FOXN1
    FOXN2 FOXN3 FOXN4 FOXO1 FOXO3
    FOXO4 FOXP1 FOXP2 FOXP3 FOXP4
    FOXQ1 FOXR1 FOXR2 FOXRED1 FOXRED2
    FOXS1 FPGS FPGT FPR1 FPR2
    FPR3 FRAG1 FRAS1 FRAS1_ FRAT1
    ENST00000325942
    FRAT2 FREM1 FREM2 FREM3 FRG1
    FRG2 FRG2C FRK FRMD1 FRMD3
    FRMD4A FRMD4B FRMD5 FRMD6 FRMD7
    FRMD8 FRMPD1 FRMPD2 FRMPD2L1 FRMPD2L2
    FRMPD3 FRMPD4 FRRS1 FRS2 FRS3
    FRY FRYL FRZB FSCB FSCN1
    FSCN3 FSD1 FSD2 FSHB FSHR
    FSIP1 FST FSTL1 FSTL3 FSTL4
    FSTL5 FTCD FTH1 FTHL17 FTHL19
    FTL FTLP2 FTMT FTO FTSJ1
    FTSJ2 FTSJ3 FTSJD1 FTSJD2 FUBP1
    FUBP3 FUCA1 FUCA2 FUK FUNDC1
    FUNDC2 FUNDC2P1 FURIN FUS FUSIP1
    FUT1 FUT10 FUT11 FUT2 FUT3
    FUT4 FUT5 FUT6 FUT7 FUT8
    FUT9 FUZ FXC1 FXN FXR1
    FXYD1 FXYD2 FXYD3 FXYD4 FXYD5
    FXYD6 FXYD7 FXYD8 FYCO1 FYN
    FYTTD1 FZD1 FZD10 FZD2 FZD3
    FZD4 FZD5 FZD6 FZD7 FZD8
    FZD9 FZR1 G0S2 G2E3 G3BP1
    G3BP2 G6PC G6PC2 G6PC3 G6PD
    GAA GAB1 GAB2 GAB3 GAB4
    GABARAP GABARAPL1 GABARAPL2 GABARAPL3 GABBR1
    GABBR2 GABPA GABPB1 GABPB2 GABRA1
    GABRA2 GABRA3 GABRA4 GABRA5 GABRA6
    GABRB1 GABRB2 GABRB3 GABRD GABRE
    GABRG1 GABRG2 GABRP GABRQ GABRR1
    GABRR2 GABRR3 GAD1 GAD2 GADD45A
    GADD45B GADD45G GADD45GIP1 GADL1 GAGE1
    GAGE10 GAGE12C GAGE12E GAGE12F GAGE12G
    GAGE12H GAGE12J GAGE2C GAGE2D GAGE2E
    GAK GAL GAL3ST1 GAL3ST2 GAL3ST3
    GAL3ST4 GALC GALE GALK1 GALK2
    GALM GALNS GALNT1 GALNT10 GALNT11
    GALNT12 GALNT13 GALNT14 GALNT2 GALNT3
    GALNT5 GALNT6 GALNT7 GALNT8 GALNT9
    GALNTL1 GALNTL2 GALNTL4 GALNTL5 GALNTL6
    GALP GALR1 GALR2 GALR3 GALT
    GAMT GAN GANAB GANC GAP43
    GAPDH GAPDHS GAPT GAPVD1 GAR1
    GARNL3 GARS GART GAS1 GAS2
    GAS2L1 GAS2L2 GAS2L3 GAS6 GAS7
    GAS8 GAST GATA1 GATA2 GATA3
    GATA4 GATA5 GATA6 GATAD1 GATAD2A
    GATAD2B GATC GATM GATS GATSL3
    GBA GBA2 GBAP GBAS GBF1
    GBG5L_HUMAN GBGT1 GBP1 GBP2 GBP3
    GBP4 GBP5 GBP6 GBP7 GBX1
    GBX2 GC GCA GCAT GCC1
    GCC2 GCDH GCET2 GCH1 GCHFR
    GCK GCKR GCLC GCLM GCM1
    GCM2 GCN1L1 GCNT1 GCNT2 GCNT3
    GCNT4 GCOM1 GCSH GDA GDAP1
    GDAP1L1 GDAP2 GDE1 GDF1 GDF10
    GDF11 GDF15 GDF2 GDF3 GDF5
    GDF6 GDF7 GDF9 GDI1 GDI2
    GDNF GDPD1 GDPD2 GDPD3 GDPD4
    GDPD5 GEFT GEM GEMIN4 GEMIN5
    GEMIN6 GEMIN7 GEMIN8 GEN1 GFAP
    GFER GFI1 GFI1B GFM1 GFM2
    GFOD1 GFOD2 GFPT1 GFPT2 GFRA1
    GFRA3 GFRA4 GFRAL GGA1 GGA2
    GGA3 GGCT GGCX GGH GGN
    GGNBP2 GGPS1 GGT1 GGT5 GGT6
    GGT7 GGTLA4 GGTLC1 GGTLC2 GH1
    GH2 GHDC GHITM GHR GHRH
    GHRHR GHRL GHSR GIF GIGYF1
    GIGYF2 GIMAP1 GIMAP2 GIMAP4 GIMAP5
    GIMAP6 GIMAP7 GIMAP8 GIN1 GINS1
    GINS2 GINS3 GINS4 GIOT-1 GIP
    GIPC1 GIPC2 GIPC3 GIPR GIT1
    GIT2 GIYD1 GIYD2 GJA1 GJA10
    GJA3 GJA4 GJA5 GJA8 GJA9
    GJB1 GJB2 GJB3 GJB4 GJB5
    GJB6 GJB7 GJC1 GJC2 GJC3
    GJD2 GJD4 GK GK2 GK3P
    GK5 GKAP1 GKN1 GKN2 GLA
    GLB1 GLB1L GLB1L2 GLB1L3 GLCCI1
    GLCE GLDC GLDN GLE1 GLE1L
    GLG1 GLI1 GLI2 GLI3 GLI4
    GLIPR1 GLIPR1L1 GLIPR1L2 GLIPR2 GLIS1
    GLIS2 GLIS3 GLMN GLO1 GLOD4
    GLOD5 GLP1R GLP2R GLRA1 GLRA2
    GLRA3 GLRA4 GLRB GLRX GLRX2
    GLRX3 GLRX5 GLRXP3 GLS GLS2
    GLT1D1 GLT25D1 GLT25D2 GLT28D1 GLT6D1
    GLT8D1 GLT8D2 GLTP GLTPD1 GLTPD2
    GLTSCR2 GLUD1 GLUD2 GLUL GLYAT
    GLYATL1 GLYATL2 GLYCTK GLYR1 GM2A
    GMCL1 GMDS GMEB1 GMEB2 GMFB
    GMFG GMIP GML GMNN GMPPA
    GMPPB GMPR GMPR2 GMPS GNA11
    GNA12 GNA13 GNA14 GNA15 GNAI1
    GNAI2 GNAI3 GNAL GNA01 GNAQ
    GNAS GNAS_ GNAS_ GNAT1 GNAT2
    ENST00000371100 NM_016592_1
    GNAZ GNB1 GNB1L GNB2 GNB2L1
    GNB3 GNB4 GNB5 GNE GNG10
    GNG11 GNG12 GNG13 GNG2 GNG3
    GNG4 GNG5 GNG7 GNG8 GNGT1
    GNGT2 GNL1 GNL2 GNL3 GNL3L
    GNLY GNMT GNPAT GNPDA1 GNPDA2
    GNPNAT1 GNPTAB GNPTG GNRH1 GNRH2
    GNRHR GNRHR2 GNS GOLGA1 GOLGA2
    GOLGA2B GOLGA3 GOLGA4 GOLGA5 GOLGA6A
    GOLGA7 GOLGA7B GOLGA8A GOLGA8E GOLGA8G
    GOLGB1 GOLIM4 GOLM1 GOLPH3 GOLPH3L
    GOLT1A GOLT1B GON4L GOPC GORAB
    GORASP1 GORASP2 GOSR1 GOSR2 GOT1
    GOT2 GP1BB GP2 GPS GP6
    GP9 GPA33 GPAA1 GPAM GPAT2
    GPATCH1 GPATCH2 GPATCH3 GPATCH4 GPATCH8
    GPBP1 GPBP1L1 GPC1 GPC2 GPC3
    GPC4 GPC5 GPC6 GPCPD1 GPD1
    GPD1L GPD2 GPER GPHA2 GPHB5
    GPHN GPI GPIHBP1 GPKOW GPLD1
    GPM6A GPM6B GPN1 GPN2 GPN3
    GPNMB GPR1 GPR101 GPR107 GPR108
    GPR109A GPR110 GPR111 GPR112 GPR113
    GPR114 GPR115 GPR116 GPR119 GPR12
    GPR120 GPR123 GPR124 GPR125 GPR126
    GPR128 GPR132 GPR133 GPR135 GPR137
    GPR137B GPR137C GPR139 GPR141 GPR142
    GPR143 GPR146 GPR148 GPR149 GPR15
    GPR150 GPR151 GPR152 GPR153 GPR155
    GPR156 GPR157 GPR158 GPR160 GPR161
    GPR162 GPR165P GPR17 GPR171 GPR172A
    GPR172B GPR173 GPR174 GPR176 GPR179
    GPR18 GPR180 GPR182 GPR183 GPR19
    GPR20 GPR21 GPR22 GPR25 GPR26
    GPR27 GPR3 GPR31 GPR32 GPR34
    GPR35 GPR37 GPR37L1 GPR39 GPR4
    GPR42 GPR44 GPR45 GPR50 GPR52
    GPR55 GPR56 GPR6 GPR61 GPR62
    GPR63 GPR64 GPR65 GPR68 GPR75
    GPR77 GPR78 GPR81 GPR82 GPR82_
    ENST00000302548
    GPR83 GPR84 GPR85 GPR87 GPR88
    GPR89A GPR89B GPR97 GPR98 GPRASP1
    GPRASP2 GPRC5A GPRC5B GPRC5C GPRC5D
    GPRC6A GPRIN1 GPRIN2 GPRIN3 GPS1
    GPS2 GPSM1 GPSM2 GPSM3 GPT
    GPT2 GPX1 GPX2 GPX3 GPX4
    GPX5 GPX6 GPX7 GPX8 GRAMD1A
    GRAMD1B GRAMD1C GRAMD2 GRAMD3 GRAMD4
    GRAP GRAP2 GRASP GRB10 GRB14
    GRB2 GRB7 GREB1 GREB1_ GREM1
    ENST00000381486
    GREM2 GRHL1 GRHL2 GRHL3 GRHPR
    GRIA3_ GRIA4
    GRIA1 GRIA2 GRIA3 ENST00000264357
    GRID1 GRID2 GRIK1 GRIK2 GRIK2_
    ENST00000421544
    GRIK3 GRIK4 GRIK5 GRIN1 GRIN2A
    GRIN2B GRIN2C GRIN2D GRIN3A GRIN3B
    GRINA GRINL1A GRINL1B GRIP1 GRIP2
    GRIPAP1 GRK1 GRK4 GRK5 GRK6
    GRK7 GRLF1 GRM1 GRM2 GRM3
    GRM4 GRM4_ GRM5 GRM6 GRM7
    ENST00000374177
    GRM8 GRN GRP GRPEL1 GRPEL2
    GRPR GRRP1 GRTP1 GRWD1 GRXCR1
    GRXCR2 GSC GSC2 GSDMA GSDMB
    GSDMC GSDMD GSG1 GSG1L GSG2
    GSK3A GSK3B GSN GSPT1 GSPT2
    GSR GSS GSTA1 GSTA2 GSTA3
    GSTA4 GSTA5 GSTCD GSTK1 GSTM1
    GSTM2 GSTM3 GSTM4 GSTM5 GSTO1
    GSTO2 GSTP1 GSTT1 GSTT2 GSTT2B
    GSTZ1 GSX1 GSX2 GTDC1 GTF2A1
    GTF2A2 GTF2B GTF2E1 GTF2E2 GTF2F1
    GTF2F2 GTF2H1 GTF2H2 GTF2H2C GTF2H3
    GTF2H4 GTF2H5 GTF2I GTF2IRD1 GTF2IRD2
    GTF2IRD2B GTF3C1 GTF3C2 GTF3C3 GTF3C4
    GTF3C5 GTF3C6 GTPBP1 GTPBP10 GTPBP2
    GTPBP3 GTPBP4 GTPBP5 GTPBP6 GTPBP8
    GTSE1 GTSF1 GTSF1L GUCA1A GUCA1B
    GUCA1C GUCA2A GUCA2B GUCY1A2 GUCY1A3
    GUCY2C GUCY2D GUCY2F GUF1 GUK1
    GUK1_ GULP1 GUSB GUSL1_ GXYLT1
    ENST00000366719 HUMAN
    GYG1 GYG2 GYLTL1B GYPA GYPB
    GYPC GYS1 GYS2 GZF1 GZMA
    GZMB GZMH GZMK GZMM H19
    H1F0 H1FNT H1FOO H1FX H2AFB1
    H2AFB2 H2AFB3 H2AFJ H2AFV H2AFX
    H2AFY H2AFY2 H2AFZ H2AFZP2 H2BFM
    H2BFVVT H3F3A H3F3B H3F3C H6PD
    HAAO HABP2 HABP4 HACE1 HACL1
    HADH HADHA HADHB HAGH HAGHL
    HAL HAMP NANDI HAND2 HAO1
    HAO2 HAP1 HAPLN1 HAPLN2 HAPLN3
    HAPLN4 HARBI1 HARS HARS2 HAS1
    HAS2 HAS3 HAT1 HAUS1 HAUS2
    HAUS3 HAUS4 HAUS5 HAUS6 HAUS7
    HAUS8 HAVCR1 HAVCR2 HAX1 HBA1
    HBA2 HBB HBD HBE1 HBEGF
    HBG1 HBG2 HBM HBP1 HBQ1
    HBS1L HBXIP HBZ HCCS HCFC1
    HCFC1R1 HCFC2 HCG9 HCK HCLS1
    HCN1 HCN2 HCN3 HCN4 HCP1
    HCP5 HCRT HCRTR1 HCRTR2 HCST
    HDAC1 HDAC10 HDAC11 HDAC2 HDAC3
    HDAC4 HDAC5 HDAC6 HDAC7 HDAC8
    HDAC9 HDC HDDC2 HDDC3 HDGF
    HDGF2 HDGFL1 HDGFRP3 HDHD1A HDHD2
    HDHD3 HDLBP HDX HEATR1 HEATR2
    HEATR3 HEATR4 HEATR5B HEATR6 HEATR7B1
    HEATR7B2 HEBP1 HEBP2 HECA HECTD1
    HECTD2 HECTD3 HECTD3_ HECW1 HECW2
    ENST00000372172
    HEG1 HEJ1 HELB HELLS HELQ
    HELT HELZ HEMGN HEMK1 HEPACAM
    HEPACAM2 HEPH HEPHL1 HERC1 HERC2
    HERC2P3 HERC3 HERC4 HERC5 HERC6
    HERPUD1 HERPUD2 HERV-FRD HES1 HES2
    HES3 HES4 HES5 HES6 HES7
    HESX1 HEXA HEXB HEXDC HEXIM1
    HEXIM2 HEY1 HEY2 HEYL HFE
    HFE2 HFM1 HGD HGF HGFAC
    HGS HGSNAT HGSNAT_ HHAT HHATL
    ENST00000458501
    HHEX HHIP HHIPL1 HHIPL2 HHLA3
    HIAT1 HIATL1 HIATL2 HIBADH HIBCH
    HIC1 HIC2 HIF1A HIF1AN HIF3A
    HIGD1A HIGD1B HIGD2A HIGD2BP HIN1L_
    HUMAN
    HINFP HINT1 HINT2 HINT3 HIP1
    HIP1R HIPK1 HIPK2 HIPK3 HIPK4
    HIRA HIRIP3 HIST1H1A HIST1H1B HIST1H1C
    HIST1H1D HIST1H1E HIST1H1T HIST1H2AA HIST1H2AB
    HIST1H2AC HIST1H2AD HIST1H2AE HIST1H2AG HIST1H2AH
    HIST1H2AI HIST1H2AJ HIST1H2AK HIST1H2AL HIST1H2AM
    HIST1H2BA HIST1H2BB HIST1H2BC HIST1H2BD HIST1H2BE
    HIST1H2BF HIST1H2BG HIST1H2BH HIST1H2BI HIST1H2BJ
    HIST1H2BK HIST1H2BL HIST1H2BM HIST1H2BN HIST1H2BO
    HIST1H3A HIST1H3B HIST1H3C HIST1H3D HIST1H3E
    HIST1H3F HIST1H3G HIST1H3H HIST1H3I HIST1H3J
    HIST1H4A HIST1H4B HIST1H4C HIST1H4D HIST1H4E
    HIST1H4F HIST1H4G HIST1H4H HIST1H4I HIST1H4J
    HIST1H4K HIST1H4L HIST2H2AA3 HIST2H2AA4 HIST2H2AB
    HIST2H2AC HIST2H2BE HIST2H2BF HIST2H3A HIST2H3C
    HIST2H3D HIST2H4A HIST2H4B HIST3H2A HIST3H2BB
    HIST3H3 HIST4H4 HIVEP1 HIVEP2 HIVEP3
    HJURP HK1 HK2 HK3 HKDC1
    HKR1 HLA-A HLA-B HLA-C HLA-DMA
    HLA-DMB HLA-DOA HLA-DOB HLA-DPA1 HLA-DPB1
    HLA-DQA1 HLA-DQA2 HLA-DQB1 HLA-DRA HLA-DRB5
    HLA-E HLA-F HLA-G HLCS HLF
    HLTF HLX HM13 HMBOX1 HMBS
    HMCN1 HMG1L10 HMG20A HMG20B HMGA1
    HMGA2 HMGB1 HMGB1L1 HMGB2 HMGB3
    HMGB4 HMGCL HMGCLL1 HMGCR HMGCS1
    HMGCS2 HMGN1 HMGN2 HMGN3 HMGN4
    HMGN5 HMGXB3 HMGXB4 HMHA1 HMHB1
    HMMR HMOX1 HMOX2 HMP19 HMX2
    HMX3 HN1 HN1L HNF1A HNF1B
    HNF4A HNF4G HNMT HNRNPA0 HNRNPA1
    HNRNPA1L2 HNRNPA2B1 HNRNPA3 HNRNPAB HNRNPC
    HNRNPCL1 HNRNPD HNRNPF HNRNPH1 HNRNPH2
    HNRNPH3 HNRNPK HNRNPL HNRNPM HNRNPR
    HNRNPU HNRNPUL1 HNRNPUL2 HNRPD HNRPDL
    HNRPF HNRPH1 HNRPL HNRPLL HNRPR
    HNRPU HOMER1 HOMER2 HOMER3 HOOK1
    HOOK2 HOOK3 HOPX HORMAD1 HOXA1
    HOXA10 HOXA11 HOXA13 HOXA2 HOXA3
    HOXA4 HOXA5 HOXA6 HOXA7 HOXA9
    HOXB1 HOXB13 HOXB2 HOXB3 HOXB4
    HOXB5 HOXB6 HOXB7 HOXB8 HOXB9
    HOXC10 HOXC11 HOXC12 HOXC13 HOXC4
    HOXC5 HOXC6 HOXC8 HOXC9 HOXD1
    HOXD10 HOXD11 HOXD13 HOXD3 HOXD4
    HOXD8 HOXD9 HP HP1BP3 HPCA
    HPCAL1 HPCAL4 HPD HPDL HPGD
    HPGDS HPN HPR HPRT1 HPS1
    HPS3 HPS4 HPS5 HPS6 HPSE
    HPSE2 HPX HR HRAS HRASLS
    HRASLS2 HRASLS5 HRAS_ HRC HRCT1
    ENST00000397594
    HRG HRH1 HRH2 HRH3 HRH4
    HRK HRNR HRSP12 HS1BP3 HS2ST1
    HS3ST1 HS3ST2 HS3ST3A1 HS3ST3B1 HS3ST4
    HS3ST5 HS6ST1 HS6ST1P HS6ST2 HS6ST3
    HSCB HSD11B1 HSD11B1L HSD11B2 HSD17B1
    HSD17610 HSD17611 HSD17612 HSD17613 HSD17614
    HSD17B2 HSD17B3 HSD17B4 HSD17B6 HSD17B7
    HSD17B8 HSD3B1 HSD3B2 HSD3B7 HSDL1
    HSDL2 HSF1 HSF2 HSF2BP HSF4
    HSF5 HSFX1 HSFY1 HSFY2 HSP90AA1
    HSP90AA2 HSP90AB1 HSP90AB2P HSP90AB6P HSP90B1
    HSPA12A HSPA12B HSPA13 HSPA14 HSPA1A
    HSPA1B HSPA1L HSPA2 HSPA4 HSPA4L
    HSPA5 HSPA6 HSPA8 HSPA9 HSPB1
    HSPB11 HSPB2 HSPB3 HSPB6 HSPB7
    HSPB8 HSPB9 HSPBAP1 HSPBP1 HSPC159
    HSPD1 HSPE1 HSPG2 HSPH1 HTATIP2
    HTATSF1 HTN1 HTN3 HTR1A HTR1B
    HTR1D HTR1E HTR1F HTR2A HTR2B
    HTR2C HTR3A HTR3B HTR3C HTR3D
    HTR3E HTR4 HTR5A HTR6 HTR7
    HTRA1 HTRA2 HTRA3 HTRA4 HTT
    HUMPPA HUNK HUS1 HUS1B HUWE1
    HVCN1 HYAL1 HYAL2 HYAL3 HYAL4
    HYDIN HYI HYLS1 HYOU1 IAH1
    IAPP IARS IARS2 IBSP IBTK
    ICA1 ICA1L ICAM1 ICAM2 ICAM3
    ICAM4 ICAM5 ICK ICMT ICOS
    ICOSLG ICT1 ID1 ID2 ID2B
    ID3 ID4 IDE IDH1 IDH2
    IDH3A IDH3B IDH3G ID11 ID12
    IDO1 IDS IDUA IER2 IER3
    IER3IP1 IER5 IER5L IFFO1 IFI16
    IFI27 IFI27L1 IFI27L2 IFI30 IFI35
    IFI44 IFI44L IFI6 IFIH1 IFIT1
    IFIT1L IFIT2 IFIT3 IFIT5 IFITM2
    IFITM3 IFITM5 IFLTD1 IFNA1 IFNA10
    IFNA13 IFNA14 IFNA16 IFNA17 IFNA2
    IFNA21 IFNA4 IFNA5 IFNA6 IFNA7
    IFNA8 IFNAR1 IFNAR2 IFNB1 IFNE
    IFNG IFNGR1 IFNGR2 IFNK IFNW1
    IFRD1 IFRD2 IFT122 IFT140 IFT172
    IFT20 IFT52 IFT57 IFT74 IFT80
    IFT81 IFT88 IGBP1 IGDCC3 IGDCC4
    IGF1 IGF1R IGF2 IGF2AS IGF2BP1
    IGF2BP2 IGF2BP3 IGF2R IGFALS IGFBP1
    IGFBP2 IGFBP3 IGFBP4 IGFBP5 IGFBP6
    IGFBP7 IGFBPL1 IGFL3 IGFL4 IGFN1
    IGHMBP2 IGHV1OR15-1 IGHV1OR15-5 IGJ IGLL1
    IGLL3 IGSF1 IGSF10 IGSF11 IGSF21
    IGSF22 IGSF3 IGSF5 IGSF6 IGSF8
    IGSF9 IGSF9B IHH IK IKBIP
    IKBKAP IKBKB IKBKE IKBKG IKZF1
    IKZF2 IKZF3 IKZF4 IKZF4_ IKZF5
    ENST00000262032
    IL10 IL10RA IL10RB IL11 IL_11 RA
    IL12A IL12B IL12RB1 IL12RB2 IL13
    IL13RA1 IL13RA2 IL15 IL15RA IL16
    IL17A IL17B IL17C IL17D IL17F
    IL17RA IL17RB IL17RC IL17RD IL17RE
    IL17REL IL18 IL18BP IL18R1 IL18RAP
    IL19 IL_1A IL1B IL1F10 IL1F5
    IL1F6 IL1F7 IL1F8 IL1F9 IL1R1
    IL1R2 IL1RAP IL1RAPL1 IL1RAPL2 IL1RL1
    IL1RL2 IL1 RN IL2 IL20 IL20RA
    IL20RB IL21 IL21 R IL22 IL22RA1
    IL22RA2 IL23A IL23R IL24 IL25
    IL26 IL27 IL27RA IL28A IL28B
    IL28RA IL29 IL2RA IL2RB IL2RG
    IL2RG_ IL3 IL31 IL31RA IL32
    ENST00000374202
    IL33 IL34 IL3RA IL4 IL411
    IL4R IL5 IL5RA IL6 IL6R
    IL6ST IL7 IL7R IL8 IL9
    IL9R ILDR1 ILDR2 ILF2 ILF3
    ILK ILKAP ILK_ ILVBL IMMP1L
    ENST00000299421
    IMMP2L IMMT IMP3 IMP4 IMP5
    IMPA1 IMPA2 IMPACT IMPAD1 IMPDH1
    IMPDH2 IMPG1 IMPG2 INA INADL
    INCA1 INCENP INE1 INF2 INF2_NEW
    ING1 ING2 ING3 ING4 ING5
    INGX INHA INHBA INHBB INHBC
    INHBE INMT INO80 INO80B INO80C
    INO80D INO80E INOC1 INPP1 INPP4A
    INPP4B INPP5A INPP5B INPP5B_ INPP5D
    ENST00000373026
    INPP5E INPP5F INPP5J INPP5K INPPL1
    INS INS-IGF2 INSC INSIG1 INSIG2
    INSL3 INSL4 INSL5 INSL6 INSM1
    INSM2 INSR INSRR INTS10 INTS12
    INTS2 INTS3 INTS4 INTS5 INTS6
    INTS7 INTS8 INTS9 INTU INVS
    IP6K1 IP6K2 IP6K3 IPCEF1 IPMK
    IPO11 IPO13 IPO4 IPO5 IPO7
    IPO8 IPO9 IPP IPPK IQCB1
    IQCC IQCD IQCE IQCF1 IQCF2
    IQCG IQCH IQCK IQGAP1 IQGAP2
    IQGAP3 IQSEC1 IQSEC2 IQSEC3 IQUB
    IRAK1 IRAK1BP1 IRAK2 IRAK3 IRAK4
    IREB2 IRF1 IRF2 IRF2BP1 IRF2BP2
    IRF3 IRF4 IRF5 IRF6 IRF7
    IRF8 IRF9 IRGC IRGQ IRS1
    IRS2 IRS4 IRX1 IRX2 IRX3
    IRX4 IRX5 IRX6 ISCA1 ISCA2
    ISCU ISG15 ISG20 ISG20L2 ISL1
    ISL2 ISLR ISLR2 ISM1 ISM2
    ISOC1 ISOC2 ISX ISY1 ISYNA1
    ITCH ITFG1 ITFG2 ITFG3 ITGA1
    ITGA10 ITGA11 ITGA2 ITGA2B ITGA3
    ITGA4 ITGA5 ITGA6 ITGA7 ITGA8
    ITGA9 ITGAD ITGAE ITGAL ITGAM
    ITGAV ITGAX ITGB1 ITGB1BP1 ITGB1BP2
    ITGB1BP3 ITGB2 ITGB3 ITGB3BP ITGB4
    ITGB5 ITGB6 ITGB7 ITGB8 ITGBL1
    ITIH1 ITIH2 ITIH3 ITIH4 ITIH5
    ITIH5L ITK ITLN1 ITLN2 ITM2A
    ITM2B ITM2C ITPA ITPK1 ITPKA
    ITPKB ITPKC ITPR1 ITPR2 ITPR3
    ITPRIP ITPRIPL1 ITPRIPL2 ITSN1 ITSN2
    IVD IVL IVNS1ABP IWS1 IYD
    IZUMO1 JAG1 JAG2 JAGN1 JAK1
    JAK2 JAK3 JAKMIP1 JAKMIP2 JAKMIP3
    JAM2 JAM3 JARID2 JAZF1 JDP2
    JHDM1D JMJD1C JMJD4 JMJD5 JMJD6
    JMJD7-PLA2G4B JMY JOSD1 JOSD2 JPH1
    JPH2 JPH3 JPH4 JRKL JSRP1
    JTB JUB JUN JUNB JUND
    JUP K0087_ K0401_ KAAG1 KAL1
    HUMAN HUMAN
    KALRN KANK1 KANK2 KANK3 KANK4
    KARCA1 KARS KAT2A KAT2B KAT5
    KATNA1 KATNAL1 KATNAL2 KATNB1 KAZALD1
    KBTBD10 KBTBD11 KBTBD2 KBTBD3 KBTBD4
    KBTBD5 KBTBD6 KBTBD7 KBTBD8 KCNA1
    KCNA10 KCNA2 KCNA3 KCNA4 KCNA5
    KCNA6 KCNA7 KCNAB1 KCNAB2 KCNAB3
    KCNB1 KCNB2 KCNC1 KCNC2 KCNC3
    KCNC4 KCND1 KCND2 KCND3 KCNE1
    KCNE1L KCNE2 KCNE3 KCNE4 KCNF1
    KCNG1 KCNG2 KCNG3 KCNG4 KCNH1
    KCNH2 KCNH3 KCNH4 KCNH5 KCNH6
    KCNH7 KCNH8 KCNIP1 KCNIP2 KCNIP3
    KCNIP4 KCNJ1 KCNJ10 KCNJ11 KCNJ12
    KCNJ13 KCNJ14 KCNJ15 KCNJ16 KCNJ2
    KCNJ3 KCNJ4 KCNJ5 KCNJ6 KCNJ8
    KCNJ9 KCNK1 KCNK10 KCNK12 KCNK13
    KCNK15 KCNK16 KCNK17 KCNK18 KCNK2
    KCNK3 KCNK4 KCNK5 KCNK6 KCNK7
    KCNK9 KCNMA1 KCNMB1 KCNMB2 KCNMB3
    KCNMB4 KCNN1 KCNN1_ KCNN2 KCNN3
    ENST00000222249
    KCNN4 KCNQ1 KCNQ2 KCNQ3 KCNQ4
    KCNQ5 KCNRG KCNS1 KCNS2 KCNS3
    KCNT1 KCNT2 KCNV1 KCNV2 KCP
    KCTD1 KCTD10 KCTD11 KCTD12 KCTD13
    KCTD14 KCTD15 KCTD16 KCTD17 KCTD18
    KCTD19 KCTD2 KCTD20 KCTD21 KCTD3
    KCTD4 KCTD5 KCTD6 KCTD7 KCTD8
    KCTD9 KCTD9L KDELC1 KDELC2 KDELR1
    KDELR2 KDELR3 KDM1A KDM1B KDM2A
    KDM2B KDM3A KDM3B KDM4A KDM4B
    KDM4C KDM4D KDM5A KDM5B KDM5C
    KDM5D KDM6A KDM6B KDR KDSR
    KEAP1 KEL KERA KHDC1 KHDRBS1
    KHDRBS2 KHDRBS3 KHK KHNYN KHSRP
    KIAA0020 KIAA0090 KIAA0100 KIAA0101 KIAA0141
    KIAA0146 KIAA0174 KIAA0182 KIAA0195 KIAA0196
    KIAA0226 KIAA0226_ KIAA0232 KIAA0240 KIAA0247
    ENST00000273582
    KIAA0284 KIAA0317 KIAA0319 KIAA0319L KIAA0355
    KIAA0368 KIAA0391 KIAA0406 KIAA0408 KIAA0415
    KIAA0415_ KIAA0427 KIAA0430 KIAA0467 KIAA0467_
    ENST00000450194 ENST00000372442
    KIAA0494 KIAA0513 KIAA0528 KIAA0556 KIAA0562
    KIAA0564 KIAA0649 KIAA0664 KIAA0664_ KIAA0672
    ENST00000322335
    KIAA0701 KIAA0746 KIAA0748 KIAA0753 KIAA0776
    KIAA0802 KIAA0831 KIAA0892 KIAA0895 KIAA0895L
    KIAA0895_ KIAA0907 KIAA0913 KIAA0922 KIAA0947
    ENST00000338533
    KIAA0953 KIAA1009 KIAA1012 KIAA1024 KIAA1033
    KIAA1045 KIAA1109 KIAA1143 KIAA1147 KIAA1161
    KIAA1191 KIAA1199 KIAA1210 KIAA1211 KIAA1217
    KIAA1244 KIAA1267 KIAA1274 KIAA1279 KIAA1324
    KIAA1324L KIAA1328 KIAA1377 KIAA1404 KIAA1407
    KIAA1409 KIAA1429 KIAA1430 KIAA1432 KIAA1443
    KIAA1462 KIAA1467 KIAA1468 KIAA1486 KIAA1509
    KIAA1522 KIAA1524 KIAA1529 KIAA1530 KIAA1539
    KIAA1542 KIAA1543 KIAA1549 KIAA1586 KIAA1598
    KIAA1609 KIAA1614 KIAA1618 KIAA1632 KIAA1644
    KIAA1671 KIAA1683 KIAA1688 KIAA1704 KIAA1712
    KIAA1715 KIAA1737 KIAA1751 KIAA1755 KIAA1772
    KIAA1797 KIAA1804 KIAA1826 KIAA1841 KIAA1853
    KIAA1875 KIAA1913 KIAA1919 KIAA1949 KIAA1958
    KIAA1967 KIAA1984 KIAA2013 KIAA2018 KIAA2022
    KIAA2026 KIDINS220 KIF11 KIF12 KIF13A
    KIF13B KIF14 KIF15 KIF16B KIF17
    KIF18A KIF18B KIF19 KIF1A KIF1B
    KIF1C KIF20A KIF20B KIF21A KIF21B
    KIF22 KIF23 KIF25 KIF27 KIF2A
    KIF2B KIF2C KIF3A KIF3B KIF3C
    KIF4A KIF5A KIF5B KIF5C KIF6
    KIF7 KIF9 KIFAP3 KIFC1 KIFC2
    KIFC3 KIN KIR2DL1 KIR2DL3 KIR2DL4
    KIR2DS4 KIR3DL1 KIR3DL2 KIR3DL3 KIR3DX1
    KIRREL KIRREL2 KIRREL3 KISS1 KISS1R
    KIT KITLG KL KLB KLC1
    KLC2 KLC3 KLC4 KLF1 KLF10
    KLF11 KLF12 KLF13 KLF14 KLF15
    KLF16 KLF17 KLF2 KLF3 KLF4
    KLF5 KLF6 KLF7 KLF8 KLF9
    KLHDC1 KLHDC10 KLHDC2 KLHDC3 KLHDC4
    KLHDC5 KLHDC6 KLHDC7A KLHDC7B KLHDC8A
    KLHDC8B KLHDC9 KLHL1 KLHL10 KLHL11
    KLHL12 KLHL13 KLHL14 KLHL15 KLHL17
    KLHL18 KLHL2 KLHL20 KLHL21 KLHL22
    KLHL23 KLHL24 KLHL25 KLHL26 KLHL28
    KLHL29 KLHL3 KLHL31 KLHL32 KLHL34
    KLHL36 KLHL38 KLHL4 KLHL5 KLHL6
    KLHL7 KLHL8 KLHL9 KLK1 KLK10
    KLK11 KLK12 KLK13 KLK14 KLK15
    KLK2 KLK3 KLK4 KLK5 KLK6
    KLK7 KLK8 KLK9 KLKB1 KLRA1
    KLRB1 KLRC1 KLRC2 KLRC3 KLRC4
    KLRD1 KLRF1 KLRG1 KLRG2 KLRK1
    KMO KNDC1 KNG1 KNTC1 KPNA1
    KPNA2 KPNA3 KPNA4 KPNA5 KPNA6
    KPNA7 KPNB1 KPRP KPTN KRAS
    KRBA1 KRBA2 KRCC1 KREMEN1 KREMEN2
    KRI1 KRIT1 KRR1 KRT1 KRT10
    KRT12 KRT13 KRT14 KRT15 KRT16
    KRT17 KRT18 KRT19 KRT2 KRT20
    KRT222 KRT23 KRT24 KRT25 KRT26
    KRT27 KRT28 KRT3 KRT31 KRT32
    KRT33A KRT33B KRT34 KRT35 KRT36
    KRT37 KRT38 KRT39 KRT4 KRT40
    KRT5 KRT6A KRT6B KRT6C KRT7
    KRT71 KRT72 KRT73 KRT74 KRT75
    KRT76 KRT77 KRT78 KRT79 KRT8
    KRT80 KRT81 KRT82 KRT83 KRT84
    KRT85 KRT86 KRT9 KRTAP1-1 KRTAP1-3
    KRTAP10-1 KRTAP10-10 KRTAP10-11 KRTAP10-12 KRTAP10-2
    KRTAP10-3 KRTAP10-4 KRTAP10-5 KRTAP10-6 KRTAP10-8
    KRTAP11-1 KRTAP12-1 KRTAP12-3 KRTAP12-4 KRTAP13-1
    KRTAP13-2 KRTAP13-3 KRTAP13-4 KRTAP15-1 KRTAP17-1
    KRTAP19-1 KRTAP19-2 KRTAP19-3 KRTAP19-4 KRTAP19-5
    KRTAP19-6 KRTAP19-7 KRTAP19-8 KRTAP2-1 KRTAP2-4
    KRTAP20-1 KRTAP20-2 KRTAP21-1 KRTAP21-2 KRTAP22-1
    KRTAP23-1 KRTAP24-1 KRTAP26-1 KRTAP27-1 KRTAP3-1
    KRTAP3-2 KRTAP3-3 KRTAP4-12 KRTAP4-2 KRTAP4-3
    KRTAP4-4 KRTAP4-5 KRTAP5-1 KRTAP5-10 KRTAP5-11
    KRTAP5-2 KRTAP5-3 KRTAP5-5 KRTAP5-6 KRTAP5-7
    KRTAP5-8 KRTAP6-1 KRTAP6-2 KRTAP8-1 KRTAP9-2
    KRTAP9-3 KRTAP9-4 KRTAP9-8 KRTAP9L2 KRTCAP2
    KRTCAP3 KRTDAP KSR1 KSR2 KTELC1
    KTI12 KTN1 KYNU KlkbI4 L1CAM
    L1TD1 L2HGDH L3MBTL L3MBTL2 L3MBTL3
    L3MBTL4 LACE1 LACRT LACTB LACTB2
    LAD1 LAG3 LAGE3 LAIR1 LAIR2
    LALBA LAMA1 LAMA2 LAMA3 LAMA4
    LAMA5 LAMB1 LAMB2 LAMB3 LAMB4
    LAMC1 LAMC2 LAMC3 LAMP1 LAMP2
    LAMP3 LANCL1 LANCL2 LANCL3 LAP3
    LAPTM4A LAPTM4B LAPTM5 LARGE LARP1
    LARP1B LARP4 LARP4B LARP6 LARP7
    LARS LARS2 LAS1L LASP1 LASS1
    LASS2 LASS3 LASS4 LASS5 LASS6
    LAT LAT2 LATS1 LATS2 LAX1
    LAYN LBH LBP LBR LBX1
    LBX2 LBXCOR1 LCA5 LCA5L LCAP
    LCAT LCE1A LCE1B LCE1C LCE1D
    LCE1E LCEIF LCE2A LCE2B LCE2C
    LCE2D LCE3A LCE3B LCE3C LCE3D
    LCE3E LCE4A LCE5A LCK LCLAT1
    LCMT1 LCMT2 LCN1 LCN10 LCN12
    LCN15 LCN2 LCN6 LCN8 LCN9
    LCOR LCORL LCP1 LCT LCTL
    LDB1 LDB2 LDB3 LDHA LDHAL6A
    LDHAL6B LDHB LDHC LDHD LDLR
    LDLRAD1 LDLRAD2 LDLRAD3 LDLRAP1 LDOC1
    LDOC1L LEAP2 LECT1 LECT2 LEF1
    LEFTY1 LEFTY2 LEKR1 LELP1 LEMD1
    LEMD2 LEMD3 LENEP LENG1 LENG8
    LENG9 LEO1 LEP LEPR LEPRE1
    LEPREL1 LEPREL2 LEPROT LEPROTL1 LETM1
    LETM2 LETMD1 LFNG LGALS1 LGALS12
    LGALS13 LGALS14 LGALS2 LGALS3 LGALS3BP
    LGALS4 LGALS7 LGALS8 LGALS9 LGALS9B
    LGALS9C LGI1 LGI2 LGI3 LGI4
    LGMN LGR4 LGR5 LGR6 LGSN
    LGTN LHB LHCGR LHFP LHFPL1
    LHFPL2 LHFPL4 LHFPL5 LHPP LHX1
    LHX2 LHX3 LHX4 LHX5 LHX6
    LHX8 LHX9 LIAS LIF LIFR
    LIG1 LIG3 LIG4 LILRA1 LILRA2
    LILRA3 LILRA4 LILRA5 LILRA6 LILRB1
    LILRB2 LILRB3 LILRB4 LILRB5 LIM2
    LIMA1 LIMCH1 LIMD1 LIMD2 LIME1
    LIMK1 LIMK2 LIMS1 LIMS2 LIMS3
    LIN28 LIN28B LIN52 LIN54 LIN7A
    LIN7B LIN7C LIN9 LINGO1 LINGO2
    LINGO4 LINS1 LIPA LIPC LIPE
    LIPF LIPG LIPH LIPI LIPJ
    LIPM LIPT1 LIPT2 LITAF LIX1
    LL0XNC01- LL0XNC01-
    LIX1L 209G1_2 237H1_1 LLGL1 LLGL2
    LLPH LMAN1 LMAN1L LMAN2 LMAN2L
    LMBR1 LMBR1L LMBRD1 LMBRD2 LMCD1
    LMF1 LMF2 LMLN LMNA LMNB1
    LMNB2 LMO1 LMO2 LMO3 LMO4
    LMO7 LMOD1 LMOD2 LMTK2 LMTK3
    LMX1A LMX1B LNP1 LNPEP LNX1
    LNX2 LOC114984 LOC120364 LOC133308 LOC139116
    LOC139249 LOC139263 LOC139431 LOC139516 LOC139542
    LOC145814 LOC148213 LOC152485 LOC153328 LOC157567
    LOC158572 LOC158730 LOC158825 LOC158957 LOC165186
    LOC168850 LOC200420 LOC203510 LOC203604 LOC220686
    LOC223075 LOC257106 LOC283232 LOC283398 LOC283412
    LOC283849 LOC284023 LOC284100 LOC284288 LOC286404
    LOC286408 LOC286411 LOC286467 LOC286478 LOC286512
    LOC286528 LOC339123 LOC340096 LOC340549 LOC340571
    LOC340578 LOC340581 LOC341457 LOC342541 LOC344165
    LOC345630 LOC347376 LOC347381 LOC347411 LOC347421
    LOC347424 LOC347549 LOC349136 LOC387867 LOC388972
    LOC389669 LOC389841 LOC389842 LOC389846 LOC389848
    LOC389858 LOC389873 LOC389888 LOC389895 LOC389899
    LOC389900 LOC389901 LOC389904 LOC390335 LOC390956
    LOC391370 LOC392434 LOC392439 LOC392459 LOC392467
    LOC392473 LOC392487 LOC392512 LOC392528 LOC392529
    LOC392531 LOC392533 LOC392539 LOC392546 LOC392549
    LOC392554 LOC392556 LOC392559 LOC401052 LOC401584
    LOC401588 LOC401599 LOC401605 LOC401611 LOC401613
    LOC401616 LOC401621 LOC402120 LOC402414 LOC402418
    LOC439951 LOC440055 LOC440345 LOC440354 LOC440917
    LOC440925 LOC440944 LOC441344 LOC441480 LOC441481
    LOC441483 LOC441485 LOC441486 LOC441488 LOC441493
    LOC441494 LOC441496 LOC441497 LOC441498 LOC441499
    LOC441504 LOC441507 LOC441510 LOC441511 LOC441513
    LOC441515 LOC441526 LOC441795 LOC442425 LOC442439
    LOC442444 LOC442447 LOC442451 LOC442452 LOC442454
    LOC442456 LOC442461 LOC442464 LOC442465 LOC442466
    LOC442470 LOC493829 LOC51058 LOC51059 LOC51123
    LOC51321 LOC541473 LOC55954 LOC56901 LOC57149
    LOC642755 LOC643751 LOC645864 LOC646049 LOC646625
    LOC646853 LOC646870 LOC646871 LOC649445 LOC649587
    LOC649618 LOC649930 LOC650875 LOC65121 LOC651271
    LOC651503 LOC651746 LOC652153 LOC652737 LOC653192
    LOC653698 LOC653720 LOC728194 LOC728350 LOC728378
    LOC729903 LOC730029 LOC730445 LOC730735 LOC731028
    LOC731173 LOC731740 LOC731796 LOC731890 LOC81691
    LOC88523 LOC91461 LOC91807 LOC92249 LOC93081
    LOH12CR1 LONP1 LONP2 LONRF1 LONRF2
    LONRF3 LOR LOX LOXL1 LOXL2
    LOXL3 LOXL4 LPA LPAL2 LPAR1
    LPAR2 LPAR3 LPAR4 LPAR5 LPAR6
    LPCAT1 LPCAT2 LPCAT3 LPCAT4 LPGAT1
    LPHN1 LPHN2 LPHN3 LPIN1 LPIN2
    LPIN3 LPL LPO LPP LPPR2
    LPPR4 LPXN LRAT LRBA LRCH1
    LRCH2 LRCH3 LRCH4 LRDD LRFN1
    LRFN2 LRFN3 LRFN4 LRFN5 LRG1
    LRGUK LRIG1 LRIG2 LRIG3 LRIT1
    LRIT2 LRIT3 LRMP LRP1 LRP10
    LRP11 LRP12 LRP1B LRP2 LRP2BP
    LRP3 LRP4 LRP5 LRP5L LRP6
    LRP8 LRPAP1 LRPPRC LRRC1 LRRC10
    LRRC14 LRRC14B LRRC15 LRRC16A LRRC16B
    LRRC17 LRRC18 LRRC19 LRRC2 LRRC20
    LRRC23 LRRC24 LRRC25 LRRC26 LRRC27
    LRRC28 LRRC29 LRRC3 LRRC30 LRRC31
    LRRC32 LRRC33 LRRC34 LRRC36 LRRC37A
    LRRC37A2 LRRC37A3 LRRC37B LRRC39 LRRC3B
    LRRC4 LRRC40 LRRC41 LRRC42 LRRC43
    LRRC45 LRRC46 LRRC47 LRRC49 LRRC4B
    LRRC4C LRRC50 LRRC52 LRRC55 LRRC56
    LRRC57 LRRC59 LRRC6 LRRC61 LRRC66
    LRRC67 LRRC68 LRRC7 LRRC8A LRRC8B
    LRRC8C LRRC8D LRRC8E LRRCC1 LRRFIP1
    LRRFIP1_ LRRFIP2 LRRIQ1 LRRIQ3 LRRK1
    ENST00000392000
    LRRK2 LRRK2_ LRRN1 LRRN2 LRRN3
    ENST00000298910
    LRRN4 LRRN4CL LRRTM1 LRRTM3 LRRTM4
    LRSAM1 LRTM1 LRTM2 LRTOMT LRWD1
    LSAMP LSG1 LSM1 LSM10 LSM11
    LSM12 LSM14A LSM14B LSM2 LSM3
    LSM4 LSM5 LSM6 LSMD1 LSP1
    LSR LSS LST1 LTA LTA4H
    LTB LTB4R LTB4R2 LTBP1 LTBP2
    LTBP3 LTBP4 LTBR LTC4S LTF
    LTK LTV1 LUC7L LUC7L2 LUC7L3
    LUM LUZP1 LUZP2 LUZP4 LXN
    LY6D LY6E LY6G5B LY6G5C LY6G6C
    LY6G6D LY6G6F LY6H LY6K LY75
    LY86 LY9 LY96 LYAR LYG1
    LYG2 LYL1 LYN LYNX1 LYNX1_
    ENST00000317543
    LYPD1 LYPD2 LYPD3 LYPD4 LYPD5
    LYPD6 LYPLA1 LYPLA2 LYPLAL1 LYRM1
    LYRM2 LYRM4 LYRM5 LYRM7 LYSMD1
    LYSMD2 LYSMD3 LYSMD4 LYST LYVE1
    LYZ LYZL1 LYZL2 LYZL4 LYZL6
    LZIC LZTFL1 LZTR1 LZTS1 LZTS2
    M6PR MAB21L1 MAB21L2 MACC1 MACF1
    MACF1_ MACROD1 MACROD2 MAD1L1 MAD2L1
    ENST00000361689
    MAD2L1BP MAD2L2 MADCAM1 MADD MAEA
    MAEL MAF MAF1 MAFA MAFB
    MAFF MAFG MAFK MAG MAGEA1
    MAGEA10 MAGEA11 MAGEA12 MAGEA13P MAGEA2
    MAGEA2B MAGEA3 MAGEA4 MAGEA5 MAGEA6
    MAGEA8 MAGEA9 MAGEA9B MAGEB1 MAGEB10
    MAGEB16 MAGEB17 MAGEB18 MAGEB2 MAGEB3
    MAGEB4 MAGEB5 MAGEB6 MAGEB6B MAGEC1
    MAGEC2 MAGEC3 MAGED1 MAGED2 MAGED4B
    MAGEE1 MAGEE2 MAGEF1 MAGEH1 MAGI1
    MAGI1_ MAGI2 MAGI3 MAGIX MAGOH
    ENST00000402939
    MAGOHB MAGT1 MAK MAK16 MAL
    MALL MALT1 MAMDC2 MAMDC4 MAML1
    MAML2 MAMLD1 MAMSTR MAN1A1 MAN1A2
    MAN1B1 MAN1C1 MAN2A1 MAN2A2 MAN2B1
    MAN2B2 MAN2C1 MANBA MANBAL MANEA
    MANEAL MANSC1 MAOA MAOB MAP1A
    MAP1B MAP1D MAP1LC3A MAP1LC3B MAP1LC3B2
    MAP1LC3C MAP1S MAP2 MAP2K1 MAP2K2
    MAP2K3 MAP2K4 MAP2K5 MAP2K6 MAP2K7
    MAP3K1 MAP3K10 MAP3K11 MAP3K12 MAP3K13
    MAP3K14 MAP3K15 MAP3K2 MAP3K3 MAP3K4
    MAP3K5 MAP3K6 MAP3K6_ MAP3K7 MAP3K8
    ENST00000374040
    MAP3K9 MAP4 MAP4K1 MAP4K2 MAP4K3
    MAP4K4 MAP4K5 MAP6 MAP6D1 MAP7
    MAP7D1 MAP7D2 MAP7D3 MAP9 MAPK1
    MAPK10 MAPK11 MAPK12 MAPK13 MAPK14
    MAPK15 MAPK1IP1L MAPK3 MAPK4 MAPK6
    MAPK7 MAPK8 MAPK8IP1 MAPK8IP2 MAPK8IP3
    MAPK9 MAPKAP1 MAPKAPK2 MAPKAPK3 MAPKAPK5
    MAPKBP1 MAPKSP1 MAPRE1 MAPRE2 MAPRE3
    MAPT 01-Mar 10-Mar 02-Mar 03-Mar
    04-Mar 05-Mar 06-Mar 07-Mar 08-Mar
    09-Mar MARCKS MARCKSL1 MARCO MARK1
    MARK2 MARK3 MARK4 MARS MARS2
    MARVELD2 MARVELD3 MAS1 MAS1L MASP1
    MASP2 MAST1 MAST2 MAST2_ MAST3
    ENST00000361297
    MAST4 MASTL MAT1A MAT2A MAT2B
    MATK MATN1 MATN4 MATR3 MAVS
    MAX MAZ MB MB3L2_ MBD1
    HUMAN
    MBD2 MBD3 MBD3L1 MBD3L2 MBD4
    MBD5 MBD6 MBIP MBL2 MBLAC1
    MBLAC2 MBNL1 MBNL1 _ MBNL2 MBNL3
    ENST00000282488
    MBOAT1 MBOAT2 MBOAT4 MBOAT7 MBP
    MBTD1 MBTPS1 MBTPS2 MC2R MC3R
    MC4R MC5R MCAM MCART1 MCART2
    MCART6 MCAT MCC MCCC1 MCCC2
    MCCD1 MCC_ MCEE MCF2 MCF2L
    ENST00000408903
    MCF2L2 MCFD2 MCHR1 MCHR2 MCL1
    MCM10 MCM2 MCM3 MCM3AP MCM4
    MCM5 MCM6 MCM7 MCM8 MCM9
    MCOLN1 MCOLN2 MCOLN3 MCPH1 MCRS1
    MCTP1 MCTP2 MCTS1 MDC1 MDFI
    MDFIC MDGA1 MDGA2 MDH1 MDH1B
    MDH2 MDK MDM1 MDM2 MDM4
    MDN1 MDP1 MDS1 MDS2 ME1
    ME2 ME3 MEA1 MEAF6 MECOM
    MECP2 MECR MED1 MED10 MED11
    MED12 MED12L MED13 MED13L MED14
    MED15 MED16 MED17 MED18 MED19
    MED20 MED21 MED22 MED23 MED24
    MED25 MED26 MED27 MED28 MED29
    MED30 MED31 MED4 MED6 MED7
    MED8 MED9 MEF2B MEF2C MEF2D
    MEFV MEGF10 MEGF11 MEGF6 MEI1
    MEIG1 MEIS1 MEIS2 MEIS3 MELK
    MEM01 MEMO1P MEN1 MEOX1 MEOX2
    MEP1A MEP1B MEPCE MEPE MERTK
    MESDC1 MESDC2 MESP1 MESP2 MEST
    MET METAP2 METRN METRNL METT10D
    METT11D1 METT5D1 METTL1 METTL10 METTL11A
    METTL12 METTL13 METTL14 METTL2A METTL2B
    METTL3 METTL4 METTL5 METTL6 METTL7A
    METTL7B METTL8 METTL9 MEX3A MEX3B
    MEX3C MEX3D MFAP1 MFAP2 MFAP3
    MFAP3L MFAP4 MFAP5 MFF MFGE8
    MFHAS1 MFI2 MFN1 MFN2 MFNG
    MFRP MFSD1 MFSD10 MFSD11 MFSD2A
    MFSD3 MFSD4 MFSD5 MFSD6 MFSD6L
    MFSD7 MFSD8 MFSD9 MGA MGAM
    MGAM_ MGAT1 MGAT2 MGAT3 MGAT4A
    ENST00000473011
    MGAT4B MGAT4C MGAT5 MGAT5B MGC15476
    MGC17624 MGC33414 MGC33530 MGC42105 MGC57359
    MGC99813 MGEA5 MGLL MGMT MGP
    MGRN1 MGST1 MGST2 MGST3 MIA
    MIA2 MIA3 MIB1 MIB2 MICA3_
    HUMAN
    MICAL1 MICAL2 MICAL3 MICALCL MICALL1
    MICALL2 MICB MIDI MID1IP1 MID2
    MIDN MIER1 MIER2 MIER3 MIF
    MIF4GD MIIP MINA MINK1 MINPP1
    MIOS MIOX MIP MIPEP MIPOL1
    MIS12 MITD1 MITF MIXL1 MKI67
    MKI67IP MKKS MKL1 MKL2 MKLN1
    MKNK1 MKNK2 MKNK2_ MKRN1 MKRN2
    ENST00000250896
    MKRN3 MKRN4P MKS1 MKX MLANA
    MLC1 MLEC MLF1 MLF1IP MLF2
    MLH1 MLH3 MLKL MLL MLL2
    MLL3 MLL4 MLL5 MLLT1 MLLT10
    MLLT11 MLLT3 MLLT4 MLLT6 MLN
    MLNR MLPH MLST8 MLST8_ MLX
    ENST00000301724
    MLXIP MLXIPL MLYCD MMAA MMAB
    MMACHC MMADHC MMD MMD2 MME
    MMEL1 MMGT1 MMP1 MMP10 MMP11
    MMP12 MMP13 MMP14 MMP15 MMP16
    MMP17 MMP19 MMP2 MMP20 MMP21
    MMP23B MMP25 MMP26 MMP27 MMP28
    MMP3 MMP7 MMP8 MMP9 MMPL1
    MMRN1 MMRN2 MN1 MNAT1 MND1
    MNDA MNS1 MNT MNX1 MOAP1
    MOBKL1A MOBKL1B MOBKL2A MOBKL2B MOBKL2C
    MOBKL3 MOBP MOCOS MOCS1 MOCS2
    MOCS3 MOG MOGAT1 MOGAT2 MOGAT3
    MOGS MON1A MON1B MON2 MORC1
    MORC2 MORC3 MORC4 MORF4L1 MORF4L2
    MORN1 MORN3 MORN4 MORN5 MOS
    MOSC1 MOSC2 MOSPD1 MOSPD2 MOSPD3
    MOV10 MOV10L1 MOXD1 MOXD1_ MPDU1
    ENST00000336749
    MPDZ MPEG1 MPG MPHOSPH10 MPHOSPH6
    MPHOSPH8 MPHOSPH9 MPI MPL MPND
    MPO MPP1 MPP2 MPP3 MPP4
    MPP5 MPP6 MPP7 MPPE1 MPPED2
    MPRIP MPST MPV17 MPV17L MPV17L2
    MPZ MPZL1 MPZL2 MPZL3 MR1
    MRAP MRAP2 MRAS MRC1 MRC1L1
    MRC2 MRE11A MREG MRFAP1 MRFAP1L1
    MRGPRD MRGPRE MRGPRF MRGPRG MRGPRX1
    MRGPRX2 MRGPRX3 MRGPRX4 MRI1 MRM1
    MRO MRP63 MRPL1 MRPL10 MRPL11
    MRPL12 MRPL13 MRPL14 MRPL15 MRPL16
    MRPL17 MRPL18 MRPL19 MRPL2 MRPL20
    MRPL21 MRPL22 MRPL23 MRPL24 MRPL27
    MRPL28 MRPL3 MRPL30 MRPL32 MRPL33
    MRPL34 MRPL35 MRPL36 MRPL37 MRPL39
    MRPL4 MRPL40 MRPL41 MRPL42 MRPL43
    MRPL44 MRPL45 MRPL46 MRPL47 MRPL49
    MRPL50 MRPL51 MRPL52 MRPL53 MRPL54
    MRPL55 MRPL9 MRPS10 MRPS11 MRPS12
    MRPS14 MRPS15 MRPS16 MRPS17 MRPS18A
    MRPS18B MRPS18C MRPS2 MRPS21 MRPS22
    MRPS23 MRPS24 MRPS25 MRPS26 MRPS27
    MRPS28 MRPS30 MRPS31 MRPS33 MRPS34
    MRPS35 MRPS36 MRPS5 MRPS6 MRPS7
    MRPS9 MRRF MRRFP1 MRS2 MRTO4
    MRVI1 MS4A1 MS4A10 MS4A12 MS4A13
    MS4A14 MS4A15 MS4A2 MS4A3 MS4A4A
    MS4A5 MS4A6A MS4A6E MS4A7 MS4A8B
    MSC MSGN1 MSH2 MSH3 MSH4
    MSH5 MSH6 MSI1 MSI2 MSL1
    MSL2 MSL3 MSLN MSLNL MSMB
    MSMP MSN MSR1 MSRA MSRB2
    MSRB3 MST1 MST1R MST4 MSTN
    MSTO1 MSX1 MSX2 MT1A MT1B
    MT1E MT1F MT1G MT1H MT1M
    MT1P2 MT1X MT2A MT3 MT4
    MTA1 MTA2 MTAC2D1 MTAP MTBP
    MTCH1 MTCH2 MTCP1 MTDH MTERF
    MTERFD1 MTERFD2 MTERFD3 MTF1 MTF2
    MTFR1 MTG1 MTHFD1 MTHFD1L MTHFD2
    MTHFD2L MTHFR MTHFS MTHFSD MTIF2
    MTIF3 MTL5 MTM1 MTMR1 MTMR10
    MTMR11 MTMR12 MTMR14 MTMR15 MTMR2
    MTMR3 MTMR3_ MTMR4 MTMR6 MTMR7
    ENST00000401950
    MTMR8 MTMR9 MTNR1A MTNR1B MTO1
    MTOR MTP18 MTPAP MTPN MTR
    MTRF1 MTRF1L MTRR MTSS1 MTTP
    MTUS1 MTUS2 MTUS2_ MTX1 MTX2
    ENST00000431530
    MUC1 MUC13 MUC15 MUC16 MUC16_
    ENST00000331986
    MUC17 MUC2 MUC21 MUC4 MUC4_
    ENST00000405167
    MUC5AC MUC7 MUCL1 MUDENG MUL1
    MUM1 MUM1L1 MURC MUS81 MUSK
    MUT MUTED MUTYH MVD MVK
    MVP MX1 MX2 MXD1 MXD3
    MXD4 MXI1 MXRA5 MXRA7 MXRA8
    MYADM MYADML2 MYB MYBBP1A MYBL1
    MYBL2 MYBPC1 MYBPC2 MYBPC3 MYBPH
    MYBPHL MYB_ MYC MYCBP MYCBP2
    ENST00000341911
    MYCBPAP MYCL1 MYCL1_ MYCL2 MYCN
    ENST00000397332
    MYCT1 MYD88 MYEF2 MYEOV MYEOV2
    MYF5 MYF6 MYH1 MYH10 MYH11
    MYH14 MYH15 MYH16 MYH2 MYH3
    MYH4 MYH6 MYH7 MYH7B MYH8
    MYH9 MYL1 MYL10 MYL12A MYL12B
    MYL2 MYL3 MYL4 MYL5 MYL6
    MYL6B MYL7 MYL9 MYLIP MYLK
    MYLK2 MYLK3 MYLK4 MYLPF MYNN
    MYO10 MYO15A MYO16 MYO18A MYO18B
    MYO1A MYO1B MYO1C MYO1D MYO1E
    MYO1F MYO1G MYO3A MYO3B MYO5A
    MYO5B MYO5C MYO6 MYO7A MYO9A
    MYO9B MYO9B_ MYOC MYOCD MYOD1
    ENST00000319396
    MYOF MYOG MYOHD1 MYOM1 MYOM2
    MYOM3 MYOT MYOZ1 MYOZ2 MYOZ3
    MYPN MYPOP MYRIP MYSM1 MYST1
    MYST2 MYST3 MYST4 MYT1 MYT1L
    MZF1 Magmas N4BP1 N4BP2 N4BP2L1
    N4BP2L2 N4BP3 N6AMT1 N6AMT2 NAA10
    NAA15 NAA16 NAA20 NAA25 NAA30
    NAA35 NAA38 NAA40 NAA50 NAAA
    NAALAD2 NAALADL1 NAB1 NAB2 NACA
    NACA2 NACA3P NACC1 NACC2 NADK
    NADSYN1 NAE1 NAF1 NAG6 NAGA
    NAGK NAGLU NAGPA NAGS NAIF1
    NAIP NALCN NALP6 NAMPT NANOG
    NANOGP1 NANOS1 NANOS2 NANOS3 NANP
    NANS NAP1L1 NAP1L2 NAP1L3 NAP1L4
    NAP1L5 NAP1L6 NAPA NAPB NAPEPLD
    NAPRT1 NAPSA NAPSB NARF NARFL
    NARG2 NARS NARS2 NASP NAT1
    NAT10 NAT14 NAT2 NAT6 NAT8
    NAT8L NAT9 NAV1 NAV2 NAV3
    NBAS NBEA NBEAL1 NBEAL1_ NBEAL2
    ENST00000449802
    NBL1 NBN NBPF11 NBPF14 NBPF15
    NBPF16 NBPF3 NBPF5 NBPF7 NBR1
    NCALD NCAM2 NCAN NCAPD2 NCAPD3
    NCAPG NCAPG2 NCAPH NCAPH2 NCBP1
    NCBP2 NCBP2L NCCRP1 NCDN NCEH1
    NCF1 NCF2 NCF4 NCK1 NCK2
    NCKAP1 NCKAP1L NCKAP5L NCKAP5_ NCKIPSD
    ENST00000405974
    NCL NCLN NCOA1 NCOA2 NCOA3
    NCOA4 NCOA5 NCOA6 NCOA7 NCOR1
    NCOR2 NCR1 NCR2 NCR3 NCRNA00086
    NCRNA00103 NCRNA00105 NCRNA00169 NCRNA00174 NCRNA00175
    NCRNA00176 NCRNA00188 NCS1 NCSTN ND4
    NDC80 NDE1 NDEL1 NDFIP1 NDFIP2
    NDN NDNL2 NDOR1 NDP NDRG1
    NDRG2 NDRG3 NDRG4 NDST1 NDST2
    NDST3 NDST4 NDUFA1 NDUFA10 NDUFA11
    NDUFA12 NDUFA13 NDUFA2 NDUFA3 NDUFA4
    NDUFA4L2 NDUFA5 NDUFA6 NDUFA7 NDUFA8
    NDUFA9 NDUFAB1 NDUFAF1 NDUFAF2 NDUFAF3
    NDUFAF4 NDUFB1 NDUFB10 NDUFB11 NDUFB2
    NDUFB3 NDUFB4 NDUFB5 NDUFB6 NDUFB7
    NDUFB8 NDUFB9 NDUFC1 NDUFC2 NDUFS1
    NDUFS2 NDUFS3 NDUFS4 NDUFS5 NDUFS6
    NDUFS7 NDUFS8 NDUFV1 NDUFV2 NDUFV3
    NEB NEBL NECAB1 NECAB2 NECAB3
    NECAP1 NECAP2 NEDD1 NEDD4 NEDD4L
    NEDD8 NEDD9 NEFH NEFL NEFM
    NEGR1 NEIL1 NEIL2 NEIL3 NEK1
    NEK10 NEK11 NEK2 NEK3 NEK4
    NEK5 NEK6 NEK7 NEK8 NEK9
    NELF NELL1 NELL2 NENF NEO1
    NES NET1 NETO1 NETO2 NEU1
    NEU2 NEU4 NEURL NEURL2 NEURL3
    NEURL4 NEURL4_ NEUROD1 NEUROD2 NEUROD4
    ENST00000315614
    NEUROD6 NEUROG1 NEUROG2 NEUROG3 NEXN
    NF1 NF2 NFAM1 NFASC NFAT5
    NFATC1 NFATC2 NFATC2IP NFATC3 NFATC4
    NFE2 NFE2L1 NFE2L2 NFE2L3 NFIA
    NFIB NFIB_ NFIC NFIL3 NFIX
    ENST00000397581
    NFKB1 NFKB2 NFKBIA NFKBIB NFKBID
    NFKBIE NFKBIL1 NFKBIL2 NFKBIZ NFRKB
    NFS1 NFU1 NFX1 NFXL1 NFYA
    NFYB NFYC NGB NGDN NGEF
    NGF NGFR NGFRAP1 NGLY1 NGRN
    NHEDC1 NHEDC2 NHEJ1 NHLH1 NHLH2
    NHLRC1 NHLRC2 NHLRC3 NHP2 NHP2L1
    NHS NHSL1 NHSL2 NICN1 NID1
    NID2 NIF3L1 NIN NINJ1 NINJ2
    NINL NIP7 NIPA1 NIPA2 NIPAL1
    NIPAL2 NIPAL3 NIPAL4 NIPBL NIPSNAP1
    NIPSNAP3A NIPSNAP3B NISCH NIT1 NIT2
    NKAIN1 NKAIN2 NKAIN4 NKAP NKAPL
    NKD1 NKD2 NKG7 NKIRAS1 NKIRAS2
    NKPD1 NKRF NKTR NKX2-1 NKX2-2
    NKX2-3 NKX2-4 NKX2-5 NKX2-6 NKX2-8
    NKX3-1 NKX3-2 NKX6-1 NKX6-2 NKX6-3
    NLE1 NLGN1 NLGN2 NLGN3 NLGN4X
    NLGN4Y NLK NLN NLRC3 NLRC4
    NLRC5 NLRP1 NLRP10 NLRP11 NLRP12
    NLRP13 NLRP14 NLRP2 NLRP3 NLRP4
    NLRP5 NLRP6 NLRP7 NLRP8 NLRP9
    NLRX1 NMB NMBR NMD3 NME1
    NME1-NME2 NME2 NME2P1 NME3 NME4
    NME5 NME6 NME7 NMI NMNAT1
    NMNAT2 NMNAT3 NMRAL1 NMS NMT1
    NMT2 NMU NMUR1 NMUR2 NM_
    001012984_2
    NM_001013679 NM_001031_4 NM_ NM_ NM_024534
    001039690_2 001080470_1
    NM_024588_3 NM_032947_3 NM_198455_2 NNAT NNMT
    NNT NOB1 NOBOX NOC2L NOC3L
    NOC4L NOD1 NOD2 NODAL NOG
    NOL11 NOL12 NOL3 NOL4 NOL6
    NOL7 NOL9 NOLC1 NOM1 NOMO1
    NOMO2 NOMO3 NONO NOP10 NOP14
    NOP16 NOP2 NOP56 NOP58 NOS1
    NOS1AP NOS1AP_ NOS2 NOS3 NOSIP
    ENST00000361897
    NOSTRIN NOTCH1 NOTCH2 NOTCH2NL NOTCH3
    NOTCH4 NOTUM NOV NOVA1 NOVA2
    NOX1 NOX3 NOX4 NOX5 NOXA1
    NOXO1 NP12_HUMAN NPAS1 NPAS2 NPAS3
    NPAS4 NPAT NPB NPBWR1 NPBWR2
    NPC1 NPC1L1 NPC2 NPDC1 NPEPPS
    NPFF NPFFR1 NPFFR2 NPHP1 NPHP3
    NPHP4 NPHS1 NPHS2 NPIP NPIPL1
    NPIPL2 NPL NPLOC4 NPM1 NPM2
    NPM3 NPNT NPPA NPPB NPPC
    NPR1 NPR2 NPR3 NPS NPSR1
    NPTN NPTX1 NPTX2 NPTXR NPVF
    NPW NPY NPY1R NPY2R NPY5R
    NPY6R NP_001073948_ NQO1 NQO2 NR0B1
    1
    NR0B2 NR1D1 NR1D2 NR1H2 NR1H3
    NR1H4 NR1I2 NR1I3 NR2C1 NR2C2
    NR2C2AP NR2E1 NR2E3 NR2F1 NR2F2
    NR2F6 NR3C1 NR3C2 NR4A1 NR4A2
    NR4A3 NR5A1 NR5A2 NR6A1 NRAP
    NRARP NRAS NRBF2 NRBP1 NRBP2
    NRCAM NRD1 NRF1 NRG1 NRG2
    NRG3 NRG4 NRGN NRIP1 NRIP2
    NRIP3 NRK NRL NRM NRN1
    NRN1L NRP1 NRP2 NRSN1 NRSN2
    NRTN NRXN1 NRXN2 NRXN3 NR_002168_
    1
    NR_002217_1 NR_002453_4 NR_002730_1 NR_002733_1 NR_002781_
    1
    NR_002938_2 NR_003034_1 NR_003148_2 NR_003276_1 NSA2
    NSD1 NSDHL NSF NSFL1C NSL1
    NSMAF NSMCE1 NSMCE2 NSMCE4A NSUN2
    NSUN3 NSUN4 NSUN5 NSUN5P1 NSUN5P2
    NSUN6 NSUN7 NT5C NT5C1A NT5C1B
    NT5C2 NT5C3 NT5C3L NT5DC1 NT5DC2
    NT5DC3 NT5E NT5M NTAN1 NTF3
    NTF4 NTHL1 NTM NTN1 NTN3
    NTN4 NTN5 NTNG1 NTNG2 NTRK1
    NTRK2 NTRK3 NTS NTSR1 NTSR2
    NUAK1 NUAK2 NUB1 NUBP1 NUBP2
    NUBPL NUCB1 NUCB2 NUCKS1 NUDC
    NUDCD1 NUDCD2 NUDCD3 NUDT1 NUDT10
    NUDT11 NUDT12 NUDT13 NUDT14 NUDT15
    NUDT16 NUDT16L1 NUDT17 NUDT19 NUDT2
    NUDT21 NUDT22 NUDT3 NUDT4 NUDT5
    NUDT6 NUDT7 NUDT8 NUDT9 NUF2
    NUFIP1 NUFIP2 NUMA1 NUMB NUMBL
    NUP107 NUP133 NUP153 NUP155 NUP160
    NUP188 NUP205 NUP210 NUP210L NUP214
    NUP35 NUP37 NUP43 NUP50 NUP54
    NUP62 NUP62CL NUP85 NUP88 NUP93
    NUP98 NUPL1 NUPL2 NUPR1 NUS1
    NUTF2 NVL NWD1 NXF1 NXF2
    NXF2B NXF3 NXF4 NXF5 NXN
    NXNL1 NXNL2 NXPH1 NXPH2 NXPH3
    NXPH4 NXT1 NXT2 NYNRIN NYX
    O00434_HUMAN O10D4_HUMAN O10J6_ O52L2_ O5AK3_
    HUMAN HUMAN HUMAN
    O60374_HUMAN O60384_HUMAN O60411_ O75863_ O95014_
    HUMAN HUMAN HUMAN
    O95431_HUMAN OAF OAS1 OAS2 OAS3
    OASL OAT OAZ1 OBFC1 OBFC2A
    OBFC2B OBP2A OBP2B OBSCN OBSCN_
    ENST00000359599
    OBSL1 OC90 OC90_ OCA2 OCEL1
    ENST00000262283
    OCIAD1 OCIAD2 OCLN OCM OCM2
    OCRL ODAM ODC1 ODF1 ODF2
    ODF2L ODF3 ODF3B ODF3L1 ODF3L2
    ODF4 ODZ1 ODZ2 OFCC1 OFD1
    OGDH OGDHL OGFOD1 OGFOD2 OGFR
    OGFRL1 OGG1 OGN OGT OGT_
    ENST00000373719
    OIP5 OIT3 OLA1 OLAH OLFM1
    OLFM2 OLFM3 OLFM4 OLFML1 OLFML2A
    OLFML2B OLFML3 OLIG1 OLIG2 OLIG3
    OLR1 OMA1 OMD OMG ONECUT1
    ONECUT2 OPA1 OPA3 OPALIN OPCML
    OPHN1 OPLAH OPN1LW OPN1MW OPN1MW2
    OPN1SW OPN3 OPN4 OPN5 OPRD1
    OPRK1 OPRL1 OPRM1 OPTC OPTN
    OR10A2 OR10A3 OR10A4 OR10A5 OR10A6
    OR10A7 OR10AD1 OR10AG1 OR10C1 OR10G2
    OR10G3 OR10G4 OR10G6 OR10G7 OR10G8
    OR10G9 OR10H1 OR10H2 OR10H3 OR10H4
    OR10H5 OR10J1 OR10J3 OR10J5 OR10K1
    OR10K2 OR10P1 OR10Q1 OR10R2 OR10R3P
    OR10S1 OR10T2 OR10V1 OR10W1 OR10X1
    OR10Z1 OR11A1 OR11G2 OR11H1 OR11H12
    OR11H4 OR11H6 OR11L1 OR12D2 OR12D3
    OR13A1 OR13C2 OR13C3 OR13C4 OR13C5
    OR13C8 OR13C9 OR13D1 OR13F1 OR13G1
    OR13H1 OR13J1 OR14A16 OR14C36 OR1411
    OR14J1 OR1A1 OR1A2 OR1B1 OR1C1
    OR1D2 OR1D4 OR1E1 OR1E2 OR1F1
    OR1G1 OR1I1 OR1J1 OR1J2 OR1J4
    OR1K1 OR1L1 OR1L3 OR1L4 OR1L6
    OR1L8 OR1M1 OR1N1 OR1N2 OR1Q1
    OR1S1 OR1S2 OR2Al2 OR2A14 OR2A2
    OR2A25 OR2A4 OR2A5 OR2AE1 OR2AG1
    OR2AG2 OR2AJ1 OR2AK2 OR2AP1 OR2AT4
    OR2B11 OR2B2 OR2B3P OR2B6 OR2C1
    OR2C3 OR2D2 OR2D3 OR2F1 OR2F2
    OR2G2 OR2G3 OR2G6 OR2H1 OR2H2
    OR2J1 OR2J2 OR2J3 OR2J3_ OR2K2
    HUMAN
    OR2L13 OR2L1P OR2L2 OR2L3 OR2L8
    OR2M1P OR2M2 OR2M3 OR2M4 OR2M5
    OR2M7 OR2S2 OR2T1 OR2T10 OR2T11
    OR2T12 OR2T2 OR2T27 OR2T3 OR2T33
    OR2T34 OR2T35 OR2T4 OR2T5 OR2T6
    OR2T8 OR2V2 OR2W1 OR2W3 OR2W5
    OR2Y1 OR2Z1 OR3A1 OR3A3 OR3A4
    OR4A13P OR4A15 OR4A16 OR4A47 OR4A5
    OR4B1 OR4C11 OR4C12 OR4C13 OR4C15
    OR4C16 OR4C3 OR4C46 OR4C5_ OR4C6
    HUMAN
    OR4D1 OR4D10 OR4D11 OR4D2 OR4D5
    OR4D6 OR4D9 OR4E2 OR4F15 OR4F16
    OR4F17 OR4F21 OR4F29 OR4F3 OR4F4
    OR4F5 OR4F6 OR4K1 OR4K13 OR4K14
    OR4K15 OR4K17 OR4K2 OR4K5 OR4L1
    OR4M1 OR4M2 OR4N2 OR4N4 OR4N5
    OR4P4 OR4Q3 OR4S1 OR4S2 OR4X1
    OR4X2 OR51A2 OR51A4 OR51A7 OR51B2
    OR51B4 OR51B5 OR51B6 OR51D1 OR51E1
    OR51E2 OR51F1 OR51F2 OR51G1 OR51G2
    OR51H1P OR51I1 OR51I2 OR51J1 OR51L1
    OR51M1 OR51Q1 OR51S1 OR51T1 OR51V1
    OR52A1 OR52A4 OR52A5 OR52B4 OR52B6
    OR52D1 OR52E2 OR52E4 OR52 E6 OR52E8
    OR52H1 OR52I1 OR52I2 OR52J3 OR52K1
    OR52K2 OR52L1 OR52M1 OR52N1 OR52N2
    OR52N4 OR52N5 OR52R1 OR52W1 OR56A1
    OR56A3 OR56A4 OR56B1 OR56B4 OR5A1
    OR5A2 OR5AC2 OR5AK2 OR5AN1 OR5AP2
    OR5AR1 OR5AS1 OR5AU1 OR5AX1 OR5B12
    OR5B17 OR5B2 OR5B21 OR5B3 OR5C1
    OR5D13 OR5D14 OR5D16 OR5D18 OR5D3P
    OR5E1P OR5F1 OR5H1 OR5H14 OR5H15
    OR5H2 OR5H6 OR5I1 OR5J2 OR5K1
    OR5K2 OR5K3 OR5K4 OR5L1 OR5L2
    OR5M1 OR5M3 OR5M8 OR5M9 OR5P2
    OR5P3 OR5R1 OR5T1 OR5T2 OR5T3
    OR5V1 OR5W2 OR6A2 OR6B1 OR6B3
    OR6C1 OR6C2 OR6C3 OR6C4 OR6C6
    OR6C65 OR6C68 OR6C70 OR6C74 OR6C75
    OR6C76 OR6F1 OR6J1_ OR6K2 OR6K3
    HUMAN
    OR6K6 OR6M1 OR6N1 OR6N2 OR6P1
    OR6Q1 OR6S1 OR6T1 OR6W1P OR6X1
    OR6Y1 OR7A10 OR7A17 OR7A5 OR7C1
    OR7C2 OR7D2 OR7D4 OR7E24 OR7E5P
    OR7G1 OR7G2 OR7G3 OR8A1 OR8B12
    OR8B2 OR8B3 OR8B4 OR8B8 OR8D1
    OR8D2 OR8D4 OR8H1 OR8H2 OR8H3
    OR8I2 OR8J1 OR8J3 OR8K1 OR8K3
    OR8K5 OR8S1 OR8U1 OR9A2 OR9A4
    OR9G1 OR9G4 OR9I1 OR9K2 OR9Q1
    OR9Q2 ORAI1 ORAI2 ORAI3 ORAOV1
    ORC1L ORC2L ORC3L ORC4L ORC5L
    ORC6L ORM1 ORM2 ORMDL1 ORMDL2
    ORMDL3 OS9 OSBP OSBP2 OSBPL10
    OSBPL10_ OSBPL11 OSBPL1A OSBPL2 OSBPL3
    ENST00000396556
    OSBPL5 OSBPL6 OSBPL7 OSBPL8 OSBPL9
    OSCAR OSCP1 OSGEP OSGIN1 OSGIN2
    OSM OSMR OSR1 OSR2 OSTC
    OSTCL OSTF1 OSTM1 OSTN OSTalpha
    OSTbeta OTC OTOA OTOF OTOF_
    ENST00000361394
    OTOG OTOP1 OTOP2 OTOP3 OTOR
    OTOS OTP OTUB1 OTUB2 OTUD1
    OTUD3 OTUD4 OTUD5 OTUD5_ OTUD6A
    ENST00000453548
    OTUD7A OTUD7B OTX1 OTX2 OVCH1
    OVCH2 OVGP1 OVOL1 OVOL2 OXA1L
    OXCT1 OXCT2 OXER1 OXGR1 OXNAD1
    OXR1 OXSM OXSR1 OXT OXTR
    P117 P2RX1 P2RX2 P2RX3 P2RX4
    P2RX5 P2RX7 P2RXL1 P2RY1 P2RY10
    P2RY11 P2RY12 P2RY13 P2RY14 P2RY2
    P2RY4 P2RY6 P2RY8 P461_HUMAN P4HA1
    P4HA2 P4HA3 P4HB P4HTM P78389_
    HUMAN
    P78561_HUMAN PA2G4 PAAF1 PABPC1 PABPC1L
    PABPC1L2A PABPC1L2B PABPC3 PABPC4 PABPC5
    PABPCP2 PABPN1 PACRG PACRGL PACS1
    PACS2 PACSIN1 PACSIN2 PACSIN3 PADI1
    PADI2 PADI3 PADI4 PADI6 PAEP
    PAF1 PAFAH1B1 PAFAH1B2 PAFAH1B3 PAFAH2
    PAG1 PAGE1 PAGE2 PAGE2B PAGE3
    PAGE4 PAGE5 PAH PAICS PAIP1
    PAIP2 PAIP2B PAK1 PAK1IP1 PAK2
    PAK3 PAK4 PAK6 PAK7 PALB2
    PALLD PALM PALM2 PALM2-AKAP2 PALMD
    PAM PAMR1 PAN2 PAN3 PANK1
    PANK2 PANK3 PANK4 PANX1 PANX2
    PANX3 PAOX PAOX_ PAP2D PAPD4
    ENST00000357296
    PAPD5 PAPD5_ PAPD7 PAPLN PAPOLA
    ENST00000436909
    PAPOLB PAPOLG PAPPA PAPPA2 PAPSS1
    PAPSS2 PAQR3 PAQR4 PAQR5 PAQR6
    PAQR7 PAQR8 PAQR9 PARD3 PARD3B
    PARD6A PARD6B PARD6G PARG PARK2
    PARK7 PARL PARP1 PARP10 PARP11
    PARP12 PARP14 PARP15 PARP16 PARP2
    PARP3 PARP4 PARP6 PARP8 PARP9
    PARS2 PARVA PARVB PARVG PASD1
    PASK PATE1 PATE2 PATZ1 PAWR
    PAX1 PAX2 PAX3 PAX4 PAX5
    PAX6 PAX7 PAX8 PAX9 PAXIP1
    PBK PBLD PBRM1 PBX1 PBX2
    PBX3 PBX4 PBXIP1 PC PCBD1
    PCBD2 PCBP1 PCBP2 PCBP3 PCBP4
    PCCA PCCB PCDH1 PCDH10 PCDH11X
    PCDH11Y PCDH12 PCDH15 PCDH17 PCDH18
    PCDH19 PCDH19_ PCDH20 PCDH24 PCDH7
    NM_020766_1
    PCDH8 PCDH9 PCDHA1 PCDHA10 PCDHA10_
    ENST00000505235
    PCDHA11 PCDHA13 PCDHA2 PCDHA3 PCDHA4
    PCDHA5 PCDHA6 PCDHA7 PCDHA8 PCDHA9
    PCDHAC1 PCDHAC2 PCDHB1 PCDHB10 PCDHB11
    PCDHB12 PCDHB13 PCDHB14 PCDHB15 PCDHB16
    PCDHB18 PCDHB2 PCDHB3 PCDHB4 PCDHB5
    PCDHB6 PCDHB7 PCDHB8 PCDHGA1 PCDHGA12
    PCDHGA12_ PCDHGA2 PCDHGA3 PCDHGA6 PCDHGB7
    ENST00000252085
    PCDHGC3 PCDHGC3_ PCDHGC4 PCDHGC5 PCDHGC5_
    ENST00000308177 ENST00000252087
    PCF11 PCGF1 PCGF2 PCGF3 PCGF5
    PCGF6 PCID2 PCIF1 PCK1 PCK2
    PCM1 PCMT1 PCMTD1 PCMTD2 PCNA
    PCNP PCNT PCNX PCNXL2 PCNXL3
    PCOLCE PCOLCE2 PCP2 PCP4 PCQAP
    PCSK1 PCSK1N PCSK2 PCSK4 PCSK5
    PCSK5_ PCSK7 PCSK9 PCTP PCYOX1
    ENST00000376767
    PCYOX1L PCYT1A PCYT1B PCYT2 PDAP1
    PDC PDCD1 PDCD10 PDCD11 PDCD1LG2
    PDCD2 PDCD2L PDCD4 PDCD5 PDCD6
    PDCD6IP PDCD7 PDCD8 PDCL PDCL3
    PDDC1 PDE10A PDE11A PDE12 PDE1A
    PDE1B PDE1C PDE2A PDE3A PDE3B
    PDE4A PDE4B PDE4B_ PDE4C PDE4D
    ENST00000423207
    PDE4DIP PDE5A PDE6A PDE6B PDE6C
    PDE6D PDE6G PDE6H PDE7A PDE7B
    PDE8A PDE8B PDE9A PDGFA PDGFB
    PDGFC PDGFD PDGFRA PDGFRB PDGFRL
    PDHA1 PDHA2 PDHB PDHX PDIA2
    PDIA3 PDIA4 PDIA5 PDIA6 PDIK1L
    PDILT PDK1 PDK2 PDK3 PDK4
    PDLIM1 PDLIM2 PDLIM3 PDLIM4 PDLIM5
    PDLIM7 PDP1 PDP2 PDPK1 PDPN
    PDPR PDRG1 PDS5B PDSS1 PDSS2
    PDX1 PDXDC1 PDXDC2 PDXK PDXP
    PDYN PDZD11 PDZD2 PDZD3 PDZD4
    PDZD7 PDZD8 PDZK1 PDZK1IP1 PDZRN3
    PDZRN4 PEA15 PEAR1 PEBP1 PEBP4
    PECI PECR PEF1 PEG10 PEG3
    PELI1 PELI2 PELI3 PELO PELP1
    PEMT PENK PEPD PER1 PER2
    PER3 PERP PES1 PET112L PEX1
    PEX10 PEX11A PEX11B PEX11G PEX12
    PEX13 PEX14 PEX16 PEX19 PEX2
    PEX26 PEX3 PEX5 PEX5L PEX6
    PEX7 PF4 PF4V1 PFAS PFDN1
    PFDN2 PFDN4 PFDN5 PFDN6 PFKFB1
    PFKFB2 PFKFB3 PFKFB4 PFKL PFKM
    PFKP PFN1 PFN2 PFN3 PFN4
    PGA3 PGA4 PGA5 PGAM1 PGAM1_
    HUMAN
    PGAM2 PGAM4 PGAM5 PGAP1 PGAP3
    PGBD1 PGBD2 PGBD3 PGBD4 PGBD5
    PGC PGCP PGD PGF PGGT1B
    PGK1 PGK2 PGLS PGLYRP1 PGLYRP2
    PGLYRP3 PGLYRP4 PGM1 PGM2 PGM2L1
    PGM3 PGM5 PGP PGPEP1 PGR
    PGRMC1 PGRMC2 PGS1 PHACTR2 PHACTR3
    PHACTR4 PHAX PHB PHC1 PHC1B
    PHC2 PHC3 PHEX PHF1 PHF10
    PHF11 PHF12 PHF13 PHF14 PHF15
    PHF16 PHF17 PHF19 PHF2 PHF20
    PHF20L1 PHF21A PHF21B PHF23 PHF3
    PHF5A PHF6 PHF7 PHF8 PHGDH
    PHIP PHKA1 PHKA2 PHKB PHKG1
    PHKG2 PHLDA1 PHLDA2 PHLDA3 PHLDB1
    PHLDB2 PHLDB3 PHLPP PHLPP2 PHOSPHO1
    PHOSPHO2 PH OX2A PHOX2B PHPT1 PHTF1
    PHYH PHYHD1 PHYHIP PHYHIPL PI15
    PI16 PI3 PI4K2A PI4K2B PI4KA
    PI4KAP2 PI4KB PIAS1 PIAS2 PIAS3
    PIAS4 PIBF1 PICALM PICK1 PID1
    PIF1 PIGA PIGB PIGC PIGF
    PIGG PIGH PIGK PIGL PIGM
    PIGN PIGO PIGP PIGQ PIGR
    PIGS PIGT PIGU PIGV PIGW
    PIGX PIGZ PIH1D1 PIH1D2 PIK3AP1
    PIK3C2A PIK3C2B PIK3C2G PIK3C3 PIK3CA
    PIK3CB PIK3CD PIK3CG PIK3IP1 PIK3R1
    PIK3R2 PIK3R3 PIK3R4 PIK3R5 PIKFYVE
    PILRA PILRB PIM1 PIM2 PIM3
    PIN1 PIN4 PINK1 PINX1 PION
    PIP PIP4K2A PIP4K2B PIP4K2C PIP5K1A
    PIP5K1B PIP5K1C PIP5KL1 PIPDX PIR
    PISD PITPNA PITPNB PITPNC1 PITPNM1
    PITPNM2 PITPNM3 PITRM1 PITX1 PITX2
    PITX3 PIWIL1 PIWIL2 PIWIL3 PIWIL4
    PJA1 PJA2 PKD1 PKD1L1 PKD1L2
    PKD1L2_ PKD1L3 PKD2 PKD2L1 PKD2L2
    ENST00000360678
    PKDREJ PKHD1 PKHD1L1 PKIA PKIB
    PKIG PKLR PKM2 PKMYT1 PKN1
    PKN2 PKN3 PKNOX1 PKNOX2 PKP1
    PKP2 PKP3 PKP4 PLA1A PLA2G10
    PLA2G12A PLA2G12B PLA2G15 PLA2G16 PLA2G1B
    PLA2G2A PLA2G2C PLA2G2D PLA2G2E PLA2G2F
    PLA2G3 PLA2G4A PLA2G4C PLA2G4D PLA2G4F
    PLA2G5 PLA2G6 PLA2G7 PLA2R1 PLAA
    PLAC1 PLAC1L PLAC8 PLAC8L1 PLAC9
    PLAG1 PLAGL1 PLAGL2 PLAT PLAU
    PLAUR PLB1 PLBD1 PLBD2 PLCB1
    PLCB2 PLCB3 PLCB4 PLCD1 PLCD3
    PLCD4 PLCE1 PLCG1 PLCG2 PLCH1
    PLCH2 PLCL1 PLCL2 PLCXD1 PLCXD2
    PLCXD3 PLCZ1 PLD1 PLD2 PLD3
    PLD4 PLD5 PLD6 PLDN PLEC
    PLEK PLEK2 PLEKHA1 PLEKHA3 PLEKHA4
    PLEKHA5 PLEKHA5_ PLEKHA6 PLEKHA7 PLEKHA8
    ENST00000429027
    PLEKHA9 PLEKHB1 PLEKHB2 PLEKHF1 PLEKHF2
    PLEKHG1 PLEKHG2 PLEKHG3 PLEKHG4 PLEKHG4B
    PLEKHG4B_ PLEKHG5 PLEKHG6 PLEKHG7 PLEKHH1
    ENST00000283426
    PLEKHH2 PLEKHH3 PLEKHJ1 PLEKHM1 PLEKHN1
    PLEKHO1 PLEKHO2 PLG PLGLB1 PLGLB2
    PLIN1 PLIN2 PLIN3 PLIN4 PLIN5
    PLK1 PLK2 PLK3 PLK4 PLLP
    PLN PLOD1 PLOD2 PLOD3 PLP1
    PLP2 PLRG1 PLS1 PLS3 PLSCR1
    PLSCR2 PLSCR3 PLSCR3_ PLSCR4 PLTP
    ENST00000324822
    PLUNC PLVAP PLXDC1 PLXDC2 PLXNA1
    PLXNA2 PLXNA3 PLXNA4 PLXNB1 PLXNB2
    PLXNB3 PLXNC1 PLXND1 PM20D1 PM20D2
    PMAIP1 PMCH PMEPA1 PMF1 PMFBP1
    PML PMM1 PMM2 PMP2 PMP22
    PMPCA PMPCB PMS1 PMS2 PMS2L1
    PMS2L11 PMS2L3 PMS2L4 PMS2L5 PMVK
    PNCK PNKD PNKP PNLDC1 PNLIP
    PNLIPRP1 PNLIPRP2 PNLIPRP3 PNMA1 PNMA2
    PNMA3 PNMA5 PNMA6A PNMAL1 PNMAL2
    PNMT PNN PNO1 PNOC PNP
    PNPLA1 PNPLA2 PNPLA3 PNPLA4 PNPLA5
    PNPLA6 PNPLA7 PNPLA8 PNPO PNPT1
    PNRC1 PNRC2 PODN PODNL1 PODXL
    PODXL2 POF1B POFUT1 POFUT2 POGK
    POGZ POL3S POLA1 POLA2 POLB
    POLD1 POLD2 POLD3 POLD4 POLDIP3
    POLE POLE2 POLE3 POLE4 POLG
    POLG2 POLH POLI POLK POLL
    POLM POLN POLQ POLR1A POLR1B
    POLR1C POLR1D POLR1E POLR2A POLR2B
    POLR2C POLR2D POLR2E POLR2F POLR2G
    POLR2H POLR2I POLR2J POLR2J2 POLR2K
    POLR2L POLR3A POLR3B POLR3C POLR3D
    POLR3E POLR3F POLR3G POLR3GL POLR3H
    POLR3K POLRMT POM121 POM121L3 POMC
    POMGNT1 POMP POMT1 POMT2 POMZP3
    PON1 PON2 PON3 POP1 POP4
    POP5 POP7 POPDC2 POPDC3 POR
    PORCN POSTN POT1 POT14_ POTE2_
    HUMAN HUMAN
    POTEA POTEB POTED POTEF POTEG
    POU1F1 POU2AF1 POU2F1 POU2F2 POU2F3
    POU3F1 POU3F2 POU3F3 POU3F4 POU4F1
    POU4F2 POU4F3 POU5F1 POU6F1 POU6F2
    PPA1 PPA2 PPAN PPAN-P2RY11 PPAP2A
    PPAP2B PPAP2C PPAPDC1A PPAPDC2 PPAPDC3
    PPARA PPARD PPARG PPARGC1A PPARGC1B
    PPAT PPBP PPCDC PPCS PPDPF
    PPEF1 PPEF2 PPFIA1 PPFIA2 PPFIA3
    PPFIA4 PPFIBP1 PPFIBP2 PPHLN1 PPIA
    PPIAL4A PPIAL4G PPIA_HUMAN PPIB PPIC
    PPID PPIE PPIF PPIG PPIH
    PPIL1 PPIL2 PPIL3 PPIL4 PPIL5
    PPIL6 PPIP5K1 PPIP5K2 PPL PPM1A
    PPM1B PPM1D PPM1E PPM1F PPM1G
    PPM1H PPM1J PPM1K PPM1L PPDX
    PPP1CA PPP1CB PPP1CC PPP1R10 PPP1R11
    PPP1R12A PPP1R12B PPP1R12C PPP1R13B PPP1R13L
    PPP1R14A PPP1R14B PPP1R14C PPP1R14D PPP1R15A
    PPP1R15B PPP1R16A PPP1R16B PPP1R1A PPP1R1B
    PPP1R1C PPP1R2 PPP1R2P9 PPP1R3A PPP1R3B
    PPP1R3C PPP1R3D PPP1R3E PPP1R3F PPP1R3G
    PPP1R7 PPP1R8 PPP1R9A PPP1R9B PPP2CA
    PPP2CB PPP2R1A PPP2R1B PPP2R2A PPP2R2B
    PPP2R2C PPP2R2D PPP2R3A PPP2R3B PPP2R3C
    PPP2R4 PPP2R5A PPP2R5B PPP2R5C PPP2R5D
    PPP2R5E PPP3CA PPP3CB PPP3CC PPP3R1
    PPP3R2 PPP4C PPP4R1 PPP4R1L PPP4R2
    PPP4R4 PPP5C PPP6C PPPDE1 PPPDE2
    PPRC1 PPT1 PPT2 PPTC7 PPWD1
    PPY PPYR1 PQBP1 PQLC1 PQLC2
    PQLC3 PRAF2 PRAME PRAMEF1 PRAMEF10
    PRAMEF12 PRAMEF13 PRAMEF14 PRAMEF16 PRAMEF17
    PRAMEF18 PRAMEF19 PRAMEF2 PRAMEF20 PRAMEF21
    PRAMEF22 PRAMEF3 PRAMEF4 PRAMEF5 PRAMEF6
    PRAMEF7 PRAMEF8 PRAMEF9 PRAMEL PRAP1
    PRB1 PRB2 PRB4 PRC1 PRCC
    PRCC_ PRCD PRCP PRDM1 PRDM10
    ENST00000353233
    PRDM11 PRDM12 PRDM13 PRDM14 PRDM15
    PRDM16 PRDM2 PRDM4 PRDM5 PRDM7
    PRDM8 PRDM9 PRDX1 PRDX2 PRDX3
    PRDX4 PRDX5 PRDX6 PREB PRELID1
    PRELID2 PRELP PREP PREPL PREX1
    PREX2 PRF1 PRG-3 PRG2 PRG3
    PRG4 PRH2 PRIC285 PRICKLE1 PRICKLE2
    PRICKLE3 PRICKLE4 PRIM2 PRIMA1 PRKAA1
    PRKAA2 PRKAA2_ PRKAB1 PRKAB2 PRKACA
    ENST00000371244
    PRKACB PRKACB_ PRKACG PRKAG1 PRKAG2
    ENST00000370685
    PRKAG3 PRKAR1A PRKAR1B PRKAR2A PRKAR2B
    PRKCA PRKCB PRKCD PRKCDBP PRKCE
    PRKCG PRKCH PRKCI PRKCQ PRKCSH
    PRKCZ PRKD1 PRKD1_ PRKD2 PRKD3
    ENST00000331968
    PRKDC PRKG1 PRKG2 PRKRA PRKRIP1
    PRKRIR PRKX PRKY PRL PRLH
    PRLHR PRLR PRM1 PRM2 PRMT1
    PRMT10 PRMT2 PRMT3 PRMT5 PRMT6
    PRMT7 PRMT8 PRND PRNP PRO1073
    PROC PROCA1 PROCR PRODH PRODH2
    PROK1 PROK2 PROKR1 PROKR2 PROL1
    PROM1 PROM2 PROP1 PROS1 PROSC
    PROX1 PROX2 PROZ PRPF18 PRPF19
    PRPF3 PRPF31 PRPF38A PRPF38B PRPF39
    PRPF4 PRPF40A PRPF40B PRPF4B PRPF4B_
    ENST00000337659
    PRPF6 PRPF8 PRPH PRPH2 PRPS1
    PRPS2 PRPSAP1 PRPSAP2 PRR11 PRR12
    PRR13 PRR14 PRR15 PRR15L PRR16
    PRR18 PRR19 PRR20A PRR21 PRR22
    PRR23B PRR23C PRR25 PRR3 PRR4
    PRR5 PRR5-ARHGAP8 PRR5L PRR5_ PRR7
    ENST00000432186
    PRR8 PRRC1 PRRG1 PRRG2 PRRG3
    PRRG4 PRRT1 PRRT2 PRRT3 PRRX1
    PRRX2 PRSS1 PRSS12 PRSS16 PRSS2
    PRSS21 PRSS22 PRSS23 PRSS27 PRSS3
    PRSS33 PRSS35 PRSS36 PRSS37 PRSS38
    PRSS42 PRSS50 PRSS7 PRSSL1 PRTFDC1
    PRTG PRTN3 PRUNE PRUNE2 PRUNE2_
    ENST00000376718
    PRX PRY PRY2 PSAP PSAPL1
    PSAT1 PSD PSD2 PSD3 PSD4
    PSD_ PSEN1 PSEN2 PSENEN PSG1
    ENST00000020673
    PSG1_ PSG2 PSG3 PSG4 PSG5
    ENST00000312439
    PSG6 PSG8 PSG9 PSIP1 PSIP1_
    ENST00000380733
    PSKH1 PSKH2 PSMA1 PSMA2 PSMA3
    PSMA4 PSMA5 PSMA6 PSMA7 PSMA8
    PSMB1 PSMB10 PSMB2 PSMB3 PSMB4
    PSMB5 PSMB6 PSMB7 PSMB8 PSMB9
    PSMC1 PSMC2 PSMC3 PSMC3IP PSMC4
    PSMC5 PSMC6 PSMD1 PSMD10 PSMD11
    PSMD12 PSMD13 PSMD13_ PSMD2 PSMD3
    ENST00000431206
    PSMD4 PSMD5 PSMD6 PSMD7 PSMD8
    PSMD9 PSME1 PSME2 PSME3 PSME4
    PSMF1 PSMG1 PSMG2 PSMG3 PSORS1C1
    PSORS1C2 PSPC1 PSPH PSPN PSRC1
    PSTK PSTPIP2 PTAFR PTAR1 PTBP1
    PTBP2 PTCD1 PTCD2 PTCD3 PTCH1
    PTCH1_ PTCH2 PTCHD1 PTCHD2 PTCHD3
    ENST00000331920
    PTCRA PTDSS1 PTDSS2 PTEN PTER
    PTF1A PTGDR PTGDS PTGER1 PTGER2
    PTGER3 PTGER4 PTGES PTGES2 PTGES3
    PTGFR PTGFRN PTGFR_ PTGIR PTGIS
    ENST00000370758
    PTGR1 PTGS1 PTGS2 PTH PTH1R
    PTH2 PTH2R PTHLH PTK2 PTK2B
    PTK2B_ PTK6 PTK7 PTMA PTMS
    ENST00000397497
    PTN PTOV1 PTP4A1 PTP4A2 PTP4A3
    PTPDC1 PTPLA PTPLAD1 PTPLAD2 PTPLB
    PTPMT1 PTPN1 PTPN11 PTPN12 PTPN13
    PTPN14 PTPN18 PTPN2 PTPN20A PTPN20B
    PTPN21 PTPN22 PTPN23 PTPN3 PTPN4
    PTPN5 PTPN6 PTPN7 PTPN9 PTPRA
    PTPRB PTPRB_ PTPRC PTPRCAP PTPRD
    ENST00000334414
    PTPRE PTPRF PTPRG PTPRH PTPRJ
    PTPRK PTPRM PTPRN PTPRN2 PTPRO
    PTPRR PTPRS PTPRT PTPRU PTPRZ1
    PTRF PTRH1 PTRH2 PTS PTTG1
    PTTG1IP PTX3 PUM1 PUM2 PURA
    PURB PURG PURG_ PUS1 PUS10
    ENST00000475541
    PUS3 PUS7 PUS7L PUSL1 PVALB
    PVR PVRIG PVRL1 PVRL2 PVRL3
    PVRL4 PWP1 PWP2 PWWP2A PWWP2B
    PXDN PXDNL PXK PXMP2 PXMP4
    PXN PXT1 PYCARD PYCR1 PYCR2
    PYCRL PYDC1 PYGB PYGL PYGM
    PYGO1 PYGO2 PYHIN1 PYROXD1 PYROXD2
    PYY PYY3 PZP ProSAPiP1 Q0VFX0_
    HUMAN
    Q13034_HUMAN Q13209_HUMAN Q15202_ Q16370_ Q1A5X8_
    HUMAN HUMAN HUMAN
    Q2M2F3_ Q2QD04_ Q2VIK4_ Q2VIK8_ Q2VIL1 _
    HUMAN HUMAN HUMAN HUMAN HUMAN
    Q3SX88_ Q3ZCN4_ Q49A61_ Q49AQ9_ Q4G0P5_
    HUMAN HUMAN HUMAN HUMAN HUMAN
    Q4G0S1_ Q4G129_ Q4G197_ Q4TT42_ Q4VXG5_
    HUMAN HUMAN HUMAN HUMAN HUMAN
    Q4VXZ3_ Q5I0X0_ Q5JSM7_ Q5JUV9_ Q5JV89_
    HUMAN HUMAN HUMAN HUMAN HUMAN
    Q5JX50_HUMAN Q5JXA8_ Q5JY96_ Q5JYU7_ Q5SWJ0_
    HUMAN HUMAN HUMAN HUMAN
    Q5T344_HUMAN Q5T669_HUMAN Q5T6S7_ Q5T740_ Q5T7C0_
    HUMAN HUMAN HUMAN
    Q5T909_HUMAN Q5TBE2_ Q5TFB2_ Q5VVH2_ Q5VZ27_
    HUMAN HUMAN HUMAN HUMAN
    Q5VZ43_HUMAN Q5W1B9_ Q69YG7_ Q69YJ1_ Q6AI01_
    HUMAN HUMAN HUMAN HUMAN
    Q6AI40_HUMAN Q6GMT2_ Q6I955_ Q6IPT3_ Q6NSH2_
    HUMAN HUMAN HUMAN HUMAN
    Q6NUR6_ Q6NZ63_ Q6P094_ Q6P462_ Q6PEB8_
    HUMAN HUMAN HUMAN HUMAN HUMAN
    Q6RGF6_ Q6TXQ4_ Q6UXU0_ Q6VEP2_ Q6YL47_
    HUMAN HUMAN HUMAN HUMAN HUMAN
    Q6ZMS4_ Q6ZNB5_ Q6ZNL0_ Q6ZNV0_ Q6ZQP8_
    HUMAN HUMAN HUMAN HUMAN HUMAN
    Q6ZQU9_ Q6ZRG5_ Q6ZRP8_ Q6ZRU5_ Q6ZSP4_
    HUMAN HUMAN HUMAN HUMAN HUMAN
    Q6ZSU1_ Q6ZSY1_ Q6ZTY5_ Q6ZU04_ Q6ZU24_
    HUMAN HUMAN HUMAN HUMAN HUMAN
    Q6ZUD9_ Q6ZUG5_ Q6ZUQ5_ Q6ZUR4_ Q6ZUS2_
    HUMAN HUMAN HUMAN HUMAN HUMAN
    Q6ZV46_HUMAN Q6ZV65_ Q6ZV72_ Q6ZVE3_ Q6ZVS6_
    HUMAN HUMAN HUMAN HUMAN
    Q6ZW54_ Q6ZWB7_ Q6ZWC0__ Q71RG6_ Q75L30_
    HUMAN HUMAN HUMAN HUMAN HUMAN
    Q75MH1_ Q75MM1_ Q76661_ Q7M4M3_ Q7Z2M6_
    HUMAN HUMAN HUMAN HUMAN HUMAN
    Q7Z2Q7_ Q7Z2S2_ Q7Z3M5_ Q7Z4Q0_ Q7Z4S1_
    HUMAN HUMAN HUMAN HUMAN HUMAN
    Q7Z5Z2_HUMAN Q7Z7K7_ Q86TT0_ Q86TU9_ Q86U10_
    HUMAN HUMAN HUMAN HUMAN
    Q86U47_HUMAN Q86U89_ Q86V52_ Q86V94_ Q86VG7_
    HUMAN HUMAN HUMAN HUMAN
    Q86X61_HUMAN Q86XG0_ Q86Y87 Q86YR2_ Q86YX8_
    HUMAN HUMAN HUMAN
    Q8IVE0_HUMAN Q8IVF9_HUMAN Q8IVN4_ Q8IVR1_ Q8IXE5_
    HUMAN HUMAN HUMAN
    Q8IXE7_HUMAN Q8IXV1_HUMAN Q8MH63_ Q8N0U1_ Q8N0W1_
    HUMAN HUMAN HUMAN
    Q8N164_HUMAN Q8N1B8_ Q8N1G8_ Q8N1I6_ Q8N1L4_
    HUMAN HUMAN HUMAN HUMAN
    Q8N1R6_ Q8N1T0_ Q8N1X6_ Q8N214_ Q8N266_
    HUMAN HUMAN HUMAN HUMAN HUMAN
    Q8N2D2_ Q8N2E2_ Q8N2W8_ Q8N3U1_ Q8N4W5_
    HUMAN HUMAN HUMAN HUMAN HUMAN
    Q8N5Q1_ Q8N642_ Q8N646_ Q8N6L5_ Q8N6V7_
    HUMAN HUMAN HUMAN HUMAN HUMAN
    Q8N6X1_ Q8N6X9_ Q8N799_ Q8N7D3_ Q8N7N0_
    HUMAN HUMAN HUMAN HUMAN HUMAN
    Q8N7N2_ Q8N7P5_ Q8N7Q6_ Q8N7Z9_ Q8N800_
    HUMAN HUMAN HUMAN HUMAN HUMAN
    Q8N822_ Q8N843_ Q8N849_ Q8N867_
    Q8N811_HUMAN HUMAN HUMAN HUMAN HUMAN
    Q8N8C5_ Q8N8C9_ Q8N8F0_ Q8N8H9_ Q8N8K0_
    HUMAN HUMAN HUMAN HUMAN HUMAN
    Q8N8P5_ Q8N8S3_ Q8N8S4_ Q8N950_ Q8N997_
    HUMAN HUMAN HUMAN HUMAN HUMAN
    Q8N9F6_ Q8N9G5_ Q8N9G9_ Q8N9H1_ Q8N9I1_
    HUMAN HUMAN HUMAN HUMAN HUMAN
    Q8N9J4_ Q8N9K3_ Q8N9Z1_ Q8N9Z5_ Q8NA17_
    HUMAN HUMAN HUMAN HUMAN HUMAN
    Q8NA34_ Q8NAG9_ Q8NAP4_ Q8NAP5_ Q8NAQ8_
    HUMAN HUMAN HUMAN HUMAN HUMAN
    Q8NAT4_ Q8NAV9_ Q8NAZ9_ Q8NB20_ Q8NB83_
    HUMAN HUMAN HUMAN HUMAN HUMAN
    Q8NBE0_ Q8NCA1_ Q8NCK2_ Q8NEQ2_ Q8NFX8_
    HUMAN HUMAN HUMAN HUMAN HUMAN
    Q8NGC8_ Q8NGD7_ Q8NGE6_ Q8NGF2_ Q8NGG1_
    HUMAN HUMAN HUMAN HUMAN HUMAN
    Q8NGK8_ Q8NGM0_ Q8NGM4_ Q8NGM6_ Q8NGP1_
    HUMAN HUMAN HUMAN HUMAN HUMAN
    Q8NGP5_ Q8NGP7_ Q8NGQ7_ Q8NGY4_ Q8NH06_
    HUMAN HUMAN HUMAN HUMAN HUMAN
    Q8NH08_ Q8NH11_ Q8NH32_ Q8NH33_ Q8NH46_
    HUMAN HUMAN HUMAN HUMAN HUMAN
    Q8NH47_ Q8NH58_ Q8NH68_ Q8NH71_ Q8NH75_
    HUMAN HUMAN HUMAN HUMAN HUMAN
    Q8NH77_ Q8NH80_ Q8NH82_ Q8NH88_ Q8NH95_
    HUMAN HUMAN HUMAN HUMAN HUMAN
    Q8NH98_ Q8NHA6_ Q8NHB0_ Q8NHB3_ Q8NHB5_
    HUMAN HUMAN HUMAN HUMAN HUMAN
    Q8NHC0_ Q8NHC1_ Q8NHC2_ Q8TAF5_ Q8TBR1_
    HUMAN HUMAN HUMAN HUMAN HUMAN
    Q8TCI8_HUMAN Q8TDK1_ Q8TDP9_ Q8TE05_ Q8WM95_
    HUMAN HUMAN HUMAN HUMAN
    Q8WTY6_ Q8WYW5_ Q8WYX1_ Q8VVZ27_ Q8VVZ91
    HUMAN HUMAN HUMAN HUMAN
    Q96AM0_ Q96CK5_ Q96DR3_ Q96HF5_ Q96HZ0_
    HUMAN HUMAN HUMAN HUMAN HUMAN
    Q96IP2_HUMAN Q96K91_HUMAN Q96M56_ Q96M66_ Q96M92_
    HUMAN HUMAN HUMAN
    Q96MC4_ Q96MT0_ Q96MZ3_ Q96NEO_ Q96NP5_
    HUMAN HUMAN HUMAN HUMAN HUMAN
    Q96PS2_ Q96PS6_ Q96QEO_ Q96RF1_ Q96R13_
    HUMAN HUMAN HUMAN HUMAN HUMAN
    Q96RW6_ Q96RY6_ Q96RY9_ Q99543-2 Q9BRP9_
    HUMAN HUMAN HUMAN HUMAN
    Q9BSD4_ Q9BSM8_ Q9BSY8_ Q9BVW6_ Q9BVX4_
    HUMAN HUMAN HUMAN HUMAN HUMAN
    Q9BZU6_ Q9C0K3_ Q9GZQ9_ Q9H2C7_ Q9H354_
    HUMAN HUMAN HUMAN HUMAN HUMAN
    Q9H410_HUMAN Q9H521_HUMAN Q9H5Q3_ Q9H614_ Q9H693_
    HUMAN HUMAN HUMAN
    Q9H6A9_ Q9H6K5_ Q9H6S2_ Q9H6Z8_ Q9H8C5_
    HUMAN HUMAN HUMAN HUMAN HUMAN
    Q9H8D1_ Q9H960_ Q9HAB5_ Q9HAC4_ Q9HAD2_
    HUMAN HUMAN HUMAN HUMAN HUMAN
    Q9HAJ0_ Q9HAZ8_ Q9HBS9_ Q9NQ39_ Q9NRE4_
    HUMAN HUMAN HUMAN HUMAN HUMAN
    Q9NRE7_ Q9NSI3_HUMAN Q9NSQ0_HUMAN Q9NT31_ Q9NU36_
    HUMAN HUMAN HUMAN
    Q9NW32_ Q9NWP0_ Q9NYD3_ Q9NYS9_ Q9NZ01-2
    HUMAN HUMAN HUMAN HUMAN
    Q9P0C7_ Q9P143_HUMAN Q9P147_HUMAN Q9P156_HUMAN Q9P184_HUMAN
    HUMAN
    Q9P1D0_ Q9P1G6_ Q9P1L5_ Q9P1M5_ Q9P2A3_
    HUMAN HUMAN HUMAN HUMAN HUMAN
    Q9UHU1_ Q9UHU9_ Q9UI72_ Q9UJN8_ Q9UK71_
    HUMAN HUMAN HUMAN HUMAN HUMAN
    Q9Y6V0-3 QARS QDPR QKI QPCT
    QPCTL QPRT QRFP QRFPR QRICH1
    QRICH2 QRSLI QSERI QSOX1 QSOX2
    QTRT1 QTRTDI R3HCCI R3HDMI R3HDM2
    R3HDML RAB10 RAB11A RAB11B RAB11FIPI
    RAB11FIP2 RAB11FIP3 RAB11FIP4 RAB11FIP5 RAB12
    RAB13 RAB14 RAB15 RAB17 RAB18
    RAB19 RAB19B RAB1A RAB1B RAB20
    RAB21 RAB22A RAB23 RAB24 RAB25
    RAB26 RAB27A RAB27B RAB28 RAB2A
    RAB2B RAB30 RAB31 RAB32 RAB33A
    RAB33B RAB34 RAB35 RAB36 RAB37
    RAB38 RAB39 RAB39B RAB3A RAB3B
    RAB3C RAB3D RAB3GAP1 RAB3GAP2 RAB3IL1
    RAB3IP RAB40A RAB40AL RAB40B RAB40C
    RAB41 RAB42 RAB43 RAB44 RAB4A
    RAB4B RAB5A RAB5B RAB5C RAB6A
    RAB6B RAB6C RAB7A RAB7L1 RAB8A
    RAB8B RAB9A RAB9B RABAC1 RABEP1
    RABEP2 RABEPK RABGAP1 RABGAP1L RABGEF1
    RABGGTB RABIF RABL2A RABL2B RABL3
    RABL4 RABL5 RAC1 RACIP4 RAC2
    RAC3 RACGAP1 RAD1 RAD17 RAD18
    RAD21 RAD23A RAD23B RAD50 RAD51
    RAD51AP1 RAD51AP2 RAD51C RAD51L1 RAD51L3
    RAD52 RAD54B RAD54L RAD54L2 RAD9A
    RAD9B RADIL RAE1 RAET1E RAET1G
    RAET1L RAF1 RAG1 RAG1AP1 RAG2
    RAGE RAI1 RAI14 RAI16 RAI2
    RALA RALB RALBPI RALGAPA1 RALGAPB
    RALGDS RALGPS1 RALGPS2 RALY RAMP1
    RAMP2 RAMP3 RAN RANBP1 RANBP10
    RANBP17 RANBP2 RANBP3 RANBP3L RANBP6
    RANBP9 RANGAP1 RANGRF RAP1A RAP1B
    RAP1GAP RAP1GAP_ RAP1GDS1 RAP2A RAP2B
    ENST00000374761
    RAP2C RAPGEF1 RAPGEF2 RAPGEF3 RAPGEF4
    RAPGEF5 RAPGEF5_ RAPGEF6 RAPGEFL1 RAPH1
    ENST00000344041
    RAPSN RARA RARB RARG RARRES1
    RARRES2 RARRES3 RARS RARS2 RASA1
    RASA2 RASA3 RASA4 RASAL1 RASAL2
    RASD1 RASD2 RASEF RASGEF1A RASGEF1B
    RASGEF1C RASGRF1 RASGRF2 RASGRP1 RASGRP2
    RASGRP3 RASGRP4 RASIP1 RASL10A RASL10B
    RASL11A RASL11B RASL12 RASL2_ RASSF1
    HUMAN
    RASSF2 RASSF3 RASSF4 RASSF5 RASSF5_
    ENST00000304534
    RASSF6 RASSF7 RASSF8 RAVER1 RAVER2
    RAX RAX2 RB1 RB1CC1 RBAK
    RBBP4 RBBP5 RBBP6 RBBP7 RBBP8
    RBBP9 RBCK1 RBKS RBL1 RBL2
    RBM10 RBM12 RBM12B RBM14 RBM15
    RBM15B RBM16 RBM17 RBM18 RBM19
    RBM22 RBM23 RBM24 RBM25 RBM26
    RBM27 RBM28 RBM3 RBM34 RBM34_
    ENST00000408888
    RBM39 RBM4 RBM41 RBM42 RBM43
    RBM45 RBM46 RBM47 RBM4B RBM5
    RBM6 RBM7 RBM8A RBM9 RBMSI
    RBMS2 RBMS3 RBMX RBMX2 RBMXL2
    RBMY1A1 RBMY1B RBMY1D RBMY1E RBMY1F
    RBMY1J RBP1 RBP2 RBP3 RBP4
    RBP5 RBP7 RBPJ RBPJL RBPMS
    RBPMS2 RBX1 RC3H1 RC3H2 RCAN1
    RCAN2 RCAN3 RCBTB1 RCBTB2 RCC1
    RCC2 RCCD1 RCE1 RCHY1 RCL1
    RCN1 RCN2 RCN3 RCOR1 RCOR2
    RCOR3 RCSD1 RCVRN RD3 RDBP
    RDH10 RDH11 RDH12 RDH13 RDH14
    RDH16 RDH5 RDH8 RDM1 RDX
    REC8 RECK RECQL RECQL4 RECQL5
    REEP1 REEP2 REEP4 REEP5 REEP6
    REEP6_ REG1A REG1B REG3A REG3G
    ENST00000395484
    REG4 REL RELA RELB RELL1
    RELL2 RELN RELT REM1 REM2
    REN RENBP RENBP_ REP15 REPIN1
    ENST00000393700
    REPS1 REPS2 RER1 RERE RERG
    RERGL RESP18 REST RET RETN
    RETNLB RETSAT REV1 REV3L REXO1
    REXO2 REXO4 RFC1 RFC2 RFC3
    RFC4 RFC5 RFESD RFFL RFK
    RFNG RFPL1 RFPL2 RFPL3 RFPL4A
    RFPL4B RFT1 RFTN1 RFTN2 RFWD2
    RFWD3 RFX1 RFX2 RFX3 RFX4
    RFX5 RFX6 RFX7 RFXANK RFXAP
    RG9MTD1 RG9MTD2 RG9MTD3 RGAG1 RGAG4
    RGL1 RGL2 RGL3 RGL3_ RGL4
    ENST00000380456
    RGMA RGN RGPD2 RGPD5 RGPD6
    RGPD7 RGR RGS1 RGS10 RGS11
    RGS12 RGS13 RGS14 RGS16 RGS17
    RGS18 RGS19 RGS2 RGS20 RGS21
    RGS22 RGS3 RGS4 RGS5 RGS6
    RGS7 RGS7BP RGS8 RGS9 RGS9BP
    RGSL1 RGSL2 RHAG RHBDD1 RHBDD2
    RHBDD3 RHBDF1 RHBDF2 RHBDL1 RHBDL2
    RHBDL3 RHBG RHCE RHCG RHD
    RHEB RHEBL1 RHO RHOA RHOB
    RHOBTB1 RHOBTB2 RHOBTB3 RHOC RHOD
    RHOF RHOG RHOH RHOJ RHOQ
    RHOT1 RHOT2 RHOU RHOV RHOXF1
    RHOXF2 RHOXF2B RHPN1 RHPN2 RIBC1
    RIBC2 RIC3 RIC8A RIC8B RICTOR
    RIF1 RILP RILPL2 RIMBP2 RIMKLA
    RIMS1 RIMS2 RIMS2_ RIMS3 RIMS4
    ENST00000436393
    RIN1 RIN2 RIN3 RING1 RINL
    RINT1 RIOK1 RIOK2 RIOK3 RIPK1
    RIPK2 RIPK3 RIPK4 RIPPLY1 RIPPLY2
    RIT1 RIT2 RL17_HUMAN RL41_HUMAN RLBP1
    RLBP1L1 RLF RLIM RLN1 RLN2
    RLN3 RLTPR RLTPR_ RMI1 RMND1
    ENST00000334583
    RMND5A RMND5B RNASE1 RNASE10 RNASE11
    RNASE12 RNASE13 RNASE2 RNASE3 RNASE4
    RNASE6 RNASE7 RNASE8 RNASE9 RNASEH1
    RNASEH2A RNASEH2B RNASEH2C RNASEK RNASEL
    RNASEN RNASET2 RND1 RND2 RND3
    RNF10 RNF103 RNF11 RNF111 RNF112
    RNF113A RNF113B RNF114 RNF115 RNF121
    RNF122 RNF123 RNF125 RNF126 RNF128
    RNF13 RNF130 RNF133 RNF134 RNF135
    RNF138 RNF139 RNF14 RNF141 RNF144A
    RNF144B RNF145 RNF146 RNF148 RNF149
    RNF150 RNF151 RNF152 RNF157 RNF160
    RNF165 RNF166 RNF167 RNF168 RNF169
    RNF17 RNF170 RNF180 RNF181 RNF182
    RNF183 RNF185 RNF186 RNF187 RNF19A
    RNF19B RNF2 RNF20 RNF207 RNF208
    RNF212 RNF213 RNF214 RNF215 RNF216
    RNF217 RNF219 RNF220 RNF222 RNF24
    RNF25 RNF26 RNF31 RNF32 RNF34
    RNF38 RNF39 RNF4 RNF40 RNF41
    RNF43 RNF44 RNF5 RNF6 RNF7
    RNF8 RNFT1 RNGTT RNH1 RNLS
    RNMT RNMTL1 RNPEP RNPEPL1 RNPS1
    ROBLD3 ROBO1 ROBO1_ ROBO2 ROBO3
    ENST00000305299
    ROBO4 ROCK1 ROCK2 ROD1 ROGDI
    ROM1 ROMO1 ROPN1 ROPN1B ROPN1L
    ROR1 ROR2 RORA RORB RORC
    ROS1 RP1 RP1-19N1_1 RP1-21O18_1 RP1-
    21O18_1_
    NEW
    RP1-241P17_4 RP1-32I10.10 RP11- RP11-45B20_2 RP11-
    274K13_2 529I10_4
    RP11-551L14.1 RP11-98I6_3 RP13- RP13-36C9_1 RP1L1
    218H24_1
    RP2 RP3-364I1_1 RP3-402G11_5 RP3-527F8_2 RP4-
    545K15_3
    RP4-765F13_3 RP5-1139I1_4 RP6-149D17_1 RP9 RPA1
    RPA2 RPA2_ RPA3 RPA4 RPAIN
    ENST00000313433
    RPAP1 RPAP2 RPAP3 RPE RPE65
    RPF1 RPF2 RPGR RPGRIP1 RPGRIP1L
    RPH3A RPH3AL RPIA RPL10 RPL10A
    RPL10AP3 RPL10L RPL11 RPL12 RPL13
    RPL13A RPL13AP25 RPL14 RPL14P5 RPL15
    RPL17P39 RPL18 RPL18A RPL19 RPL21
    RPL21P128 RPL21P20 RPL21P44 RPL22 RPL23
    RPL23A RPL23AP82 RPL24 RPL26 RPL26L1
    RPL27 RPL27A RPL27AP6 RPL28 RPL29
    RPL29P12 RPL3 RPL30 RPL31 RPL32
    RPL32P3 RPL32P36 RPL34 RPL35 RPL35A
    RPL35P1 RPL36 RPL36A RPL36AL RPL36P14
    RPL37 RPL37A RPL38 RPL39 RPL39L
    RPL3L RPL4 RPL41 RPL5 RPL6
    RPL7 RPL7A RPL7L1 RPL8 RPL9
    RPL9P7 RPLP0 RPLP1 RPLP1P3 RPLP2
    RPN1 RPN2 RPP14 RPP21 RPP25
    RPP30 RPP38 RPP40 RPRD1A RPRD1B
    RPRM RPRML RPS10 RPS11 RPS12
    RPS13 RPS14 RPS15 RPS15A RPS15P4
    RPS16 RPS17 RPS18 RPS19 RPS19BP1
    RPS2 RPS20 RPS20P14 RPS21 RPS23
    RPS24 RPS25 RPS26 RPS26P11 RPS26P3
    RPS27 RPS27A RPS27AP17 RPS27L RPS28
    RPS29 RPS2P55 RPS3 RPS3A RPS3AP6
    RPS4X RPS4Y1 RPS4Y2 RPS5 RPS6
    RPS6KA1 RPS6KA2 RPS6KA3 RPS6KA4 RPS6KA5
    RPS6KA6 RPS6KB1 RPS6KB2 RPS6KC1 RPS6KL1
    RPS6P1 RPS7 RPS7P4 RPS8 RPS9
    RPSA RPTN RPTOR RPUSD1 RPUSD2
    RPUSD3 RPUSD4 RQCD1 RRAD RRAGA
    RRAGB RRAGC RRAGD RRAS RRAS2
    RRBP1 RREB1 RRH RRM1 RRM2
    RRM2B RRN3 RRP1 RRP12 RRP15
    RRP1B RRP7A RRP8 RRP9 RRS1
    RS1 RSAD1 RSAD2 RSBN1 RSBN1L
    RSC1A1 RSF1 RSL1D1 RSL24D1 RSPH1
    RSPH10B RSPH10B2 RSPH3 RSPH4A RSPH6A
    RSPH9 RSPO1 RSPO2 RSPO3 RSPO4
    RSPRY1 RSRC1 RSRC2 RSU1 RTBDN
    RTCD1 RTDR1 RTEL1 RTF1 RTKN
    RTKN2 RTN1 RTN2 RTN3 RTN4
    RTN4IP1 RTN4R RTN4RL2 RTP1 RTP2
    RTP3 RTP4 RTTN RUFY1 RUFY2
    RUFY3 RUNDC1 RUNDC2A RUNDC2B RUNDC3B
    RUNX1 RUNX1T1 RUNX1T1_ RUNX2 RUNX3
    ENST00000265814
    RUSC1 RUSC2 RUVBL1 RUVBL2 RWDD1
    RWDD2A RWDD2B RWDD3 RWDD4A RXFP1
    RXFP2 RXFP3 RXFP4 RXRA RXRB
    RXRG RYK RYR1 RYR2 RYR3
    S100A1 S100A10 S100A11 S100A12 S100A13
    S100A14 S100A16 S100A2 S100A3 S100A4
    S100A5 S100A6 S100A7 S100A7A S100A7L2
    S100A8 S100A9 S100B S100G S100P
    S100PBP S100Z S1PR1 S1PR2 S1PR3
    S1PR4 S1PR5 SAA1 SAA2 SAA3P
    SAA4 SAAL1 SAC3D1 SACM1L SACS
    SAE1 SAFB SAFB2 SAGE1 SALL1
    SALL2 SALL3 SALL4 SAMD10 SAMD11
    SAMD12 SAMD13 SAMD14 SAMD3 SAMD4A
    SAMD4B SAMD5 SAMD7 SAMD8 SAMD8_
    ENST00000372690
    SAMD9 SAMD9L SAMHD1 SAMM50 SAMSN1
    SAP130 SAP18 SAP30 SAP30BP SAP30L
    SAPS1 SAPS2 SAPS3 SAR1A SAR1B
    SARDH SARNP SARS SARS2 SART1
    SART3 SASH1 SASH3 SASS6 SAT1
    SAT2 SATB1 SATB2 SATL1 SAV1
    SBDS SBF1 SBF2 SBK1 SBK2
    SBNO1 SBSN SC4MOL SC5DL SC65
    SCAF1 SCAI SCAMP2 SCAMP3 SCAMP4
    SCAND1 SCAND3 SCAP SCAPER SCARA3
    SCARA5 SCARB1 SCARB2 SCARF1 SCARF2
    SCCPDH SCD SCD5 SCEL SCFD1
    SCFD2 SCG2 SCG3 SCGB1A1 SCGB1C1
    SCGB1D1 SCGB1D2 SCGB1D4 SCGB2A1 SCGB2A2
    SCGB3A1 SCGB3A2 SCGBL SCGN SCHIP1
    SCLT1 SCLY SCMH1 SCML1 SCML2
    SCML4 SCN10A SCN11A SCN1A SCN1B
    SCN2A SCN2B SCN3A SCN3B SCN4A
    SCN4B SCN5A SCN7A SCN9A SCNM1
    SCNN1A SCNN1B SCNN1D SCNN1G SCO1
    SCO2 SCOC SCP2 SCPEP1 SCRG1
    SCRIB SCRN1 SCRN2 SCRN3 SCRT1
    SCRT2 SCTR SCUBE1 SCUBE2 SCUBE3
    SCXB SCYL1 SCYL2 SCYL3 SDAD1
    SDC1 SDC2 SDC3 SDC4 SDCBP
    SDCBP2 SDCCAG1 SDCCAG3 SDCCAG3L SDCCAG8
    SDF2 SDF2L1 SDF4 SDHA SDHAF1
    SDHAF2 SDHB SDHC SDHD SDK1
    SDPR SDR16C5 SDR42E1 SDR9C7 SDS
    SDSL SEC11B SEC11C SEC13 SEC14L1
    SEC14L2 SEC14L3 SEC14L4 SEC16B SEC22A
    SEC22C SEC23A SEC23B SEC23IP SEC24A
    SEC24B SEC24C SEC24D SEC31A SEC31B
    SEC61A1 SEC61A2 SEC61B SEC61G SEC62
    SEC63 SECISBP2 SECISBP2L SECTM1 SEH1L
    SEL1L SEL1L2 SELE SELENBP1 SELI
    SELL SELM SELP SELPLG SELV
    SEMA3A SEMA3B SEMA3C SEMA3D SEMA3E
    SEMA3F SEMA3G SEMA4A SEMA4B SEMA4C
    SEMA4D SEMA4F SEMA4G SEMA5A SEMA5B
    SEMA6A SEMA6B SEMA6C SEMA6D SEMA7A
    SEMG1 SEMG2 SENP1 SENP2 SENP3
    SENP5 SENP6 SENP7 SENP8 15-Sep
    SEPHS1 SEPHS2 SEPN1 SEPP1 SEPSECS
    01-Sep 10-Sep 11-Sep 12-Sep 02-Sep
    03-Sep 04-Sep 05-Sep 06-Sep 08-Sep
    09-Sep SEPX1 SERAC1 SERBP1 SERF1A
    SERF1B SERF2 SERGEF SERHL SERHL2
    SERINC1 SERINC2 SERINC3 SERINC4 SERP1
    SERP1_ SERP2 SERPINA1 SERPINA10 SERPINA11
    ENST00000491660
    SERPINA12 SERPINA13 SERPINA2 SERPINA3 SERPINA4
    SERPINA5 SERPINA6 SERPINA7 SERPINA9 SERPINA9_
    ENST00000337425
    SERPINB1 SERPINB10 SERPINB11 SERPINB12 SERPINB13
    SERPINB2 SERPINB3 SERPINB4 SERPINB5 SERPINB6
    SERPINB7 SERPINB8 SERPINB9 SERPINC1 SERPIND1
    SERPINE1 SERPINE2 SERPINF1 SERPINF2 SERPING1
    SERPINH1 SERPINI1 SERPINI2 SERTAD1 SERTAD2
    SERTAD3 SERTAD4 SESN1 SESN2 SESN3
    SESTD1 SET SETBP1 SETD1A SETD1B
    SETD2 SETD2_ SETD3 SETD4 SETD5
    ENST00000409792
    SETD6 SETD7 SETD8 SETDB1 SETDB2
    SETMAR SETX SEZ6 SEZ6L SEZ6L2
    SF1 SF3A1 SF3A2 SF3A3 SF3B1
    SF3B14 SF3B2 SF3B3 SF3B4 SF3B5
    SF4 SFI1 SFMBT1 SFMBT2 SFN
    SFPQ SFRP1 SFRP2 SFRP4 SFRP5
    SFRS1 SFRS11 SFRS12 SFRS12IP1 SFRS13B
    SFRS14 SFRS15 SFRS16 SFRS17A SFRS18
    SFRS2 SFRS2IP SFRS3 SFRS4 SFRS5
    SFRS6 SFRS7 SFRS8 SFRS9 SFT2D1
    SFT2D2 SFT2D3 SFTA2 SFTPA1B SFTPA2
    SFTPA2B SFTPB SFTPC SFTPD SFXN1
    SFXN2 SFXN3 SFXN4 SFXN5 SG223_
    HUMAN
    SG269_HUMAN SGCA SGCB SGCE SGCG
    SGCZ SGEF SGIP1 SGK1 SGK2
    SGK3 SGMS1 SGMS2 SGOL1 SGOL2
    SGPL1 SGPP1 SGPP2 SGSH SGSM1
    SGSM2 SGSM3 SGTA SGTB SH2B1
    SH2B3 SH2D1A SH2D1B SH2D2A SH2D3A
    SH2D3C SH2D4A SH2D4B SH2D5 SH2D6
    SH3BGR SH3BGRL SH3BGRL2 SH3BGRL3 SH3BP1
    SH3BP2 SH3BP4 SH3BP5 SH3BP5L SH3D19
    SH3D20 SH3GL1 SH3GL2 SH3GL3 SH3GLB1
    SH3GLB2 SH3KBP1 SH3PXD2A SH3PXD2B SH3RF1
    SH3RF2 SH3TC1 SH3TC2 SH3YL1 SHANK1
    SHANK2 SHANK3 SHARPIN SHB SHBG
    SHC1 SHC1_ SHC2 SHC3 SHC4
    ENST00000448116
    SHCBP1 SHD SHE SHF SHFM1
    SHH SHISA2 SHISA3 SHISA4 SHISA5
    SHKBP1 SHMT1 SHMT2 SHOC2 SHOX
    SHOX2 SHPK SHPRH SHQ1 SHROOM1
    SHROOM2 SHROOM3 SHROOM4 SI SIAE
    SIAH1 SIAH1L SIAH2 SIAH3 SIDT1
    SIDT2 SIGIRR SIGLEC1 SIGLEC10 SIGLEC11
    SIGLEC12 SIGLEC12_ SIGLEC14 SIGLEC15 SIGLEC5
    ENST00000439889
    SIGLEC6 SIGLEC7 SIGLEC8 SIGLEC9 SIGMAR1
    SIK1 SIK2 SIK3 SIKE1 SIL1
    SILV SIM1 SIM2 SIN3A SIN3B
    SIP1 SIPA1 SIPA1L1 SIPA1L2 SIPA1L3
    SIRPA SIRPB1 SIRPB2 SIRPD SIRPG
    SIRT1 SIRT2 SIRT3 SIRT4 SIRT5
    SIRT6 SIRT7 SIT1 SIVA1 SIX1
    SIX2 SIX3 SIX4 SIX5 SIX6
    SK681 SKA1 SKA3 SKAP1 SKAP2
    SKI SKIL SKIP SKIV2L SKIV2L2
    SKP1 SKP2 SLA SLA2 SLAIN1
    SLAMF1 SLAMF6 SLAMF7 SLAMF8 SLAMF9
    SLBP SLC10A1 SLC10A2 SLC10A3 SLC10A4
    SLC10A5 SLC10A6 SLC10A7 SLC11A1 SLC11A2
    SLC12A1 SLC12A2 SLC12A3 SLC12A4 SLC12A5
    SLC12A6 SLC12A7 SLC12A8 SLC12A9 SLC13A1
    SLC13A2 SLC13A3 SLC13A4 SLC13A5 SLC14A1
    SLC14A2 SLC15A1 SLC15A2 SLC15A3 SLC15A4
    SLC16A1 SLC16A10 SLC16A11 SLC16Al2 SLC16A13
    SLC16A14 SLC16A2 SLC16A3 SLC16A4 SLC16A5
    SLC16A6 SLC16A7 SLC16A8 SLC16A9 SLC17A1
    SLC17A2 SLC17A3 SLC17A4 SLC17A5 SLC17A6
    SLC17A7 SLC17A8 SLC17A9 SLC18A1 SLC18A2
    SLC18A3 SLC19A1 SLC19A2 SLC19A3 SLC1A1
    SLC1A2 SLC1A3 SLC1A4 SLC1A5 SLC1A6
    SLC1A7 SLC20A1 SLC20A2 SLC22A1 SLC22A10
    SLC22A11 SLC22Al2 SLC22A13 SLC22A14 SLC22A15
    SLC22A16 SLC22A17 SLC22A18 SLC22A2 SLC22A20
    SLC22A23 SLC22A25 SLC22A3 SLC22A4 SLC22A5
    SLC22A6 SLC22A7 SLC22A8 SLC22A9 SLC23A1
    SLC23A2 SLC23A3 SLC24A2 SLC24A3 SLC24A4
    SLC24A5 SLC24A6 SLC25A1 SLC25A10 SLC25A11
    SLC25Al2 SLC25A13 SLC25A14 SLC25A15 SLC25A16
    SLC25A17 SLC25A18 SLC25A19 SLC25A2 SLC25A20
    SLC25A21 SLC25A22 SLC25A23 SLC25A24 SLC25A25
    SLC25A27 SLC25A28 SLC25A29 SLC25A3 SLC25A30
    SLC25A31 SLC25A32 SLC25A33 SLC25A34 SLC25A35
    SLC25A36 SLC25A37 SLC25A38 SLC25A39 SLC25A4
    SLC25A40 SLC25A42 SLC25A43 SLC25A44 SLC25A45
    SLC25A46 SLC25A5 SLC25A6 SLC26A1 SLC26A10
    SLC26A11 SLC26A2 SLC26A3 SLC26A4 SLC26A5
    SLC26A6 SLC26A7 SLC26A8 SLC26A9 SLC27A1
    SLC27A2 SLC27A3 SLC27A4 SLC27A5 SLC27A6
    SLC28A1 SLC28A2 SLC28A3 SLC29A1 SLC29A2
    SLC29A3 SLC29A4 SLC2A1 SLC2A10 SLC2A11
    SLC2A12 SLC2A13 SLC2A14 SLC2A2 SLC2A3
    SLC2A4 SLC2A4RG SLC2A5 SLC2A6 SLC2A7
    SLC2A8 SLC2A9 SLC30A1 SLC30A10 SLC30A2
    SLC30A3 SLC30A4 SLC30A5 SLC30A6 SLC30A7
    SLC30A8 SLC30A9 SLC31A1 SLC31A2 SLC32A1
    SLC33A1 SLC34A1 SLC34A2 SLC34A3 SLC35A1
    SLC35A2 SLC35A3 SLC35A4 SLC35A5 SLC35B1
    SLC35B2 SLC35B3 SLC35B4 SLC35C1 SLC35C2
    SLC35D1 SLC35D2 SLC35D3 SLC35E1 SLC35E2
    SLC35E3 SLC35E4 SLC35F1 SLC35F2 SLC35F3
    SLC35F5 SLC36A1 SLC36A2 SLC36A3 SLC36A4
    SLC37A1 SLC37A2 SLC37A3 SLC37A4 SLC38A1
    SLC38A10 SLC38A11 SLC38A2 SLC38A3 SLC38A4
    SLC38A5 SLC38A6 SLC38A7 SLC38A8 SLC38A9
    SLC39A1 SLC39A10 SLC39A11 SLC39Al2 SLC39A13
    SLC39A14 SLC39A2 SLC39A3 SLC39A4 SLC39A5
    SLC39A6 SLC39A7 SLC39A8 SLC39A9 SLC3A1
    SLC3A2 SLC40A1 SLC41A1 SLC41A2 SLC41A3
    SLC43A1 SLC43A2 SLC43A3 SLC44A1 SLC44A2
    SLC44A3 SLC44A4 SLC44A5 SLC45A1 SLC45A2
    SLC45A3 SLC45A4 SLC46A2 SLC46A3 SLC47A1
    SLC47A2 SLC48A1 SLC4A1 SLC4A10 SLC4A11
    SLC4A1AP SLC4A2 SLC4A3 SLC4A4 SLC4A5
    SLC4A7 SLC4A8 SLC4A9 SLC4A9_ SLC5A1
    ENST00000506757
    SLC5A10 SLC5A11 SLC5A12 SLC5A2 SLC5A3
    SLC5A4 SLC5A5 SLC5A6 SLC5A7 SLC5A8
    SLC5A9 SLC6A1 SLC6A11 SLC6Al2 SLC6A13
    SLC6A14 SLC6A15 SLC6A16 SLC6A17 SLC6A18
    SLC6A19 SLC6A2 SLC6A20 SLC6A3 SLC6A4
    SLC6A5 SLC6A6 SLC6A7 SLC6A8 SLC6A9
    SLC7A1 SLC7A10 SLC7A11 SLC7A13 SLC7A14
    SLC7A2 SLC7A3 SLC7A4 SLC7A5 SLC7A6
    SLC7A6OS SLC7A7 SLC7A8 SLC7A9 SLC8A1
    SLC8A2 SLC8A3 SLC9A1 SLC9A10 SLC9A11
    SLC9A2 SLC9A3 SLC9A3R1 SLC9A3R2 SLC9A4
    SLC9A5 SLC9A6 SLC9A7 SLC9A8 SLC9A9
    SLCO1A2 SLCO1B1 SLCO1B3 SLCO1C1 SLCO2A1
    SLCO2B1 SLCO3A1 SLCO4A1 SLCO4C1 SLCO5A1
    SLCO6A1 SLFN11 SLFN12 SLFN13 SLFN14
    SLFN5 SLFNL1 SLIT1 SLIT2 SLIT3
    SLITRK1 SLITRK2 SLITRK3 SLITRK4 SLITRK5
    SLITRK6 SLK SLMAP SLMO1 SLMO2
    SLN SLPI SLTM SLU7 SLURP1
    SMAD1 SMAD2 SMAD3 SMAD4 SMAD5
    SMAD5OS SMAD6 SMAD7 SMAD9 SMAP1
    SMAP2 SMARCA1 SMARCA2 SMARCA4 SMARCA5
    SMARCAD1 SMARCAL1 SMARCB1 SMARCC1 SMARCC2
    SMARCD1 SMARCD2 SMARCD3 SMARCE1 SMC1A
    SMC1B SMC2 SMC2L1 SMC3 SMC4
    SMC5 SMC6 SMCHD1 SMCP SMCR7
    SMCR7L SMCR8 SMEK1 SMEK1_ SMEK2
    ENST00000417249
    SMG1 SMG5 SMG6 SMG7 SMN1
    SMN2 SMNDC1 SMO SMOC1 SMOC2
    SMOX SMPD1 SMPD2 SMPD3 SMPD4
    SMPDL3A SMPDL3B SMPX SMR3A SMR3B
    SMS SMTN SMTNL2 SMU1 SMUG1
    SMURF1 SMURF2 SMYD1 SMYD2 SMYD3
    SMYD4 SMYD5 SNAI1 SNAI2 SNAI3
    SNAP23 SNAP25 SNAP29 SNAP47 SNAPC1
    SNAPC2 SNAPC3 SNAPC4 SNAPC5 SNAPIN
    SNCA SNCAIP SNCB SNCG SND1
    SNED1 SNF8 SNIP1 SNN SNPH
    SNRK SNRNP200 SNRNP25 SNRNP27 SNRNP35
    SNRNP48 SNRNP70 SNRPA SNRPA1 SNRPB
    SNRPB2 SNRPC SNRPD1 SNRPD2 SNRPD3
    SNRPE SNRPEL1 SNRPF SNRPG SNRPN
    SNTA1 SNTBI SNTB2 SNTG1 SNTG2
    SNTN SNUPN SNURF SNW1 SNX1
    SNX10 SNX11 SNX12 SNX13 SNX14
    SNX15 SNX16 SNX17 SNX18 SNX19
    SNX2 SNX20 SNX21 SNX22 SNX24
    SNX25 SNX27 SNX3 SNX30 SNX31
    SNX32 SNX33 SNX4 SNX5 SNX6
    SNX7 SNX8 SNX9 SOAT1 SOAT2
    SOBP SOCS1 SOCS2 SOCS3 SOCS4
    SOCS5 SOCS6 SOCS7 SOD1 SOD2
    SOD3 SOHLH1 SOHLH2 SOLH SON
    SORBS1 SORBS2 SORBS3 SORCS1 SORCS2
    SORCS3 SORD SORL1 SORT1 SOS1
    SOS2 SOST SOSTDC1 SOX1 SOX10
    SOX11 SOX12 SOX13 SOX14 SOX15
    SOX17 SOX18 SOX2 SOX21 SOX3
    SOX30 SOX4 SOX5 SOX6 SOX7
    SOX8 SOX9 SP1 SP100 SP110
    SP140 SP140L SP2 SP3 SP4
    SP5 SP6 SP8 SPA17 SPACA1
    SPACA3 SPACA4 SPACA5 SPACA5B SPAG1
    SPAG11A SPAG11B SPAG16 SPAG17 SPAG4
    SPAG5 SPAG6 SPAG7 SPAG8 SPAG9
    SPAM1 SPANX-N1 SPANXA1 SPANXA2 SPANXB1
    SPANXC SPANXD SPANXN1 SPANXN2 SPANXN3
    SPANXN4 SPANXN5 SPARC SPARCL1 SPAST
    SPATA1 SPATA12 SPATA13 SPATA16 SPATA17
    SPATA18 SPATA19 SPATA2 SPATA20 SPATA21
    SPATA22 SPATA2L SPATA4 SPATA5 SPATA5L1
    SPATA6 SPATA7 SPATA8 SPATA9 SPATC1
    SPATS1 SPATS2 SPC25 SPCS1 SPCS2
    SPDEF SPDYA SPDYC SPDYE1 SPDYE2
    SPEF1 SPEF2 SPEF2_ SPEG SPEM1
    ENST00000356031
    SPEM1_ SPEN SPERT SPESP1 SPFH1
    ENST00000323383
    SPG11 SPG20 SPG21 SPG7 SPHAR
    SPHK1 SPHK2 SPHKAP SPI1 SPIB
    SPIC SPIN1 SPIN2A SPIN2B SPIN3
    SPIN4 SPINK1 SPINK2 SPINK4 SPINK5
    SPINK5L2 SPINK5L3 SPINK6 SPINK7 SPINK9
    SPINLW1 SPINLW1_ SPINT1 SPINT2 SPINT4
    ENST00000336443
    SPIRE1 SPIRE2 SPN SPNS1 SPNS2
    SPNS3 SPO11 SPOCD1 SPOCK1 SPOCK2
    SPOCK3 SPON2 SPOP SPOPL SPP1
    SPP2 SPPL2A SPR SPRED1 SPRED2
    SPRED3 SPRN SPRR1A SPRR1B SPRR2A
    SPRR2B SPRR2D SPRR2E SPRR2F SPRR2G
    SPRR3 SPRR4 SPRY1 SPRY2 SPRY3
    SPRY4 SPRYD3 SPRYD4 SPRYD5 SPRYD5_
    ENST00000327733
    SPSB1 SPSB2 SPSB3 SPSB4 SPTA1
    SPTAN1 SPTB SPTBN1 SPTBN2 SPTBN4
    SPTBN5 SPTLC1 SPTLC2 SPTLC3 SPTY2D1
    SPZ1 SQLE SQRDL SQSTM1 SR140_
    HUMAN
    SRA1 SRBD1 SRC SRCAP SRCRB4D
    SRD5A1 SRD5A3 SREBF1 SREBF2 SRF
    SRFBP1 SRGAP1 SRGAP2P1 SRGAP3 SRGN
    SRI SRL SRM SRMS SRP14
    SRP19 SRP54 SRP68 SRP72 SRP9
    SRP9L1 SRPK1 SRPK2 SRPK3 SRPK3_
    ENST00000489426
    SRPR SRPRB SRPX SRPX2 SRR
    SRRD SRRM1 SRRM2 SRRT SRXN1
    SRY SS18 SS18L1 SS18L2 SSB
    SSBP1 SSBP2 SSBP3 SSBP4 SSFA2
    SSH1 SSH2 SSH3 SSNA1 SSPN
    SSR1 SSR2 SSR3 SSR4 SSRP1
    SSSCA1 SST SSTR1 SSTR2 SSTR3
    SSTR4 SSTR5 SSU72 SSX1 SSX2
    SSX2IP SSX3 SSX4 SSX4B SSX5
    SSX6 SSX7 SSX9 ST13 ST14
    ST18 ST20 ST3GAL1 ST3GAL2 ST3GAL3
    ST3GAL4 ST3GAL5 ST3GAL6 ST5 ST6GAL1
    ST6GAL2 ST6GALNAC1 ST6GALNAC2 ST6GALNAC3 ST6GALNAC4
    ST6GALNAC5 ST6GALNAC6 ST7 ST7L ST8SIA1
    ST8SIA2 ST8SIA3 ST8SIA4 ST8SIA5 ST8SIA6
    STAB1 STAB2 STAC STAC2 STAC3
    STAG1 STAG2 STAG3 STAG3L1 STAG3L3
    STAG3L4 STAM STAM2 STAMBP STAMBPL1
    STAP1 STAP2 STAR STARD10 STARD13
    STARD3 STARD3NL STARD4 STARD5 STARD6
    STARD7 STARD8 STARD8_ STARD9 STAT1
    ENST00000252336
    STAT2 STAT3 STAT4 STAT5A STAT5B
    STAT6 STATH STAU1 STAU2 STBD1
    STC1 STC2 STEAP1 STEAP2 STEAP3
    STEAP4 STIL STIM1 STIM2 STIP1
    STK10 STK11 STK11IP STK16 STK17A
    STK17B STK19 STK24 STK25 STK3
    STK31 STK32A STK32B STK32C STK33
    STK35 STK36 STK38 STK38L STK39
    STK4 STK40 STMN1 STMN2 STMN3
    STMN4 STOM STOML1 STOML2 STOML3
    STON1 STON1- STON2 STOX1 STOX2
    GTF2A1L
    STRA13 STRA6 STRA8 STRADA STRADB
    STRAP STRBP STRC STRN STRN3
    STRN4 STS STT3A STT3B STUB1
    STX10 STX11 STX12 STX16 STX17
    STX18 STX19 STX1A STX1B STX2
    STX3 STX4 STX5 STX6 STX7
    STX8 STXBP1 STXBP2 STXBP3 STXBP4
    STXBP5 STXBP5L STXBP6 STYK1 STYX
    STYXL1 SUB1 SUCLA2 SUCLG1 SUCLG2
    SUCNR1 SUDS3 SUFU SUGT1 SULF1
    SULF2 SULT1A1 SULT1A2 SULT1A3 SULT1A4
    SULT1B1 SULT1C2 SULT1C3 SULT1C4 SULT1E1
    SULT2A1 SULT2B1 SULT4A1 SULT6B1 SUMF1
    SUMF2 SUMO1 SUMO1P1 SUMO2 SUMO3
    SUMO4 SUN1 SUN2 SUN3 SUN5
    SUOX SUPT16H SUPT3H SUPT4H1 SUPT5H
    SUPT6H SUPT7L SUPV3L1 SURF1 SURF2
    SURF4 SURF5 SURF6 SUSD1 SUSD2
    SUSD3 SUSD4 SUSD5 SUV39H1 SUV39H2
    SUV420H1 SUV420H2 SUZ12 SUZ12P SV2A
    SV2B SV2C SVEP1 SVIL SVIP
    SVOPL SWAP70 SYAP1 SYCE1 SYCE2
    SYCN SYCP1 SYCP2 SYCP2L SYCP3
    SYDE1 SYDE2 SYF2 SYK SYMPK
    SYN1 SYN2 SYN3 SYNC SYNCRIP
    SYNE1 SYNE1_ SYNE2 SYNGAP1 SYNGAP1_
    ENST00000265368 ENST00000293748
    SYNGR1 SYNGR2 SYNGR3 SYNGR4 SYNJ1
    SYNJ2 SYNJ2BP SYNM SYNPO SYNPO2
    SYNPO2L SYNRG SYP SYPL1 SYPL2
    SYP_ SYS1 SYT1 SYT10 SYT11
    ENST00000263233
    SYT12 SYT13 SYT14 SYT14L SYT15
    SYT15_ SYT16 SYT17 SYT2 SYT3
    ENST00000374328
    SYT4 SYT5 SYT6 SYT7 SYT8
    SYT9 SYTL1 SYTL2 SYTL3 SYTL4
    SYTL5 SYVN1 SgK069 SgK085 SgK110
    SgK223 SgK269 SgK424 SgK493 SgK494
    SgK495 T T183B_ TAAR1 TAAR2
    HUMAN
    TAAR5 TAAR6 TAAR8 TAB1 TAB2
    TAB3 TAC1 TAC3 TAC4 TACC1
    TACC2 TACC3 TACO1 TACR1 TACR2
    TACR3 TACSTD2 TADA1 TADA2A TADA2B
    TADA3L TAF1 TAF10 TAF11 TAF12
    TAF13 TAF15 TAF1A TAF1B TAF1C
    TAF1D TAF1L TAF2 TAF3 TAF4
    TAF4B TAF5 TAF5L TAF6 TAF6L
    TAF7 TAF7L TAF8 TAF9 TAF9B
    TAGAP TAGLN TAGLN2 TAGLN3 TAL1
    TAL2 TALDO1 TANC1 TANK TAOK1
    TAOK2 TAOK3 TAP1 TAP2 TAP2_
    ENST00000458336
    TAPBP TAPBPL TAPT1 TARBP1 TARBP2
    TARDBP TARS TARS2 TARSL2 TAS1R1
    TAS1R2 TAS1R3 TAS2R1 TAS2R10 TAS2R13
    TAS2R14 TAS2R16 TAS2R19 TAS2R20 TAS2R3
    TAS2R38 TAS2R4 TAS2R41 TA52R42 TAS2R5
    TAS2R50 TAS2R60 TAS2R7 TAS2R8 TAS2R9
    TASP1 TAT TATDN1 TATDN2 TATDN3
    TAX1BP1 TAX1BP3 TAZ TBC1D1 TBC1D10A
    TBC1D10C TBC1D12 TBC1D13 TBC1D14 TBC1D15
    TBC1D16 TBC1D17 TBC1D19 TBC1D2 TBC1D20
    TBC1D21 TBC1D22A TBC1D22B TBC1D23 TBC1D24
    TBC1D25 TBC1D26 TBC1D28 TBC1D29 TBC1D2B
    TBC1D3 TBC1D30 TBC1D3B TBC1D3C TBC1D3E
    TBC1D3F TBC1D3G TBC1D3H TBC1D3P2 TBC1D4
    TBC1D5 TBC1D7 TBC1D8B TBC1D9B TBCA
    TBCB TBCC TBCCD1 TBCD TBCE
    TBCEL TBCK TBK1 TBKBP1 TBL1X
    TBL1XR1 TBL1Y TBL2 TBL3 TBP
    TBPL1 TBPL2 TBR1 TBRG1 TBRG4
    TBX1 TBX10 TBX15 TBX18 TBX19
    TBX2 TBX20 TBX21 TBX22 TBX3
    TBX4 TBX5 TBX6 TBXA2R TBXAS1
    TC2N TCAP TCEA1 TCEA2 TCEAL1
    TCEAL2 TCEAL3 TCEAL4 TCEAL5 TCEAL6
    TCEAL7 TCEAL8 TCEANC TCEB1 TCEB2
    TCEB3 TCEB3B TCEB3C TCERG1 TCERG1L
    TCF12 TCF15 TCF19 TCF20 TCF21
    TCF23 TCF25 TCF3 TCF4 TCF7
    TCF7L1 TCF7L2 TCFL5 TCHH TCHHL1
    TCHP TCIRG1 TCL1A TCL1B TCL6
    TCN1 TCN2 TCOF1 TCP1 TCP10
    TCP10L TCP11 TCP11L1 TCP11L2 TCTA
    TCTE1 TCTE3 TCTEX1D1 TCTEX1D2 TCTEX1D4
    TCTN1 TCTN2 TCTN3 TDG TDGF1
    TDH TDO2 TDP1 TDRD1 TDRD10
    TDRD3 TDRD5 TDRD6 TDRD7 TDRD9
    TDRKH TEAD1 TEAD2 TEAD4 TEC
    TECPR1 TECPR2 TECR TECRL TECTA
    TECTB TEDDM1 TEF TEK TEKT1
    TEKT2 TEKT3 TEKT4 TEKT5 TELO2
    TENC1 TEP1 TEPP TERF1 TERF2
    TERF2IP TERT TES TESC TESK1
    TESK2 TET1 TET2 TEX10 TEX101
    TEX11 TEX12 TEX13A TEX13B TEX14
    TEX15 TEX19 TEX2 TEX261 TEX264
    TEX28 TEX9 TF TFAM TFAP2A
    TFAP2B TFAP2C TFAP2D TFAP2E TFAP4
    TFB1M TFB2M TFCP2 TFCP2L1 TFDP1
    TFDP2 TFDP3 TFE3 TFEB TFEC
    TFF1 TFF2 TFF3 TFG TFIP11
    TFPI TFPI2 TFPT TFR2 TFRC
    TFSM1_HUMAN TG TGDS TGFA TGFB1
    TGFB1I1 TGFB2 TGFB3 TGFBI TGFBR1
    TGFBR2 TGFBR3 TGFBRAP1 TGIF1 TGIF2
    TGIF2LX TGIF2LY TGM1 TGM2 TGM3
    TGM4 TGM5 TGM6 TGM7 TGOLN2
    TGS1 TH TH1L THADA THAP1
    THAP10 THAP11 THAP2 THAP3 THAP4
    THAP5 THAP6 THAP7 THAP8 THAP9
    THBD THBS1 THBS2 THBS3 THBS4
    THEG THEM4 THEM5 THEMIS THG1L
    THNSL1 THNSL2 THOC1 THOC2 THOC3
    THOC4 THOC5 THOC6 THOC7 THOP1
    THPO THRA THRAP3 THRB THRSP
    THSD1 THSD4 THSD7A THSD7B THTPA
    THUMPD1 THUMPD2 THUMPD3 THY1 THYN1
    TIA1 TIAF1 TIAL1 TIAM1 TIAM2
    TICAM1 TICAM2 TIE1 TIF1 TIFA
    TIFAB TIGD1 TIGD2 TIGD3 TIGD4
    TIGD5 TIGD6 TIGD7 TIGIT TIMD4
    TIMELESS TIMM10 TIMM13 TIMM17A TIMM17B
    TIMM22 TIMM23 TIMM44 TIMM50 TIMM8A
    TIMM8B TIMM9 TIMP1 TIMP2 TIMP3
    TIMP4 TINAG TINAGL1 TINF2 TIPARP
    TIPIN TIPRL TIRAP TJAP1 TJP1
    TJP2 TJP3 TK1 TK2 TKT
    TKTL1 TKTL2 TLCD1 TLCD2 TLE1
    TLE3 TLE4 TLE6 TLK1 TLK2
    TLL1 TLL2 TLN1 TLN2 TLR1
    TLR10 TLR2 TLR3 TLR4 TLR5
    TLR6 TLR7 TLR8 TLR9 TLX1
    TLX2 TLX3 TM2D1 TM2D2 TM2D3
    TM4SF1 TM4SF18 TM4SF19 TM4SF2 TM4SF20
    TM4SF5 TM6SF1 TM6SF2 TM7SF2 TM7SF3
    TM7SF4 TM9SF1 TM9SF2 TM9SF3 TM9SF4
    TMBIM1 TMBIM4 TMBIM6 TMC1 TMC2
    TMC3 TMC4 TMC5 TMC6 TMC7
    TMC8 TMCC1 TMCC2 TMCC3 TMCO1
    TMCO2 TMCO3 TMCO4 TMCO5A TMCO6
    TMCO7 TMED1 TMED10 TMED2 TMED3
    TMED4 TMED5 TMED6 TMED7 TMED8
    TMED9 TMEFF1 TMEFF2 TMEM100 TMEM101
    TMEM102 TMEM104 TMEM105 TMEM106A TMEM106B
    TMEM106C TMEM107 TMEM108 TMEM109 TMEM11
    TMEM110 TMEM111 TMEM115 TMEM116 TMEM117
    TMEM119 TMEM120B TMEM121 TMEM123 TMEM125
    TMEM126A TMEM126B TMEM127 TMEM128 TMEM129
    TMEM130 TMEM131 TMEM132A TMEM132B TMEM132C
    TMEM132D TMEM132E TMEM133 TMEM134 TMEM135
    TMEM136 TMEM138 TMEM139 TMEM140 TMEM141
    TMEM143 TMEM144 TMEM145 TMEM146 TMEM147
    TMEM149 TMEM14A TMEM14B TMEM14C TMEM150A
    TMEM150B TMEM151A TMEM154 TMEM155 TMEM156
    TMEM159 TMEM160 TMEM161A TMEM161B TMEM163
    TMEM164 TMEM165 TMEM167A TMEM167B TMEM168
    TMEM169 TMEM17 TMEM170A TMEM170B TMEM171
    TMEM173 TMEM174 TMEM175 TMEM176A TMEM176B
    TMEM177 TMEM178 TMEM179 TMEM179B TMEM18
    TMEM180 TMEM181 TMEM182 TMEM183A TMEM184A
    TMEM184B TMEM184C TMEM185A TMEM185B TMEM186
    TMEM187 TMEM189 TMEM189- TMEM19 TMEM190
    UBE2V1
    TMEM192 TMEM194A TMEM195 TMEM196 TMEM198
    TMEM199 TMEM2 TMEM20 TMEM200A TMEM200B
    TMEM201 TMEM202 TMEM203 TMEM204 TMEM205
    TMEM206 TMEM207 TMEM209 TMEM211 TMEM214
    TMEM215 TMEM217 TMEM218 TMEM219 TMEM22
    TMEM220 TMEM222 TMEM225 TMEM229B TMEM25
    TMEM26 TMEM27 TMEM30A TMEM30B TMEM31
    TMEM33 TMEM35 TMEM37 TMEM38A TMEM38B
    TMEM39A TMEM39B TMEM40 TMEM41A TMEM41B
    TMEM42 TMEM43 TMEM44 TMEM45A TMEM45B
    TMEM47 TMEM48 TMEM49 TMEM5 TMEM50A
    TMEM50B TMEM51 TMEM52 TMEM53 TMEM54
    TMEM55A TMEM55B TMEM56 TMEM57 TMEM59
    TMEM59L TMEM60 TMEM61 TMEM62 TMEM63A
    TMEM63B TMEM64 TMEM65 TMEM66 TMEM67
    TMEM68 TMEM69 TMEM70 TMEM71 TMEM72
    TMEM74 TMEM78 TMEM79 TMEM80 TMEM81
    TMEM82 TMEM85 TMEM86A TMEM86B TMEM87A
    TMEM87B TMEM88 TMEM89 TMEM8A TMEM8B
    TMEM8C TMEM9 TMEM90A TMEM9OB TMEM91
    TMEM92 TMEM93 TMEM95 TMEM97 TMEM98
    TMEM99 TMEM9B TMF1 TMIE TMIGD1
    TMIGD2 TMLHE TMOD1 TMOD2 TMOD3
    TMOD4 TMPO TMPO_ TMPPE TMPRSS11A
    ENST00000266732
    TMPRSS11B TMPRSS11D TMPRSS11E TMPRSS11E2 TMPRSS11F
    TMPRSS13 TMPRSS2 TMPRSS2_ TMPRSS3 TMPRSS4
    ENST00000332149
    TMPRSS6 TMPRSS7 TMPRSS9 TMSB10 TMSB15A
    TMSB15B TMSB4X TMSB4Y TMSL2 TMSL3
    TMTC1 TMTC2 TMTC3 TMTC4 TMUB1
    TMUB2 TMX1 TMX2 TMX3 TMX4
    TNAP TNC TNF TNFAIP1 TNFAIP2
    TNFAIP3 TNFAIP6 TNFAIP8L1 TNFAIP8L2 TNFAIP8L3
    TNFRSF10A TNFRSF10B TNFRSF10C TNFRSF10D TNFRSF11A
    TNFRSF11B TNFRSF12A TNFRSF13B TNFRSF13C TNFRSF14
    TNFRSF17 TNFRSF18 TNFRSF19 TNFRSF1A TNFRSF1B
    TNFRSF21 TNFRSF25 TNFRSF4 TNFRSF6B TNFRSF8
    TNFRSF9 TNFSF10 TNFSF11 TNFSF12 TNFSF12-
    TNFSF13
    TNFSF13 TNFSF13B TNFSF14 TNFSF15 TNFSF18
    TNFSF4 TNFSF8 TNFSF9 TNIK TNIP1
    TNIP2 TNIP3 TNK1 TNK2 TNK2_
    ENST00000381916
    TNKS TNKS1BP1 TNKS2 TNMD TNN
    TNNC1 TNNC2 TNNI1 TNNI2 TNNI3
    TNNI3K TNNT1 TNNT2 TNNT3 TNP1
    TNPO1 TNPO2 TNPO3 TNR TNRC18
    TNRC6A TNRC6B TNS1 TNS3 TNS4
    TNXB TNXB_ TOB1 TOB2 TOB2P1
    ENST00000375247
    TOE1 TOLLIP TOM1 TOM1L1 TOM1L2
    TOMM20 TOMM20L TOMM22 TOMM34 TOMM40
    TOMM40L TOMM5 TOMM7 TOMM70A TOP1
    TOP1MT TOP2A TOP2B TOP3A TOP3B
    TOP3B_ TOPBP1 TOPORS TOR1A TOR1AIP1
    ENST00000357179
    TOR1AIP2 TOR1B TOR2A TOR3A TOX
    TOX2 TOX3 TOX4 TP53 TP53AIP1
    TP53BP1 TP53BP2 TP53I11 TP53I13 TP53I3
    TP53INP1 TP53INP2 TP53RK TP53TG1 TP53TG5
    TP63 TP73 TPBG TPCN1 TPCN2
    TPD52 TPD52L1 TPD52L2 TPD52L3 TPH1
    TPH2 TPI1 TPK1 TPM1 TPM2
    TPM3 TPM4 TPM4_ TPMT TPO
    ENST00000344824
    TPP1 TPP2 TPPP TPPP2 TPPP3
    TPR TPRA1 TPRG1 TPRG1L TPRKB
    TPRX1 TPRXL TPSAB1 TPSD1 TPSG1
    TPST1 TPST2 TPT1 TPTE TPTE2
    TPX2 TRA2A TRA2B TRABD TRAD
    TRADD TRAF1 TRAF2 TRAF3 TRAF3IP1
    TRAF3IP2 TRAF3IP3 TRAF4 TRAF5 TRAF6
    TRAF7 TRAFD1 TRAIP TRAK1 TRAK2
    TRAM1 TRAM1L1 TRAM2 TRANK1 TRAP1
    TRAPPC1 TRAPPC10 TRAPPC2 TRAPPC2L TRAPPC3
    TRAPPC4 TRAPPC5 TRAPPC6A TRAPPC6B TRAPPC9
    TRAT1 TRDMT1 TRDN TREM1 TREM2
    TREML1 TREML2 TREML4 TRERF1 TREX1
    TREX2 TRH TRHDE TRHR TRIAP1
    TRIB1 TRIB2 TRIB3 TRIM10 TRIM11
    TRIM13 TRIM14 TRIM15 TRIM16 TRIM16L
    TRIM17 TRIM2 TRIM21 TRIM22 TRIM23
    TRIM24 TRIM25 TRIM26 TRIM27 TRIM28
    TRIM29 TRIM3 TRIM31 TRIM32 TRIM33
    TRIM34 TRIM35 TRIM36 TRIM37 TRIM38
    TRIM39 TRIM4 TRIM40 TRIM41 TRIM42
    TRIM43 TRIM44 TRIM45 TRIM46 TRIM47
    TRIM48 TRIM49 TRIM5 TRIM50 TRIM52
    TRIM54 TRIM55 TRIM56 TRIM58 TRIM59
    TRIM6 TRIM6-TRIM34 TRIM60 TRIM61 TRIM62
    TRIM63 TRIM64C TRIM65 TRIM66 TRIM67
    TRIM68 TRIM69 TRIM7 TRIM71 TRIM72
    TRIM73 TRIM74 TRIM8 TRIM9 TRIML1
    TRIML2 TRIO TRIOBP TRIOBP_ TRIP10
    ENST00000344404
    TRIP11 TRIP12 TRIP13 TRIP4 TRIP6
    TRIT1 TRMT1 TRMT11 TRMT112 TRMT12
    TRMT2A TRMT2B TRMT5 TRMT6 TRMT61A
    TRMT61B TRMU TRNAU1AP TRNP1 TRNT1
    TRO TROAP TROVE2 TRPA1 TRPC1
    TRPC3 TRPC4 TRPC4AP TRPC5 TRPC6
    TRPM1 TRPM2 TRPM3 TRPM4 TRPM5
    TRPM6 TRPM7 TRPM8 TRPS1 TRPT1
    TRPV2 TRPV3 TRPV4 TRPV5 TRPV6
    TRRAP TRUB1 TRUB2 TRYX3 TSC1
    TSC2 TSC22D1 TSC22D2 TSC22D3 TSC22D4
    TSC2_ TSEN15 TSEN2 TSEN34 TSEN54
    ENST00000219476
    TSFM TSG101 TSGA10 TSGA10IP TSGA13
    TSGA14 TSHB TSHR TSHZ1 TSHZ2
    TSHZ3 TSKS TSKU TSLP TSN
    TSNARE1 TSNAX TSNAXIP1 TSPAN1 TSPAN11
    TSPAN12 TSPAN13 TSPAN14 TSPAN15 TSPAN16
    TSPAN17 TSPAN18 TSPAN2 TSPAN3 TSPAN31
    TSPAN32 TSPAN33 TSPAN4 TSPAN5 TSPAN6
    TSPAN7 TSPAN8 TSPAN9 TSPO TSPO2
    TSPY2 TSPY3 TSPYL1 TSPYL2 TSPYL5
    TSPYL6 TSR1 TSR2 TSSC1 TSSC4
    TSSK1B TSSK2 TSSK3 TSSK4 TSSK6
    TST TSTA3 TSTD2 TTBK1 TTBK2
    TTC1 TTC12 TTC13 TTC14 TTC15
    TTC16 TTC17 TTC18 TTC19 TTC21A
    TTC21B TTC22 TTC23 TTC26 TTC27
    TTC29 TTC3 TTC30A TTC31 TTC32
    TTC33 TTC35 TTC36 TTC37 TTC38
    TTC39A TTC39B TTC39C TTC3L TTC4
    TTC5 TTC6 TTC7A TTC7B TTC8
    TTC9B TTC9C TTF1 TTF2 TTK
    TTL TTLL1 TTLL10 TTLL11 TTLL12
    TTLL13 TTLL2 TTLL3 TTLL4 TTLL5
    TTLL6 TTLL6_ TTLL7 TTLL9 TTN
    ENST00000393382
    TTN_ TTN_ TTPA TTPAL TTR
    ENST00000356127 ENST00000360870
    TTRAP TTYH1 TTYH2 TTYH3 TUB
    TUBA1A TUBA1B TUBA1C TUBA3C TUBA3D
    TUBA3E TUBA4A TUBA4A_ TUBA8 TUBAL3
    ENST00000392088
    TUBB TUBB1 TUBB2A TUBB2B TUBB2C
    TUBB3 TUBB4 TUBB4Q TUBB6 TUBB8
    TUBD1 TUBE1 TUBG1 TUBG2 TUBGCP2
    TUBGCP3 TUBGCP4 TUBGCP5 TUBGCP6 TUFM
    TUFT1 TULP1 TULP2 TULP3 TULP4
    TUSC1 TUSC2 TUSC3 TUSC4 TUSC5
    TUT1 TWF1 TWF2 TWIST1 TWISTNB
    TWSG1 TXK TXLNA TXLNB TXN
    TXN2 TXNDC11 TXNDC12 TXNDC15 TXNDC16
    TXNDC17 TXNDC2 TXNDC3 TXNDC5 TXNDC6
    TXNDC8 TXNDC9 TXNIP TXNL1 TXNL2
    TXNL4A TXNL4B TXNRD1 TXNRD2 TXNRD3IT1
    TYK2 TYMP TYMS TYR TYRO3
    TYROBP TYRP1 TYSND1 TYW1 TYW3
    U258_HUMAN U2AF1 U2AF1L4 U2AF2 U2D3L_
    HUMAN
    U464_HUMAN U66061_1 U66061_1_ UACA UAP1
    ENST00000390396
    UAP1L1 UBA1 UBA2 UBA3 UBA5
    UBA52 UBA6 UBA7 UBAC1 UBAC2
    UBAP1 UBAP2 UBAP2L UBASH3A UBASH3B
    UBB UBC UBD UBE2A UBE2B
    UBE2C UBE2CBP UBE2D1 UBE2D2 UBE2D3
    UBE2D4 UBE2E1 UBE2E2 UBE2E3 UBE2F
    UBE2G1 UBE2G2 UBE2H UBE2I UBE2J1
    UBE2J2 UBE2K UBE2L3 UBE2L6 UBE2M
    UBE2N UBE2NL UBE2O UBE2Q1 UBE2Q2
    UBE2R2 UBE2S UBE2T UBE2U UBE2V1
    UBE2V2 UBE3A UBE3B UBE3C UBE4A
    UBE4B UBFD1 UBIAD1 UBL3 UBL4A
    UBL4B UBL5 UBL7 UBLCP1 UBN1
    UBN2 UBOX5 UBP1 UBQLN1 UBQLN2
    UBQLN3 UBQLN4 UBQLNL UBR1 UBR2
    UBR3 UBR3_ UBR4 UBR5 UBR7
    ENST00000272793
    UBTD1 UBTD2 UBTF UBXN1 UBXN10
    UBXN11 UBXN2A UBXN2B UBXN4 UBXN6
    UBXN7 UBXN8 UCHL1 UCHL3 UCHL5
    UCK1 UCK2 UCKL1 UCMA UCN
    UCN2 UCN3 UCP1 UCP2 UCP3
    UEVLD UFC1 UFD1L UFM1 UFSP1
    UFSP2 UGCG UGDH UGGT1 UGGT2
    UGP2 UGT1A1 UGT1A10 UGT1A3 UGT1A4
    UGT1A5 UGT1A6 UGT1A7 UGT1A8 UGT1A9
    UGT2A1 UGT2A3 UGT2B11 UGT2B15 UGT2B17
    UGT2B28 UGT2B4 UGT2B7 UGT3A1 UGT3A2
    UGT8 UHMK1 UHRF1 UHRF1BP1 UHRF1BP1L
    UHRF2 UIMC1 ULBP1 ULBP2 ULBP3
    ULK1 ULK2 ULK3 ULK4 UMOD
    UMODL1 UMPS UNC119 UNC119B UNC13B
    UNC13D UNC45A UNC45B UNC50 UNC5A
    UNC5B UNC5C UNC5CL UNC5D UNC80
    UNC93A UNC93B6 UNCX UNG UNG_
    ENST00000242576
    UNK UNKL UNQ1887 UNQ3045 UNQ9391
    UPB1 UPF1 UPF2 UPF3A UPF3B
    UPK1A UPK1B UPK2 UPK3A UPK3B
    UPP1 UPP2 UPRT UQCC UQCR11
    UQCRB UQCRC1 UQCRC2 UQCRFS1 UQCRH
    UQCRQ URB2 URGCP URM1 UROC1
    UROD UROS URP2 USF1 USF2
    USH1C USH1G USH2A USHBP1 USMG5
    USMG5P1 USO1 USP1 USP10 USP11
    USP12 USP13 USP14 USP15 USP16
    USP17L2 USP18 USP19 USP2 USP20
    USP21 USP22 USP24 USP25 USP26
    USP27X USP28 USP29 USP3 USP30
    USP31 USP32 USP33 USP34 USP35
    USP35_ USP36 USP37 USP38 USP39
    ENST00000263311
    USP4 USP41 USP42 USP43 USP44
    USP45 USP46 USP47 USP48 USP49
    USP5 USP50 USP51 USP53 USP54
    USP54_ USP6 USP6NL USP7 USP8
    ENST00000408019
    USP9X USP9Y USPL1 UST UTF1
    UTP11L UTP14A UTP14C UTP15 UTP18
    UTP20 UTP23 UTP3 UTP6 UTRN
    UTS2 UTS2D UTS2R UTY UVRAG
    UXT VAC14 VAMP1 VAMP2 VAMP3
    VAMP4 VAMP5 VAMP7 VAMP8 VANGL1
    VANGL2 VAPA VAPB VARS VARS2
    VASH1 VASH2 VASN VASP VAT1
    VAT1L VAV1 VAV2 VAV3 VAX1
    VAX2 VBP1 VCAM1 VCAN VCL
    VCP VCPIP1 VCX VCX2 VCX3A
    VCY VCY1B VDAC1 VDAC2 VDAC3
    VDAC4 VDR VEGFA VEGFB VEGFC
    VENTX VEPH1 VEZF1 VGF VGLL1
    VGLL2 VGLL3 VGLL4 VHL VHLL
    VIL1 VILL VIM VIP VIPAR
    VIPR1 VIPR2 VIT VKORC1 VKORC1L1
    VLDLR VMA21 VMAC VMO1 VN1R1
    VN1R2 VN1R4 VN2R1P VNN1 VNN2
    VNN3 VPRBP VPREB1 VPREB3 VPS11
    VPS13A VPS13B VPS13C VPS13D VPS16
    VPS18 VPS24 VPS25 VPS26A VPS26B
    VPS28 VPS29 VPS33A VPS33B VPS35
    VPS36 VPS37A VPS37B VPS37C VPS37D
    VPS39 VPS41 VPS45 VPS4B VPS52
    VPS53 VPS54 VPS72 VPS8 VRK1
    VRK2 VRK3 VSIG1 VSIG2 VSIG4
    VSIG7 VSIG8 VSNL1 VSTM1 VSTM2B
    VSTM2L VSX1 VSX2 VTA1 VTCN1
    VTI1A VTI1B VTN VWA1 VWA2
    VWA3A VWA3B VWA5A VWC2 VWCE
    VWDE VWF WAC WAPAL WARS
    WARS2 WAS WASF1 WASF2 WASF3
    WASF4 WASL WBP1 WBP11 WBP2
    WBP2NL WBP4 WBP5 WBSCR16 WBSCR17
    WBSCR22 WBSCR27 WBSCR28 WDFY1 WDFY2
    WDFY3 WDFY4 WDHD1 WDR11 WDR12
    WDR13 WDR16 WDR17 WDR18 WDR19
    WDR20 WDR23 WDR24 WDR25 WDR26
    WDR27 WDR27_ WDR3 WDR31 WDR33
    ENST00000333572
    WDR34 WDR35 WDR36 WDR37 WDR38
    WDR4 WDR41 WDR43 WDR44 WDR44_
    ENST00000435384
    WDR45 WDR45L WDR46 WDR47 WDR48
    WDR49 WDR5 WDR51A WDR51B WDR52
    WDR52_ WDR53 WDR54 WDR55 WDR57
    ENST00000393845
    WDR59 WDR5B WDR6 WDR60 WDR61
    WDR62 WDR63 WDR64 WDR65 WDR66
    WDR67 WDR69 WDR7 WDR70 WDR72
    WDR73 WDR75 WDR76 WDR77 WDR78
    WDR8 WDR81 WDR82 WDR82_ WDR83
    ENST00000296490
    WDR85 WDR88 WDR89 WDR90 WDR91
    WDR92 WDR93 WDSU B1 WDTC1 WDYHV1
    WEE1 WEE2 WFDC1 WFDC10A WFDC10B
    WFDC11 WFDC12 WFDC13 WFDC2 WFDC3
    WFDC5 WFDC6 WFDC8 WFDC9 WFIKKN1
    WFIKKN2 WFS1 WHAMM_ WHSC1 WHSC1L1
    ENST00000234505
    WHSC2 WIF1 WIPF1 WIPF2 WIPF3
    WIPI1 WIPI2 WISP1 WISP2 WISP3
    WIT1 WIZ WLS WNK1 WNK2
    WNK3 WNK4 WNT1 WNT10A WNT10B
    WNT11 WNT16 WNT2 WNT2B WNT3
    WNT3A WNT4 WNT5A WNT5B WNT6
    WNT7A WNT7B WNT8A WNT8B WNT9A
    WNT9B WRAP53 WRB WRN WRNIP1
    WSB1 WSB2 WSCD1 WSCD2 WT1
    WTAP WTIP WWC1 WWC2 WWC3
    WWOX WWP1 WWP2 WWTR1 XAB1
    XAB2 XAF1 XAGE1C XAGE1D XAGE2
    XAGE3 XAGE5 XBP1 XCL1 XCL2
    XCR1 XDH XG XIAP XIRP1
    XIRP2 XIRP2_ XK XKR3 XKR4
    ENST00000409728
    XKR5 XKR6 XKR7 XKR8 XKR9
    XKRX XPA XPC XPNPEP1 XPNPEP2
    XPNPEP3 XPO1 XPO4 XPO5 XPO6
    XPO7 XPOT XPR1 XRCC1 XRCC2
    XRCC3 XRCC4 XRCC5 XRCC6 XRCC6BP1
    XRN1 XRN2 XRRA1 XXyac- XYLB
    YX155B6_1
    XYLT1 XYLT2 YAF2 YAP1 YARS
    YARS2 YBX1 YBX2 YDJC YEATS2
    YEATS4 YES1 YIF1A YIF1B YIPF1
    YIPF2 YIPF3 YIPF4 YIPF5 YIPF6
    YJEFN3 YKT6 YLPM1 YME1L1 YOD1
    YPEL1 YPEL2 YPEL3 YPEL4 YPEL5
    YRDC YSK4 YSK4_ YTHDC1 YTHDC2
    ENST00000375845
    YTHDF1 YTHDF2 YV009_ YWHAB YWHAE
    HUMAN
    YWHAG YWHAH YWHAQ YWHAZ YY1
    YY1AP1 YY2 ZACN ZADH1 ZADH2
    ZAK ZAN ZAP70 ZAR1 ZAR1L
    ZBBX ZBBX_ ZBED1 ZBED2 ZBED3
    ENST00000455345
    ZBED4 ZBP1 ZBTB1 ZBTB10 ZBTB11
    ZBTB12 ZBTB16 ZBTB17 ZBTB2 ZBTB20
    ZBTB22 ZBTB24 ZBTB25 ZBTB26 ZBTB3
    ZBTB32 ZBTB33 ZBTB34 ZBTB37 ZBTB38
    ZBTB39 ZBTB4 ZBTB40 ZBTB41 ZBTB43
    ZBTB44 ZBTB45 ZBTB46 ZBTB48 ZBTB49
    ZBTB5 ZBTB6 ZBTB7A ZBTB7B ZBTB7C
    ZBTB8A ZBTB8B_ ZBTB8OS ZBTB9 ZC3H10
    ENST00000291374
    ZC3H11A ZC3H12A ZC3H12B ZC3H12B_ ZC3H12C
    ENST00000338957
    ZC3H13 ZC3H14 ZC3H15 ZC3H18 ZC3H3
    ZC3H4 ZC3H6 ZC3H7A ZC3H7B ZC3H8
    ZC3HAV1 ZC3HAV1L ZC3HC1 ZC4H2 ZCCHC10
    ZCCHC11 ZCCHC12 ZCCHC13 ZCCHC14 ZCCHC16
    ZCCHC17 ZCCHC24 ZCCHC3 ZCCHC4 ZCCHC5
    ZCCHC6 ZCCHC7 ZCCHC8 ZCCHC9 ZCRB1
    ZCWPW1 ZCWPW2 ZDHHC1 ZDHHC11 ZDHHC11_
    ENST00000424784
    ZDHHC12 ZDHHC13 ZDHHC14 ZDHHC15 ZDHHC16
    ZDHHC18 ZDHHC19 ZDHHC21 ZDHHC23 ZDHHC24
    ZDHHC3 ZDHHC4 ZDHHC5 ZDHHC6 ZDHHC7
    ZDHHC8 ZDHHC9 ZEB1 ZEB2 ZER1
    ZFAND1 ZFAND2A ZFAND2B ZFAND3 ZFAND5
    ZFAND6 ZFAT ZFC3H1 ZFHX3 ZFHX4
    ZFP1 ZFP106 ZFP112 ZFP14 ZFP161
    ZFP2 ZFP28 ZFP3 ZFP30 ZFP36
    ZFP36L1 ZFP36L2 ZFP37 ZFP41 ZFP42
    ZFP57 ZFP64 ZFP64_ ZFP82 ZFP90
    ENST00000361387
    ZFP91 ZFP91-CNTF ZFP92 ZFPL1 ZFPM1
    ZFPM2 ZFR ZFR2 ZFX ZFY
    ZFYVE1 ZFYVE16 ZFYVE19 ZFYVE20 ZFYVE21
    ZFYVE26 ZFYVE27 ZFYVE28 ZFYVE9 ZG16B
    ZGPAT ZHX1 ZHX2 ZHX3 ZIC1
    ZIC2 ZIC3 ZIC4 ZIC5 ZIK1
    ZIM2 ZIM3 ZKSCAN1 ZKSCAN2 ZKSCAN3
    ZKSCAN4 ZKSCAN5 ZMAT1 ZMAT2 ZMAT3
    ZMAT4 ZMAT5 ZMIZ1 ZMIZ2 ZMPSTE24
    ZMYM1 ZMYM2 ZMYM3 ZMYM4 ZMYM5
    ZMYM6 ZMYND10 ZMYND11 ZMYND12 ZMYND15
    ZMYND17 ZMYND19 ZMYND8 ZNF10 ZNF100
    ZNF101 ZNF107 ZNF10_ ZNF114 ZNF117
    ENST00000228289
    ZNF12 ZNF121 ZNF123 ZNF124 ZNF131
    ZNF132 ZNF133 ZNF134 ZNF135 ZNF136
    ZNF138 ZNF14 ZNF140 ZNF141 ZNF142
    ZNF143 ZNF146 ZNF148 ZNF154 ZNF155
    ZNF157 ZNF16 ZNF160 ZNF165 ZNF167
    ZNF169 ZNF17 ZNF174 ZNF175 ZNF177
    ZNF18 ZNF180 ZNF181 ZNF182 ZNF184
    ZNF185 ZNF189 ZNF19 ZNF192 ZNF193
    ZNF195 ZNF197 ZNF198 ZNF2 ZNF20
    ZNF200 ZNF202 ZNF205 ZNF207 ZNF211
    ZNF212 ZNF213 ZNF214 ZNF215 ZNF217
    ZNF219 ZNF22 ZNF221 ZNF222 ZNF223
    ZNF224 ZNF227 ZNF229 ZNF23 ZNF230
    ZNF232 ZNF233 ZNF235 ZNF236 ZNF238
    ZNF239 ZNF24 ZNF248 ZNF25 ZNF251
    ZNF253 ZNF254 ZNF256 ZNF257 ZNF257_
    ENST00000435820
    ZNF259 ZNF26 ZNF260 ZNF263 ZNF264
    ZNF266 ZNF267 ZNF271 ZNF273 ZNF274
    ZNF275 ZNF276 ZNF277 ZNF278 ZNF28
    ZNF280A ZNF280B ZNF280C ZNF280D ZNF281
    ZNF282 ZNF283 ZNF285A ZNF286A ZNF287
    ZNF292 ZNF295 ZNF296 ZNF3 ZNF30
    ZNF300 ZNF304 ZNF311 ZNF317 ZNF318
    ZNF319 ZNF32 ZNF320 ZNF321 ZNF322A
    ZNF322B ZNF323 ZNF324 ZNF324B ZNF326
    ZNF329 ZNF330 ZNF331 ZNF333 ZNF334
    ZNF335 ZNF337 ZNF33A ZNF33B ZNF34
    ZNF341 ZNF343 ZNF345 ZNF346 ZNF347
    ZNF35 ZNF350 ZNF354A ZNF354B ZNF354C
    ZNF358 ZNF362 ZNF365 ZNF366 ZNF367
    ZNF37A ZNF382 ZNF383 ZNF384 ZNF385
    ZNF385A ZNF385B ZNF385C ZNF385D ZNF391
    ZNF394 ZNF395 ZNF396 ZNF397 ZNF397OS
    ZNF398 ZNF407 ZNF408 ZNF41 ZNF410
    ZNF414 ZNF414_ ZNF415 ZNF416 ZNF417
    ENST00000393927
    ZNF418 ZNF419 ZNF420 ZNF423 ZNF425
    ZNF426 ZNF428 ZNF429 ZNF43 ZNF430
    ZNF431 ZNF432 ZNF432_ ZNF434 ZNF436
    ENST00000354939
    ZNF438 ZNF439 ZNF440 ZNF441 ZNF442
    ZNF443 ZNF444 ZNF445 ZNF446 ZNF449
    ZNF45 ZNF451 ZNF454 ZNF460 ZNF462
    ZNF467 ZNF468 ZNF470 ZNF471 ZNF473
    ZNF474 ZNF479 ZNF48 ZNF480 ZNF483
    ZNF484 ZNF485 ZNF486 ZNF488 ZNF490
    ZNF491 ZNF492 ZNF492_ ZNF493 ZNF496
    ENST00000456783
    ZNF497 ZNF498 ZNF500 ZNF501 ZNF502
    ZNF503 ZNF506 ZNF507 ZNF510 ZNF511
    ZNF512 ZNF512B ZNF513 ZNF514 ZNF516
    ZNF517 ZNF518B ZNF519 ZNF521 ZNF524
    ZNF526 ZNF527 ZNF528 ZNF529 ZNF530
    ZNF532 ZNF534 ZNF536 ZNF540 ZNF541
    ZNF543 ZNF544 ZNF546 ZNF547 ZNF548
    ZNF549 ZNF550 ZNF551 ZNF552 ZNF554
    ZNF555 ZNF556 ZNF557 ZNF558 ZNF559
    ZNF560 ZNF561 ZNF562 ZNF563 ZNF564
    ZNF565 ZNF566 ZNF567 ZNF568 ZNF569
    ZNF57 ZNF570 ZNF571 ZNF572 ZNF573
    ZNF574 ZNF575 ZNF576 ZNF577 ZNF579
    ZNF580 ZNF581 ZNF582 ZNF583 ZNF584
    ZNF585A ZNF585B ZNF586 ZNF587 ZNF589
    ZNF592 ZNF593 ZNF594 ZNF596 ZNF597
    ZNF599 ZNF600 ZNF605 ZNF606 ZNF607
    ZNF608 ZNF609 ZNF610 ZNF611 ZNF613
    ZNF614 ZNF615 ZNF616 ZNF618 ZNF619
    ZNF620 ZNF621 ZNF622 ZNF623 ZNF624
    ZNF625 ZNF626 ZNF627 ZNF628 ZNF628_
    ENST00000391718
    ZNF630 ZNF638 ZNF639 ZNF641 ZNF642
    ZNF643 ZNF644 ZNF645 ZNF646 ZNF648
    ZNF649 ZNF652 ZNF653 ZNF654 ZNF655
    ZNF658 ZNF658B ZNF660 ZNF662 ZNF664
    ZNF665 ZNF667 ZNF668 ZNF669 ZNF67
    ZNF670 ZNF671 ZNF672 ZNF673 ZNF674
    ZNF675 ZNF676 ZNF677 ZNF678 ZNF680
    ZNF682 ZNF684 ZNF687 ZNF688 ZNF689
    ZNF69 ZNF691 ZNF692 ZNF696 ZNF697_
    ENST00000271263
    ZNF699 ZNF7 ZNF70 ZNF700 ZNF701
    ZNF703 ZNF704 ZNF705A ZNF705D ZNF706
    ZNF707 ZNF708 ZNF709 ZNF71 ZNF710
    ZNF711 ZNF713 ZNF714 ZNF738 ZNF74
    ZNF746 ZNF747 ZNF750 ZNF75A ZNF75D
    ZNF76 ZNF761 ZNF763 ZNF764 ZNF765
    ZNF765_ ZNF767 ZNF768 ZNF77 ZNF770
    ENST00000396408
    ZNF772 ZNF773 ZNF774 ZNF775 ZNF776
    ZNF777 ZNF780A ZNF781 ZNF782 ZNF784
    ZNF785 ZNF786 ZNF787 ZNF788 ZNF789
    ZNF79 ZNF790 ZNF791 ZNF793 ZNF799
    ZNF8 ZNF80 ZNF800 ZNF804A ZNF804B
    ZNF81 ZNF816A ZNF821 ZNF826 ZNF827
    ZNF828 ZNF829 ZNF83 ZNF830 ZNF831
    ZNF833 ZNF834 ZNF835 ZNF836 ZNF837
    ZNF839 ZNF84 ZNF841_ ZNF843 ZNF846
    ENST00000359973
    ZNF85 ZNF862 ZNF879 ZNF90 ZNF90_
    ENST00000418063
    ZNF91 ZNF91_ ZNF92 ZNF93 ZNFX1
    ENST00000300619
    ZNHIT1 ZNHIT2 ZNHIT3 ZNHIT6 ZNRD1
    ZNRF1 ZNRF2 ZNRF3 ZNRF4 ZP1
    ZP2 ZP3 ZP4 ZPBP ZPBP2
    ZPLD1 ZRANB1 ZRANB2 ZRANB3 ZRSR2
    ZSCAN1 ZSCAN10 ZSCAN16 ZSCAN18 ZSCAN2
    ZSCAN20 ZSCAN21 ZSCAN22 ZSCAN23 ZSCAN29
    ZSCAN4 ZSCAN5A ZSWIM1 ZSWIM2 ZSWIM3
    ZSWIM4 ZSWIM5 ZSWIM7 ZUFSP ZW10
    ZWILCH ZWINT ZXDA ZXDB ZXDC
    ZYG11B ZYX ZZEF1 ZZZ3 dJ341D10_1
    hCG_1642425 hCG_1644301 hCG_17324 hCG_1757335 hCG_1793639
    hCG_2000329 hCG_2015269 hCG_2023776 hCG_2026038 hCG_38941
    mir-223 mir-424
  • TABLE 4
    Exemplary transposable elements in GBM microvesicles
    GenBank
    Name Accession No.
    Homo sapiens transposon-derived Buster1 [NM_021211]
    transposase-like protein gene (LOC58486)
    Human endogenous retrovirus H [U88896]
    protease/integrase-derived ORF1, ORF2, and
    putative envelope protein mRNA, complete cds
    Human endogenous retrovirus type C oncovirus [M74509]
    sequence
    Human endogenous retroviral H protease/ [U88898]
    integrase-derived ORF1 mRNA, complete cds,
    and putative envelope protein mRNA, partial cds.
    Homo sapiens Cas-Br-M (murine) ecotropic [NM_005188]
    retroviral transforming sequence (CBL)
    Homo sapiens endogenous retroviral sequence K, [NM_001007236]
    6 (ERVK6)
    Homo sapiens endogenous retroviral family W, [NM_014590]
    env(C7), member 1 (syncytin) (ERVWE1)
    Homo sapiens Cas-Br-M (murine) ecotropic [NM_170662]
    retroviral transforming sequence b (CBLB)
    Homo sapiens mRNA containing human [AF026246]
    endogenous retrovirus H and human endogenous
    retrovirus E sequences
    Homo sapiens cDNA FLJ11804 fis, clone [AK021866]
    HEMBA1006272, moderately similar to
    RETROVIRUS-RELATED PROTEASE (EC
    3.4.23.—).
    Human DNA/endogenous retroviral long terminal [M32220]
    repeat (LTR) junction mRNA, clone lambda-LTR22
    ALU8_HUMAN (P39195) Alu subfamily SX [THC2390306]
    sequence contamination warning entry, partial
    (7%)
    AA436686 zv59a12.s1 Soares_testis_NHT [AA436686]
    Homo sapiens cDNA clone IMAGE:
    757918 3′ similar to contains Alu
    repetitive element
    ALU6_HUMAN (P39193) Alu subfamily SP [THC2314369]
    sequence contamination warning entry, partial
    (19%)
    ALU1_HUMAN (P39188) Alu subfamily J [THC2320431]
    sequence contamination warning entry, partial
    (8%)
    BF476310 naa21a07.x1 NCI_CGAP_Pr28 [BF476310]
    Homo sapiens cDNA clone IMAGE:
    3255444 3′ similar to contains Alu
    repetitive element; contains element
    MIR MIR repetitive element
    ALU4_HUMAN (P39191) Alu subfamily SB2 [THC2284657]
    sequence contamination warning entry, partial
    (4%)
    LIN1_NYCCO (P08548) LINE-1 reverse [THC2379144]
    transcriptase homolog, partial (5%)
    od56h08.s1 NCI_CGAP_GCB1 Homo sapiens [AA827885]
    cDNA clone IMAGE: 1371999 3′ similar to
    gb: M19503 LINE-1 REVERSE
    TRANSCRIPTASE HOMOLOG (HUMAN)
    B28096 line-1 protein ORF2 - human [THC2281068]
    (Homo sapiens), partial (4%)
    Homo sapiens LINE-1 type transposase domain [NM_019079]
    containing 1 (L1TD1)
    Q6D545 (Q6D545) Transposase transposon [THC2407148]
    tn1721 (Fragment), partial (12%)
    Human clone 279131 defective mariner [U92025]
    transposon Hsmar2 mRNA sequence
    Homo sapiens retrotransposon gag domain [NM_001024455]
    containing 4 (RGAG4)
    Homo sapiens transposon-derived Buster3 [NM_022090]
    transposase-like (LOC63920)
    Homo sapiens retrotransposon gag domain [NM_020769]
    containing 1 (RGAG1)
    Human EST clone 251800 mariner transposon [U80770]
    Hsmar1 sequence
    Homo sapiens SET domain and mariner [NM_006515]
    transposase fusion gene (SETMAR)
    Homo sapiens tigger transposable element derived [NM_032862]
    5 (TIGD5)
    Homo sapiens tigger transposable element derived [NM_145702]
    1 (TIGD1)
    Homo sapiens pogo transposable element with [NM_017542]
    KRAB domain (POGK)
    Homo sapiens pogo transposable element with [NM_015100]
    ZNF domain (POGZ), transcript variant 1
    Homo sapiens tigger transposable element derived [NM_030953]
    6 (TIGD6)
    Homo sapiens piggyBac transposable element [NM_152595]
    derived 4 (PGBD4)
  • TABLE 5
    Human transposable elements.
    The list is adapted from Repbase-GIRI.
    http://www.girinst.org/, accessed Jan. 31, 2011.
    Type of Transposon ID
    CR1 CR1_HS
    CR1 L3
    DNA transposon LOOPER
    DNA transposon MER105
    DNA transposon MER116
    DNA transposon MER28
    DNA transposon MER45B
    DNA transposon MER45R
    DNA transposon MER53
    DNA transposon MER63A
    DNA transposon MER63B
    DNA transposon MER69C
    DNA transposon MER75
    DNA transposon MER75B
    DNA transposon MER85
    DNA transposon MER91A
    DNA transposon MER91C
    DNA transposon MER99
    DNA transposon ZAPHOD
    Endogenous Retrovirus HERV1_LTR
    Endogenous Retrovirus HERV15I
    Endogenous Retrovirus HERV18
    Endogenous Retrovirus HERV23
    Endogenous Retrovirus HERV30I
    Endogenous Retrovirus HERV38I
    Endogenous Retrovirus HERV39
    Endogenous Retrovirus HERV4_LTR
    Endogenous Retrovirus HERV46I
    Endogenous Retrovirus HERV52I
    Endogenous Retrovirus HERV57I
    Endogenous Retrovirus HERVFH19I
    Endogenous Retrovirus HERVG25
    Endogenous Retrovirus HERVH48I
    Endogenous Retrovirus HERVL_40
    Endogenous Retrovirus HERVP71A_I
    Endogenous Retrovirus HUERS-P2
    Endogenous Retrovirus HUERS-P3B
    Endogenous Retrovirus MER31
    Endogenous Retrovirus MER31_I
    Endogenous Retrovirus MER34B_I
    Endogenous Retrovirus MER41F
    Endogenous Retrovirus MER41I
    Endogenous Retrovirus MER4BI
    Endogenous Retrovirus MER57A_I
    Endogenous Retrovirus MER57I
    Endogenous Retrovirus MER61A
    Endogenous Retrovirus MER84I
    Endogenous Retrovirus PRIMA4_I
    Endogenous Retrovirus PRIMA41
    Endogenous Retrovirus PRIMAX_I
    ERV1 HARLEQUIN
    ERV1 HERV17
    ERV1 HERV19I
    ERV1 HERV3
    ERV1 HERV35I
    ERV1 HERV4_I
    ERV1 HERV49I
    ERV1 HERV9
    ERV1 HERVE
    ERV1 HERVI
    ERV1 HERVIP10F
    ERV1 HERVIP10FH
    ERV1 LOR1I
    ERV1 LTR06
    ERV1 LTR1
    ERV1 LTR10B
    ERV1 LTR10B2
    ERV1 LTR10C
    ERV1 LTR10D
    ERV1 LTR10F
    ERV1 LTR12B
    ERV1 LTR12C
    ERV1 LTR12D
    ERV1 LTR12E
    ERV1 LTR15
    ERV1 LTR17
    ERV1 LTR1B
    ERV1 LTR1B1
    ERV1 LTR1C
    ERV1 LTR1C2
    ERV1 LTR1D
    ERV1 LTR1E
    ERV1 LTR1F
    ERV1 LTR2
    ERV1 LTR21A
    ERV1 LTR21B
    ERV1 LTR21C
    ERV1 LTR23
    ERV1 LTR24
    ERV1 LTR24B
    ERV1 LTR24C
    ERV1 LTR25
    ERV1 LTR26
    ERV1 LTR26E
    ERV1 LTR27
    ERV1 LTR2752
    ERV1 LTR27B
    ERV1 LTR27C
    ERV1 LTR27D
    ERV1 LTR27E
    ERV1 LTR28
    ERV1 LTR28B
    ERV1 LTR28C
    ERV1 LTR29
    ERV1 LTR2B
    ERV1 LTR2C
    ERV1 LTR30
    ERV1 LTR31
    ERV1 LTR34
    ERV1 LTR35
    ERV1 LTR35B
    ERV1 LTR36
    ERV1 LTR37A
    ERV1 LTR37B
    ERV1 LTR38
    ERV1 LTR38A1
    ERV1 LTR38B
    ERV1 LTR38C
    ERV1 LTR39
    ERV1 LTR4
    ERV1 LTR43
    ERV1 LTR43B
    ERV1 LTR44
    ERV1 LTR45
    ERV1 LTR45B
    ERV1 LTR45C
    ERV1 LTR46
    ERV1 LTR48
    ERV1 LTR48B
    ERV1 LTR49
    ERV1 LTR51
    ERV1 LTR56
    ERV1 LTR58
    ERV1 LTR59
    ERV1 LTR60
    ERV1 LTR60B
    ERV1 LTR61
    ERV1 LTR64
    ERV1 LTR65
    ERV1 LTR6A
    ERV1 LTR6B
    ERV1 LTR70
    ERV1 LTR71A
    ERV1 LTR71B
    ERV1 LTR72
    ERV1 LTR72B
    ERV1 LTR73
    ERV1 LTR76
    ERV1 LTR77
    ERV1 LTR78B
    ERV1 LTR8
    ERV1 LTR81AB
    ERV1 LTR8A
    ERV1 LTR8B
    ERV1 LTR9
    ERV1 LTR9A1
    ERV1 LTR9B
    ERV1 LTR9C
    ERV1 LTR9D
    ERV1 MER101
    ERV1 MER101B
    ERV1 MER110
    ERV1 MER110A
    ERV1 MER110I
    ERV1 MER21I
    ERV1 MER31B
    ERV1 MER34
    ERV1 MER34B
    ERV1 MER34C
    ERV1 MER34C2
    ERV1 MER39
    ERV1 MER39B
    ERV1 MER41A
    ERV1 MER41B
    ERV1 MER41C
    ERV1 MER41D
    ERV1 MER41G
    ERV1 MER48
    ERV1 MER49
    ERV1 MER4A
    ERV1 MER4A1
    ERV1 MER4B
    ERV1 MER4C
    ERV1 MER4CL34
    ERV1 MER4D
    ERV1 MER4D1
    ERV1 MER4E
    ERV1 MER4E1
    ERV1 MER50
    ERV1 MER50B
    ERV1 MER50I
    ERV1 MER51A
    ERV1 MER51B
    ERV1 MER51C
    ERV1 MER51D
    ERV1 MER51E
    ERV1 MER52A
    ERV1 MER52AI
    ERV1 MER52C
    ERV1 MER52D
    ERV1 MER57A1
    ERV1 MER57B2
    ERV1 MER57F
    ERV1 MER61B
    ERV1 MER61C
    ERV1 MER65B
    ERV1 MER65C
    ERV1 MER65D
    ERV1 MER66_I
    ERV1 MER66A
    ERV1 MER66B
    ERV1 MER66C
    ERV1 MER66D
    ERV1 MER67A
    ERV1 MER67B
    ERV1 MER67C
    ERV1 MER67D
    ERV1 MER72
    ERV1 MER72B
    ERV1 MER83
    ERV1 MER83AI
    ERV1 MER83B
    ERV1 MER83BI
    ERV1 MER83C
    ERV1 MER84
    ERV1 MER87
    ERV1 MER87B
    ERV1 MER89
    ERV1 MER89I
    ERV1 MER90
    ERV1 MER92A
    ERV1 MER92B
    ERV1 PABL_A
    ERV1 PABL_AI
    ERV1 PABL_B
    ERV1 PABL_BI
    ERV1 PRIMA4_LTR
    ERV1 PrimLTR79
    ERV2 HERVK11DI
    ERV2 HERVK11I
    ERV2 HERVK13I
    ERV2 HERVK3I
    ERV2 HERVK9I
    ERV2 LTR13
    ERV2 LTR13A
    ERV2 LTR14
    ERV2 LTR14A
    ERV2 LTR14B
    ERV2 LTR14C
    ERV2 LTR22A
    ERV2 LTR22B
    ERV2 LTR22B1
    ERV2 LTR22B2
    ERV2 LTR22C2
    ERV2 LTR22E
    ERV2 LTR3
    ERV2 LTR3B
    ERV2 LTR5
    ERV2 LTR5B
    ERV2 MER11A
    ERV2 MER11C
    ERV2 MER11D
    ERV2 MER9
    ERV2 MER9B
    ERV2 RLTR10B
    ERV2 RLTR10C
    ERV3 ERV3-16A3_I
    ERV3 ERV3-16A3_LTR
    ERV3 ERVL
    ERV3 HERV16
    ERV3 HERVL
    ERV3 HERVL74
    ERV3 LTR16
    ERV3 LTR16A1
    ERV3 LTR16A2
    ERV3 LTR16C
    ERV3 LTR16D
    ERV3 LTR16E
    ERV3 LTR18A
    ERV3 LTR18B
    ERV3 LTR18C
    ERV3 LTR19A
    ERV3 LTR19B
    ERV3 LTR19C
    ERV3 LTR32
    ERV3 LTR40A
    ERV3 LTR40B
    ERV3 LTR40C
    ERV3 LTR41
    ERV3 LTR41B
    ERV3 LTR41C
    ERV3 LTR42
    ERV3 LTR47A
    ERV3 LTR47A2
    ERV3 LTR47B
    ERV3 LTR47B2
    ERV3 LTR50
    ERV3 LTR52
    ERV3 LTR53
    ERV3 LTR53B
    ERV3 LTR55
    ERV3 LTR57
    ERV3 LTR62
    ERV3 LTR66
    ERV3 LTR69
    ERV3 LTR75
    ERV3 LTR75B
    ERV3 LTR77B
    ERV3 LTR7A
    ERV3 LTR7B
    ERV3 LTR7C
    ERV3 MER21
    ERV3 MER21A
    ERV3 MER54_EC
    ERV3 MER54A
    ERV3 MER54B
    ERV3 MER68B
    ERV3 MER68C
    ERV3 MER70A
    ERV3 MER70B
    ERV3 MER70C
    ERV3 MER73
    ERV3 MER74B
    ERV3 MER74C
    ERV3 MER76
    ERV3 MER77
    ERV3 MER88
    ERV3 MLT1G
    ERV3 MLT1G1
    ERV3 MLT1G2
    ERV3 MLT1G3
    ERV3 MLT1H
    ERV3 MLT1H1
    ERV3 MLT1H2
    ERV3 MLT1I
    ERV3 MLT1K
    ERV3 MLT1L
    ERV3 MLT1N2
    ERV3 MLT2A1
    ERV3 MLT2A2
    ERV3 MLT2C2
    ERV3 MLT2D
    ERV3 MSTB
    ERV3 MSTD
    ERV3 RMER10B
    ERV3 THE1A
    ERV3 THE1C
    ERV3 THE1D
    hAT CHARLIE10
    hAT CHARLIE2A
    hAT CHARLIE2B
    hAT CHARLIE3
    hAT CHARLIE5
    hAT CHARLIE6
    hAT CHARLIE7
    hAT CHARLIE8
    hAT CHARLIE9
    hAT CHESHIRE
    hAT CHESHIRE_A
    hAT CHESHIRE_B
    hAT FORDPREFECT
    hAT FORDPREFECT_A
    hAT MER103B
    hAT MER103C
    hAT MER106
    hAT MER106B
    hAT MER107
    hAT MER112
    hAT MER113
    hAT MER113B
    hAT MER117
    hAT MER119
    hAT MER1A
    hAT MER1B
    hAT MER20
    hAT MER20B
    hAT MER30B
    hAT MER33
    hAT MER45
    hAT MER45C
    hAT MER5B
    hAT MER63D
    hAT MER80B
    hAT MER81
    hAT MER94
    hAT MER94B
    hAT MER96
    hAT MER96B
    hAT MER97A
    hAT MER97B
    hAT MER97C
    L1 HAL1B
    L1 IN25
    L1 L1
    L1 L1HS
    L1 L1M1B_5
    L1 L1M2_5
    L1 L1M2A_5
    L1 L1M2A1_5
    L1 L1M2B_5
    L1 L1M2C_5
    L1 L1M3B_5
    L1 L1M3C_5
    L1 L1M4B
    L1 LlM6B_5end
    L1 L1MA1
    L1 L1MA2
    L1 L1MA3
    L1 L1MA4
    L1 L1MA4A
    L1 L1MA5
    L1 L1MA5A
    L1 L1MA6
    L1 L1MA7
    L1 L1MA8
    L1 L1MA9
    L1 L1MB1
    L1 L1MB2
    L1 L1MB3
    L1 L1MB3_5
    L1 L1MB4
    L1 L1MB5
    L1 L1MB8
    L1 L1MC1
    L1 L1MC2
    L1 L1MC4
    L1 L1MCA_5
    L1 L1MCB_5
    L1 L1MCC_5
    L1 L1MD1
    L1 L1MD2
    L1 L1MD3
    L1 L1MDB_5
    L1 L1ME_ORF2
    L1 L1ME1
    L1 L1ME2
    L1 L1ME3
    L1 L1ME3A
    L1 L1ME4A
    L1 L1MEA_5
    L1 L1MEB_5
    L1 L1MED_5
    L1 L1MEE_5
    L1 L1PA10
    L1 L1PA11
    L1 L1PA12
    L1 L1PA12_5
    L1 L1PA13
    L1 L1PA13_5
    L1 L1PA14
    L1 L1PA14_5
    L1 L1PA15
    L1 L1PA16
    L1 L1PA16_5
    L1 L1PA17_5
    L1 L1PA2
    L1 L1PA3
    L1 L1PA4
    L1 L1PA5
    L1 L1PA6
    L1 L1PA7
    L1 L1PA7_5
    L1 L1PA8
    L1 L1PB1
    L1 L1PB2
    L1 L1PB2c
    L1 L1PB3
    L1 L1PB4
    L1 L1PBA_5
    L1 L1PBA1_5
    L1 L1PBB_5
    L1 L1PREC1
    L1 L1PREC2
    LTR Retrotransposon HARLEQUINLTR
    LTR Retrotransposon HERV-K14CI
    LTR Retrotransposon HERV-K14I
    LTR Retrotransposon HUERS-P3
    LTR Retrotransposon LOR1
    LTR Retrotransposon LTR11
    LTR Retrotransposon MER4I
    LTR Retrotransposon MER51I
    LTR Retrotransposon MER52B
    LTR Retrotransposon MER61D
    LTR Retrotransposon MER61E
    LTR Retrotransposon MER61F
    LTR Retrotransposon MER61I
    LTR Retrotransposon MER95
    LTR Retrotransposon PTR5
    LTR Retrotransposon THE1_I
    Mariner/Tc1 GOLEM_A
    Mariner/Tc1 GOLEM_C
    Mariner/Tc1 HSMAR1
    Mariner/Tc1 HSMAR2
    Mariner/Tc1 HSTC2
    Mariner/Tc1 KANGA2_A
    Mariner/Tc1 MADE1
    Mariner/Tc1 MARINER1_EC
    Mariner/Tc1 MARNA
    Mariner/Tc1 MER44A
    Mariner/Tc1 MER44B
    Mariner/Tc1 MER44C
    Mariner/Tc1 MER6B
    Mariner/Tc1 MER8
    Mariner/Tc1 TIGGER1
    Mariner/Tc1 TIGGER2
    Mariner/Tc1 TIGGER5
    Mariner/Tc1 TIGGER6B
    Mariner/Tc1 TIGGER7
    Mariner/Tc1 TIGGER8
    Mariner/Tc1 TIGGER9
    Mariner/Tc1 ZOMBI_A
    Merlin Merlin1_HS
    SINE SVA
    SINE1/7SL AluYa5
    SINE1/7SL AluYb8
    SINE1/7SL AluYb9
    SINE1/7SL AluYk13
    SINE3/5S AmnSINE1_HS
    Transposable Element MER54
    Transposable Element TARE
  • TABLE 6
    Satellite correlated genes. Adapted
    from Ting et al.(Ting et al., 2011)
    Gene Names
    A2ML1
    ABCA9
    ACADSB
    ACBD7
    ADAMTSL3
    ALG11
    ANGEL2
    ANKRD20A1
    AP1S3
    APOL4
    APOL6
    ATP10B
    BNC1
    C11ORF72
    C11ORF74
    C12ORF5
    C13ORF29
    C15ORF2
    C15ORF28
    C17ORF77
    C1ORF130
    C1ORF69
    C1ORF84
    C21ORF82
    C3ORF20
    C6ORF170
    C7ORF44
    C7ORF46
    C8ORF12
    C9ORF68
    CAGE1
    CCBP2
    CCDC122
    CCDC52
    CD3EAP
    CDON
    CENPM
    CES3
    CES7
    CHRM5
    CLCC1
    COX18
    CPM
    CPSF2
    CYP46A1
    DBF4B
    DCHS2
    DDO
    DHRS4L2
    DKFZP434L187
    DKFZP779L1853
    DNAH5
    DNAH8
    DSG3
    DUSP19
    DZIP3
    EEF2K
    F2RL3
    FAM111B
    FAM122C
    FAM22G
    FAM75A2
    FAM83D
    FAT3
    FBXO15
    FBXW10
    FCF1
    FER
    FGF5
    FLJ11292
    FLJ41649
    FLJ43763
    FUT1
    GALNT13
    GBP4
    GK5
    GLIPR1L2
    GPR110
    GPR157
    GTPBP10
    GTSE1
    GUSBP1
    HERC4
    HESRG
    HIF3A
    HMGA2
    HRH4
    HUNK
    HYDIN
    IL12RB1
    IPO9
    KCTD18
    KIAA1245
    KIAA1257
    KIAA1328
    KIR3DX1
    LEPRE1
    LOC147804
    LOC349196
    LOC440313
    LOC441242
    LOC441426
    LOC642980
    LOC643406
    LOC649305
    LOC91948
    LRRC2
    LTV1
    LYRM2
    LYRM7
    MCFD2
    MED18
    MORC4
    MSH5
    MTBP
    MX2
    MYH1
    MYO3B
    MYOM3
    NBPF1
    NEB
    NHEDC1
    NIPSNAP3B
    NME7
    NMNAT1
    NUP43
    ODF2L
    OR11H1
    OR11H12
    OR4F16
    OR4K15
    OR7D2
    OR7E156P
    ORC6L
    PCBD2
    PDDC1
    PGPEP1
    PHACTR4
    PHTF1
    PLA2G2D
    PLEKHA5
    PRKRIR
    PRND
    PXMP4
    QTRTD1
    RASGRP3
    REXO1L1
    RGR
    RNF125
    SIGLEC10
    SIGLEC8
    SIRPB1
    SLC13A2
    SLC14A2
    SLC16A12
    SLC19A3
    SLC1A6
    SLC27A1
    SLC31A1
    SMU1
    SP100
    STRC
    STX17
    TAOK1
    TCL6
    TEX9
    TGFB2
    TIGD1
    TNFRSF19
    TRIM43
    TRPM3
    TTN
    ULBP1
    USPL1
    UTP14C
    WDR17
    WDR31
    XKR9
    XRCC2
    ZFYVE20
    ZMYM1
    ZMYND17
    ZNF100
    ZNF192
    ZNF208
    ZNF273
    ZNF320
    ZNF331
    ZNF37A
    ZNF383
    ZNF431
    ZNF445
    ZNF471
    ZNF480
    ZNF490
    ZNF492
    ZNF493
    ZNF528
    ZNF562
    ZNF621
    ZNF623
    ZNF667
    ZNF670
    ZNF7
    ZNF720
    ZNF804B
    BC029464
    BC082237
    BC050580
    BC039319
    AK096834
    BC042893
    BC043508
    HBET1
    NR_003246
    LOC643079
    BC040190
    AK095450
    BC036442
    DKFZP761G18121
    AK092337
    KIAA0379
    FLJ44076
    AX748237
    AX747345
    AX747165
    CR627148
    UNQ2963
    DKFZP667M2411
    AK125319
    AK125996
    AK026805
    AK129982
    CR592614
    AK095077
    BC035989
    CR623134
    AK026100
    RP1-140A9.6
    AX747405
    NR_002828
    NR_003130
    BIRC4BP
    AK054836
    AX747417
    AY314745
    NR_001318
    AX747586
    AK125128
    AK055694
    BC035084
    WUGSC:H_DJ0855D2
    1.2
    CR596262
    AX746734
    AK024378
    BC037952
    BC041998
    BC008050
    NR_003133
    AX748369
    BC043541
    AK131347
    FLJ00140
    CR620525
    AX748243
    AX747639
    AX746484
    CR605783
    AK097143
    BC052952
    AK124179
    FLJ16008
    BC073807
    BC015784
    CR592225
    BC031280
    DKFZP686F19123
    AX747440
    AK096469
    AK124893
    AX747721
    AK123584
    NR_003263
    DKFZP762C213
    BC094791
    CR627394
    AK124673
    NR_002910
    FRABIN
    BC069727
    BC037884
    BX648696
    CR627383
    BC034569
    AX747308
    AK123585
    BC011779
    DKFZP686H1615
    BC070093
    BX537874
    AX748226
    CR598144
    BC040189
    AL832479
    NR_002939
    AL833449
    BC047600
    KIAA1031
    AK095766
    AL832786
    BC035181
    NR_002220
    DQ596646
    NM_001001704
    AL832797
    AK129672
    AK123838
    AX746771
    C20ORF38
    AX746989
    LOC285382
    MGC102966
    AK124194
    FLJ45337
    AK126334
    AK057596
    NR_003128
    AK096077
    DERP7
    AK098126
    BC033330
    BC029555
    LOC129881
    AK097527
    BX648961
    AK096499
    AK097777
    AK091028
    FLJ37953
    PTPN1L
    AK096196
    AK056351
    AX746750
    LOC440053
    BC068605
    UNQ9369
    PFDN6L
    AK125042
    AK125489
    BC013681
    AK056866
    AX747590
    AX746620
    FLJ00310
    NM_001042703
    AK094618
    AX748002
    BC041646
    AJ617629
    AL833139
    AK097428
    AK056105
    MGC13098
    AK127557
    KIAA1456
    BC069809
    LOC441108
    NM_001039909
    AK096291
    BX537710
    BC041449
    NR_002836
    CR598129
    BC035112
    CR613732
    DQ597733
    AX747172
    AK128266
    TCAM-1
    BC050344
    BC047380
    AL832439
    BC042121
    BC041426
    C15ORF20
    AK125310
    DKFZP434P055
    KIAA0010
    COX18HS
    BC038578
    AY314748
    AK023134
    AK131313
    BC041865
    AX746851
    LOC606495
    AK127238
    LOC441282
    BOZF1
    AK026825
    AK128305
    AL713649
    DQ573949
    AK091996
    CR606964
    HSKRP1
    AX747556
    NR_003266
    CR749689
    BC049371
    AX747988
    FLJ35848
    WHDC1L1
    AK126491
    AK024841
    AX746688
    FLJ37357
    FLJ44955
    BC040631
    CR627135
    DKFZP451M2119
    CR627206
    AK127460
    BC019672
    HERV-HHHLA1
    FUSION
    AK057632
    FLJ00264
    NY-REN-7
    AK125288
    AF086203
    LOC94431
    BC043415
    AK098333
    BC042588
    AX747864
    AY314747
    AK128216
    BC044257
    AX747062
    BX649144
    AL137270
    PP8961
    AK056558
    AK094845
    AX747742
    AK095981
    CTRP6
    NR_002821
    AX746880
    AK125817
    AK056417
    AK026469
    AK090984
    AK131520
    AL833246
    AK125832
    BC041455
    AF380582
    AX747658
    AX721193
    BC047626
    FLJ44060
    KIAA0982
    AK093513
    BC038431
    BX161428
    DKFZP686O248
    AK096335
    BX640887
    BC009626
    AY338954
    BC036412
    NM_001001681
    AK056892
    DQ573361
    BC041466
    NR_002210
    FLJ33706
    KIAA1767
    MBL1P1
    BC071776
    AK127888
    NR_002943
    AX747340
    LOC401252
    AX746585
    AK091594
    AK096412
    FLJ34047
    AX747756
    BC090058
    CR611653
    AL137733
    BX537706
    NR_001565
    MGC4836
    MGC29891
    AK098240
    AX748249
    C1ORF140
    AK055868
    BC122562
    BC041363
    BC047625
    BC021741
    AK056524
    BX647358
    AK023515
    AK125311
    AK123891
    LOC339809
    AK128523
    AK094859
    PJCG6
    AX748371
    UNQ3037
    AK054880
    AK094224
    AL833510
    KENAE1
    BC012110
    BC052779
    AK097893
    BC105727
    AK091527
    WBSCR23
    BC043378
    AK056246
    LOC401898
    AK023856
    UNQ1849
    BC048997
    FLJ36492
    KIAA2023
    AK054869
    CR749689
    BC029555
    AK024378
    NR_002821
    DKFZP686F19123
  • TABLE 7
    Categories of repeated DNA.
    Size of
    Class repeat Major chromosomal location(s)
    ‘Megasatellite’ DNA several Various locations on selected
    (blocks of hundreds of kb chromosomes
    kb in some cases)
    RS447 4.7 kb ~50-70 copies on 4p15 plus several
    copies on distal 8p
    untitled 2.5 kb ~400 copies on 4q31 and 19q13
    untitled 3.0 kb ~50 copies on the X chromosome
    Satellite DNA (blocks 5-171 bp Especially at centromeres
    often from 100 kb to
    several Mb in length)
    α (alphoid DNA) 171 bp Centromeric heterochromatin of all
    chromosomes
    β (Sau3 A family) 68 bp Centromeric heterochromatin of 1, 9,
    13, 14, 15, 21, 22 and Y
    Satellite 1 (AT-rich) 25-48 bp Centromeric heterochromatin of most
    chromosomes and other hetero-
    chromatic regions
    Satellites
    2 and 3 5 bp Most, possibly all, chromosomes
    Minisatellite DNA 6-64 bp At or close to telomeres of all
    (blocks often within chromosomes
    the 0.1-20 kb range)
    telomeric family 6 bp All telomeres
    hypervariable family 9-64 bp All chromosomes, often near
    telomeres
    Microsatellite DNA 1-4 bp Dispersed throughout all
    (blocks often chromosomes
    less than 150 bp)
  • TABLE 8
    Repeated DNA elements.
    The list is adapted from Repbase-GIRI.
    http://www.girinst.org/, accessed Jan. 31, 2011.
    Name of Repeat
    (AC)n
    (AG)n
    (AT)n
    (C)n
    (CAA)n
    (CAAA)n
    (CAAAA)n
    (CAAAAA)n
    (CCA)n
    (CCCCA)n
    (CCCCAA)n
    (CCCCCA)n
    (CCCGAA)n
    (CCCTAA)n
    (CCCTCA)n
    (CCTA)n
    (CG)n
    (CGAA)n
    (CGGA)n
    (CTA)n
    (CTCCA)n
    (GAA)n
    (GAAA)n
    (GAAAA)n
    (GAAAAA)n
    (GACA)n
    (GAGACA)n
    (GCA)n
    (GCC)n
    (GCCA)n
    (GCCC)n
    (GCCCA)n
    (GCCCC)n
    (GCCCCA)n
    (GCCCCC)n
    (GCGCA)n
    (GCTCA)n
    (GGA)n
    (GGAA)n
    (GGAGA)n
    (GGAGAA)n
    (GGCA)n
    (GGCCC)n
    (GGGA)n
    (GGGAGA)n
    (GGGGA)n
    (GGGGGA)n
    (TAA)n
    (TAAA)n
    (TAAAA)n
    (TAAAAA)n
    (TACA)n
    (TACAA)n
    (TAGA)n
    (TAGAA)n
    (TATACA)n
    (TCA)n
    (TCAA)n
    (TCACCA)n
    (TCCA)n
    (TCCCA)n
    (TCTAA)n
    (TGAA)n
    (TGGAA)n
    (TGGCCC)n
    (TTAA)n
    (TTAAA)n
    ACRO1
    ALR
    ALR
    ALR1
    ALR2
    ALRa
    ALRa
    ALRb
    BSR
    BSRa
    >BSRb
    >BSRd
    >BSRf
    >CER
    >D20S16
    >GGAAT
    >GSAT
    >GSATII
    >GSATX
    >HSAT4
    >HSAT5
    >HSAT6
    >HSATI
    >HSATII
    >LSAU
    >MSR1
    >REP522
    >SAR
    >SATR1
    >SATR2
    >SN5
    >SUBTEL_sat
    >SUBTEL2_sat
    >SVA2
    >TAR1
  • TABLE 9
    Examples of non-coding RNAs in nature.
    Non-coding RNA Abbreviation Example of function Reference
    Transfer RNA tRNA Translation (Aitken et al.,
    2010)
    Ribosomal RNA rRNA Translation (Aitken et al.,
    2010)
    Signal recognition 7SL RNA or Translocation of proteins across the (Gribaldo and
    particle RNA SRP RNA Endoplasmatic Reticulum Brochier-
    Armanet, 2006)
    Small nuclear RNA snRNA Splicing (Valadkhan,
    2010)
    Small nucleolar RNA snoRNA Guides chemical modifications of (Kiss, 2002)
    other RNAs (like methylation and
    pseudouridylation).
    Short Interspersed SINE The most common SINE is the Alu (Mariner et al.,
    repetitive elements element (~10% of the genome). Alu 2008)
    is upregulated in response to stress
    and binds RNA polymerase II to
    suppress transcription.
    microRNA miRNA Post-transcriptional gene silencing (Bartel, 2009)
    Small interfering RNA siRNA Post-transcriptional gene silencing (Elbashir et al.,
    2001)
    Piwi-interacting RNA piRNA Transciptional gene silencing, (Taft et al., 2010)
    defense against retrotransposons
    Ribonuclease P RNase P Ribozyme involved in tRNA (Guerrier-Takada
    maturation et al., 1983)
    Ribonuclease MRP RNase MRP Ribozyme involved in rRNA (Li et al., 2002)
    maturation as well as mitochondrial
    DNA replication
    Y RNA Y RNA RNA processing, DNA replication (Lerner et al.,
    1981)
    Telomerase RNA Telomere synthesis (Feng et al.,
    1995)
    Antisense RNA aRNA Transcriptional attenuation/mRNA (Katayama et al.,
    degradation/mRNA stabilisation/ 2005)
    translation block
    Long ncRNA, large Long ncRNA, regulation of gene transcription, (Kapranov et al.,
    intervening ncRNA lincRNA post-transcriptional regulation, 2007)
    (>200 nt) epigenetic regulation
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Claims (1)

We claim:
1. A method for assaying a biological sample from a subject in aid of diagnosis, prognosis or monitoring of a disease or other medical condition in the subject, comprising the steps of:
a. obtaining or using a microvesicle fraction from a biological sample from a subject;
b. extracting nucleic acid from the fraction; and
c. detecting the presence or absence of a biomarker in the extracted nucleic acid;
wherein the biomarker is a genetic aberration associated with diagnosis, prognosis, status or stage of a disease or other medical condition, and wherein the genetic aberration is in or corresponds to:
i. a c-myc gene;
ii. a transposable element;
iii. a retrotransposon element;
iv. a satellite correlated gene;
v. a repeated DNA element;
vi. non-coding RNA other than miRNA; or
vii. a fragment of any of the foregoing.
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