US20200399714A1 - Cancer-related biological materials in microvesicles - Google Patents
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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
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
-
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 inFIG. 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 inFIG. 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 inFIG. 1 . -
FIG. 5 shows a graph depicting the quantification, size distribution and RNA yield of microvesicles purified from theglioblastoma cell line 20/3 in the same manner as inFIG. 1 . -
FIG. 6 shows a graph depicting the quantification, size distribution and RNA yield of microvesicles purified from theglioblastoma cell line 11/5 in the same manner as inFIG. 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 inFIG. 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 inFIG. 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 inFIG. 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 inFIG. 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 inFIG. 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 fromGBM 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 inFIG. 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 inFIG. 15 except that the present plot only depicts relative levels of DNA transposons. -
FIG. 18 shows a MA plot similar to the plot inFIG. 15 except that the present plot only depicts relative levels of L1 sequences. -
FIG. 19 shows a MA plot similar to the plot inFIG. 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 inFIG. 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 fromGBM 11/5 cells. Both 18S and 28S rRNA peaks are detectable (arrowheads).FIG. 25B depicts the profile ofexoDNA 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 inFIG. 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 DNAFIG. 31A or exoDNAFIG. 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. - 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 onchromosome 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 andpresenilin 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.
- 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. - 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.
- 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 inexon 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 c15 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. - 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 ). - 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 inFIGS. 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 inFIG. 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 ). - 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.
- 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. - 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 inFIGS. 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 1Homo 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)
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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US17/014,540 Abandoned US20200399714A1 (en) | 2010-08-31 | 2020-09-08 | Cancer-related biological materials in microvesicles |
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EP2475988B1 (en) | 2009-09-09 | 2018-11-14 | The General Hospital Corporation | Use of microvesicles in analyzing nucleic acid profiles |
EP2475989A4 (en) | 2009-09-09 | 2013-02-27 | Gen Hospital Corp | Use of microvesicles in analyzing kras mutations |
WO2011050341A1 (en) | 2009-10-22 | 2011-04-28 | National Center For Genome Resources | Methods and systems for medical sequencing analysis |
AU2011205230A1 (en) * | 2010-01-13 | 2012-08-02 | Caris Life Sciences Switzerland Holdings Gmbh | Detection of gastrointestinal disorders |
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US20130040833A1 (en) | 2010-05-12 | 2013-02-14 | The General Hospital Corporation | Use of microvesicles in analyzing nucleic acid profiles |
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2011
- 2011-08-31 US US13/819,539 patent/US20140045915A1/en not_active Abandoned
- 2011-08-31 WO PCT/US2011/050041 patent/WO2012031008A2/en active Application Filing
-
2016
- 2016-02-01 US US15/012,111 patent/US10793914B2/en active Active
-
2020
- 2020-09-08 US US17/014,540 patent/US20200399714A1/en not_active Abandoned
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WO2023004080A3 (en) * | 2021-07-21 | 2023-03-23 | Mercy Bioanalytics, Inc. | Compositions and methods for detection of pancreatic cancer |
WO2023070121A1 (en) * | 2021-10-22 | 2023-04-27 | The Wistar Institute Of Anatomy And Biology | Compositions and methods for treatment of mic60 depleted cancers and metastasis |
WO2023244632A1 (en) * | 2022-06-17 | 2023-12-21 | Merck Sharp & Dohme Llc | Genome wide tumor derived gene expression based signatures associated with poor prognosis for melanoma patients with early stage disease |
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US20160153053A1 (en) | 2016-06-02 |
WO2012031008A2 (en) | 2012-03-08 |
US20140045915A1 (en) | 2014-02-13 |
WO2012031008A3 (en) | 2012-11-01 |
US10793914B2 (en) | 2020-10-06 |
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