AU780210B2 - Mammalian genes involved in viral infection and tumor suppression - Google Patents

Description

P/00/011 28/5/91 Regulation 3.2

AUSTRALIA

Patents Act 1990

ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT Name of Applicant: Actual Inventor Vanderbilt University Mr Donald H Rubin Edward L Organ Raymond D Dubois WRAY ASSOCIATES 239 Adelaide Terrace Perth, WA 6000 Address for service is: Attorney code: WR Invention Title: Mammalian Genes Involved in Viral Infector and Tumor Suppression The following statement is a full description of this invention, including the best method of performing it known to me:- 1/2 MAMMALIAN GENES INVOLVED IN VIRAL INFECTION AND TUMOR

SUPPRESSION

BACKGROUND

Field of the Invention The present invention provides methods of identifying cellular genes used for viral growth or for tumor progression. Thus, the present invention relates to nucleic acids related to and methods of reducing or preventing viral infection and for suppressing tumor progression. The invention also relates to methods for screening for additional such genes.

Background art Various projects have been directed toward isolating and sequencing the genome of various animals, notably the human. However, most methodologies provide nucleotide sequences for which no function is linked or even suggested, thus limiting the o 15 immediate usefulness of such data.

The present invention, in contrast, provides methods of screening only for nucleic acids that are involved in a specific process, viral infection or tumor progression, and further, for nucleic acids useful in treatments for these processes because by this method only nucleic acids which are also nonessential to the cell are 20 isolated. Such methods are highly useful, since they ascribe a function to each isolated gene, and thus the isolated nucleic acids can immediately be utilized in various specific methods and procedures.

For, example, the present invention provides methods of isolating nucleic acids encoding gene products used for viral infection, but nonessential to the cell. Viral infections of the intestine and liver are significant causes of human morbidity and mortality. Understanding the molecular mechanisms of such infections will lead to new approaches in their treatment and control.

Viruses can establish a variety of types of infection. These infections can be generally classified as lytic or persistent, though some lytic infections are considered persistent. Generally, persistent infections fall into two categories: chronic (productive) infection, infection wherein infectious virus is present and can be recovered by traditional biological methods and latent infection, infection wherein viral genome is present in the cell but infectious virus is generally not produced except during intermittent episodes of reactivation. Persistence generally involves stages of both productive and latent infection.

Lytic infections can also persist under conditions where only a small fraction of the total cells are infected (smoldering (cycling) infection). The few infected cells release virus and are killed, but the progeny virus again only infect a small number of the total cells. Examples of such smoldering infections include the persistence of lactic dehydrogenase virus in mice (Mahy, Br. Med. Bull. 41: 50-55 (1985)) and adenovirus infection in humans (Porter, D.D. pp. 784-790 in Baron, ed. Medical Microbiology 2d ed. (Addison-Wesley, Menlo Park, CA 1985)).

Furthermore, a virus may be lytic for some cell types but not for others. For example, evidence suggests that human immunodeficiency virus (HIV) is more lytic for T cells than for monocytes/macrophages, and therefore can result in a productive :15 infection of T cells that can result in cell death, whereas HIV-infected mononuclear phagocytes may produce virus for considerable periods of time without cell lysis.

(Klatzmann, et al. Science 225:59-62 (1984); Koyanagi, et al. Science 241:1673-1675 (1988); Sattentau, et al. Cell 52:631-633 (1988)).

Traditional treatments for viral infection include pharmaceuticals aimed at 20 specific virus derived proteins, such as HIV protease or reverse transcriptase, or recombinant (cloned) immune modulators (host derived), such as the interferons.

However, the current methods have several limitations and drawbacks which include high rates of viral mutations which render anti-viral pharmaceuticals ineffective. For immune modulators, limited effectiveness, limiting side effects, a lack of specificity all limit the general applicability of these agents. Also the rate of success with current antivirals and immune-modulators has been disappointing.

The current invention focuses on isolating genes that are not essential for cellular survival when disrupted in one or both alleles, but which are required for virus replication. This may occur with a dose effect, in which one allele knock-out may confer the phenotype of virus resistance for the cell. As targets for therapeutic intervention, inhibition of these cellular gene products, including: proteins, parts of proteins (modification enzymes that include, but are not restricted to glycosylation, lipid modifiers [myriolate, lipids, transcription elements and RNA regulatory molecules, may be less likely to have profound toxic side effects and virus mutation is less likely to overcome the 'block' to replicate successfully.

The present invention provides a significant improvement over previous methods of attempted therapeutic intervention against viral infection by addressing the cellular genes required by the virus for growth. Therefore, the present invention also provides an innovative therapeutic approach to intervention in viral infection by providing methods to treat viruses by inhibiting the cellular genes necessary for viral infection.

Because these genes, by virtue of the means by which they are originally detected, are nonessential to the cell's survival, these treatment methods can be used in a subject without serious detrimental effects to the subject, as has been found with previous methods. The present invention also provides the surprising discovery that virally infected cells are dependent upon a factor in serum to survive. Therefore, the present invention also provides a method for treating viral infection by inhibiting this serum survival factor. Finally, these discoveries also provide a novel method for removing virally infected cells from a cell culture by removing, inhibiting or disrupting this serum survival factor in the culture so that non-infected cells selectively survive.

The selection of tumor suppressor gene(s) has become an important area in the 20 discovery of new target for therapeutic intervention of cancer. Since the discovery that cells are restricted from promiscuous entry into the cell cycle by specific genes that are capable of suppressing a 'transformed' phenotype, considerable time has been invested in the discovery of such genes. Some of these genes include the gene associated by rhabdomyosarcoma (Rb) and the p53 (apoptosis related) encoding gene. The present invention provides a method, using gene-trapping, to select cell lines that have transformed phenotype from cells that are not transformed and to isolate from these cells a gene that can suppress a malignant phenotype. Thus, by the nature of the isolation process, a function is associated with the isolated genes. The capacity to select quickly tumor suppressor genes can provide unique targets in the process of treating or preventing, and even for diagnostic testing of, cancer.

DETAILED DESCRIPTION OF THE INVENTION The present invention utilizes a "gene trap" method along with a selection process to identify and isolate nucleic acids from genes associated with a particular function. Specifically, it provides a means of isolating cellular genes necessary for viral infection but not essential for the cell's survival, and it provides a means of isolating cellular genes that suppress tumor progression.

The present invention also provides a core discovery that virally infected cells become dependent upon at least one factor present in serum for survival, whereas noninfected cells do not exhibit this dependence. This core discovery has been utilized in the present invention in several ways. First, inhibition of the "serum survival factor" can be utilized to eradicate persistently virally infected cells from populations of non-infected cells. Inhibition of this factor can also be used to treat virus infection in a subject, as further described herein. Additionally, inhibition of or withdrawal of the serum survival 15 factor in tissue culture allows for the detection of cellular genes required for viral replication yet nonessential for an uninfected cell to survive. The present invention further provides several such cellular genes, as well as methods of treating viral infections by inhibiting the functioning of such genes.

Furthermore, the present invention provides a method for isolation of cellular 20 genes utilized in tumor progression.

The present method provides several cellular genes that are necessary for viral i growth in the cell but are not essential for the cell to survive. These genes are important for lytic and persistent infection by viruses. These genes were isolated by generating gene trap libraries by infecting cells with a retrovirus gene trap vector, selecting for cells in which a gene trap event occurred in which the vector had inserted such that the promoterless marker gene was inserted such that a cellular promoter promotes transcription of the marker gene, inserted into a functioning gene), starving the cells of serum, infecting the selected cells with the virus of choice while continuing serum starvation, and adding back serum to allow visible colonies to develop, which colonies were cloned by limiting dilution. Genes into which the retrovirus gene trap vector inserted were then isolated from the colonies using probes specific for the retrovirus gene trap vector. Thus nucleic acids isolated by this method are isolated portions of genes.

Thus the present invention provides a method of identifying a cellular gene necessary for viral growth in a cell and nonessential for cellular survival, comprising (a) transferring into a cell culture growing in serum-containing medium a vector encoding a selective marker gene lacking a functional promoter, selecting cells expressing the marker gene, removing serum from the culture medium, infecting the cell culture with the virus, and isolating from the surviving cells a cellular gene within which the marker gene is inserted, thereby identifying a gene necessary for viral growth in a cell and nonessential for cellular survival. The present invention also provides a method of identifying a cellular gene used for viral growth in a cell and nonessential for cellular survival, comprising transferring into a cell culture growing in serumcontaining medium a vector encoding a selective marker gene lacking a functional promoter, selecting cells expressing the marker gene, removing serum from the culture medium, infecting the cell culture with the virus, and isolating from the surviving cells a cellular gene within which the marker gene is inserted, thereby identifying a gene necessary for viral growth in a cell and nonessential for cellular survival. In any selected cell type, such as Chinese hamster ovary cells, one can readily determine if serum starvation is required for selection. If it is not, serum starvation may 20 be eliminated from the steps.

Alternatively, instead of removing serum from the culture medium, a serum factor required by the virus for growth can be inhibited, such as by the administration of an antibody that specifically binds that factor. Furthermore, if it is believed that there are no persistently infected cells in the culture, the serum starvation step can be eliminated and the cells grown in usual medium for the cell type. If serum starvation is used, it can be continued for a time after the culture is infected with the virus. Serum can then be added back to the culture. If some other method is used to inactivate the factor, it can be discontinued, inactivated or removed (such as removing the anti-factor antibody, with a bound antibody directed against that antibody) prior to adding fresh serum back to the culture. Cells that survive are mutants having an inactivating insertion in a gene necessary for growth of the virus. The genes having the insertions can then be isolated by isolating sequences having the marker gene sequences. This mutational process disturbs a wild type function. A mutant gene may produce at a lower level a normal product, it may produce a normal product not normally found in these cells, it may cause the overproduction of a normal product, it may produce an altered product that has some functions but not others, or it may completely disrupt a gene function. Additionally, the mutation may disrupt an RNA that has a function but is never translated into a protein. For example, the alpha-tropomyosin gene has a 3' RNA that is very important in cell regulation but never is translated into protein. (Cell pg 1107-1117, 12/17/93).

As used herein, a cellular gene "nonessential for cellular survival" means a gene for which disruption of one or both alleles results in a cell viable for at least a period of time which allows viral replication to be inhibited for preventative or therapeutic uses or 'use in research. A gene "necessary for viral growth" means the gene product, either protein or RNA, secreted or not, is necessary, either directly or indirectly in some way 15 for the virus to grow, and therefore, in the absence of that gene product a functionally available gene product), at least some of the cells containing the virus die.

For example, such genes can encode cell cycle regulatory proteins, proteins affecting the vacuolar hydrogen pump, or proteins involved in protein folding and protein modification, including but not limited to: phosphorylation, methylation, glycosylation, 20 myrislation or other lipid moiety, or protein processing via enzymatic processing. Some examples of such genes are exemplified herein, wherein some of the isolated nucleic acids correspond to genes such as vacuolar H+ATPase, alpha tropomyosin, gas5 gene, ras complex, N-acetyl-glucosaminyltransferase I mRNA, and calcyclin.

Any virus capable of infecting the cell can be used for this method. Virus can be selected based upon the particular infection desired to study. However, it is contemplated by the present invention that many viruses will be dependent upon the same cellular genes for survival; thus a cellular gene isolated using one virus can be used as a target for therapy for other viruses as well. Any cellular gene can be tested for relevancy to any desired virus using the methods set forth herein, in general, by inhibiting the gene or its gene product in a cell and determining if the desired virus can grow in that cell. Some examples of viruses include HIV (including HIV-1 and HIV-2); 7 parvovi-us; papillomaviruses;, hantaviruses; influenza viruses influenza A, B and C viruses); hepatitis viruses A to G; caliciviruses; astrovir-uses; rotaviruses; coronaviruses, such as human respiratory coronavirus; picornaviruses, such as human rhinovirus and enterovirus; ebola virus; human herpesvirus 1-S V- human cytomegalovirus; human adenovii-us; Epstein-Barr virus; hantaviruses; for animal, the animal counterpart to any above listed human virus, animal retroviruses, such as simian immunodeficiency virus, avian immunodeficiency virus, bovine immunodeficiency virus, feline irmmunodeficiency virus, equine infectious anemia virus, caprine arthritis encephalitis virus or visna virus.

The nucleic acids comprising cellular genes of this invention were isolated by the above method and as set forth in the examples. The invention includes a nucleic acid comprising the nucleotide sequence set forth in SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO.7, SEQIDNO.S9, SEQIDNO:9, SEQIDNO:iO, SEQIDNO:l1, SEQID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, NO 17, NO.22, NO:27, NO:32, NO: 3 7, NO:42, NO:47, NO:52, NO:57, NO:62, NO:67, NO:72, SEQ ID NO: I18, SEQ ID NO: 2' SEQ ID NO:28, SEQ ID NO:33.

SEQ ID NO:3 8, SEQ ID NQ:43, SEQ ID NO:48, SEQ ID NO: 53, SEQ ID NO.-58, SEQ ID NO: 63, SEQ ID NO:68, SEQ ID NO: 73, SEQ ID NO: 19, SEQ ID NO:24, SEQ ID NO:29, SEQ ID N0:34, SEQ ID NO:39, SEQ ID NO:44, SEQ ID NO:49, SEQ ID NO: 54, SEQ ID NO:59, SEQ ID N0-64, SEQ ID NO:69, SEQ ID NO:20, SEQ ID NO:25, SEQ ID NO:30, SEQ ID NO:35, SEQ IDj NO:40, SEQ ID NO:45.

SEQ ID NO: 50, SEQ ID NO.-55, SEQ ID NO:60, SEQ ID NO:65, SEQ ID NO: 70, SEQ ID NO:21, SEQ ID NO:26, SEQ ID NO:.3 1, SEQ ID NO.36, SEQ ID NO:41, SEQ ID NO:46, SEQ ID NO-S 1, SEQ ID NO:56, SEQ MD NO:6I, SEQ ID NO: 66, SEQ ID SEQ ID SEQ JID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQIDNO:71, SEQID SEQ ID NO:74 or SEQ ID NO:75 (this list is sometimes referred to herein as "SEQ ID NO:S through SEQ ID NO:75' for brevity). Thus these nucleic acids can contain, in addition to the nucleotides set forth in each SEQ ID NO in the sequence listing, additional nucleotides at either end of the molecule. Such additional nucleotides can be added by any standard method, as Known in the art, such as recombinant methods and synthesis methods. Examples of such nucleic acids comprising the nucleotide sequence set forth in any entry of the sequence listing contemplated by this invention include, but are not limited to, for example, the nucleic acid placed into a vector; a nucleic acid having one or more regulatory region promoter, enhancer, polyadenylation site) linked to it, particularly in functional manner, i.e. such that an mRNA or a protein can be produced; a nucleic acid including additional nucleic acids of the gene, such as a larger or even full length genomic fragment of the gene, a partial or full length cDNA, a partial or full length RNA. Making and/or isolating such larger nucleic acids is further described below and is well known and standard in the art.

The invention also provides a nucleic acid encoding the protein encoded by the gene comprising the nucleotide sequence set forth in SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO: 17, 15 SEQ ID NO:22, SEQ ID NO:27, SEQ ID NO:32, SEQ ID NO:37, SEQ ID NO:42, SEQ ID NO:47, SEQ ID NO:52, SEQ ID NO:57, SEQ ID NO:62, SEQ ID NO:67, SEQ ID NO:72, SEQ ID NO: 18, SEQ ID NO:23, SEQ ID NO:28, SEQ ID NO:33, SEQ ID NO:38, SEQ ID NO:43, SEQ ID NO:48, SEQ ID NO:53, SEQ ID NO.58, SEQ ID NO:63, SEQ ID NO:68, SEQ ID NO:73, SEQ ID NO: 19, SEQ ID NO:24, SEQ ID NO:29, SEQ ID NO:34, SEQ ID NO:39, SEQ ID NO:44, SEQ ID NO:49, SEQ ID NO:54, SEQ ID NO:59, SEQ ID NO:64, SEQ ID NO:69, SEQ ID NO:20, SEQ ID NO:25, SEQ ID NO:30, SEQ ID NO:35, SEQ ID NO:40, SEQ ID NO:45, SEQ ID NO:50, SEQ ID NO:55, SEQ ID NO:60, SEQ ID NO:65, SEQ ID NO:70, SEQ ID NO:21, SEQ ID NO:26, SEQ ID NO:31, SEQ ID NO:36, SEQ ID NO:41, SEQ ID NO:46, SEQ ID NO:51, SEQ ID NO:56, SEQ ID NO:61, SEQ ID NO:66, SEQ ID NO:71, SEQ ID NO:74 or SEQ ID NO:75 as well as allelic variants and homologs of each such gene. The gene is readily obtained using standard methods, as described below and as is known and standard in the art. The present invention also contemplates any unique fragment of these genes or of the nucleic acids set forth in any of SEQ ID NO:5 through SEQ ID NO:75. Examples of inventive fragments of the inventive genes are the nucleic acids whose sequence is set forth in any of SEQ ID NO:5 through SEQ ID NO:75. To be unique, the fragment must be of sufficient size to distinguish it from other known sequences, most readily determined by comparing any nucleic acid fragment to the nucleotide sequences of nucleic acids in computer databases, such as GenBank. Such comparative searches are standard in the art. Typically, a unique fragment useful as a primer or probe will be at least about 20 to about 25 nucleotides in length, depending upon the specific nucleotide content of the sequence. Additionally, fragments can be, for example, at least about 30, 40, 50, 100, 200 or 500 nucleotides in length. The nucleic acids can be single or double stranded, depending upon the purpose for which it is intended.

The present invention further provides a nucleic acid comprising the regulatory region of a gene comprising the nucleotide sequences set forth in SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ IDNO:8, SEQ ID NO:9, SEQ ID NO:10. SEQ ID NO:11. SEQ ID NO:12, SEQ ID NO:13, SEQ IDNO:14, SEQ ID NO:15, SEQ ID NO:16.

NO:21, 15 NO:26, NO:31, NO:36, NO:41, NO:46, NO:51, NO:56, NO:61, NO:66, NO:71, SEQ ID NO:17, SEQ ID NO:22, SEQ ID NO:27, SEQ ID NO:32, SEQ ID NO:37, SEQ ID NO:42, SEQ ID NO:47, SEQ ID NO:52, SEQ ID NO:57, SEQ ID NO:62, SEQ ID NO:67, SEQ ID NO:72, SEQ ID NO: 18, SEQ ID NO:23, SEQ ID NO:28, SEQ ID NO:33, SEQ ID NO:38, SEQ ID NO:43, SEQ ID NO:48, SEQ ID NO:53, SEQ ID NO:58, SEQ ID NO:63, SEQ ID NO:68, SEQ ID NO:73, SEQ ID NO:19, SEQ ID NO:24, SEQ ID NO:29, SEQ ID NO:34, SEQ ID NO:39, SEQ ID NO:44, SEQ ID NO:49, SEQ ID NO:54, SEQ ID NO:59, SEQ ID NO:64, SEQ ID NO:69, SEQ ID NO:74, SEQ ID NO:20, SEQ ID NO:25, SEQ ID NO:30, SEQ ID NO:35, SEQ ID NO:40, SEQ ID NO:45, SEQ ID NO:50, SEQ ID NO:55, SEQ ID NO:60, SEQ ID NO:65, SEQ ID NO:70.

SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID Additionally provided is a construct comprising such a regulatory region functionally linked to a reporter gene. Such reporter gene constructs can be used to screen for compounds and compositions that affect expression of the gene comprising the nucleic acids whose sequence is set forth in any of SEQ ID NO: 5 through SEQ ID NO: The nucleic acids set forth in the sequence listing are gene fragments; the entire coding sequence and the entire gene that comprises each fragment are both contemplated herein and are readily obtained by standard methods, given the nucleotide sequences presented in the sequence listing (see. Sambrook et al., Molecular Cloning: A Laboratory Manual, 2nd Ed., Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, 1989; DNA cloning: A Practical Approach, Volumes I and II, Glover, D.M. ed., IRL Press Limited, Oxford, 1985). To obtain the entire genomic gene, briefly, a nucleic acid whose sequence is set forth in any of SEQ ID NO:1 through SEQ ID NO:83, or preferably in any of SEQ ID NO:5 through SEQ ID NO:83, or a smaller fragment thereof, is utilized as a probe to screen a genomic library under high stringency conditions, and isolated clones are sequenced. Once the sequence of the new clone is determined, a probe can be devised from a portion of the new clone not present in the previous fragment and hybridized to the library to isolate more clones containing fragments of the gene. In this manner, by repeating this process in organized fashion, one can "walk" along the chromosome and eventually obtain nucleotide sequence for the entire gene. Similarly, one can use portions of the present fragments, or additional fragments obtained from the genomic library, that contain open reading frames to 15 screen a cDNA library to obtain a cDNA having the entire coding sequence of the gene.

Repeated screens can be utilized as described above to obtain the complete sequence S. :from several clones if necessary. The isolates can then be sequenced to determine the nucleotide sequence by standard means such as dideoxynucleotide sequencing methods (see, Sambrook et al., Molecular Cloning. A'LaboratoryManual, 2nd Ed., Cold 20 Spring Harbor Laboratory, Cold Spring Harbor, New York, 1989).

The present genes were isolated from rat; however, homologs in any desired species, preferably mammalian, such as human, can readily be obtained by screening a human library, genomic or cDNA, with a probe comprising sequences of the nucleic acids set forth in the sequence listing herein, or fragments thereof, and isolating genes specifically hybridizing with the probe under preferably relatively high stringency hybridization conditions. For example, high salt conditions in 6X SSC or 6X SSPE) and/or high temperatures of hybridization can be used. For example, the stringency of hybridization is typically about 5"C to 20"C below the T, (the melting temperature at which half of the molecules dissociate from its partner) for the given chain length. As is known in the art, the nucleotide composition of the hybridizing region factors in determining the melting temperature of the hybrid. For 20mer probes, 11 for example, the recommended hybridization temperature is typically about 55-58 C.

Additionally, the rat sequence can be utilized to devise a probe for a homolog in any specific animal by determining the amino acid sequence for a portion of the rat protein, and selecting a probe with optimized codon usage to encode the amino acid sequence of the homolog in that particular animal. Any isolated gene can be confirmed as the targeted gene by sequencing the gene to determine it contains the nucleotide sequence listed herein as comprising the gene. Any homolog can be confirmed as a homolog by its functionality.

Additionally contemplated by the present invention are nucleic acids, from any desired species, preferably mammalian and more preferably human, having 98%, 85%, 80%, 70%, 60%. or 50% homology, or greater, in the region of homology, to a region in an exon of a nucleic acid encoding the protein encoded by the gene comprising the nucleotide sequence set forth in any of SEQ ID NO:5 through SEQ ID NO:75 of the sequence listing or to homologs thereof Also contemplated by the 15 present invention are nucleic acids, from any desired species, preferably mammalian and Se" more preferably human, having 98%, 95%, 90%, 85%, 80%, 70%, 60%, or homology, or greater, in the region of homology, to a region in an exon of a nucleic acid comprising the nucleotide sequence set forth in any of SEQ ID NO:5 through SEQ ID of the sequence listing or to homologs thereof These genes can be synthesized 20 or obtained by the same methods used to isolate homologs, with stringency of hybridization and washing, if desired, reduced accordingly as homology desired is decreased, and further, depending upon the G-C or A-T richness of any area wherein variability is searched for. Allelic variants of any of the present genes or of their homologs can readily be isolated and sequenced by screening additional libraries following the protocol above. Methods of making synthetic genes are described in U.S.

Patent No. 5,503,995 and the references cited therein.

The nucleic acid encoding any selected protein of the present invention can be any nucleic acid that functionally encodes that protein. For example, to functionally encode, allow the nucleic acid to be expressed, the nucleic acid can include, for example, exogenous or endogenous expression control sequences, such as an origin of replication, a promoter, an enhancer, and necessary information processing sites, such as ribosome binding sites, RNA splice sites, polyadenylation sites, and transcriptional terminator sequences. Preferred expression control sequences can be promoters derived from metallothionine genes, actin genes, immunoglobulin genes, CMV, adenovirus, bovine papilloma virus, etc. Expression control sequences can be selected for functionality in the cells in which the nucleic acid will be placed. A nucleic acid encoding a selected protein can readily be determined based upon the amino acid sequence of the selected protein, and, clearly, many nucleic acids will encode any selected protein.

The present invention additionally provides a nucleic acid that selectively hybridizes under stringent conditions with a nucleic acid encoding the protein encoded by the gene comprising the nucleotide sequence set forth in any sequence listed herein any of SEQ ID NO:5 through SEQ ID NO:75). This hybridization can be specific.

The degree of complementarity between the hybridizing nucleic acid and the sequence to which it hybridizes should be at least enough to exclude hybridization with a nucleic acid 15 encoding an unrelated protein. Thus, a nucleic acid that selectively hybridizes with a nucleic acid of the present protein coding sequence will not selectively hybridize under stringent conditions with a nucleic acid for a different, unrelated protein, and vice versa.

Typically, the stringency of hybridization to achieve selective hybridization involves hybridization in high ionic strength solution (6X SSC or 6X SSPE) at a temperature that 20 is about 12-25°C below the (the melting temperature at which half of the molecules dissociate from its partner) followed by washing at a combination of temperature and salt concentration chosen so that the washing temperature is about 5°C to 20 0 C below the T, of the hybrid molecule. The temperature and salt conditions are readily determined empirically in preliminary experiments in which samples of reference DNA immobilized on filters are hybridized to a labeled nucleic acid of interest and then washed under conditions of different stringencies. Hybridization temperatures are typically higher for DNA-RNA and RNA-RNA hybridizations. The washing temperatures can be used as described above to achieve selective stringency, as is known in the art. (Sambrook et al., Molecular Cloning: Laboratory Manual, 2nd Ed., Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, 1989; Kunkel et al. Methods Enzymol. 1987:154:367, 1987). Nucleic acid fragments that selectively hybridize to any given nucleic acid can be used, as primers and or probes for further hybridization or for amplification methods polymerase chain reaction (PCR), ligase chain reaction (LCR)) A preferable stringent hybridization condition for a DNA:DNA hybridization can be at about 68"C (in aqueous solution) in 6X SSC or 6X SSPE followed by washing at 68 0

C.

The present invention additionally provides a protein encoded by a nucleic acid encoding the protein encoded by the gene comprising any of the nucleotide sequences set forth herein any of SEQ ID NO: 5 through SEQ ID NO:75). The protein can be readily obtained by any of several means. For example, the nucleotide sequence of coding regions of the gene can be translated and then the corresponding polypeptide can be synthesized mechanically by standard methods. Additionally, the coding regions of the genes can be expressed or synthesized, an antibody specific for the resulting *polypeptide can be raised by standard methods (see, Harlow and Lane, Antibodies: A Laborrry Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor, New 15 York, 1988), and the protein can be isolated from other cellular proteins by selective hybridization with the antibody. This protein can be purified to the extent desired by standard methods of protein purification (see, Sambrook et al., Molecular Cloning: A Laboratory Manual, 2nd Ed., Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, 1989). The amino acid sequence of any protein, polypeptide or peptide of 20 this invention can be deduced from the nucleic acid sequence, or it can be determined by sequencing an isolated or recombinantly produced protein.

The terms "peptide," "polypeptide"and "protein" are used interchangeably herein and refer to a polymer of amino acids and includes full-length proteins and fragments thereof As used in the specification and in the claims, can mean one or more, depending upon the context in which it is used. An amino acid residue is an amino acid formed upon chemical digestion (hydrolysis) of a polypeptide at its peptide linkages.

The amino acid residues described herein are preferably in the isomeric form.

However, residues in the isomeric form can be substituted for any L-amino acid residue, as long as the desired functional property is retained by the polypeptide.

Standard polypeptide nomenclature (described in J. Biol. Chem., 243:3552-59 (1969) and adopted at 37 CFR 1.822(b)) is used herein.

14 As will be appreciated by those skilled in the art, the invention also includes those polypeptides having slight variations in amino acid sequences or other properties.

Amino acid substitutions can be selected by known parameters to be neutral (see, e.g., Robinson WE Jr, and Mitchell WM., AIDS 4:S151-S162(1990)). Such variations may arise naturally as allelic variations due to genetic polymorphism) or may be produced by human intervention by mutagenesis of cloned DNA sequences), such as induced point, deletion, insertion and substitution mutants. Minor changes in amino acid sequence are generally preferred, such as conservative amino acid replacements, small internal deletions or insertions, and additions or deletions at the ends of the molecules. Substitutions may be designed based on, for example, the model of Dayhoff, et al. (in Atlas of Protein Sequence and Structure 1978, Nat'l Biomed. Res. Found., Washington, These modifications can result in changes in the amino acid sequence, provide silent mutations, modify a restriction site, or provide other specific mutations. Likewise, such amino acid changes result in a different nucleic acid encoding 15 the polypeptides and proteins. Thus, alternative nucleic acids are also contemplated by such modifications.

The present invention also provides cells containing a nucleic acid of the invention. A cell containing a nucleic acid encoding a protein typically can replicate the DNA and, further, typically can express the encoded protein. The cell can be a 20 prokaryotic cell, particularly for the purpose of producing quantities of the nucleic acid, or a eukaryotic cell, particularly a mammalian cell. The cell is preferably a mammalian cell for the purpose of expressing the encoded protein so that the resultant produced protein has mammalian protein processing modifications.

Nucleic acids of the present invention can be delivered into cells by any selected means, in particular depending upon the purpose of the delivery of the compound and the target cells. Many delivery means are well-known in the art. For example, electroporation, calcium phosphate precipitation, microinjection, cationic or anionic liposomes, and liposomes in combination with a nuclear localization signal peptide for delivery to the nucleus can be utilized, as is known in the art.

The present invention also contemplates that the mutated cellular genes necessary for viral growth, produced by the present method, as well as cells containing these mutants can also be useful. These mutated genes and cells containing them can be isolated and/or produced according to the methods herein described and using standard methods.

It should be recognized that the sequences set forth herein may contain minor sequencing errors. Such errors can be corrected, for example, by using the hybridization procedure described above with various probes derived from the described sequences such that the coding sequence can be reisolated and resequenced.

As described in the examples, the present invention provides the discovery of a "serum survival factor" present in serum that is necessary for the survival of persistently virally infected cells. Isolation and characterization of this factor have shown it to be a protein, to have a molecular weight of between about 50 kD and 100 kD, to resist inactivation in low pH pH2) and chloroform extraction, to be inactivated by boiling for about 5 minutes and in low ionic strength solution about 10 mM to about 50 mM). The present invention thus provides a purified mammalian serum 15 protein having a molecular weight of between about 50 kD and 100 kD which resists inactivation in low pH and resists inactivation by chloroform extraction, which S. :inactivates when boiled and inactivates in low ionic strength solution, and which when S* removed from a cell culture comprising cells persistently infected with reovirus selectively substantially prevents survival of cells persistently infected with reovirus.

20 The factor, fitting the physical characteristics described above, can readily be verified by adding it to non-serum-containing medium (which previously could not support survival of persistently virally infected cells) and determining whether this medium with the added putative factor can now support persistently virally infected cells, particularly cells persistently infected with reovirus. As used herein, a "purified" protein means the protein is at least of sufficient purity such that an approximate molecular weight can be determined.

The amino acid sequence of the protein can be elucidated by standard methods.

For example, an antibody to the protein can be raised and used to screen an expression library to obtain nucleic acid sequence coding the protein. This nucleic acid sequence is then simply translated into the corresponding amino acid sequence. Alternatively, a portion of the protein can be directly sequenced by standard amino acid sequencing methods (amino-terminus sequencing). This amino acid sequence can then be used to generate an array of nucleic acid probes that encompasses all possible coding sequences for a portion of the amino acid sequence. The array of probes is used to screen a cDNA library to obtain the remainder of the coding sequence and thus ultimately the corresponding amino acid sequence.

The present invention also provides methods of detecting and isolating additional serum survival factors. For example, to determine if any known serum components are necessary for viral growth, the known components can be inhibited in, or eliminated from, the culture medium, and it can be observed whether viral growth is inhibited by determining if persistently infected cells do not survive. One can add the factor back (or remove the inhibition) and determine whether the factor allows for viral growth.

Additionally, other, unknown serum components can also be found to be essential for viral growth. Serum can be fractionated by various standard means, and fractions added to serum free medium to determine if a factor is present in a reaction 15 that allows viral growth previously inhibited by the lack of serum. Fractions having this activity can then be further fractionated until the factor is relatively free of other components. The factor can then be characterized by standard methods, such as size o. fractionation, denaturation and/or inactivation by various means, etc. Preferably, once the factor has been purified to a desired level of purity, it is added to cells in serum free 20 medium to confirm that it bestows the function of allowing virus to grow when serumfree medium alone did not. This method can be repeated to confirm the requirement for the specific factor for any desired virus, since each serum factor found to be required by any one virus can also be required by many other viruses. In general, the closer the viruses are related and the more similar the infection modes of the viruses, the more likely that a factor required by one virus will be required by the other.

The present invention also provides methods of treating virus infections utilizing applicants' discoveries. The subject of any of the herein described methods can be any animal, preferably a mammal, such as a human, a veterinary animal, such as a cat, dog, horse, pig, goat, sheep, or cow, or a laboratory animal, such as a mouse, rat, rabbit, or guinea pig, depending upon the virus.

The present invention provides a method of reducing or inhibiting, and thereby treating, a viral infection in a subject, comprising administering to the subject an inhibiting amount of a composition that inhibits functioning of the serum protein described herein, i.e. the serum protein having a molecular weight of between about kD and 100 kD which resists inactivation in low pH and resists inactivation by chloroform extraction, which inactivates when boiled and inactivates in low ionic strength solution, and which when removed from a cell culture comprising cells persistently infected with the virus prevents survival of at least some cells persistently infected with the virus, thereby treating the viral infection. The composition can comprise, for example, an antibody that specifically binds the serum protein, or an antisense RNA that binds an RNA encoded by a gene functionally encoding the serum protein *Any virus capable of infecting the selected subject to be treated can be treated by the present method. As described above, any serum protein or survival factor found by 15 the present methods to be necessary for growth of any one virus can be found to be necessary for growth of many other viruses. For any given virus, the serum protein or factor can be confirmed to be required for growth by the methods described herein. The cellular genes identified by the examples using reovirus, a mammalian pathogen, and a rat cell system have general applicability to other virus infections that include all of the 20 known as well as yet to be discovered human pathogens, including, but not limited to: human immunodeficiency viruses HIV-1, HIV-2); parvovirus; papillomaviruses; hantaviruses; influenza viruses influenza A, B and C viruses); hepatitis viruses A to G; caliciviruses; astroviruses; rotaviruses; coronaviruses, such as human respiratory coronavirus; picornaviruses, such as human rhinovirus and enterovirus; ebola virus; human herpesvirus HSV-1-9); human cytomegalovirus; human adenovirus; Epstein-Barr virus; hantaviruses; for animal, the animal counterpart to any above listed human virus, animal retroviruses, such as simian immunodeficiency virus, avian immunodeficiency virus, bovine immunodeficiency virus, feline immunodeficiency virus, equine infectious anemia virus, caprine arthritis encephalitis virus or visna virus.

A protein inhibiting amount of the composition can be readily determined, such as by administering varying amounts to cells or to a subject and then adjusting the effective amount for inhibiting the protein according to the volume of blood or weight of the subject. Compositions that bind to the protein can be readily determined by running the putatively bound protein on a protein gel and observing an alteration in the protein's migration through the gel. Inhibition of the protein can be determined by any desired means such as adding the inhibitor to complete media used to maintain persistently infected cells and observing the cells' viability. The composition can comprise, for example, an antibody that specifically binds the serum protein. Specific binding by an antibody means that the antibody can be used to selectively remove the factor from serum or inhibit the factor's biological activity and can readily be determined by radio immune assay (RIA), bioassay, or enzyme-linked immunosorbant (ELISA) technology.

The composition can comprise, for example, an antisense RNA that specifically binds an RNA encoded by the gene encoding the serum protein. Antisense RNAs can be synthesized and used by standard methods Anlisense RNA and DNA, D. A.

Melton, Ed., Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (1988)).

The present methods provide a method of screening a compound for treating a viral infection, comprising administering the compound to a cell containing a cellular gene functionally encoding a gene product necessary for reproduction of the virus in the cell but not necessary for survival of the cell and detecting level of the gene product produced, a decrease or elimination of the gene product indicating a compound for treating the viral infection. The present methods also provide a method of screening a compound for effectiveness in treating a viral infection, comprising administering the compound to a cell containing a cellular gene functionally encoding a gene product necessary for reproduction of the virus in the cell but not necessary for survival of the cell and detecting the level of the gene product produced, a decrease or elimination of the gene product indicating a compound effective for treating the viral infection. The cellular gene can be, for example, any gene provided herein, any of the genes comprising the nucleotide sequences set forth in any of SEQ ID NO:1 through SEQ ID or any other gene obtained using the methods provided herein for obtaining such genes. Level of the gene product can be measured by any standard means, such as by detection with an antibody specific for the protein. The level of gene product can be compared to the level of the gene product in a control cell not contacted with the compound. The level of gene product can be compared to the level of the gene product in the same cell prior to addition of the compound. Relatedly, the regulatory region of the gene can be functionally linked to a reporter gene and compounds can be screened for inhibition of the reporter gene. Such reporter constructs are described herein.

The present invention provides a method of selectively eliminating cells persistently infected with a virus from an animal cell culture capable of surviving for a first period of time in the absence of serum, comprising propagating the cell culture in the absence of serum for a second time period which a persistently infected cell cannot survive without serum, thereby selectively eliminating from the cell culture cells persistently infected with the virus. The second time period should be shorter than the first time period. Thus one can simply eliminate serum from a standard culture medium composition for a period of time by removing serum containing medium from the culture container, rinsing the cells, and adding serum-free medium back to the container), then, after a time of serum starvation, return serum to the culture medium.

15 Alternatively, one can inhibit a serum survival factor from the culture in place of the step of serum starvation. Furthermore, one can instead interfere with the virus-factor interaction. Such a viral elimination method can periodically be performed for cultured cells to ensure that they remain virus-free. The time period of serum removal can greatly vary, with a typical range being about I to about 30 days; a preferable period can be about 3 to about 10 days, and a more preferable period can be about 5 days to about 7 days. This time period can be selected based upon ability of the specific cell to survive without serum as well as the life cycle of the virus, for reovirus, which has a life cycle of about 24 hours, 3 days' starvation of cells provides dramatic results.

Furthermore, the time period can be shortened by also passaging the cells during the starvation, in general, increasing the number of passages can decrease the time of serum starvation (or serum factor inhibition) needed to get fill clearance of the virus from the culture. While passaging, the cells typically are exposed briefly to serum (typically for about 3 to about 24 hours). This exposure both stops the action of the trypsin used to dislodge the cells and stimulates the cells into another cycle of growth, thus aiding in this selection process. Thus a starvation/serum cycle can be repeated to optimize the selective effect. Other standard culture parameters, such as confluency of the cultures, pH, temperature, etc. can be varied to alter the needed time period of serum starvation (or serum survival factor inhibition). This time period can readily be determined for any given viral infection by simply removing the serum for various periods of time, then testing the cultures for the presence of the infected cells by ability to survive in the absence of serum and confirmed by quantitating virus in cells by standard virus titration and immunohistochemical techniques) at each tested time period, and then detecting at which time periods of serum deprivation the virally infected cells were eliminated. It is preferable that shorter time periods of serum deprivation that still provide elimination of the persistently infected cells be used. Furthermore, the cycle of starvation, then adding back serum and determining amount of virus remaining in the culture can be repeated until no virtually infected cells remain in the culture.

Thus, the present method can further comprise passaging the cells, i.e., transferring the cell culture from a first container to a second container. Such transfer can facilitate the selective lack of survival of virally infected cells. Transfer can be 15 repeated several times. Transfer is achieved by standard methods of tissue culture (see, Freshney, Culture of Animal Cells, A Manual of Basic Technique, 2nd Ed. Alan R.

Liss, Inc., New York, 1987).

The present method further provides a method of selectively eliminating from a cell culture cells persistently infected with a virus, comprising propagating the cell culture in the absence of a functional form of the serum protein having a molecular weight of between about 50 kD and 100 kD which resists inactivation in low pH and resists inactivation by chloroform extraction, which inactivates when boiled and inactivates in low ionic strength solution, and which when removed from a cell culture comprising cells persistently infected with reovirus substantially prevents survival of cells persistently infected with reovirus. The absence of the functional form can be achieved by any of several standard means, such as by binding the protein to an antibody selective for it (binding the antibody in serum either before or after the serum is added to the cells; if before, the serum protein can be removed from the serum by, binding the antibody to a column and passing the serum over the column and then administering the survival protein-free serum to the cells), by administering a compound that inactivates the protein, or by administering a compound that interferes with the interaction between the virus and the protein.

Thus, the present invention provides a method of selectively eliminating from a cell culture propagated in serum-containing medium cells persistently infected with a virus, comprising inhibiting in the serum the protein having a molecular weight of between about 50 kD and 100 kD which resists inactivation in low pH and resists inactivation by chloroform extraction, which inactivates when boiled and inactivates in low ionic strength solution, and which when removed from a cell culture comprising cells persistently infected with reovirus substantially prevents survival of cells persistently infected with reovirus. Alternatively, the interaction between the virus and the serum protein can be disrupted to selectively eliminate cells persistently infected with the virus.

Any virus capable of some form of persistent infection may be eliminated from a cell culture utilizing the present elimination methods, including removing, inhibiting or 15 otherwise interfering with a serum protein, such as the one exemplified herein, and also including removing, inhibiting or otherwise interfering with a gene product from any cellular gene found by the present method to be necessary for viral growth yet nonessential to the cell. For example, DNA viruses or RNA viruses can be targeted.

One can readily determine whether cells infected with a selected virus can be selectively 20 removed from a culture through removal of serum by starving cells permissive to the virus of serum (or inhibiting the serum survival factor), adding the selected virus to the cells, adding serum to the culture, and observing whether infected cells die by titering levels of virus in the surviving cells with an antibody specific for the virus).

A culture of any animal cell any cell that is typically grown and maintained in culture in serum) that can be maintained for a period of time in the absence of serum, can be purified from viral infection utilizing the present method. For example, primary cultures as well as established cultures and cell lines can be used. Furthermore, cultures of cells from any animal and any tissue or cell type within that animal that can be cultured and that can be maintained for a period of time in the absence of serum can be used. For example, cultures of cells from tissues typically infected, and particularly persistently infected, by an infectious virus could be used.

22 As used in the claims "in the absence of serum" means at a level at which persistently virally infected cells do not survive. Typically, the threshold level is about 1% serum in the media. Therefore, about 1% serum or less can be used, such as about 0.75%, 0.50%. 0.25% 0. 1% or no serum can be used.

As used herein, "selectively eliminating" cells persistently infected with a virus means that substantially all of the cells persistently infected with the virus are killed such that the presence of virally infected cells cannot be detected in the culture immediately after the elimination procedure has been performed. Furthermore, "selectively eliminating" includes that cells not infected with the virus are generally not killed by the method. Some surviving cells may still produce virus but at a lower level, and some may be defective in pathways that lead to death by the virus. Typically, for cells persistently infected with virus to be substantially all killed, more than about 90% of the cells, and more preferably less than about 95%, 98%, 99%, or 99.99% of viruscontaining cells in the culture are killed.

The present method also provides a nucleic acid comprising the regulatory region of any of the genes. Such regulatory regions can be isolated from the genomic sequences isolated and sequenced as described above and identified by any characteristics observed that are characteristic for regulatory regions of the species and by their relation to the start codon for the coding region of the gene. The present invention also provides a construct comprising the regulatory region functionally linked to a reporter gene. Such constructs are made by routine subcloning methods, and many :i vectors are available into which regulatory regions can be subcloned upstream of a marker gene. Marker genes can be chosen for ease of detection of marker gene product.

The present method therefore also provides a method of screening a compound for treating a viral infection, comprising administering the compound to a cell containing any of the above-described constructs, comprising a regulatory region of one of the genes comprising the nucleotide sequence set forth in any of SEQ ID NO: I through SEQ ID NO:75 functionally linked to a reporter gene, and detecting the level of the reporter gene product produced, a decrease or elimination of the reporter gene product indicating a compound for treating the viral infection. Compounds detected by this method would inhibit transcription of the gene from which the regulatory region was isolated, and thus, in treating a subject, would inhibit the production of the gene product produced by the gene, and thus treat the viral infection.

The present invention additionally provides a method of reducing or inhibiting a viral infection in a subject, comprising administering to the subject an amount of a composition that inhibits expression or functioning of a gene product encoded by a gene comprising the nucleic acid set forth in any of SEQ ID NO: 1 through SEQ ID or a homolog thereof, thereby treating the viral infection, the composition can comprise, for example, an antibody that binds a protein encoded by the gene. The composition can also comprise an antibody that binds a receptor for a protein encoded by the gene.

Such an antibody can be raised against the selected protein by standard methods, and can be either polyclonal or monoclonal, though monoclonal is preferred. Alternatively, the composition can comprise an antisense RNA that binds an RNA encoded by the gene. Furthermore, the composition can comprise a nucleic acid functionally encoding an antisense RNA that binds an RNA encoded by the gene. Other useful compositions 15 will be readily apparent to the skilled artisan.

The present invention further provides a method of reducing or inhibiting a viral infection in a subject comprising mutating ex vivo in a selected cell from the subject an endogenous gene comprising the nucleic acid set forth in any of SEQ ID NO:1 through SEQ ID NO:75, or a homolog thereof, to a gene form incapable of producing a functional gene product of the gene or a gene form producing a reduced amount of a functional gene product of the gene, and replacing the cell in the subject, thereby reducing viral infection of cells in the subject. The cell can be selected according to the typical target cell of the specific virus whose infection is to be reduced, prevented or inhibited. A preferred cell for several viruses is a hematopoietic cell. When the selected cell is a hematopoietic cell, viruses which can be reduced or inhibited from infection can include, for example, HIV, including HIV-L and HIV-2.

The present invention also provides a method of reducing or inhibiting a viral infection in a subject comprising mutating ex vivo in a selected cell from the subject an endogenous gene comprising a nucleic acid isolated by a method comprising transferring into a cell culture growing in serum-containing medium a vector encoding a selective marker gene lacking a functional promoter, selecting cells 24 expressing the marker gene, removing serum from the culture medium, (d) infecting the cell culture with the virus, and isolating from the surviving cells a cellular gene within which the marker gene is inserted, to a mutated gene form incapable of producing a functional gene product of the gene or to a mutated gene form producing a reduced amount of a functional gene product of the gene, and replacing the cell in the subject, thereby reducing viral infection of cells in the subject. Thus the mutated gene form can be one incapable of producing an effective amount of a functional protein or mRNA, or one incapable of producing a functional protein or mRNA, for example. The method can be performed wherein the virus is HIV. The method can be performed in any selected cell in which the virus may infect with deleterious results. For example, the cell can be a hematopoietic cell. However, many other virus-cell combinations will be apparent to the skilled artisan.

The present invention additionally provides a method of increasing viral infection 15 resistance in a subject comprising mutating ex vivo in a selected cell from the subject an endogenous gene comprising a nucleic acid isolated by a method comprising transferring into a cell culture growing in serum-containing medium a vector encoding a selective marker gene lacking a functional promoter, selecting cells expressing the marker gene, removing serum from the culture medium, (d) infecting the cell culture with the virus, and isolating from the surviving cells a cellular gene within which the marker gene is inserted, ito a mutated gene form incapable of producing a functional gene product of the gene or a gene form producing a reduced amount of a functional gene product of the gene, and replacing the cell in the subject, thereby reducing viral infection of cells in the subject.

The virus can be HIV, particularly when the cell is a hematopoietic cell. However, many other virus-cell combinations will be apparent to the skilled artisan.

The present invention provides a method of identifying a cellular gene that can suppress a malignant phenotype in a cell, comprising transferring into a cell culture incapable of growing well in soft agar or Matrigel a vector encoding a selective marker gene lacking a fUnctional promoter, selecting cells expressing the marker gene, and isolating from selected cells which are capable of growing in soft agar or Matrigel a cellular gene within which the marker gene is inserted, thereby identifying a gene that can suppress a malignant phenotype in a cell. This method can be performed using any selected non-transformed cell line, of which many are known in the art.

The present invention additionally provides a method of identifying a cellular gene that can suppress a malignant phenotype in a cell, comprising transferring into a cell culture of non-transformed cells a vector encoding a selective marker gene lacking a functional promoter, selecting cells expressing the marker gene, and isolating from selected and transformed cells a cellular gene within which the marker gene is inserted, thereby identifying a gene that can suppress a malignant phenotype in a cell. A to non-transformed phenotype can be determined by any of several standard methods in the art, such as the exemplified inability to grow in soft agar, or inability to grow in Matrigel.

The present invention further provides a method of screening for a compound for suppressing a malignant phenotype in a cell comprising administering the compound 15 to a cell containing a cellular gene functionally encoding a gene product involved in establishment of a malignant phenotype in the cell and detecting the level of the gene product produced, a decrease or elimination of the gene product indicating a compound effective for suppressing the malignant phenotype Detection of the level, or amount, of gene product produced can be measured, directly or indirectly, by any of several 20 methods standard in the art protein gel, antibody-based assay, detecting labeled RNA) for assaying protein levels or amounts, and selected based upon the specific gene product.

The present invention further provides a method of suppressing a malignant phenotype in a cell in a subject, comprising administering to the subject an amount of a composition that inhibits expression or functioning of a gene product encoded by a gene comprising the nucleic acid set forth in SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79, SEQ ID NOS80, SEQ ID NO:81, SEQ ID NO:82 or SEQ ID NO:83, or a homolog thereof, thereby suppressing a malignant phenotype. The composition can, for example, comprise an antibody that binds a protein encoded by the gene. The composition can, as another example, comprise an antibody that binds a receptor for a protein encoded by the gene. The composition can comprise an antisense RNA that binds an RNA encoded by the gene. Further, the composition can comprise a nucleic acid functionally encoding an antisense RNA that binds an RNA encoded by the gene.

Diagnostic or therapeutic agents of the present invention can be administered to a subject or an animal model by any of many standard means for administering therapeutics or diagnostics to that selected site or standard for administering that type of functional entity. For example, an agent can be administered orally, parenterally (e.g, intravenously), by intramuscular injection, by intraperitoneal injection, topically, transdermally, or the like. Agents can be administered, as a complex with cationic liposomes, or encapsulated in anionic liposomes. Compositions can include various amounts of the selected agent in combination with a pharmaceutically acceptable carrier .and, in addition, if desired, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, diluents, etc. Parental administration, if used, is generally characterized by injection. Injectables can be prepared in conventional forms, either as 15 liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Depending upon the mode of administration, the agent can be optimized to avoid degradation in the subject, such as by encapsulation, etc.

Dosages will depend upon the mode of administration, the disease or condition to be treated, and the individual subject's condition, but will be that dosage typical for and used in administration of antiviral or anticancer agents. Dosages will also depend upon the composition being administered, a protein or a nucleic acid. Such dosages are known in the art. Furthermore, the dosage can be adjusted according to the typical dosage for the specific disease or condition to be treated. Furthermore, viral titers in culture cells of the target cell type can be used to optimize the dosage for the target cells in vivo, and transformation from varying dosages achieved in culture cells of the same type as the target cell type can be monitored. Often a single dose can be sufficient; however, the dose can be repeated if desirable The dosage should not be so large as to cause adverse side effects. Generally, the dosage will vary with the age, condition, sex and extent of the disease in the patient and can be determined by one of skill in the art. The dosage can also be adjusted by the individual physician in the event of any complication.

For administration to a cell in a subject, the composition, once in the subject, will of course adjust to the subject's body temperature. For ex vivo administration, the composition can be administered by any standard methods that would maintain viability of the cells, such as by adding it to culture medium (appropriate for the target cells) and adding this medium directly to the cells. As is known in the art, any medium used in this method can be aqueous and non-toxic so as not to render the cells non-viable. In addition, it can contain standard nutrients for maintaining viability of cells, if desired.

For in vivo administration, the complex can be added to, for example, a blood sample or a tissue sample from the patient, or to a pharmaceutically acceptable carrier, saline and buffered saline, and administered by any of several means known in the art.

"Examples of administration include parenteral administration, by intravenous injection including regional perfusion through a blood vessel supplying the tissues(s) or 15 organ(s) having the target cell(s), or by inhalation of an aerosol, subcutaneous or intramuscular injection, topical administration such as to skin wounds and lesions, direct transfection into, bone marrow cells prepared for transplantation and subsequent transplantation into the subject, and direct transfection into an organ that is subsequently transplanted into the subject. Further administration methods include oral 20 administration, particularly when the composition is encapsulated, or rectal administration, particularly when the composition is in suppository form. A pharmaceutically acceptable carrier includes any material that is not biologically or otherwise undesirable, the material may be administered to an individual along with the selected complex without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained.

Specifically, if a particular cell type in vivo is to be targeted, for example, by regional perfusion of an organ or tumor, cells from the target tissue can be biopsied and optimal dosages for import of the complex into that tissue can be determined in vitro, as described herein and as known in the art, to optimize the in vivo dosage, including concentration and time length. Alternatively, culture cells of the same cell type can also be used to optimize the dosage for the target cells in vivo.

For either ex vivo or in vivo use, the complex can be administered at any effective concentration. An effective concentration is that amount that results in reduction, inhibition or prevention of the viral infection or in reduction or inhibition of transformed phenotype of the cells A nucleic acid can be administered in any of several means, which can be selected according to the vector utilized, the organ or tissue, if any, to be targeted, and the characteristics of the subject. The nucleic acids, if desired in a pharmaceutically acceptable carrier such as physiological saline, can be administered systemically, such as intravenously, intraarterially, orally, parenterally, subcutaneously. The nucleic acids can also be administered by direct injection into an organ or by injection into the blood vessel supplying a target tissue. For an infection of cells of the lungs or trachea, it can be administered intratracheally. The nucleic acids can additionally be administered 15 topically, transdermally, etc.

The nucleic acid or protein can be administered in a composition. For example, the composition can comprise other medicinal agents, pharmaceutical agents, carriers, adjuvants, diluents, etc. Furthermore, the composition can comprise, in addition to the vector, lipids such as liposomes, such as cationic liposomes DOTMA, DOPE, DC-cholesterol) or anionic liposomes. Liposomes can further comprise proteins to facilitate targeting a particular cell, if desired. Administration of a composition comprising a vector and a cationic liposome can be administered to the blood afferent to a target organ or inhaled into the respiratory tract to target cells of the respiratory tract.

Regarding liposomes, see, Brigham et al. Am..I. Resp. Cell. Mol. Biol. 1:95-100 (1989); Felgner et al. Proc. Natl. Acad Sci USA 84:7413-7417 (1987); US. Pat.

No.4,897,3 5 For a viral vector comprising a nucleic acid, the composition can comprise a pharmaceutically acceptable carrier such as phosphate buffered saline or saline. The viral vector can be selected according to the target cell, as known in the art. For example, adenoviral vectors, in particular replication-deficient adenoviral vectors, can be utilized to target any of a number of cells, because of its broad host range. Many other viral vectors are available, and their target cells known..

EXAMPLES

Selective elimination of virallv infected cells from a cell culture Rat intestinal cell line-I cells (RIE-I cells) were standardly grown in Dulbecco's modified eagle's medium, high glucose, supplemented with 10% fetal bovine serum. To begin the experiment, cells persistently infected with reovirus were grown to near confluence, then serum was removed from the growth medium by removing the medium, washing the cells in PBS, and returning to the flask medium not supplemented with serum. Typically, the serum content was reduced to 1% or less. The cells are starved for serum for several days, or as long as about a month, to bring them to quiescence or growth arrest. Media containing 10% serum is then added to the quiescent cells to stimulate growth of the cells. Surviving cells are found to not to be persistently infected cells by immunohistochemical techniques used to establish whether 15 cells contain any infectious virus (sensitivity to I infectious virus per ml of homogenized cells).

Cellular Genomic DNA Isolation Gene Trap Libraries: The libraries are generated by infecting the RIE-1 cells with a retrovirus vector (U3 gene-trap) at a ratio of less than one retrovirus for every ten cells. When a U3 gene trap retrovirus integrates within an actively transcribed gene, the neomycin resistance gene that the U3 gene trap retrovirus encodes is also transcribed, this confers resistance to the cell to the antibiotic neomycin. Cells with gene trap events are able to survive exposure to neomycin while cells without a gene trap event die. The various cells that survive neomycin selection are then propagated as a library of gene trap events. Such libraries can be generated with any retrovirus vector that has the properties of expressing a reporter gene from a transcriptionally active cellular promoter that tags the gene for later identification.

Reovirus selection: Reovirus infection is typically lethal to RIE-1 cells but can result in the development of persistently infected cells. These cells continue to grow while producing infective reovirus particles. For the identification of gene trap events that confer reovirus resistance to cells, the persistently infected cells must be eliminated or they will be scored as false positives. We have found that RIE-1 cells persistently infected with reovirus are very poorly tolerant to serum starvation, passaging and plating at low density. Thus, we have developed protocols for the screening of the RIE-1 gene trap libraries that select against both reovirus sensitive cells and cells that are persistently infected with reovirus.

1. RIE-1 library cells are grown to near confluence and then the serum is removed from the media. The cells are starved for serum for several days to bring them to quiescent or growth arrest.

2. The library cells are infected with reovirus at a titer of greater than ten reovirus per cell and the serum starvation is continued for several more days.

3. The infected cells are passaged, (a process in which they are exposed to serum for three to six hours) and then starved for serum for several more days.

4. The surviving cells are then allowed to grow in the presence of serum until 15 visible colonies develop at which point they are cloned by limiting dilution.

MEDIA: DULBECCO'S MODIFIED EAGLE'S MEDIUM, HIGH GLUCOSE (DME/HIGH) Hyclone Laboratories cat. no. SH30003.02.

NEOMYCIN: The antibiotic used to select against the cells that did not have a U3 gene trap retrovirus. We used GENETICIN, from Sigma. cat. no. G9516.

RAT INTESTINAL CELL LINE-I CELLS (RIE-1 CELLS): These cells are from the laboratory of Dr Ray Dubois (VAMC). They are typically cultured in Dulbecco's Modified Eagle's Medium supplemented with 10% fetal calf serum.

REOVIRUS: Laboratory strains of either serotype 1 or serotype 3 are used. They were originally obtained from the laboratories of Bernard N. Fields (deceased). These viruses have been described in detail.

RETROVIRUS: The U3 gene trap retrovirus used here were developed by Dr. Earl Ruley (VAMC) and the libraries were produced using a general protocol suggested by him.

SERUM: FETAL BOVINE SERUM Hyclone Laboratories cat. no. A-1115-L.

Genes Necessary for Viral Infection Characteristics of some of the isolated sequences include the following: SEQ ID NO: 1- rat genomic sequence of vacuolar H+ATPase (chemically inhibiting the activity of the gene product results in resistance to influenza virus and reovirus) SEQ ID NO:2- rat alpha tropomyosin genomic sequence SEQ ID NO:3- rat genomic sequence of murine and rat gas5 gene (cell cycle regulated gene) SEQ ID NO:4- rat genomic sequence of p162 of ras complex, mouse, human (cell cycle regulated gene) SEQ ID NO:5- similar to N-acetyl-glucosaminyltransferase I mRNA, mouse, human (enzyme located in the Golgi region in the cell; has been found as part of a DNA containing virus) SEQ ID NO:6- similar to calcyclin, mouse, human, reverse complement (cell cycle regulated gene) SEQ ID NO:7- contains sequence similar to :LOCUS AA254809 364 bp mRNA EST 15 DEFINITION mz75a10.rl Soares mouse lymph node NbMLN Mus musculus cDNA clone 719226 SEQ ID NO:8- contains a sequence similar to No SW:RSPI _MOUSE Q01730 RSP-I

PROTEIN

SEQ ID NO:9- contains 5' UTR ofgbJU25435fHSU25435 Human transcriptional repressor (CTCF) mRNA, complete cds, Length 3780 SEQ ID NO:38- similar to cDNA of retroviral origin SEQ ID NO: 50- trapped AYU-6 genetic element Isolation of cellular genes that suppress a mnlignant phenotype We have utilized a gene-trap method of selecting cell lines that have a transformed phenotype (are potentially tumor cells) from a population of cells (RIE-1 parentals) that are not transformed. The parental cell line, RIE-1 cells, does not have the capacity to grow in soft agar or to produce tumors in mice. Following genetrapping, cells were screened for their capacity to grow in soft agar. These cells were cloned and genomic sequences were obtained 5' or 3' of the retrovirus vector (SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83). All of the cell lines behave as if they are tumor cell lines, as they also induce tumors in mice.

Of the cell lines, two are associated with the enhanced expression of the prostaglandin synthetase gene II or COX 2. The COX 2 gene has been found to be increased in pre-malignant adenomas in humans and overexpressed in human colon cancer. Inhibitors of COX 2 expression also arrests the growth of the tumor. One of the cell lines, xl8 (SEQ ID NO:76), has disrupted a gene that is now represented in the EST (dbest) database, but the gene is not known (not present in GenBank).

(SEQ ID NO:76): >02-X18H-t7.., identical to: gblW55397jW55397 mbl3h04.rl Life Tech mouse brain Mus at 1.0e-114. x18 has also been sequenced from the vector with the same EST being found. (SEQ ID NO:77): >x8_b4_2.. (SEQ ID NO:78): >x7_b4.. (SEQ ID NO:79): >x4-b4.. (SEQ ID NO:80): (SEQ ID NO:81): S"i >x15-b4. (SEQ ID NO:82): >xl3-re.., reverse complement. (SEQ ID NO:83): >x12 b4..

Each of the genes from which the provided nucleotide sequences is isolated represents a tumor suppressor gene. The mechanism by which the disrupted genes other than the gene comprising the nucleic acid which sequence is set forth in SEQ ID NO:76 may suppress a transformed phenotype is at present unknown. However, each one represents a tumor suppressor gene that is potentially unique, as none of the genomic sequences correspond to a known gene. The capacity to select quickly tumor suppressor genes may provide unique targets in the process of treating or preventing (potential for diagnostic testing) cancer.

Isolation of entire genomic genes An isolated nucleic acid of this invention (whose sequence is set forth in any of SEQ ID NO: I through SEQ ID NO: 83), or a smaller fragment thereof, is labeled by a detectable label and utilized as a probe to screen a rat genomic library (lambda phage or yeast artificial chromosome vector library) under high stringency conditions, high salt and high temperatures to create hybridization and wash temperature 5-20C.

Clones are isolated and sequenced by standard Sanger dideoxynucleotide sequencing methods. Once the entire sequence of the new clone is determined, it is aligned with the probe sequence and its orientation relative to the probe sequence determined. A second and third probe is designed using sequences from either end of the combined genomic sequence, respectively. These probes are used to screen the library, isolate new clones, which are sequenced. These sequences are aligned with the previously obtained sequences and new probes designed corresponding to sequences at either end and the entire process repeated until the entire gene is isolated and mapped. When one end of the sequence cannot isolate any new clone, a new library can be screened. The complete sequence includes regulatory regions at the 5' end and a polyadenylation signal at the 3' end.

9*t Isolation of cDNAs An isolated nucleic acid (whose sequence is set forth in any of SEQ ID NO:1 :oo. through SEQ ID NO:83, and preferably any of SEQ ID NO:5 through SEQ ID NO:83), or a smaller fragment thereof, or additional fragments obtained from the genomic library, that contain open reading frames, is labeled by a detectable label and utilized as a probe to screen a portions of the present fragments, to screen a cDNA library. A rat cDNA library obtains rat cDNA; a human cDNA library obtains a human cDNA.

Repeated screens can be utilized as described above to obtain the complete coding sequence of the gene from several clones if necessary. The isolates can then be sequenced to determine the nucleotide sequence by standard means such as dideoxynucleotide sequencing methods.

at Serum survival factor isolation and characterization The lack of tolerance to serum starvation is due to the acquired dependence of the persistently infected cells for a serum factor (survival factor) that is present in serum.

The serum survival factor for persistently infected cells has a molecular weight between and 100 kD and resists inactivation in low pH (pH2) and chloroform extraction. It is inactivated by boiling for 5 minutes [once fractionated from whole serum (50 to 100 kD fraction)], and in low ionic strength solution [10 to 50 mM] 34/1 The factor was isolated from serum by size fraction using centriprep molecular cut-off filters with excluding sizes of 30 and 100 kd (Millipore and Amnicon), and dialysis tubing with a molecular exclusion of 50 kd. Polyacrylamide gel electrophoresis and silver staining was used to determine that all of the resulting material was between 50 and 100 kd, confirming the validity of the initial isolation. Further purification was performed on using ion exchange chromatography, and heparin sulfate adsorption columns, followed by HPLC. Activity was determined following adjusting the pH of the serum fraction (30 to 100 kd fraction) todifferent pH conditions using HCI and readjusting the pH to pH 7.4 prior to assessment of biologic activity. Low ionic strength sensitivity was determined by dialyzing the fraction containing activity into low ionic strength solution for various lengths of time and readjusting ionic strength to physiologic conditions prior to determining biologic activity by dialyzing the fraction against the media. The biologic activity was maintained in the aqueous solution following chloroform extraction, indicating the factor is not a lipid. The biologic activity 15 was lost after the 30 to 100 kd fraction was placed in a 00"C water bath for 5 minutes.

solated nucleic acids Tagged genomic DJAS isolated were sequenced by standard methods using Sanger dideoxynucleotide sequencing. The nucleotide sequences of these nucleic acids 20 are set forth herein as SEQ ID NO:1 through SEQ ID NO:75 (viral infection genes) and SEQ ID NO:76 through SEQ TD NO:83 (tumor suppressor genes). The sequences were .run through computer databanks in a homology search. Sequences for some of the "6b" sequences [obtained from genomic library 6, flask b] SEQ ID NO:37, 38, 39, S42, 61, 65, 66, 69) correspond to a known gene, alpha tropomyosin, and some of the others correspond to the vacuolar-H'-ATPase. These sequences are associated with both acute and persistent viral infection and the cellular genes which comprise them. e., alpha tropomyosin and vacuolar-H'-ATPase, can be targets for drug treatments for viral infection using the methods described above. These genes can be therapy targets particularly because disruption of one or both alleles results in a viable cell.

34/2 Throughout the specification, unless the context requires otherwise, the word "comprise" or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

*o *o o SEQUENCE LISTING GENERAL

INFORMATION:

APPLICANT: VANDERBILT

UNIVERSITY

305 Kirkland Hall Nashville, TN 37240 (ii) TITLE OF INVENTION: MAMMALIAN GENES INVOLVED IN VIRAL

INFECTION

(iii) NUMBER OF SEQUENCES: 83 (iv) CORRESPONDENCE

ADDRESS:

ADDRESSEE: Needle Rosenberg, P.C.

STREET: 127 Peachtree Street, Suite 1200 CITY: Atlanta STATE: Georgia COUNTRY:

USA

ZIP: 30303-1811 COMPUTER READABLE FORM: MEDIUM TYPE: Floppy disk S* COMPUTER: IBM PC compatible OPERATING SYSTEM: PC-DOS/MS-DOS SOFTWARE: PatentIn Release Version #1.30 (vi) CURRENT APPLICATION

DATA:

APPLICATION NUMBER: FILING DATE:

CLASSIFICATION:

(viii) ATTORNEY/AGENT INFORMATION: NAME: Selby, Elizabeth REGISTRATION NUMBER: 38,298 REFERENCE/DOCKET NUMBER: 22000.0061/P (ix) TELECOMMUNICATION

INFORMATION:

TELEPHONE: 404 688 0770 TELEFAX: 404 688 9880 INFORMATION FOR SEQ ID NO:1: SEQUENCE CHARACTERISTICS: LENGTH: 828 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1: AAAAAAAAAT TACCATTTTT GGGNGAACCT TTNATANTTN GTTCCTAGAG GGNGAGTCAG GGGTAAAAAA AACGATNAAG GGAGTTGNGG CGATTGGAGA AGCTATTATG AAGGGATAAA 120 ANACTTAGGT TGAGCCGGCG GGTGGGGTGT ATTCTTGGGG TGGNGAAAAG NNAGATCAAC 180 ATGAGATTTT TTTGTTTTAG GTTTTGCATG TTGTAATGCA ATANTTTAAC CTGATTTTAT 240

GTGCAGGATG

ACCGGTGAGT

ATATGGAGCG

AGACGTCTGC

GGGCCCCGGG

GCCTCGCT CC

ACGCGAGCGC

GGCGGGGTCG

CC CGTC GT CC

CCTGAGGTTT

CCGCGCAGCC

CTACGGCCCC

ATGGAGCAGT

GGCGGGTAGC

CCCACCGGCG

GGCCGCCATC

CCTT CGCATC

TAGCCCGCCG

GTGAGCAGGA

GCAGAGAAGG

GCCCCTGGGG

GGACCAGTGA

AGGGCCCATA

CAAAGTGGTA

TTGNTCT

GCG

CGCCGCTTCG

CCGCCTGCTG

CCTNAAGGGC

ACACAGGAAA

CGGGTATCAT

ccGATGGGCC

AGACCCAGGC

CATTGTCCAA

CAGCCCATGG

GT GCTGGTAT

AGAATCTTCT

AGCTTGCCCT

CNGCANGCNA

AGGAACACCG

TCGNTCCACC

CAAAAAGGTA

AAGGCCGAAC

GGGCTGCTGG

GGGCGTGGCC

TTAGAGCGCA

TTCGTCTGCT

CTTCCCCGCT

GA.AXAkGT GTANTCGAAkC

CTGTATGNTA

GGGTTCGP.GA

GTTGGGCCCC

AGAGCCT GGA CATATCAT GG GC GCCqTGACT CGCTCT1CTCT

TGCAGACATG

300 360 420 480 540 600 660 '720 780 828 GNGGACATTG

AAAGACCCTA

INFORMATION FOR SEQ ID NO:2:* SEQUENCE

CHARACTERISTICS:

LENGTH: 845 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genornic) (xi) SEQUENCE DESCRIPTION; SEQ ID N0:2; T CNCCTAAGA

CCNNGGACCC

AAGGGNANGN

CNCGGCCGNT

GCGNCGNCGG

GATGNNGGGG

~AACGGTGNG

CGCGNAGTTG

CNAAAPAA7A

TTCTAGGNGT

NCCNCCGGGG

CCCCNGGAGC

CNTCCCGACA

TCTATTTNNG

NANGAGANP.G

ACCNAGGGGA

GGNNAAACAN

CCNTGGGCCN

CCCCCCCAAC

AATTG14NAAT

NGNAGNNGTT

GCNGGGGACG

AAANAANNGN

CAN.GNTGNGG

GGAGTTT GTT

GTCTANNAGG

TAGTAGGCGT

NTT CATGGGC

AAAGAGCCKT

ATTGGGCGAA

GATCCANC CT

CATNTNTTCC

GCCCCCCANC

AATATGGC

GG

CCAI-IGT GNCN

TGGTAAGGGG

CCGCTNCGTT

TCCNTCTACC

CCG;TGGCNAA

CNGGNGGCGT

CGTATGTTAG

CNNGCAACAA

TTTADLANCT

TCCNTNACTT

GTTTTNAf CA

CAT'TTTGNNT

CAGCGGNGAC

GC-AGANNTGG

GCCCGGGGTG

CGGCCCTGGA

GTNCCCTGCT

CCCCAT CNAN

TGNCGACAGN

ACCTNTCGAA

ACNAAAGGAN

NNGNCCNGTT

TTCNTCCCCN

CCNG14GGCCC CNGN14CCTGG

ANCAGTAGCC

AGC GGC GGCG

GANGANATTT

TGNAGCCCNG

GNGGAC-CGAmC

GCNCNCCAGT

GGCCNNCGTC

GGACGCGNNA

TGAYLATAGNG

GCNTTAAATT

CGGCAGTGCN

GGAGAGANTN

AGNGCAGGCA

GAGCGGGCKJC

CNN GGGCNGC

NGCCNGTGCC

C-ANCTGCA14T

NAGCTTCCTT

GAT GGGANNN

AATAGATAGG

GTTAGATGGN AATGGAGAnNT ANATACCGGG

CTTAGCTTCG

120 180 240 300 360 420 480 540 600 660 720 '780 840 GGGGG 845 INFORMATION FOR SEQ ID NO: 3: SEQUENCE CHAJRACTERISTICS: LENGTH: 818 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3: C. C C C

C.

C.

C.

C

TACACCTrrG

GCCCCGGNCT

ATAAAGCCN

TAANNGTGGG

TNNWNGGCAA

TGAAAAAGAT

TTNTAGACCA

AGTAAGCAGT

AACAPAGCCA

ATAAATAGCA

AAACTAAAGA

GATCCCCCAC

CCACATGGCC

TGAAGGAPTNT

C7TGTGGAAT N CNNN NNGGGC

GGGGCGAGNT

GAGGGAT CAA

AGTGCCACCA

CCATTTATTA

ATTTACATAA

TCTAAGCAGG

AATCCACACT

GCTTTGTAGC

ACCTCTTAGC

GACTCCGCCA

CACAAATCAA

TT CT ATTTA

GTACCGAAGA

CATT CACCNG

CGTAACC-TTA

AGACANATNA

NA-ACTGAGCC

AGATTTNTTC

CTTTTTCGTA

GCCATTCACA

TGCCTGAGCA

TGGTGCCATG

T CGATCCAAC

CTTGCCAAGT

CGGCGCNANT

AGGATTTTCN

GGCNGCAATA

GTATGAAATC

TTTGTTATTT

ACAAACAACA

CCCAGCAATN

TCCATGTGGT

ACCAATTCCA

CGTGCCTTCT

ATTCTCATCT

AGGGCAGCTT

AGACACCT

NCNCTCTTCA AAATTACGC G1ANGAAN

ANAANGTAT

CATAT CATTT

AAACAAANTN

TNNAATNTTT

CCCNNNCCAC

TTAACAGT CC

TCATTCGGCG

A14GAGGCAAGN

CCCATTACAA

CACAATG OCT CTATATCC GT

TACCCCACAT

TATTTGCTCT

CCTTTTCCAN

CCCAAANAAG

T CCCTNTATA

TTTTTTTNNT

AC.AAGTTNCA

COCCACOTAC

GCACTTACAG

TCCATAACTC

GGAAPTACCCA

GCCGCATCT C

CCCACCTACT

TTCATCT CCC

GGCCNGCTAN

120 240 300 360 420 480 540 600 660 720 780 818 INFORMATION FOR SEQ ID NO:4:.

SEQUENCE CHARACTERISTICS: LENGTH: 857 base pairs TYPE: nucleic acid STRAN,1DEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genornic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4: TGGAAACANT GNCNTAAACGT TNACTTNNNA GATArrGAN\N AANNTNCCGN AAAANAACCT CNNNNACAAT CTCNCAANNA TTTNAANGAA GCCGAATAA ATCNAAANTC GCANTTAAAA AAALMAGGGN NAVNGNNTTN NGGTTNAANA NAAGGGGGT NTNCCCGTTT

TTTTTTTAGG

ATCCTGGGAG

TAACCNACAG

CAGTAAGGGA TGGGGCCCTA TTCCG1'TAAG

TATTTTGACC

CGCGNCCAGA

TTNTGCGAAN

TCGCAGATNT

GACCGCAGAT

GGAGAAAATT

TCTTGGGGTT

GGCACCCATC

GCCACGTCAG

GCGGAGCATG

CGCAP.AGGCC

GCGAGGGATT

AANGGGGTCT

GGCGAGGCGC

GTGGAAGCTC

GAACCNAAAA

TTTTTA14CAA TTTC CAGGGG

GTCATTTTGG

TTTCNTTTCC

CCNTCCCGNG

CTCACGCTCG

TGCN1TNTAAC TT CNTTTCNG

GCGATAGTTC

TTNGNANAAG

CGAACACCAT

ATGTNTC CGC

GAATGACTGT

CACCTTATGT

ACCCAAASAA

CGACGCCAGC

ATCCGGGGCT

TCTCTGGCCG

CCCTCCGCCT

GGNGNTCCTT

TGACAGGANA

ACAGCCGTTG

TGTAGACACT

C CGNTGGAGC CACAACT GTT

ACGCNTGCGC

CGGGCGGCGG

GCTGGGCGCG

CCTCTTCCCG

CCGGT CAGNA NGAC CTTAAA

GCTTTTTTAG

AGTGGTGGCC

CTCGCTGCCC

GCAGAGAAAG

CGCTGCCGCC

GGCGACTGCT

GTCCAGGCCA

240 300 360 420 480 540 600 660 720 780 CTAGGGAGTT C GCTGAC GCC GGGTGAACTG AGCGTACCGC CTGAAAGACC

CCACAAGTAG

GTTTGGCAAG

TAGAAAG

INFORMATION FOR SEQ ID SEQUENCE CHARACTERISTICS: LENGTH: 896 base pairs TYPE: nucleic. acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SE-Q !D

GGGAGAAAGG

TTTAACGGGG

NTAAGAGGGN

AGGGTTCCCG

AGGTGTTTTT

ATT GGCAAGG

GGGGAAAGGT

NTCCATGGAA

GGNTCTTGTG

AGACTAGAGT

GGCGACNTTT ATTGGTCCNG

GAGNGGGGG

GGAGGCCCCG

GGGGGTNTCC

GAGAAT GGGG

TTTTTTTTTT

AAATTTTTTT

CCCCNATTNA

GAGTGGCTTT

CTTGAGAATA

GTTNTAGATT

GNNGAGGAA~T

GNNNTTNTTN

NGGATAAAAN4

TTTGTTCANA

CCTAINCCTCC

ACAAAATGNG

TNTGGNGAAG

TTGTTGGCCA

NTAGGTCTTC

7 CCCGGGGGA

GAATNGTGGN

GATTGGCAAC

AANAGGAA

TTGAAPAATA

TTTCAGNGGA

TTCATTTTCC

GCTTTATNGT

ANGTTTCCAG

NCAAATGGGT

GGAANAAJAAA

GCACCGGGGG

TCACCCCGGN

TGATT CAAGT GT GGGAACAG

GTGTGGCCCA

TTAAC CT-1NA CTT CATTTNT

TCACCAGTCC

CAAGATCCGC

GGCAAGGAAG

TAGTTGTACC

TAAAAAGTA

GGGTTC CCAA

CCCATTGTGT

NNACT GTAAN

AANACTATTT

TTGGCTTTTT

120 IS0 240 300 360 420 480 540 c00 AGTATGGAAA TCACCAGTAA TGGCAATATA ACATCCCTGC TTCTGTTTCT

TAGAAGGCTN

39 NATTACAGTG TGTTCAAACT CCGTGTCATT GCAACAGGTT AAACTAACTT TNTACGTAGG ACATCAGGGT ATTGACATTC TCATCCTAAkA GTCAGTTTGT CTGTTTCCAG AGGAGGAACT GAAGCAGTGG TTCTTTAAGT AACTGACTCA GGGCTTTCCT GCCTGGCGCG CCTGCCAGGC ATNGTGTAGC ATTGTACTGC ATCTTCTTTG ACCAGTTTCC CCAGGTGAAG AGCCTG INFORMATION FOR SEQ ID NO:6, SEQUENCE CHARACTERISTICS: LENGTH-: 937 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomnic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6: GGGCCCCCCC CCCCCNAN4TT AA4TTTTNGGG AAGAAAAAAG GGAAA.AAANT TTGGGGTCAG

GAAAAANGAA

NAGAGGTCCC

TTTAT CAGAT

ACATATTAGT

GGNGGTCACC

AGAGATGCGG

CAGCATCAGT

NTGGCTGGTA

CTGAACACGG

AGAATCCTTC

GGGCTGGGAG

TCCCCTGGGC

CCATCCCCTC

GCGT CCCT CT

AGACCCCACA

GTTGGNAANC

TTNNTTCCNN

TACCCGNGNG

CAGATTATAC

ACACAGGAGA

TAGACT GACT

ATTGTTCCCA

GAGGTTCAGC

PATTAGAGGG

ATCCTGCTCC

GTGTGTTTGC

GGGCNTCACC

GACCACTCTT

AAGazTCTGT C

ATGTAGNTTT

GNNGGGGNGN

GG.AAAAGTTT

TCACCTGGGG

ATAGCAAANA

T GTATTATCC GTTCC CTTTT

GTCCCCNTCA

ACACATACCA

ArACTCGATGT

CAGTCCGGAC

CTTGCCTCAG

GATGCTGGCC

TTGGCGCTTC

CACTNCCTGG

GrGCAAGCTAG CAGNATTN GA

AAAAGGGGTT

ACCCTTTACNM

TAGTTAGGAG

GCAGTATTAG

CGNTTGGAGT

CACTGATTCG

GAGTTACGAG

CTCCGGCTTG

GTCCAGGCAA

GCGNTGGGTG

ACTATAAGGC

ATTGTCGACG

TCTAGGGGTT

CAAAGGT

ANAGTGGGGG

CAATTAACTT

GGTGGCGGGA

CACAAN4GAAT AGAGTTGAGAz GACCTT GCCA

AACTTTAAGG

TCACGTGCCA

CACTGGT CTT

CAAGGGCGTG

GGGTTGGGGC

CAGCCAGACT

TGTGGTGAGC

ANNTTAATTT

NGGATCNCCA

CAT TN GAAAN

CATTTATGGT

ACCATATNTT

TTAGAGGCAAL

J CACTGATCT

GAAGGGCAAA

CTCTTGCANT

GAAAGTGAGG

GTGCCAGCAC

GCGACACAGT

TCTCACTGGG

AAGCNTTTTC CTGCCCTGAA INFORMATION -FOR SEQ ID 10:'7: Wi SEQUENCE CHARACTERISTICS: LENGTH: 888 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:7:

A.AAAGGGGGC

AAAANTACTT

GGCCGGAAGC

TTCCTTTccT

TTTTCNGTNA

NATTNN GGTT

TTTTCCCNGC

GTAAATTACA

TAAACATTAC

CCCAAANAAA

CAAGGGANGA

CCTGATTCCN

ATA14GACTTT

TCCTCAGTCA

CCCAGCGGNG GGGGGTTGTC CAAGGAATCA AAANGTGGGG

NGGGGGGGAA

TTAAAAAAGG

CTCGGACNGG

TATNTTAGCA

AAGGAALAGCA

AGNAATTGGN

T TTTAAGACA

ATGGGTA.GG

CCTTCATCCN

AAT14TTCAAA

CATGGGCAGG

TTTGNTGTCA

CCTGATGGNG

GCTTCTGAGC

CNGCCNNANA

TTTCNNTGTT

AATN GCCGGC

GGGGGGGGAN

TCCCAGAGAG

GGCA14GATAN4

GCTTGGCACA

GAGGNAGTTA

AGNAGCCCCN

WTAGGGNACA

CACA GA CANT

ACGCTGCCGT

CT CAGGGT CC

GACNNTCACN

ATANANGAC G TTCNGGGGNG

AGGACAAGGA

CAGGAAACCA

AAACACGGAN

NGCCAAGAAA

TATNNGGCAG

GGCCAGGGTA

ACACAAGCAT

TGGGGAACGT

GAATCAGTGN

GCTCCAGGGA

GANGGGACAC

CAGCAGGCAC

AAAAGGGNAC

NCGAGTTGGG

AAAAAGGGAA

ATNGGCCTGT

CAGGTNATTA

AGTAGGGCA14

TCNTGGCGGG

TAAGCCAAGC

TCAGAGACTC

CAACCTT CCC

TNCCTCGTGG

GCACNGGGAT

NGGGNTTM GG

GAANNGGGTT

C CAAAATT CT CCA-1AGGTA-4 GTATGGAT GT

TCTCACATAT

NTA14GACTCA

CAGGGGCACC

GGAINGTGAGT

TAGCACACAT

120 180 240 300 360 420 480 540 600 660 720 780 840 AGT GGCAANG AC CTCATTCT AAGGAGCTGG CTAGTAGA TCTCGTCTGT CCCACTGAAA INFORMATION FOR SEQ ID NO:8: SEQUENCE

CHARACTERISTICS:

LENGTH: 980 base pairs TYPE: nuclei-c acid STRA4NDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genolnic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:8: AGAAATGAAA AAGAAGGAAA GCTAAAAATA

GATTATAAGT

GAAAAAAAG AAA3AAGAACA CAGAGAAGAA

TAAAGGAGAA

AGAAAGAAAA AACGGAAAAG PAACCTAGAA

AATAAAAAAA

AGAAAGGAGA AAGACTTACC TAGAGCC CAG AAATAGAGAA AGAAGAGGAG AGAAAAAGGA TTAGAGAGGG

TGAGGTAGAA

AGAAAAAAAC TAACAAAGAT GCATATAAAC

AGAGAGAAGA

GTTCTATTTG

GAAAAAGGAA

CAAAGTATCC

ACTAGAAA

GGA.AGAAAAG

TGATTAAGAT

AAAAAAGAAA

GAGAAAAAAA

GATAAGGAAG

AAAATGGAGA

ACAAGAAAGC

TAGAGAAAAA

GACCAAAGAG

GAAGAAAGAG

GTAGAGAAGG

GCACCGAGCT

LAAAAAAAAAA

TGACAGAAGT

TGAA.ACGGGC

GCCAATGAGG

ACCCGGAGAG

GACGGTACTT

AGAAGGTAGA

GGCAAAAGCA

GACCATTCCC

GAACCTGGTT

TGAJAAAATAA

AGCAGGCAGG

GGCAGAT CCA

AAGGGCAGGA

GTAATTTTTT

TAGTATACAT

CAGGACAAAT

AAGGAATAAG

TACCCCATAG

ATCACACAGG

ATTCCTTCGG

AAGCCAGCCA

CATCCGCAAA

AACCATATCA

TTTTACGGGA

CGTTTTGCCC

AAAACAAAAA

ATAATAGCAC

GGGGGAACGA

CAGGAGTGGT

GCGGAGAACT

GCACCCCAGC

GTCCTCAAGG

AGCCGA1GC CT

AGCGTCCAGC

GAGTGGTCAG

CAGGAGGGGA

CAATAGCAGG

CCC CGGAATC

ATAGCACGGC

AGAAGAGGAT

CCAAACAGAA

GAGCATCGGC

CGGGACGGCT

CAAGTTAGTG

ATTCTTTTGT

GAAGGGGAAA

ACAGTAAAGG

AAAATACAAG

GTTCCGGGCA

GGGAACTCCT

GCAGCCGCAA

GAGGCCCGGA

GCCATGAGAC

GGC CGGAAGC

TATCCCCAAC

420 480 540 600 660 720 780 840 900 960 980 AGAACC GTAA GCTAGAAATA INFORMAT.ON FOR. SEQ ID NO:9: SEQUENCE CHARACTERISTICS: LENGTH-: 845 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) IMOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:9: TCNCCTAAGA NA14GAGANAC GTTAGATCCN AATGGAGANT

CCNNGGACCC

AAGGGNA14GN

CNCGCCCGNT

GCGNCGNCGG

GATGNNGGGG

AAAC GGTGNG

CCGNAGTTG

CXAAAAAAAA

TTCTAGGNGT

NCCNCCGGGG

CCCCNGGAGC

CNTCCCGACA

ACCNAGGGGA

GCNNAAACAN

CCNTGGGCCN

CCCCCCCAAC

AATTGNNAAT

NGNAGNNGTT

GC14GGGGACG

AA.PN.ANNGN

CA14GNTGNGG

GGAGTTTGTT

GTCTANNAGG

TAGTAGGCGT

AAAGAGCCNT

ATTGGCAA

CAT CCANCCT CAT14TNTTCC GCC CCC CANC ,AATAT CGCGGC C CANCT GN CN

TGGTAACGG

CCGCTNCGTT

TCCNTCTACC

CCGTGGCNAA

C14GG14GGCGT CN14GCAACAA TTTAAAA14CT

TCCNTNACTT

GTTTT NAN CA

CATTTTGNNT

CAGC GGNGAC GGAGA-1NTGG

GCCCGGGGTG

CGGCCCTG3A

CTNCCCTGCT

CCCCATCNA14

TGNCGACAGN

A14ATACCGGG

ACNAAAGGAN

NNGNCCNGTT

TTCNTCCCCN

CCNGNGGCCC

CN CNNCCTGG

ANCAGTAGCC

AGCGGCGC

GANGANATTT

TGNAGCCCN G

GNGGASGCGAC

GC14CNCCAGT

GGCCNNCGTC

CT TA CCT TC

CGGAAAGAGG

T CAAATAGNG

GCNTTAAATT

CGGCAGTGCN

GC;.AAGANTN

AGNGCAGGCA

GAGCGGGCNC

CNNGGGCNGC

NC CCNGTGCC CAN CT GCANT NAGCT T CCT T GAT GGGA.NNN 120 180 240 300 360 420 480 540 600 660 '72 0 780 TCTATTTNNG NTTCATGGGC CGTATGTTAG ACCTNTCGAA GGACGCGNNA

AATACATAGG

GGGGG

INFORMATION FOR SEQ ID SEQUENCE CHARA4CTERISTICS: LENGTH: 528 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (qenomic) (xi) SEQUENCE DESCRIPTION: SEQ ID 840 845 120 180 240 300 360 420 480 528 ACCTTTCNGC GAACGGNGNG GAAAAGNC4C CAAACAAAAA

GACCCCNNTG

4 4

GGATTTNNTA

C CCGGCAAAT14

TGCNCCCNNA

GTTT CGGAAT

TTNNAATTAA

CCTATTACCN

CTTATANGCA

GGATGGAGCA

CTTGGGGGN

TATT CCCGGC

CAGCGGAAT

CCTNNTACCC

CT CGCGTTCN

CATTCTGGGG

GGAACNCCCT

ATTCNGGAGC

TNAGGGGCAA

CCNNATTNTG

CCAATTTCNG

NGANTGCACG

TTGGAAACGA

ACGNAITAGTT

CNGCACAT

GT

GTTTTTTANN

CCCCACGT

ANTATTGAAN

CGJAGANC CNG

GGNTGCCCTT

GANATCCCTN

NACCTTCANT

NGGGNNANCC

GGCGATTGCC

NNTNTCCGAC

NGNGACCCGG

AN4GATNNCTG

CTTTGNNTTT

AN CTAATGC C

CAGCCTGCG

GTTCAATC

CAT CTAACTT

NGGGGNCNTG

GCACTTNTTC

CTGJAGCGTTT

AN4NTCACACG AANC CAT NGA CCNGACCTAT

ATGCGCNGAA

INFORMATION FOR SEQ ID NO:ll: (ii SE-QUENCE

CHARACTERISTICS:

LENGTH: 927 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genornic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:11: AANACGGTTT AATAAGGGGG ATGTTCAAAA CNCCACTCCC

GGGCAANAAA

AGGGGGCGAG AA}JGGATTCG NGTATAGTTT CCCACCACAA

ACCTNCTTCC

GGGGGNAACC CACCNCATCA TTATGGGCTC AAGGCAGCAC

CCACCCATTT

AGTCACTTTT TTTTGCTAYA ATCAAAGTTC CTTCGAACAT

NTCCTTTTAT

TTGCTGTTAA ATTAGCANTT TNTCNCAGTT TCAAAGTTNT

GGTTCCNGAC

ATTGCTTCAC CGCTTNTTTT GNCGCCAGGAA AGCAGACCCN

TGTTNGCAGG

ANAAAAAATT

ATTTTTT CGG

TTCGGGGGNA

CCAAGGAGTT

NAGNTTTGTA

GCGAGITTCCN

120 180 240 300 360 43 ATTTTTAGTT CCCATTTGGT GTTTCCNTAG GTAATGGAGT NTGAGTTGAG TCCCTTNTCC TATCAGCCGG GGTGGCATTC CAGCCAGATT AGATTT CAGT NTCNTTTNTA ACAGGGAAGT GCAGCCTTTC CACCCCCArLVJ GAGTGAAC CC TGC CNTTTCA CGTTGGCTTA GCATGCAGAT TNTTTGGCTC CATGCCCGGA TGAAACTTCC ATTATCATAG AATGGCAGGC AGGTCCTTTG GGCCNAATGA GATGGNTCAN TGAGCAAAGG

CGNTTACTGC

TAGTNTTGGA ATTCACAGGG TAGAAGTTGA ANACNTTTGA TAGCAGGGCA GNNGTGGTGC ATHCCTTTAA TTTGGGCTAC NGAACCTTGG CAAGTAGAGG ANGTCGT INFORMATION FOR SEQ ID NO:12: SEQUENCE CHARACTERISTICS; LENGTH: 911 base pairs TYPE: nucleic acid STRXNDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (geflomic) CTGCAGACAG TTTGAGTNTA TGTCCAAAGG AGGAATCCAG TAGACACACC CGGCCAGNTT GCTTTTACCC AATTTACTTT GCAGCTGACA TGGGAGGCTT CGGTTAAAAC CAGGAGCCTG CAACCCTGAT GCCTTCAGTT CTCTTCAAAA GTTGTCCCTG TTTGTG;VkAG ATATCCACAJA 420 480 540 600 660 720 780 840 900 927 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:12: GGGAGTTT GC

ATANNATACT

NTATCGTCTN

NCTCTATNTT

GTGNGGGGAN

GGGGAGANNA

TGCA24AGANA CCTNC GGGGG

GTNNGTNTCC

TCCCNTANCC

TNTATNTNNT

ACTCCCTTCC

TCNTTN4CNTN CCC CCCAAAT

CTACNNTNCC

GGGGN14TCTN

CTCNCCTCAC

CTCNNAGAGT

TACNCTTCTC

AATGGGGCTC

CT TNT NTNTA N CNT GNT CCA

CTGGGGGNGT

ATATATTTGG

CGGGGCCTIJG

NGGAAAACCC

T14GGGCATTT CCCC CTNAN4G

AAATGTTTGN

ATATNTGCGIN

GTATNGNGAA

TCNT CTCT CT

NGAGNCTCTT

AATCN CCTNT

AAAATCTCAA

NTATTATNTN

GGTCNTTACC

AAANTTTATT

TTTTCNAAAC

TTTCTTTTCC

TNT CAAGGGC

GCTCCCCGGG

ACTCTTTCTC

GAACTGNNAG

NTAGAGTGNG

ATATTTCCCC

CNCCATT14TT

ATTTGTGTCT

TNT NTATATN

AAAACCCCNT

NCCNNCCNTT

NGGNT TT C CC

CCTCACCNAA

AAGAGAATAT

NAAAATANNT

NNCCACAN14A

TGTNTNTGGG

ATGTANAAAA

NCCCCTCTCN

14NNANNN GC G CTTNTCC CAA C14TATNTTAT

TTTTNTCTCA

NNGNTCCTTT

CTTTTNNCNT

C CCC NT TT NC

NNTCTCTCTC

CTCTN'TCNCG

AAAGCGCCCA

GCGCGTTCTC

CC14CANNTGT

CCATATATNA

TGTTTNTATT

ACNCTATNTC

ATACNTATAN

CTTTTCNTC14 T CTNTTAAT

CCCNCTCAAA

CTCCCCCCNC

TCTCAGAGNG CCNATTACGC NACAGGGGGN GTCTCAC.7NT ATAANCTCAT 120 180 240 300 360 420 480 540 600 660 720 780 840 CCCCCCCAAA NTGNGAATAC CCTGNTTTTC AGNGGNNNNG AAALAATCCCT CCCC6ANGGN GCCCCCCTCC

T

1NFORMATION FOR SEQ ID NO: 13: SEQUENCE CH1ARACTERISTICS: LENGTH: 880 base pairs TYPE: nucleic acid STRANDEDNESS: double tD) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:13: GGGCACCAAC GGNGGAAGAG TTTTCCANGG TADNAAGAAAG NAGGANTGGG NCGANAAN1AA

TTANTTTTNA

GAAACCCTCN1

TTTCNTTTTT

TTAAACGTAA

TAANGNAAGNV

14CTTTAANAC

ANGGGTAAGT

CNTTGATCGN

TTTCTTCCTN

AT GGGCADGGT

GNCTGTCACA

GNGNNGGAGA

TTNTGAGCNT

CAAGGGCGTC

AAAAGGNCAC

GACGGTTTTC

GAGCAAATTG

CGCAGNTTTG

GGTTCAAGAG

AGGTNNNAAA

GNTTGG-CACA

GNGGTTGTTT

GGTGCCNCAN

TGGGTACAGA

CAGACACTGC

CGCTNCAGNG

CTGGTCC CNG

TCCACAAGAC

CAGATANAAA

NN GANTNTTA

CCAGCAGGGA

GA14AAACACA AGAnGCCGATG

AATNNGGCTG

GNCCAGGGTA

ACACCGCNTT

GGNGAACGAC

ATCAGTGTTC

TCCCAGGGAC

ANGGGACACT

CAGAGNACAG

AG CGT GN CNA

AAACTTTTNA

AANAGATTCA

ACNGACNAGA

GNTNACAT GG

AAATNGCCNG

CTGTTTATAA

AGTAGGCATN

AAAGAAANGT

AAGCCAAGCG

AGAC-ACT CCA

AACCCTCCGG

CCTGGTGGTA

T GGN4AATGAC

GTAGATAAGT

GGGGNGT'TAA

GGGGAAGCAC

GGNTNGC-TTT

AAAGACCTGG

GTCCAAAATC

CNATAGNTAA

NAArGAAkTGT

TTAAAAATAT

NAT GANT CAC

GGGGCACCCA

GATGTGAGGN

GCACACATTC

TTTTTTCTTA

NPAAAANCCN

GAGATTATCT

TTGNATNCNN

GNNATTAGGG

TTTTTCCTTG

GTGAANNACA

TAAACATNAC

CCCTGGrGCTG

AGGAGACGAC

GATTC CNTCA

NANGAC-TTCC

TTCAGTCNGA

CTTGNGNCTC

120 180 240 300 360 420 480 540 600 660 720 780 840 880 INFORMATION FOR SEQ ID 140:14: SEQUENCE CHARACTERISTICS- LENGTH: 923 base pairs TYPE: nucleic acid STRANDED14ESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genornic) (xi) SEQUENCE DESCRIPTION4: SEQ ID NO: 14:

GC-GAGGAGTA

GTNGCGTAGG

CCANI4GTNAA

TTNNTTGNAA

GCCNGCGNGN

NTGGNNNATA

CCCGCGAGAG

CTNNGANANN

CTNNCACACC

GGTTNTTTAC

CCCANGGTGA

TNCNGAGTCA.

NACTGNTCCA

GTGANNGGAC

CCCNGCPLGAG

CNGGANGGGT

NNACAAAGAG

NCAACTNTGG

CCNAGATTCG

ATCNGGCNAG

CCCNGCTCTC

CCCGNGGNAA

ATNNGGCTGN

CCAGGTI7AGT

NNPAAANNP.A

ACGACNA.NCC

GTGTTCAGAG

GGNNCNNCCC

ACTTCGTGGH

CACT14TNGCA

CCGACGTAAN

ATAGGAACGG

CGGGGGTGGG

AGGGACGGAC

GGAGGGTNGG

ACANGNNGGA

GGGCGNGTCC

TGTTNATCNC

GTCCCNTNCA

AAAAJAAANTC

.MANCTNTTGA

A14TTCNGCGG TCCGGTTGN G

GGTGNCNCAC

ATGNCTTTNT

TNTNT cACAG

GGNCGNNAAC

ACNNAAGGCG

NGGANTATCN

TTNNNNGGTT

C GNGGGTNTT

AAAAIJTCTTN

KATAGGTAGN

NGGTATGTTA

ACCNTCCCGG

NTNACAAGGG

CACCCCTGAT

AGTCNAAGAC

ATTCGTCGGT

TTGTTCTGGG

GNAAGNCGPLN

NTNNCNTNTN

NGNGGCNNNA

TAT CCNTNTT

T-ICNGGNGACN

TNNGGTGAGG

TTCCCTGCTT

TCAACCNNCA

ANACGTTACC

GCNT GNT GNT

ACGACGTGNG

TCCCNCGGNN

TTC14GGNNGG CGGCTTA14GA GCTTCC14AAT A1GAGGAGGG GAAAAGGCC G

GAAGGTTTNW

NGLTN CGA14T

NCCCCAGT-T

AAGNN GCNT C

NTNCNACAGG

NGGGGP.NGT G

NNTG-ATCGGG

TCCTNGGGGC

CAGGTTGNC G

GTNACACAGA

TGACNCTACK

HCNTCTNGGT

GGGTCCT CCC AAAAGNCNGC TTTAGCTGTA ATA INFORMATION FOR SEQ ID NO: SEQUENCE CHARACTERISTICS: LENGTH: 830 base pairs TYPE:- nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID ANANAGAGTA ANTAANANALA GAGGAAGAGA NAAGAAAGNA GAAGGNAAGG GN14GGCGAGG AAAAAAGGAA AGGAGAANAA TAAAAGAAAA AGTGAGGAAG NAGAAAAAAZG NAAAGNGGAG ATAGNAGAT4A GGNCCGGNGG ANAAAAGANT NAGNTGAAAG AATAAAGAN4N PANGGCGANAA GG.AAAGAAGA NCGAGNATTA AGGAAAGA14N NGGGGGGAGG GAAN'GAGGCG AAflTCNNGAG ANCAGTNNAN AATNAGGAGN AGANANGAAG NNNAN4GANGA AGG.AGGGGAA AGAGIGGNACA GTA14AGTAAC CNACNNCNGC GAGNGNGCCA AATAGGTNGC GCCAGCNACA CCNGGGCGAG GGGGCATCA14 GAGCCAAGGG GAGCGGGTCC AGNCNTAGTT

ANANAAANGG

GAAGGAGTAN

AGATTAANGA

G.AAANAAGAG

AAGGCAAGAG

t3AAAAAACAA

NGGCCCGAGC

NTGAAPAGGAA

AGGGGAGGNG GGNAGATATT ATATGGTCGN

GCCCCCCCCN

AGGNGT GANN AGCAGGGCCN TNTT GGNTGN GGGATCGNGC GGACNTTCCG CNGNGCCTTC CGTAGGCCCA

NTGTCAP.ATG

ATGCCGGNGN TAGNGANTGA TGCGGGGGCC

NGCCCCCCCG

CNGTGGCCGC CATNACGGAG TTCCCAGTGG

TGAGNGTGCG

GCCGCCGGTC CCCGCAGACA GGAACGCGGA

GCGNNCCCTG

CTTGAAAGAC TNNACNAAAN GACGCNGATT

TGTAGAALAAG

INFORMATION FOR SEQ ID NO:16: SEQUENCE CHAkRACTERISTICS: LENGTH: 166 base oairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic)

GTGTC:TCCGGT

ATGATCAGAG,

TATTCAAGCC

GNTTTCCG7CC

GAGNTGAGGC

CGCTNGAACG

GAAAAAAAAA

ACCNGAGGCC

GGTTNGAAGG

CCCGCAGCCN

CCCGCGGGTC

TA14GGGNCCA

S.

S.b

S

S.

S.

S.

S

S S

S

(Xil SEQUENCE DESCRIPTION: SEQ ID NO: 16: ATTCTTCAGC TTTTGCNTAG AGGAA.AAAGA ATGGATTGTT TCTAGGACAA

CCTGCTGAGG,

TGCTCACCNA GNGTTCTCTC TCTCTCTCTC TCTCTCTCTC TCTCTCTCTC

TCTCTCTCTC

TNTGNCTCTC TCCTGAANNT CCCCANAGGN NCTTNGCAGN AAAA14G INFORMATION FOR SEQ ID NO:17: SEQUENCE

CHARACTERISTICS:

LENGTH: 162 base pairs TYPE: nucleic acid STRA11DEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:17: CNTTTTNCTG CNAAGNNCCT NTGGGGANNT TCAGGAGAGA GNCANAGAGA

GAGAGAGAGA

GAGAGAGAGA GAGAGAGAGA GAGAGAGAGA GAACNCT1NGG TGAGCACCTC

AGCAGGTTGT

CCTAGAA-ACA ATCCATTCTT TTTCCTCTAN GCAAAAGCTG

AA

INFORMATION FOR SEQ ID NO:18: SEQUENCE

CHARACTERISTICS:

LENGTH: 871 base pairs TYPE: nucleic acid STRA14DEDNESS: double TOPOLOGY: linear 540 600 660 720 780 840 880 120 166 120 162 (ii) MOLECULE TYPE; DNA (geflofic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:18: GAATAAAACC CCAGAAAGGT TTTAAAACAT TCCCTATAGA AGTTGATNAA TThAAPLkTAAT

TGGAGGTGAA

MTTTTGGGG

TTN GTAT TAT

TAAAAGGTAG

TGGACAGAAA

CGATTTAGGC

TGCAGATNT G

CAGGCTTGGG

GGCGCCGGTG

TGGCAGAGAC

CGC CCACAGG

AAAAGGGGGG

CATCGGCCCG

ATACACAGAG

GTTTTAT GNA TTAAAAAC CC

GAGAATCGTA

TATTAAGAGT

CAAGTTATTT

ACGGCTTGGT

C CCAGCATGA

AGAAAGGACT

AACGCCAGAT

CCTTACCGCA

CCCAAAACCA

GCCCCAATCA

GGTTTTTCAA

NAAANGAATT

TTANGGATT C

TCAATAGCCC

TATTCTTAAG

CCACAGTATG

TCCTTAGGTT

GAAGAGAGGG

TCATCTTGCC

CTGCAGAGC

GCACAAAGCG

TATPAGCCNT

TGCCCCCCCC

TTAAT CAATA

GGACCGATCA

NGTTGATTTT

AAGATAACAG

ATCCNGCACT

GTATCAGAAG

ATTGCCACAG

GGAACCAAGT

ATGNTCANTC

ATTCCGGCCT

CGCCACCCGG

GGACCAGGCC

CCAGCATTCG

AAAAAATAAA

ATTTCCAACA

AAATCAAGCA

ACT CTAAAAG

TTGGAAAATT

GAGTAAAGAG

CA-ACGGTCTT

TCTTCAGGGA

AGCCAAACTG

TTAACCGCTT

AGGTCCCGCC

CCCGGCC C CT CCCCCCTC

TTACNTACNT

AATTTATTTT

GTAAATATAT

TTAAAAG-TAT

TAAAACCAAG

ACACCACACG

CC CC GCAAG

CCNCACGGGC

CAAACCCTTN

TCCCACACTC

AGT CAAAACA

CCCCCAGGA

CT CCCGCT CC @600 0@ S. S t.

0005 0605 0 S. S U S *5 S. S *0 04 .455 0 3900 CGCGATGGGC CCTTATGCTC CCGATACGCA T INFORMATION FOR SEQ ID NO:19: e SEQUENCE CHARACTERISTICS: LENGTH: 936 base pairs TYPE: nucleic acid S. STRA4DEDNESS; double so TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genociic) (xi) SEQUENCE DESCRIPTIC14: SEQ ID NO:19: TCGGATTCAA AAATTCGAAC TTANTTTTTN AGGAAATTTN TTTTTAAAAT GCNNTNGCC ACCAATTAAA ANCNGTTTCA ATTNAAAANG ATTCCCGCCC TTTNCTCCAN GCAATTAACC AACTAATTTG GNTTGCNACC ACTNGTTTTG AGGCATTTTA A1AACAAATT AACAGGCNC- CCATNTTCAA CCGGNGNTAG TGAAACNGAC CNTTTTCCCG CCGCCCTTT CCNATTNGTT TCCTTTTTTA ATGCNGAAAAA AAATN4ATGGT TTTATATCAT CCTTNTTGGC ATCACCACAT TNTAATT CCC

GAAAAANCCA

CGCCTNTAAA

NTTCTTTTNA

GCAT TAACAG TGGCNATT CA

ATTAAAACAG

GGGTTTGATT

TTTCCTTTTC

TTTTNACATT

CTGAGGATAA

CTGCGGAGAA

CC CC GAGTGC

AGAAGCTGAG

TAGCCTGGGA

AAAGTNCCCA

ATCATTCATG

GC-CCTGACCC

GGACTGAAAA

TTTGTGCCNT

CAGTGAAGTG

AGTATGCGTG

AGCGTTAGT C

GCTGAGGATT

GTAAGATT CA CAN NGN CTTT

ATNGGCTTTT

GCCNACCTTC

CAGGCGAATG

GCT GTGCGCC

CTCTCTAGCA

CTCGATAAC

AAC CGGCCAA CAT CTCTCAG

GTCTTTGNTA

CCCAACTAAC

TCCCCATTAC

GCTTGCTTAG

AATCATTTCN

CCTCTCTCAT

TTCTTCTGCG

ATTACTCAC

TGTGCTGGGG

TAACAAGTTG

ACAGCCTGCA

AACTCC

CAT GNAAACA

CTGAGGTCCA

GTCCTCTCTT

TT CCCTCTTT

CACCAACCCG

ATGACACAGA.

GATTTTAAAT

T GAATCACGC

GGCATTAAGC

CAAAGACCCA

GCACTCCTT

GAGGGTCCAT

TAAGTGCCCCC

GAGATCTGCC

CCACCGTT GA

GGAATCACAC

TCCCAGGAGC

CACCGAACTC

420 480 540 600 660 720 780 840 900 936 INFORMATION FO0R SEQ ID SEQUENCE CHARACTERISTICS: LENGTH: 888 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE- TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID

AGCNNGGGC

TAA.NAANCTT

TGCTNNCT CT

AAATATTTCA

NTC CACCTAG

GATTTCTTTT

CNCCTAACTC

AGANTAATTA

TTGAATATAC

NAACCATG-N

TAATCTTCAT

CACCATAACC

ACTAAATGNT

ATATATATAT

AAN CGAAAAA

ATNGNGAAA

AjAAAATTC

TTNTCAACAA

TACCAAACAT

TNT GCTTCTT C CAT CTTAAT ATCTTACTAAn

ACACCCCTTC

ATTTTACATT

ACACACCACC

GGGAC CATCA

ATATATATAT

CCTTTTANTT

AAGATTTATT

TCTAACAAAA

CNNANCCCNT

TNTAAACTCA

TATTTAAAAT

GAAACATAAT

AATATTANCC

TGTGATTCGN

CTTC CTNNGA

AGTNTAGGAA

CAATACCCCN

ATATATATAT

AANATGACCT

ATA.AGATTTT

CCNTTTTTGT

AGGGAAGGAC

ACGGTTAACAT

TCAATATTCA

TTCAATAATT

ATCCAAATAG

GGGACNT CCC

GCANCCTCCT

GTGAGGNTCT

TAACCNTCTC

ATATA.TATAT

TTTT GGGCGA

TTATAANATT

TTTTTGTTNT

ATCATATGCA

CACACTCAAN

GGATTTCATT

TCCAAACAAT

NTAATAAACA

CATAAGGCTT

CCCTCTTAAG

CTTTAATCTC

CANAGAACTC

ATATATNTAT

AANACAAA.NT

TTNGGGGGCC

CCAACNACTT

TATTTTCANA

TCCCANGACN

TATACTAACA

NTCATTTTTC

AATAGATANCG

CTTTCTATAA

AAAANCACTC

TTACCAAAGT

TAAAAGCNTC

ATAAAGAGC

GC-CAAACTTN TTTATNTCCA AANTTTTCT TTNCCCGCCN

AACCAGTTTT

120 180 240 300 360 420 480 540 600 660 -720 780 840 49 AGTATTGA,A GACNTNCACC AATNGAGCTG GCNAGCTAGA AGAGGTCG INFORMAkTION FOR SEQ ID NO:21: SEQUENCE CHARACTERISTICS: LENGTH: 903 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2l:

CTTGGAAGGT

TTTGGAAACT

TCAAAGTTCC

AAN'ATGTTTT

GAGGGAGAGA

GGTTTTCGGC

TGAINATNACC

CGGAGCGCCA

CGCGCCCGCC

CCTTGGCCCG

AGCACCALTGT

TTGTGTAGCA

ATAAAAATAA

GTCAGTTCCC

'I'CGGGAGTGC

C GT1

TTTTTTTTTG

CATGGNTTGG

TTTGGAT TNA

GAGCCGGATC

AGCCGCNGCG

CCGTTTCTTG

ATTACTGCCC

CGNGAGCTGC

CGCACCCCAG

GAT CAGGZLAG

GCCCGCCGCG

CCGGCATATT

GAAGCCGCCA

GGACACCGTG

GTTGAAGTTA

AAGTANAACT

CGGNGGNGGA

CGCANTCGGG

GGTTCGGAGN

TCGGTGATGT

CGATNTGGTG

GTTTTCCCTG

CGCAAGGGAG

TCTGGCTCCN

GCCACTGGTG

TAAGGCCGGA

GCAGCGCTCT

AAAGACCTTC

NTTGGGGATT

TTTATTCAGA

ATT GGGGAGN

GGTTTCTACC

TTTTAAGGTT

TTNGTACAAG

TTTAT GTTTG;

GCCGCGCGGC

GGGTCCCCTT

TCCATTTCC C GGAT GGCNTT

GCAGGP.ATCC

GCGCAGCGAG

ACCTATAGNG

GGGGGAAAAA

AGNGAAAGTT

GGAGAGAGAA

GGCAGAGCCA

TNTTAATCTT

CTTTCATTTC

CCCGTTCNTG

CCGAGGGGGT

CATTTTTTTT

NTCCCGACTG

CGCTGGCCTG

CGGCGCTCAC

CTGCTGCTGC

CNTGGCAAGC

TTAAAAGGAT

TTAATAATGAl

GAGAGAGAGAL

GGACGGAGAG

GGAAGGT GTC

TTCAGGATTT

CGCNTGGCCC

GGGTGGGGGG

CATTGACTTC

AAGGGAAACA

ANGTAGGGGG

ACGCGGCCTG

GCCAGCCAGN

TAGAAGAGGT

TTTTTTNNCA AAANCCNGGG NGGGTTTTTT TTAANAAANA GGNGAAAAGA iNFORMALTION FOR SEQ ID NO:22: SEQUENCE CHARACTERISTICS; LENGTH: 918 base pairs TYPE: nucleic acid STRANDEDNJESS: double TOPOLOGY! linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPT:OCN: SEQ ID 140:22:

TCGGGGGCALG

CNTATTNGTT

AAGGGANAN4G

NGATTCTGTC

TGCCTGAGAA

CTAATNTGCA

CNAGGGGGAG

GTTGNTCTGG

TGAAGTCCGG

GGGCAAGGTT

CGGCGGCGGT

GCTTAGAGCA

ATTGGCTGGA

CTAACAAAAA

CT GGCAGTTT

GAAAANTTTG

TTNGGCCCNG

CAGGGAAGGG

AGTTTC GCTT

AATTTCAATG

TTTNGGGATN

ACCCAANTAA

TAATAGAGCA

CCGTGCGAAA

I AAC GT CCAT

AGCAACCAGC

CCGCAGGGCC

AGTGGTTAGT

GTAACCAGC G

AAATACAAAC

GGGTTTTCGN

AAAGTAAANA

N GGNATTTTA

TAAGCAAAGG

GGTGGCAATT

TGTCCCTGGG

CCCAAAGGAC

GATTGCTCAN

CGAT CAGAGC

GTTCTTTTGC

TGAATGAAAG

CAGAAAATTG

GACGGAAAAC

GAAATGCCCC

AAAAPAAAAAA

ATTTTTTTTT

TNTCCAJANTT

NGANGAAGGG

CTTAGGACTC

GTCCNTAAGN

T GAPATTAT C

AAACACGGTT

CC GGGAAGPA TT GGCGAGCT

ATGACAGCGG

GCCGCGGGCG

TGT GGGCTTT C CTAAACTAA

ANGGGCANAA

NAAAANATGG

TCNGGTTCCT

NNAGTTTCAG

AGGACAGGAT

TCCGGACCGG

ATGGCAG!CNA

GTTCCATTTG

ATCATCCCAG

TCGCCTTCGG

CTCNTTCGGA

GGTGTGTTGG

ACCAAATGTA

AGGTGGTGTC

ACCCGGTNAA

AAAAATTGAA

ACTTTTTTCC

AAGTTAGGCT

TCAGNGNGGA

GANAGATGTT

CNNACCAGTA

GATATATCCN

GCACGGAGCG

AATCCGGAGG

TTGGCTCTGC

TCTTT CTGTG

AAACGGAGTA

AGTAGTCTCT

120 180 240 300 360 420 480 540 600 660 720 780 840 900 918 a.

a a a a.

C a NATCTCTTT TAGGCATTGT TTTGAAAGTC CCCACAAGGN TTTGCAAGTA AN4AAGT CG INFORMATION FOR SEQ ID NO:23: SEQUENCE CHARACTERISTICS: LENGTH: 309 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID tNo:23: AGAGAGGGTT TAGCACAGGC AGCNTATTCC CAGTTTGTGC TGTAGAACTG

GAACCTCAGG

C CTCATT CTG AAA.TNTGCAG CCNTCCCCAG CATCCTTCNT GGCACAGCNT

GGCACAGACN

TGNTAAGTGT CTATTAGTGA CTAATACAAA GGAGTATTTC AGAACGTTGG

CACATCTCAG

CACGTTGCAA CTGGCTGGAG CTGGTTGAGC TCTTGCTGCT TCCATATCCC

TTTGTAGCTG

CTCTCCACTT TTCTGAACCC CGGGTCCATG TGAAAGTCCC CACAAGGNNC

TTTGCAAGTA

GAGAAGNCG

INFORMATION FOR SEQ ID NO:24: SEQUENCE CHARACTERISTICS: LENGTH: 904 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genor-nic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:24: TTTCATTTAA AACNCGGGGG NTGAACCCAA TCTTNANGGT GGCAGTGNGG NNGATCTTAA

CGGTTTTTNA

TTTTATAN G TTCAGCC GAG GAT CGATTTG

AATCATTNGA

TGAGAAGNAC

TGCATAAGCC

CAT CTT CTCT

CTCCAAGCAA

GAGGGGTGGG

TGGGATCTGA

ACTGCCAAGG

ATTATTTCAC

GAAATT GAGA

GNCG

GAAAAAAAAR

AAAAAAGAT G

CATTACCTGA

AGTTTCAGGA

TGAGGATGAA

ACTATGATAA

ATGGGAGACA

GCCCCATTCT

ATACCAGAAC

GTAAGGGCAG

GGGCAAGAGA

rGATTTGGGAC

CGGACCAGAG

GCTAT GAGCT

TNCTTCGCTC

ATPACGAAAT

NAGTAATGAA

TCAATTCAGT

'FGGTGAGTGA

CAAGTGTCTC

AATTCTTTTC

GTTTTCCACC

TGGAGGAGAA

TGGCGCTCAT

ACCTGTAAGC

TTCTCCATCT

CTGTAGCAGA

AGGNGCGAAA

NCACCCCCAA

TTTAAAAAC C

GGTNTTCCGG

TACC GNT GAC

GTGATGATGA

ACT CCACATT

NNACACAATT

ACAGGTCTGC

AATTC CAGTC

TCCTNACATG

TTGATTTGAT

CTCTCTCTAA

GATGAGCTCC

GNCCCCACAA

GCCTCCCNTT

GTCGTTAGAG

AGGGTTGCCT

CATCCACCNN

TGATGATGAT

AAGGTTTGCC

AATAGTNTCT

AGCGGGCTAC

CACTGAGTCA

GTGTCTTCTC

TTCCACTGCT

CCTGAAATCC

AAGTTT GAA

AGNNTTTGCC

CTTANCAGCT

GAAATGAAGG

TCCAATCCCA

CCTCCNGTAT

GAY GAAGGGA

TGNAAATTAG

TANYCCTTC

AGCTTCCALGT

TGGGCAGGGG

TTGCCTAGCC

GACTGGAGTC

TTAGGATTCT

TGAGAAAGGG

AAGTAGAAAA

120 180 240 300 360 420 480 540 600 660 720 '780 840 900 904 INFORMATION FOR SEQ ID SEQUENCE CHAR-ACTERISTICS: LENGTH: 883 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID GGGGGGGGAA ACTTNTTTAT NTGGAAAANT TTTGTTTNGG CGGGNAAGGA GTTTTTAANA ANGTTAAQGG AAAAAGCTTT TANTTAA.NAT GACCTTTOT GGGGAAANAC AAANTTGGTN NGTGTATTNG NGAAAPAGAT TTATTATAAkG ATTTTTTATA ANATTTTNGG GGGGGAAATA

TTTC-AAANAA

CGTACTTNTC

CTTTTTAGGA

AACTCTNTGC

AATTACCATC

TATACAT CTT

ATCGNACACC

TTCATATTTT

TAACCACGACA

ATCNTGCCAC

TATATATATA

TCAAACACNT

AATTCTGTAA

AACAACN NAN

AACATTNTAA

TTCTTTATTT

TTAATGAAAC

ACTAAAATAT

CCTTCTGTGA

ACATTCTTCC

CCACCACTNT

CAT CAGAATA

TATATATATA

NCAC CAATNG

CAAAACCNTT

CCCNTAGCCA

ACTCAACCTT

AAAATTCAAT

ATAATTTCAA

TAN CCAT GCA

TTCCNGGCAC

TNNCACCANC

ACGAAGT GAG

CCCCNTAAGC

TATATATATA

ACCTCGCNAG

TTTGTTTTTT

ACCACAT CAT

AACATGACAC

ATTCACCATT

TAATTTCCAA

AATAGNTAAT

NTGGCCCATAA

CTCCTCCCTG

CNTCTCTTTA

NTGTCCANAG

TATATATATA

CTAGAACAG

GTTNTCCAAC

ATCCATATTT

TCAANTCCCA

TCATTTATAC

ACAATNT CAT

AAACAAATAC

CGCTTCTTTC

TTAACARAn~k

ATGTCTTAC

AACTCTAAAA

TN4TATATAAA

TCG

NACTTNT OCA

TCANACATTT

NCACNCNCGT

TAACAACANTT

TTTT CT? GAA

ATANGNAACC

TATAATAATC

CACTCCACCA

AAACTACTAA

GCNT CATATA

CACGCACTAT

240 300 360 420 480 540 600 660 720 780 840 683 a a a a paa.

INFORMATION FOR SEQ ID 14:26: SEQUENCE CHARACTERISTICS: LENGTH: 924 base pairs TYPE: nucleic. acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID 140:2'6: TTTCGPACGN TTTTNACGAA AGAAAN4TCTN TTTNAGCCNA GCAACCCTA TTCCCACG

TTCCCCCAAA

TNT? NNAANA AGCAATC CT C

TCTTTCACCC

AAACCTCTAT

CCATCCTACG

ACCAGTCACA

ACAACCT CC?

TGTGACTCCT

CCNTCCCCCC

TCCCCAAAAA

AT TT TGG T?

AAAATAATAC

TNACCNTCAC

CACTTATTTT

TACTTTTGCC

CAATCCNTGC

ATAGATGAGA

CCCTACCATC

TACACCAAAC

NTCCCTTACC

'TTCNTTTTC

CACCCTTCCT

TAATACTACT

GAATTGG CC A

TTGTTTTGTC

ACACTTACTG

ACACAT? CAT

NTCACCCACC

TCCAATCCAC

TCATCCCATC

ATTNACATAC

GTTCCTATAC

TAAAAAGCC T

ACTAATACTA

ACTACTTT C?

CATCCCATCA

TCTNTCNCNT

ACTCCCCAC-A

C CCA CAT CA

ATTTCCAGC

AACACCCCCA

ACATAAT CAT

TCACTCCTAC

TNCCCTAAAA

TTAATAATAA

TAT? TA SCA

CTCCTNTCAA

TCCTTNCACC

CTTACACTAA

TCCACCCACA

GTCACATCAN

TTCACTAACC

T CAT TC CT C

CTCCCATCT

CCCCCCNANCG

TAATAATTC

CCACCTCTTT

TTCCTTTNAA

ACTTTCAACT

ATCTTC C AT CTAACAC

TCCCAACAC

AACCCT CATS

ACCACCCGAA

TTNTATAAAC

120 180 240 300 360 420 480 540 600 660 720 AAATTNTAAA GAAANTCATT GGTTCATACAi CGTAAGAAGp. CATCAAP.ACA GAACT GAGGC 780 AAGTTGGGAA GAGAAATGGG ATTAGTAGGA GAGGGTCAAG AAAAGGCAA GGTATGTGCA 840 CATGCATGAA TACATTGTAT ACATGTATGA AAG?4GCCACA ATGATGA2NTT ALCCCCANATG 900 GNNGTTTGGC AAGTAAAAGA GTCG 924 INFORMATION FOR SEQ ID NO:27: SEQUENCE CHARACTERISTICS: LENGTH: 482 base pairs (3 TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (qenomic) (xi) SEQUENCE DESCR~IPTION: SEQ ID NO:27: TCTCTCCTGA GGGGGGTTTT NTGGA14GAAT AGAAGAANuAJ4 ACCNCCTC'T rGTTTCNTCC TGTGGNGNNC CCTGCTGNTJA AAGNNGATTT NCNCGGTGNT ATACA14NTAA GAAGGAGGAT 120 CTCTCCCCCC ATTGTNA14AG AACCCCGTGT GTGGGGAGGG GGTGTNGCCA CNANCCAGAN 180 NTGGCCCNNG GGTCNTCTCC CCACTCN'rNT GNATAACNTC TNNCCTCCAC kkANACCCCA 240 NANAAAANJCA. CCCCNCNTGT GAGNNCNGCA GANGCGCCCT NTNACAAGAN AAGAGNNCAT 300 *.GTGNTGTGGC CCTGTGCTNN GACANTNTAN ACTCTTCTNT NG14GGGGNGN GGNCTGTGGT 360 TTTATA.AGAG NGTGTNNCCG TGGGGGGGAG AGTANTCNTT TTATATAGAG AGANAGNGNC 420 CTGTGNAAAC TNCCTCTaLLG AAGAGCACCN TGGTGTCTC TCCCATCTNC TAGNAGGGGA 480 GG482 INFORMATION FOR SEQ ID NO:28: SEQUENCE CHARACTERISTICS: LENGTH; 460 base pairs TYPE: nucleic acid STRANDEDNESS: doubie TOPOLOGY: linear MOLECULE TYPE: DNA (genornic) (Xi) SEQUENCE DESCRIPTIO4: SEQ ID NO:-28: TAGCTTCTCT GTGAGcGGTA GAACTCAAGC TCCCCCATGA ACAGGCTTTG GGGTTCCTGC CATCCCCTGG GGCTGTTCAT TAGGTGCCCA CACAGACTTC TCATGC-CATG ACTCACACTT 120 GACGTCACAG AGCACACAJA GAGCACAAAA GCAGGCTGAC CACATCCGGC CATGCACACC 180 CCTTTAJCAG TCCCAAGCTT TCTCTCTCTC TTCTAAGTCA CTGCCCTGGG AAGACGGTTT 240 54 CATACCCAAG CTGATGTGC.A CTTATTTCT'T TGTGTTATTG CTCTGACAGT CTCACAGTGC TCTGCAAACA CTCTGCATTC GCCTTTACCA CACCAGAAGA AATTCCTCTT TGTGCAGGGA AAAATACATT CGTCTTAGTA GCTTCTACTT TCCAGCTTG'r CCCTAGTCTG TCTGATATGT GGTTACGTJAN TGTTAGGGGC CAC GGAAGGG GGGGGGGGGG INFORMATION FOR SEQ ID NO:29: SEQUENCE CHARACTERISTICS: LENGTH: 465 base pairs TYPE: nucleic acid STRAN~DEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:29: TCCCAAGACA AGAGGGGCTG ?AGAACGGGG GGGGGAAGAA TCAGGAGTGT CCCACATAALA GACGGCACCT ANATCTGTCT CTCTCGGTGT CTCCTCCCCA GGTGAGCTCT CTAGACAAGA GAGAGACTGT CACAGAGAGA GAGAGATGTG GGAGATCAGA GNCNCCGAC:A CCTAGGGGAC AAATGGGGAT CTCTTTTTTT GAGACAGGGG GTCTCTGTGC AACACTTGCT GTTCTGGAGA TGTTCTGTAG CCCCCAACTC AGAGAGCCTC CTCCTTTNCA CAAC-TGTGTC GCCGCCGCCG CATCACCAGG CTATATTTAC TATTATCTCT ATTACTATTG TTGTGTGTTG GGATGCTCAC GC.ATAACCCT ANCTATCCTA GTGATAGACC CCACC INFORM'ATION FOR SE-Q ID SEQUENCE CHARACTERISTICS: LENGTH: 568 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic)

GTCGCTGCTT

CCTGGGGCAG

TCACCCCT GT

TTTCTCTCTC

ACCAGGGTGT

CCGCCGCCGC

TGTTGAGACA

120 180 240 300 360 420 465 (xi) SEQUENCE DESCRIPTION: SEQ ID TNNCNNTTNC CTGNGGCCGN GTANCTCTGA GNGANAGTNT CCCCGAGAGG GGGGGTCTCA CNNTAGNTNT ANANAGTATN GNGTGCTCGA GTTTNNAGAG AGCTCTCTCT NNNTCTCTCT CCCCNGAGCT ATNGN4T TAG GGNTATGGCA CNNCNCGT CT CTCNNCNCCN TATNGAGNGG TGNGNTATNG GGGNGAGAGT NTCTGCCCGA GACCCACATT CTCNGAGT14N GGN AGAGTNT GGGAGACACA CANCTCCGGG 14ANATCTNTC TCCNCCCCCC CAGGGGCGGT GGTNCANATN GNCNACAGAG CCNCNGNNTT NTATGTGGAG AGGGGATATC NCANCNCACN

CCCNGAGCAC

AGGNTCCACA CNCAGAGANG TGTCTCTCCC CANCACACAA GCACNTCTGG TGAGNTCTAJq GTTTTGNGAG AGACNNTGCC CTGTCTCCCT TTTCCCCGCT CTNACACACA

TGAGAGGGTG

TGCACATCTT CCCCATGTCC CTCTCTA.A. CCNCCCCAGA NTTTTGNGGT TNTGTGCAAjN ACCCTTTTCA CNCTCANGGG

AGATNTTT

INFORMATION FOR SEQ ID NO:31: SEQUENCE

CHARACTERISTICS:

LENGTH: 920 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (qenomic) 360 420 480 540 568

B.

a.

(XI) SEQUENCE DESCRIPTION: SEQ ID NO:31: GAGGGTTAN~T TGGCCCAANT CGGCAATCAT CCNGGGAAGA

AGA.NGNCAGC

ATCGGAAGAT CAAGGACGCA ATTCGNGGGG GGGGATGGAT

AGNNGCNAJAJ

AGNNGGATTG GNAGGNAAAA TTAAACGGGA GTTGTAATCC

AAAAGGACG;T

ACAAATCCGG NAGTAAGCAG GAAGCACAGT GAANTTGGGG GAGGCAGNG-1 AAAAATNGTT TTTTTAATCC CAATANGGTC AACANGTAGG

CAA.NTGGATN

TATATCTTAG CGCAAGNTTN TCACCCATTG GTCCAACCCA

TATAACATGG

TNTNTGAGCN TGGCACAATT TTT14ACCCAT TAGTTCCCA

GGCAGATCGC

GAANA)AAATC CCAATTCCAT GGTGGCCCAG TGTGTCCAGC

CACCAATANT

CAATTAAATC ACCACATGAA GGAATACATA ACACAATAC ATC TGATCCA TATPAATTTGC TCACNTAGAC ATACAAAATC CTGTACATTC

CATCTCTTA

AACAAACTAT AAATGTGTAG AGAGGAATTT TAATATCCAC

TTCCATGTTC

TCCTCTCTCC CAGTCTCCTC CTCCTCCTTT AAAACTTTTT

TCTCCCACCC

TTTGTCCNAA GGACGGGCCT TGTTNTATCC TGNACCTGCN

TTCGTCTGCA

ATCCCACAGG CAGGACTGGA GCAATGGCTC ATTGGTTAAG

AGCACTTGCT

PAGACCAGGG TGCAATTCTC AGAGCACTNC ACTGCTNCAC

ACTGAAAJGAC

GGTTTGGCA

GTAGAAGAGA

INFORMA~TION FOR SEQ ID NO:32:- SEQUENCE

CHARACTERISTICS:

LENGTH: 176 base pairs TYPE: nucleic acid STRANDEDNESS: double 3GTTTNGGCA I GGGNACNGA kCAAGGCAAAJA

GGNGNAJNTA

TATTAGATAT

CGGTc3GTNAA

CACCATGCCA

TTCTTGAATT

ATTGATAAGA

GAATATT

CAT

TCTTGGCTGC

ATCATTTTTT

TAAGGCCATC

GATCTTGAAG

CCCACNNGTA

120 180 240 300 360 420 480 540 600 660 720 780 840 900 920 TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:32: TTGACCATAT TATTTTTATT CACGTTGGGA CAAAAGAGCA AACGCAAAGG ATAGGAAACG AAAGGAATTA ATTTCCTTTC AATAGAGATA TCGGTTTTTT TTAGAGGGAA AAAATTGAGT 120 ATTAGAAAAT PAAAATAGGT TTCGGAATTT CCGGAAAGAC CACTAAATTG, TAGGTT 176 INFORMATION FOR SEQ ID NO:33: Wi SEQUENCE CHARACTERISTICS: LENGTH: 336 base pairs TYPE: nucleic acid STRANJDEDNESS: double TOPOLOGY: linear 0: 0%(ii) MOLECULE TYPE: DNA (genoinic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:33: AAAAGGGNTN CCGAAN4AAAA ANAATTNGGA. TCTTNTGGGG GCCCNGAGGN AAALrAAAANA NTAANCNGGG GGNGACCCAG NGAANAGACA AATTNTTTTN CCNGGAGTCC TTGGGGTGNN 120 ANGCCA.AACN GNCGTTTAN4N GNAAENNNGNC GNGNTACCNC TTCGGAGNGG GGGCGCTGN 180 AAAGAATNGT GAGAATN-CN4G TTACNNGTGT TGNTTNATCN GAGATAGTNG TNTGTAACPA 240 *CCCCGATTCA GCCNGAAAGT TACGCATATG CGNANCGTTG TGTGAATCGA ACCTGGNNAA 300 AACAGACCCA TNGNCAAGNG GCAGACCNAA CGGAAC 336 INFORMATION FOR SE-Q ID NO:34: SEQUENCE CHARACTERISTICS: LENGTH: 92 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:34: TGAATAAGGG TACAJAAGATT GTGTTTCAGA GGAGAGAGGT AACAAGAA.AA GACTCCTAAC GCAATGGCCA GAGGGCCAAG AAAAAGGGAA A 9 INFORMATION FOR SEQ ID SEQUENCE CHARACTERISTICS: LENGTH: 838 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID GGNGTNATTT TCTTCTNGTG AANTCTTTNC CAAATCCGNG GGTNTGNCCC ANNGCCCCNN

TTTATACACN

ANATATGNGA

NGACCCTCTN

AAAATATNNC

GCACAGNGCC

ATNNACANAC

TTTTTNCCCC

CCCNTTTNNA

TTTAAAAAAN

GTNTNCCTTN

CNCCCNCTGT

CCTCTTNTCC

NNATTACNCN

CTCAGTTTGA

NGGNGNTTTA

NNTTCGCSGGG

CTGTGTTNTN

CCCNADNAAAT

TCAGAAATNT

GNCGCCCCCT

AACANTTTTT

CC.ATAT NC CC

TTCCCCCTTT

N4GAGATTTT T

TNNNCCAAAA

GTNTCCCCAN

TTTATATATN

GN GGGAGATT

TCCCCCTCNC

AT NCC CCTTN

TTNTAATNTG

N NAAA CCC CC

GTTNGGGCTN

CCTNTTT GAG

TNNAAAAACN

TCCT CNTNNT

CNCTATATGT

NTTGGNGflG N GN CCC NATA

TCTCTCTGNN

CGAAAANAAT

TCTACCNCCC

GGNNAAAAAA

NCTNTTNANA

GGGTNTNCCA

ACNTTTAAA-N

TCNGGCCCCT

NNCTAATTCC

14NNCTNAATT NTCGAINAT GY

GGGTATNTGG

TAACNCAGAG

GTAGNGCNCT

TTTNTNCAPA

CTCAAAN4ACA

ATCTNNGNTG

GANAAATATG;

NCCCTTCACT

AACCCTCTCC

TNGCCCCCCT

NTTNTTCNAN

NTNGGGNAGG

CCCATNTTAA

GTAANACAN

ATCTGTGTAA

CNNCTGAGAN

AANANANAAT

CCNCNNT±

GNNTTNTCCC

TANACTCNTA

CTCTTTGTGG

CTAATTCCTC

TTTCTNACTC

TCTANATNNC

TTCCAACC

NNTGTTNCNA NCGCANGNTN NCCCCNCCTT INFORMATION FOR SEQ ID NO:36: SEQUENCE CHARACTERISTICS: LENGTH: 314 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID ND:36: CAAACCAGAA ATGGCCCAAG GGTCATCTCC CCACTCAGTA TGAATAACAT CTAACCTCCA CAAPAAACCCC AAAAAAAAAC ACCCCAGATG TGAGAACAGC AGAAGCGCCC TATAACAAGA AAAGAGAACA TGTGATGTGG CCCTGTGCTA AGACAATATA AACTCTTCTA TAGAGGGGAG AGGACTGTGG TTTTATAAGA GAGTGTAACC GTGGGGGGGA GAGTAATCAT TTTTATATAG 120 180 240 58 AGAGAAAGAG ACCTGTGAAA ACTACCTCTG AGAAGAGCAC CATGGTGTTC TCTCCCATCT ACTAGAAGGG GAGG INFORMATION FOR SEQ ID NO:37: SEQUENCE CHARACTERISTICS: LENGTH: 226 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:37: AGGGGGGGAA ACCCCTTCGC CNCGGGCCTA TCGNAANTTT TNNTCCACCG TAAAANATTT NC CANGNGCN C CATGTANGG ATTGN GGGNG TAGTGGGGGG AAC GATTNT G GAGGGGCCTA AAAGGNANAT AGAGGACGTA TTGTATTTGG TTTTGCNGAG CCAGTACCTT NGAAAAAGGT TGGTATTTTT GATCCGGCAA CAACCACNGT GGTAGNGTGT TTTTTT INFORMATION FOR SEQ ID NO:38: SEQUENCE CHARACTERISTICS: LENGTH: 843 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genornic) (Xi) SEQUENCE DESCRIPTION: SEQ ID NO:38: GAATTAAAAC GGGAPAGATT GGAATTCAAT TTCTTACAGC CAAAAGCTAG ACCGGGCATA

TAGGAGATTA

ATTATTTAA

CAGTCCTAGG

TTGATCAGGC

TCACTGAAAG

GGCCACAGAC

ACAGGAAACA

AACCAGCCTG

AGCACACT CC

TCTATCTGCT

TTTC GATTTA

AGCAGGTTCC

TTTCAGAAGA

CAGCAATCAT

GAGATTATTC

CCAGGGTAAG

CTGTCCAGGC

AGTTAATGAG

GGGCCATATC

TTGTTATCAC

GCACCTTCCA

GGGAAGTTCC

GTTCAAACAC

ACAACAGT GT

TAGGTTTGGA

CCCTGTAGCC

AGGACTGGCA

AAAAATTAAT

TCAACTAGGT

AGATATGTTT

AAGC CTGCCC

AAGATAGGCC

GGGTCTTCAG

TTGTTGTAGT

GATACAAAAT

AGC-ACTAGCA

AGCCATAAAG

GGGACGTCTG

GTCCTCCAGC

G.2ATGAGC CA

CAGATTTAAA

TAGAGGTAAT

GAkAGACGG

ATTACCTTTT

TAAAAGAATA

GGCCATAAAG

ATAAGGAAAA

GCAGGAAGAC

CCCTGACTTA

ATTGTATGTA

GTTTAGGGGT

GGTAT GCAAG

AAAGTGTAGA

CTAAT GGTTG

AACCCCAAAA

AAAAAGGAGC

GGARTGCAGG

ATCTCCCCCTA

TAGCACGTAC

ACCACGCCAA

we 59 AACCCCCTAG CTTTGTCTAT ATAACCGTCT GACTTTTGAG TTTCGTGTTC AACTCCTCTG TATCTTGGGT GAGACACGTG TTGGCCCGGA GCTT1CGTTAT TATTAAACGA CCTCTTGCTA TTACATCATG ACCAGTCTGG TCCTGTTGTA. AGACATTGGC AAAAGAGCCT GAAAACTAGA

AAA

INFORMATION FOR SEQ ID, NO:39: SEQUENCE CHRACTERISTICS: LENGTH: 943 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genormic) (xi) SEQUENCE DESCRIPTION: SEQ ID No:39: TTTTTTTTTT GGAAAAACGG GT'ITAATAAG GGGNANGN'JAT CCGAACCCCC: ACTCGGGNGA 720 780 840 843 AAGGAAAN4AA

CTAGTCCCAT

CCACCCCATT

AN\ATGTCCGT

AAGTTTGTGT

AGACCNhTGT

ATGGGTCTGC

GCATTNT GTC

GGGAAGTTAG

NTTTCAGNTT

CCCGGAGCAG

CNTTTGCGGT

ACTGCC.AACC

TTTGACTCTT

TACTTGTGAT

AANAATANGG

TNTTCGGGGG

TTTTCGGGGG

TTNATCCAAG

TCNNGAGNAG

TTGGGAGGGA

AGACAC-TNTG

CAAAGGAGGA

ACACACCCGG

TNACCCAATT

CTGACAT GGG

TAAAACCAGG

CTGAT GCCNT

CAAAAGTTGT

AGTCCCACAA

GGGGAANAAN1

GGGAAAGGGA

TAAGTCNGTT

GNGTTTTGGG

TTTGTAATT G

GATCCAATTT

AAGTNTAT GA

AA!PCCAGCAG

CCAGTTGCAG

TACTTTCGTT

AGGCTTTGAA

AGCNTGGGCC

CAGTTTAGTN

CCTGTAGCAG

GGANCTTNGC

GANTTGGN'GG

NGGCATGAAT

TTTTTITTGGT

TGTTNNAATT

GTTCAGCNGG

TNTAGTTCCC

GTT1GGTCCCT

C-AGACTAGA

CC TTT CCAC C

GGCTTAGCAT

ACTTCCATTA

AATGAGATGG

TT GGAATTCA C-GCAzGTrGGTG

TAATGCTTTA

AATGGGGTGA

ANATCAAAGT

AGNATTTNNG

TTTTTTTGTG

ATTTGGCTGT

TCTCNTATCA

TTTCAGTNTC

CCCAA-NGAGT

GCAGANTCTT

TCATAGAATG

NTCANTGAGC

CAGGGTAGAA

CCAC GACAAA

AGGCNGGCAC

TCCTTTCGGA

NGAGTTTCAA

NCAGGAAAGC

TT CCTTAGTLA

GCCCGGGGTG

CTTTNTAACA

GAACCCTGCC

TGGCTCCATG

GCAGGCAGGT

AAGGCGCTT

GTTGAAAA.CC

120 180 240 300 360 420 480 540 600 660 720 780 840 900 GTGCAIACNT TTAA.TTGNN G AAGTAAGAAG TCG INFORX~kTION FOR SEQ ID 1-O:40: SEQUENCE CHARACTERISTICS: LENGTH: 904 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID

ACTTCTCTAC

CTAAGACTTG

CTTrCTCAGG

AGCTACACAC

ACATGGCTGC

AATATTAATA

TTTACACACT

TGTTTTAATA

TTATTGTTTT

TTTTTAAAC C

AATATCTCCC

TCCAGAATCC

GTTTTTAAAT

CC CAACAT C

TGATTGAGGT

TTGCCATGGT CCTTGTGGAA TCTTTCAATC TGTGTCCTTA GAACGCTAAG

ACCTTGGCTC

CAGGT GTTTT

CCCTCCAAGC

CTCAGCACCT

AATGAGACTT

CTGTGGAGCT

TTTTATAT GT

GTTC-AAAPAA

TCTCTCCTGC

TTTTACCCTG

TAATTTTATT

CACCTGrCCTT

CTCCCCCCCT

GGTCCCCCCT

CCAGGGCGGG

CGTTTAAGAA

CAATCTGGAG

CCCTAAATGA

AACCT GATGG

GTTACAAGGT

TTGTCTTTTA

AAAAGTTTTA

CAAAGGAAAC

GAAACATTAA

TTT TAT TAAA CAAAACC CCC

AATAACACCT

CTTTTTTGCC

CTGGGACTTG

AATAAAC CAT

TGGCTCTGCC

AGGGAACAGA

CTCAAGGCTC

CAGTCAGTCA

AAAAACCTAA

CACAATGATC

CAAGCAAACT

AAATAAGGAT

AAAAAATAAA

CTGGAAATTT

GATTGATACC

GTTTGATTTC

GCCACCCCGT

CCAAGTCCGG

CAACCCCCAC

GTGTCTCCTG

TCAGGGGGCT

TTTGCATGGG

GAT CTATATC

AAAAAGTTCA

TTTTCCAGAA

CCCTGAATTA

ACCCCCTT.AA

TTAAAATTTT

CACCAATTTT

CCCCGTTAAA

GAAAAGGGCT

GCAGACTGAG

TGCTGGGAAA

TGGCCTTGAA

TTTTTTTGTT

ACAGACAATC

TTTTTACATT

AAT.GAAGTCT

ACCTGATAAG

AAAATTCTAT

CTGACGGGCG

TTTTTTGTTC

C CACTGTGGG

AAATTTAGAA

120 180 240 300 360 420 480 540 600 660 720 780 840 900 904 p

C

p.

C

CP

A.AAG

INFORMATION FOR SEQ ID NO:41:.

SEQUENCE CKPARACTERISTICS: LENGTH: 917 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:41: AAGGGGGGNG AAATTTAGNG GACNAAAATT ATTCCTTAAG GGCCNCCTTT CTTCAGGGAA NANGGGGGaDA GGAGATANTN CGGC CCTT OT CC GCCTTTTN GGANACGATA GGGNC GGTTC GGNTTGGAAA TTTTTCCTCC AAAATTNCCA ACAAAAATNG TTTTTCCCCT TCCTTCAAAA AGAAAATTGG TTTTT"TTGNN GGCTTNGGGG NGTCNGGAAG TCANAACCCN GNGTATTATT GCNTTCCAGC CCCACCCGTN AGTTCATTGG TAATTCCTAT TCGTTCGGNT CAANATAATT CGGNACTTCC GCTTCCNAAT GGATCCCTTC TCCcCNGGTT

CCCACCCCCA

CAGTGACNTA

TGTGTTANAA

CNNGCNTTCG

AC CCC CTCCN

CANNTNGTGT

AGACAGTC GG TccA7AAAGCT

NTCCAATCCG

NGACCACCNT

GATCCTTNTT

AAAACAN'NA

GGCGGGCNGT

'CCACGCCTT

CAATTCCNGA

CCNATCTC CA

CGCTGTCCTC

GAGCGCNTCG

TGGTTNTTTA

CGGTCTTTCC

NAANAANCT C

NTCTGCCTTC

CNTCCAGNTT

CCGCGGCGGG

TAGGCCGTTC

TTTCCGGGNC

61

AANGATTNGG

GATATTTCC G

GGTGGGTCTT

GGCTCATTTT

CGCCTCGCCC

TCCACGTGAC

CAGCTTNTGT

GGCCGGGCAG

CCTATNCTN C T'rCCATTNNG

GNTNTCCGTG

TGATCCGCTT

AGTCTC GAGT

TTCCGNTTCG

GNTTNTTCGG

GCTCGTCCCG

I4TGGGGNATN

CCTGATTTTT

GNGTNTrCCAN TTTTTCCGGA TTATCGCAAG

CNTTTCTAGC

CACGTTGCTT

TATTCTCAGC

GTTCTTTCCG

CNTCCCAGTN

GNTGTGCCGC

TAGGGCGGGC

TTAAACCATT

AAGGAAGNAA

420 480 540 600 660 720 780 840 900 917 es *0 ~0 0 *00*

S

*00* *0

S

00 S S S GNCNAGTAAA

GGANCTC

INFORMATION FOR SEQ 1D NO:42: Ci) SEQUENCE CH-ARACTERISTICS: LENGTH: 835 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear Cii) MOLECULE TYPE: DNA (genomia) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:42: GGNCCCCTAN NGATTGGCCN4 TTGATCAAGA NGGGACCATC CTGNACCTGG

NGGTNGNTGT

TTCCGCTTGG

NTPNTTTTTT

GATACCTCAG

TCCGAfl.CTTT

TACCAAGCTG

GCTTCTGTAA

CACACACACA

CAAAC.L~kTAA CTTTGIkTGA

AAAAGTGACA

TGATCTAATC

ATAGCTCATC

GACGGAGATG

TGTTNTGGTC

NTCCTT GTGA

TCAATTCCCN

GTTGGTAACC

CTTGTCCCCT

CACACACACA

AAGAAAAPAA

CAGCAAGATA

ATCCTTACTC

AGTTTTATTT

TGAGGATGAG

GTTGTTTTTG

CAGACCGTTT

ACCCAGGGTG

GACTAACCAT

TGAGTTCAGT

AACTACCCCC

CACACAGAGA

TAAAATCTCA

AAGTAAAC CA

CAGCCCTTCC

GAGGCAGGGG

TTTGAAC CTC

CGG.AGTAGTT

TGATTTAGCC

CAGNTGGTTC

TGATGTCAAG

CCCTGGAAC C

AATACACGCA

GAGAGAGAGA

TTTA.ATTTTC

AAGCACACTG

TGCTATGTTG

CTCATGTAGC

TGACCCTCCT

TCNGNGGGTT

GCNGCNGACA

AGCAGGATAG

TTGAGTGTTT

CACATGGGGA

TGCGCGCGCG

GAGAGAGAGA

ATTAGTATAA

TAGAAGGGAT

GCAGTCTTGC

CCAGGAGGAT

CATT CT CCAG

TGAGGCGCGG

GTA.ATGGGGC

ATGTACAGCC

AA.ATGCTTGC

GAGAGAACAT

CGCGCACACA

GAGAGAAGCA

TACCTTGATT

TACGCAACTG

TGGGAGCCAT

GGTCAAATCC

TTCTCCATAT

CCTGAGTGCT GGCACTGAAA GACNCCACNA GTAGCCTTGG CAGGCTAGAA ANGNT INFORMATION FOR SEQ ID NO:43: SEQUENCE CHARACTERISTICS: LENGTH: 924 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:43: GTNTTTTNGC C GNGGGAATT TAAGGGNGAT TTGGAGACTT TNGAATTTTC GAAJLNGTTC CA 0*6

AAATAGANNT

TAGATTTNTA

CTTGTTTATG

AGANGAGGAT

AC.ATAATTGG

GAAGATGGAG

ATAGCAAMCAT

ATGTANTCTT

GTCAAAT GAG ACAATC CTAT

GTGTGTGTGT

TGTGTGTATG

TCATTGTAAG

CTTCAGCTGT

ACAGGAGCTT

TNAGGNCAAT

TGGAAACCCT

GGAA1GGTGN

TGGGGAATAG

AACATTAAGG

AGTATTGTAT

TAAAAAAGAT

TGTTTATCAG

ACNGCATAGA

CCCAAATGTT

TTGTGTGTGT

TCTATTGCAT

ATATTGTGCT

TAAkAGGCTAG

AGCAAGNTAA

GGGNTTGGGG

GGGGGTTCCA

GATAGCAGCC

AACAATGAGA

AAATATATCC

TTCAGATAGA

AGTAAT CTAA

GTTTTACTTC

TCCCCAGAGA

TGCGTAGACT

GTGTGTCCCG

TAGTAGAGAT

GTAT GTGATA

ACTCACTACC

TAGO

CAGNGGNGCT

GTTTAATCCC

NGAAACAGAG

GTCTTGGTAA

ATGCATTCTG

GATANGACTA

TTTCACATAA

TCAGAAATTG

ACAGAGAGAC

CAAGCTCGTA

CACATGCTTG

GTTAAGGTTG

AGAATCAATG

AAAAATAGNG

TTTTTAAATC

TTCATCATCT

GTTTTTATTA

TATTNTTCNG

TACTT GCAAA

TACCTGTTAT

CCATTACTAC

CAGCATCTCC

TGGGAAATCA

TCAGCTCATA

AGTAT GCATG

AATGTATTTT

TAACAAGGCT

CNATCAGT GT

AN*ANAAGT.AT

TGAAATATNA.

TTACTGTTAG

GAAACAACNG

TTGCTCCAAG

TTTTTTCATT

TAAAGTATAT

TACAGAGC CT

TTGAAATTAC

AGATCAGTGT

TGTGCATGCA

CTGCTCATGG

GGAGAGAT GA

GAANTTCCCC

0505 5 0050 00 S 00

S.

INFORMATION FOR SEQ ID NO:44: (ai) SEQUENCE CHARACTERISTICS: LENGTH: 435 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:44: 6 GATTCCAGAG AGAGGAGTGA ACTGGCAGAT AP.G5 TGTGCTTTCG CTCACTATGC ACCCATGACA

CAAGJ

GCAGAGTATA CACTGGTTGG GTAAATGAAG

AGGA(

GGATAT GGAC TTCAAATTTG ATGAACAAGSC

AATT

TATGAAGACC C GTTTGCAAPA GCAGTGGTC.A

TAAG

GAGAGAGAGA GAGAGAG1NAA GAGAGAGAGN

GTGT

TTGGTTNATA ACAANATNTA CCTTTGGGCN

CTTTJ

NCAAGCTAGA

AAGGT

INFORMATION FOR SEQ ID No: SEQUENCE CHARAkCTERISTICS: LENGTH: 919 base oairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) 3

CAGTCA

nLTCACA

GAGACA

CAAATG

rkGAGAA

GTTGTT

NGAAAG

GCATAATGGC

GGGTACAGGC

GAGTGGGAAG

AGTATCGTGG

AAGAGAGAGA

GTTGTTGTTG

ACT1'ZTNCACA

TTAGATACC-A

CTGGACCATG

TCGGCTTAGT

GCTTGANTGG

GAGAGAGAGA

TTGTTGTTTA

AAGGAGCTTG

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: CCCCNGTTAC CCNGA.NGTTT ACNNGTTGGA TTAALANGGGN NNNAAAACGG GTGGGGNNAA

ACGAATTTTT

GAAA~NGGAAA

NTTNGTTCAG

NCCNGGAANG

TTGGGGNGAT

GTTTTCCTTC

NGTGAAACAA

TAGATTGAAC

NATAANNTN

TAAAGCTTAT

CCNTCGGGGA

AGP.ACCATCC

GGAGCTAGAG

TTAGCAGAGG

TTGGCAAGTT

TGTNCNCGAC

GGAAATAAAA

TAGGGTTCGG

TACCTTGGGN

TTTNNGCCCC

CAGAGAGAGG

ACCAGGNTNT

CTGCAGAGTT

TGNTGACCAT

TTCAGTNTCA

GAATGTGGGA

AGGGAACCTG

CT CCAA'TAG

TTGTNTTGAC

AATGAAGTC

CCNTCCCCGG

ANATT'1TTTTT

GCCCGGGAGG

AGGGA'ITACC

ACCTGGACCA

GTTAGGTTC

C

GAAGAGACCA

GC CTGTTACC

NTCAGCAAGT

CCCGCTGGGG

GGTGGCGATG

TGCGTTTGAAL

GAGCTGTGAT

C AC CCA G14CT

TTGGGGNTGG

TNAAGGAAGT

NAAGGCAAN-4

NTGNAATTTN

NTTTNGGGAA

TTCAGGGGNT

GNCGGGGGGG

TGAAGTTGTC

GTCACCTTCG

AGANACATTC

TGGGAGGGAT

GGTNTGAGTT

CAGGCTGTGT

ATTGAATTGN

NGAAATAAGT

TCCTTNCCAC

TTGAANTNCA

TTTAAGAAAA

ANGCAGAAAC

TCCAAGGACG

GGGGAGGGGG

ACCNTTTNAC

TTGCCAGGAC

AGGGCATGGG

TCGAGAGAAG

ACACACAGGC

GTGTGTGCTG

G(INTNNTCC C

TTTAAGGTGG

AAAAAA'JTNG

NTTAAJAAATT

NNTGGGTNTT

GTTCCAGNGN

GGGACCAA

CCGTTNTAGA

C14ACANACTT

ACAAGTTTCT

CGTCCCCCAG

AGAATGCTTA

TGCT CAGGAA GAAGGGC GAG

AAANGGANNT

64 INFORMATION FOR SEQ ID NO:46: SEQUENCE CH.AR~ACTERISTICS: LENGTH: 915 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SE-Q ID NO:46: TTTTTTGGAA TNTTGGAACC NCGNTTTGGA AGAAGACCTT TNNNNTNCAA TTGGGGAANA ATAACC GGGG

GNNGGNAGGG

TTGTTThAAA

TTATTTTCCT

ATCAC CACGG ATTTC CAT

CATACC-TGCN

GATTC CTGAA

GTCAGTAGAC

AGGGTAGACA

ATTTTCCTGG

GTCCTAGCTG

CACATGGCTG

CCCATCTGGG

C CAAACC TT G G14GGAGGTTA AGAGGNTTG C

TTTAACNTTT

NGTTTAAAAN

AA-ACCTCN GT

TAGTTNTGGC

GGAGTGAAGG

A'NAAANAGC

GCTGACAGGC

CAGGAGTGGA

GGTGCTCCTC

CCTCAGNTCA

GACCCNTACA

GGAAGGGGGG

NTATNNCGGT

NGGGCNTGNT

GAAGGTGAAG

GTNTTTTTAT

GAAACCTTCT

CTTCCCTTTC

TTTGGGA.AAG

CGNAGGGCAG

CCGCCCACTT

AGAAGTTGGT

AGTTACATCT

AACC GGAAAC

AATTTANGGN

AAAi-ANATTC C

TGNGGAAGTT

CCCTTCAACC

CCGGGTTATT

TTCGNTTT1NA

TTGATCCTGC

CTTNTCGTCC

GGGGAGGGAC

CCCGGGGTGA

TGGCTCCTGC

ATCGAGTCTT

CCAAGTGTCT

CCAAGAGGCG

TTGTACTNAN

NGGGGGGAGG

TGGAATTGTC

ANGAGGTGGG

TNTTTGTC CT

TGGAGGNGAG

CTNGTGTTTC

TTCTTCCATT

AGAGTGTCCA

AACCACAAGG

NTTC GCTGTC

TGAGCCCTGA

CTCAGGGGTT

GAAACATGCT

GGATTNCCAC

TAATTTNTTG

CNAANGGATT

GCCNTTGCAT

TCGTACATTT

TTAAAT14TCN

CTGAGTGNGA

CCCTTCCGAA

GGGCTTGCGT

CAGAGGCCCC

TCACCCCAGA

CTCATTNTCT

CAGTGTTAGC

T CAT TTAJATT

AANGXNAAAG

GCNAGNTAGA NAGGT INFORMATION FOR SEQ ID NO:472: SEQUENCE CHARACTERISTICS: LENGTH: 849 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE. DNA (genornic) (xi) SEQUENCE DESCRIPTION: SEQ ID tiO:47: GTTPLANANG A-DAAAGN4GGG GGTGACAGGG GGNGANACCC NTTGCGCCGG GCTATGGATT

NTNGGCACCG

GAGGGGCCAA

GTGTTNGATC

AAAAGATNTC

ACAATTCACA

GGTTTTCTCA

TCAAAGGGA

TAAGTAATCT

GAATCACAAT

CGCGTCCTTN

CCTCCTTNTA

AGGCCTTAAA

AAACCATGTC

AATATTAAC

ANAAGATTTN

AAGGANAAGG

GGN'APACAAC

AGGAGATCTT

AGATTTGTTC

ANAAAT GGH

NTTTGAAGGA

CCCGGANTAC

TTCCTAACCA

GTGATGGTTT

TCCCTCCCTT

CTTGTGATCC

CAGNNACTTC

CAGGNGACAN

AGGAN GATTG

CACGNGNAGN

GATTTTTTTC

ACAGGGAGNT

TCAGT CAGGT

GTGCTTTGTC

TGNNGANGCG

TANGANTNTT

CAAAGTCNGG

CCTTTTTTCC

TCCTGTCTCA

CTCCTAATCC

GGAAGGTGGN

ATTGGTTNGG

GNGTTTTTGT

GGGTCGAGCT

CNAGGAGGTG

GNTTGCCTAG

CTGTGGAGC.A

TTCCCAGAGA

GTTAATCTCA

AATATNTTTT

TTTCACAGGA

GCCTCCTAGG

CATCTTCAG-A

NGGOGANGG

GAGCAGTACT

7 GCAGCAGAG

ANGTTGGGGG

GTCCCANTAG

ATCTTTCATT

AT'?GACTCAA

GGTCCCCCGT

CCACATAAAC

CCTCCATCCC

TCTCANNATG

TOT TAAGATG TAT CCTTTA.A

GGAAAGTTTN

TGGAAAGAGT

ANRAAGNGAGA

ATGNGAGGGN

CCGGTAGGGG

AGTTCCTC CC

TCAATAAACN

AGTNACCAGT

CCACAATTCT

TCCTTTCCTT

CAGCCCAGTC

ACCCAAATGT

GACCAAATTA

120 180 240 300 360 420 480 540 600 660 720 780 840 849 9* INFORMATION FOR SEQ ID NO:48: SEQUENCE CHARACTERISTICS: LENGTH: 925 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genornic) (xi) SEQUENCE DESCRIPTION: SEQ ID 110:48: AAAAAAANAA ATNTTGGNGG ACCNAANACC ACC.AATGGGT TTTGGGGTCC GANCGNNCAA

ACNTGNTTTC

GTTCCAAACC

TNAGTATCTA

AGNTGTNTAA

GN7AAAAANNA

NNATTAATAA

CACACTGTGA

GTTCCGTTTT

NGAGATGNGG

ANT GTTNTT1C

CNATGTTTTC

GTTAAGAGGG

TNAACCCGTG

ATGTGGTANG

GCAGNCAATT

CAGTGGTTTA

GTTCGGNTGA

NTTGAGCNTT

TGGNTTTNTT

GCNCAATTTA

GCCATTTNGA

AAGGGGCTGA

GAGACAGTAG

GAGGAGGTTA

TGTNACANNA

AGGTAGSNCA

CAGACCNAGN

TGNNTAAACT

GGCGGGGNGG

GATTGACACC

GGGGN GTT GG

NNTANTCGGA

TCCACGACAG

TNTCGGGAGN

ANACTGGCAN

TNCA14GGNNN

TGC-GGTTTTA

GGAATCCNTT

TGAGTTAAAC

TTANGATNCT

NCAANTNCGC

NGANAGGTGC

GATGGNGCCA

AGGTGTTNGG

NGGACNANGG

AGGGTTNAAG

T GGC-GANGTT

TTCNGAACNN

CAATNNTAGG

ATCGGCCNTT

AGACCCCACG

CAC CNACTGA

GGGCNAGACG

TCCCCNGNGC

120 180 240 300 360 420 480 540 600 66 CNTTCTAGCC TNGAGCAGNT TCNAGAGAAN TATTCGNCGG GTATAGGTCG CCCCNANGAC GCNAAACGAC CGNGAGCGAG GGCGGAACAG CCAATCAGTT CGANTTATCG TGTNTGTTNG CGGGGTTTGA TCCCNGAGTT AGNTCAATGA GCCCANAACC CTGAGTGGAG GNACCGTCAT GGGAGGAGAG GNGAGTCACC NGGTACCTGG CATACNGATG GACCATCCAG TANTTGGATN GGAGGGCGAT ATNGTNANTC TTAGGGGNTC TCCTGAGGAG GGNATACCCG TGAGT'rCCGT AAGGGCGTTN GCAAGTAAINA AGTCG INFORMATION FOR SEQ ID NO:49: SEQUENCE CHARACTERISTICS: LENGTH: 827 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:49: GCCAGTTGCC CTCAGATGNC CNATACCCCA CNGGGGGNGT CTCNCCCCTC TCTCAANTGT

C

ACACACACTT

TGTGTGT GCA

GCCCTAAAAT

G14CCCNNATA

TTTNTAANAC

ATATACACNA

GCGCAANGAG

ATCT CGGGAC

TTGNGAAAAC

NANATNTNTC

TCTCCCCNTN

NGGANAATAT

CCCCATAGAC

CNTGTGNGTG

GTTNTNTGTT

CCCNGACANN

AT CTCTCCCC

GTGTGTNAGA

AGNGCAGNGT

TCNNCCTCAG

TCANNTGTGT

TCTCAAAACA

ACATCTCTCG

TNCCCCCCTG

ACNGGGGACC

TGTGTGNTGC

CNCCACTNGG

GAATGTGTGN

NNNATATCTN

CACAC CCC CA

GCTTACTCCT

CNCATTCTCT

ATAGTGCTCT

TGTGCATGNG

NGNNAANLANA

NGACCANTCC

ATAGCTCTAG

CCCAAACACA

NCCTCATNTN

NTNCCCATNN

TTNTTTNNTN

CACCCCAAAT

CGCCCCCTCT

ATCTCCCANA

GNGTGTNACC

CGTGTAACAC

AATATATCCC

CTCCCCGGAG

GGGGAAAACA

GGGGTNTCTC

NACATACCCC

GCGCTNTCAC

N GGGTCTCA

GNGCGGGGGG

AGAAAACTCA

AANACACAGA

CCNAGNCCAC

TCNCCATCTC

CTCNNTTANC

ACCNANCCCC

AAAT N TTAT N

TTCCCCAGNG

CCNNGNCTCN

CACCACAGNT

TGGAGACNAC

AGGGCTCTTA

CACTNTTNAG

GNNACCCTNT

ACCCCC.ATAA

TCGGGCNNGC

C CC CGTGTCC

CCCGTGGANA.

120

ISO

240 300 360 420 480 540 600 660 720 78 CCCCCCCCNG GNATCAACCC CCCCGGGTAN ACAACCCCCG GAACCCC INFORMATION FOR SEQ ID SEQUENCE CHARACTERISTICS: LENGTH: 899 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear 67 (ii) MOLECULE TYPE: DNA (genomic) (mi) SEQUENCE DESCRIPTION: SEQ ID 140:50: AAA.AATT GTA AGGAGTTGGG GGNATCCCCC ATAATTNAAA NAGGC-AACAA NCCNTAAAGG

GAGGGNNGGG

GGAATTTGTT

AGGAAGT SAT

TGAATTTGAG

GAGGAGCAAG

ACAGATGAGA

ATNTGGAAAA

TACGTTCAGC

GTCTTCAATG

GATTCGCTCA

GTT GGATTNT

GCAGGGGGGG

TCCCGGGGCT

AANGGCCAAN

ANAATTTTNN

ACCNGGGTTA

TGAGT GCAGG

GGNTGGGCAG

ACGTTATTGG

GTTCTGGNTT

CCC CCCACCC

GACCTGCCAA

GTAGTTAAGC

NTGAGGCATG

C GGG C GGAC C

GAGTTGGAAT

ATTGGNTTAA

TAATGGAAAT

TCAAGTNAAA

T GAAGTGAGA

TGTAGGTGGT

AGGACAGGCA

CAGGCTTGAT

TTACGGAAGT

T CAGAAAGCA

AGTCTTAACT

TTCAGGCAAG

GGCAGGGGAC

CCGCGGCTAC

AAANAGTA.N

NGGGCACTTC

CNTGATTCTT

CTTGGGAGNA

GNGGTGGTCC

CPAGTGTTAC

GC TTGGCC C

TNTCGTCACT

AGSCSGCTT

GGTTNTSGCT

CTCCAAAGTT

TGAGCASTGS

CC GTGAGST C

GGGC-TGCAAC

AATTGGSANS

CSNGNNGAGG

CAGGTCATC

TTCCTGSGGT

TGAAATGCAA

SCAACTGTGN

GAGANTAGTG

TTCCGGGTGC

SCTGTGCTCT

SCGACATGGT

GAGCTGGT ST

TTAGCCACTC

TCTTGAAAGA

ATAAAACCCC

GAAAGGATAT

CCACCCAAG

GSCGGGGAG

ATCCCTGTAG

ACTITTCC CT S

GCTAATCAGA

NTAGGTGTAS

CTGTCCTGCC

G.AGCACAGGG

GGTGGGTCTT

ACTAGACCCA

CCCCAC GAG TTTGSTTSAT CCANACACAA 120 180 240 300 360 420 480 540 600 660 720 780 840 899 GCGGCAGTTT CTGAATAACT TTCCTTSTAG INFORMATION FOR SEQ ID NO:51: SEQUENCE CHARACTERISTICS: LENGTH: 952 base pairs TYPE: nucleic acid STPANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (geriomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:51: AAAACATTCG CNAGACTTGT AATAATTNCC NGTTNGGGGA AkANASNGGN GGGCNSGGGA NCCGAGSTTC CCCCCAAATT TCTTANNAAT TGAGSCANAT AACCCAN4NGN TCNNNAAGSN GGGGTTTTTC. CCNTTNGCCC CCTTSSGGNT ACCNTNAGTT AACSSSGANA ACCCGCCNTG TCCTNNGGGA GSQGGGTTCC NCSTNGTGGG TTTCAGTTCG GACCAGGTCG TTNACTCGAA AACNGCTCCG CCGCTNGSCN GNCTCTTCAN NSCTAACGNG GTAAGTATTT TCATGTGTCC

NTGNGCTTCG

TNANGGGGGG

TNACAANTTG

CTNCGGAGTT

CNGTATNCAC

GAACGT GTTA 120 180 240 300 360 CACTCCAAGT ATCCCCATCT GCANCAACCN CCCCTTACCN CCACCNTCTN CACGNCTCCA ACCNGCNANC NCAAGATNCC TCCNCACTGC NNCATCACAC, GGACNCACCT ACGCNGCCAA CCCGNANACC GACANNCNAC NCCCNCNCTN CTTTGCTATC NACAGTCGCA AACCNTCTCC CGACCNTCNG ATCATGTCNT CCGGTCGNTG TCCACTTCNC CACCCGGCAG NTAACCCACC CAGATCGACA GATNTGTTAG GCGCTCTCT GACGTTNACC ATAACANTNT CACACACAAT TTCACTCACG CTCAAAGACC TACCTGAALAT

CG

INFORMATION FOR SEQ ID NO:52: SEQUENCE CHARACTERISTICS: LENGTH: 967 base pairs TYPE: nucleic acid STRANDEDNESS: double ID) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic)

ACACCCACAC

TCCACACTGC

ACAGACTTCN

TCNGCTACNA

ACATAACCNC

AGACAATTCN

NC GANAG CAN

CCANTTGTAA

CCTCATCNGN

CACNACCCAN

TGNATTGCAT

CCANCCZAGG

TCCTCACTAT

GATNTNTCCG

NNGAGNCC

NTCNC CAAC

S

S.

5S (xi) SEQUENCE DESCRIPTION: SEQ ID NO:52: CCCNGCCCTT AAAANACATT ANGCCTTTTC CCNCCGGAAN CCCCNNCCNC AAAN CCT TC C

CGCCTTCGTA

CAAATNTTAG

NAGGCGTNT

CGAAAAACAT

NCNNAAAATT

TTNTCCAATT

NGCAACATTC

NTCAGAAACT

NCNCACATTC

ATAAATNNAA

NCCCCTGGAT

CCNTACCTGC

GCACAACCCG

TCTCATCGGT

ATTTGTC CCC NGCC CANAAC

TAAACGCAAN

TTCACGANAC

TNANACNCAT

TTCTTCTTTN

TCAG GCTTCT

CGGCTCAATC

TCACTCTACA

ACATNCTTAN

CACTCTTTAT

CACTACCAT

GCACATATCA

CATAAAGTCT

AACAA.AAATT

NAAAAACAN

AACACCCCCC

NTCAATTTTT

TATTGCTCCN

TNT CCATTT C

TCATTCTCAC

ATGTC CAGAC

ACCATGTCAC

GCCAGCCTCT

TTCCATTATC

CTCCTAGTTC

AAACTATCCT

AC CATAAAGA CC CGCCCCN AAT TCT TTN C

GCGCGNTTTT

TNCCGTCCAA

ACCTTTCTCC

CCCACCAGCA

TCTAACACCA

TTCCNCACTT

CCAATCCCCA

ATTTCTATCG

CCAT CTTTAA

TGACAATCAT

CNATCTAACA

CT CAT CAGAT

CAAAAAJNNAC

TTTTCCACNC

TNTTNCAACC

CTTCACTCCC

TTC CCNTCCC

CCGACTCACC

CNTCTTCNG

CCCACATAAC

TCAAATCTCT

ACAAACCACN

CACTAATCCT

CATTTTCT CC AAT CTTACTT

CTCACTAACC

C CCANTNCCC CACNNC CNAA

CGAAANC

GCATTCCCC

TNCCAAAATT

CACCTTNTC

TTCTNCCCNA

ACATAGTCT T

TCTCTCANCN

ACC CATATTT

CCTCTGCATT

GCATCAGT

CAAATGARCT

CAACTCTTTT

120 180 240 300 360 420 480 540 600 660 '72 0 780 840 900 69 GGCCAGAACT CAATGAGGTN GTCCCATTTG ANTTACCCCA AAGGNJGCNTT AGCAAGTA.AA

AGGGNCG

INFORMATION FOR SEQ ID WO:53: SEQUENCE CHAkRACTERISTICS:.

LENGTH: 700 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ji) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:53: GGNGTGCTGG GATTATAGAT GCACTCCCCC AAATCCAGCT TTTTACCTGA TACCGGAGGA S

AGGAACGGAA

GTCTGTCTGT

TTTATTATTT

CATCTTTTGN

GGGTCTGGGG

CTNTCAGNGN

CAAGAGCCCC

NANCTNNAGG

C GATTACTTT

NNTTCATAAN

GTCCNCCGGC

CTCAGCTTCC

ATGTATGACT

CTCAGGCAGC

AGAAGTCTGT

ATCTAGGGNA

NNAGCNNNNN

GAACC CCCNA T14CAAACCNT CN4CN NCNC TC TTGCACCGrGA

TGAGCTGGTG

NGGGTCTNTC

TGCAACAGAA

NATGCAGGGA

GCATNTCCTN

AANTT14CCNT

NCAACCTNG

TGCCACNCCC

I-CNCTTN4CC

AGCAGTTTCA

TTAT GGCTGT

TGGGGGTCTG

AACAAC14GGC

GATCTNGAGT

TCNGCGTCTT

CGAGCAGCCC

CNACAATTGG

TCGCNCNATG

CAT GGGNMGC CC CCTN CCCC

CCCACTGAGC

GCACCACCAT

TTAGNCAGTC

TGTAAATN GT

TTATNCAGAG

GGTTTGGGNG

AGGGATTTTN

GGNNTTTCCC

C CNANCC CCC

ACACTCCCTT

CATCTCCCTG

AC-CTGGCTTC

TGTTAAZCTAC

TTTGACAAAT

GAAAGGTGT

AANGANGGAT

GCTTTCAACG

CCNCCCCCCC

AA.AAC GT CGT

CNCCCNCNTN

120 130 240 300 360 420 480 540 600 660 700 TNTTAACNGG NGGCGCAAGN CCTTTCTTNC INFORMATION FOR SEQ ID NO:54: SEQUENCE CHARACT *ERISTICS:.

LENGTH: 229 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (geno-mic) SEQUENCE DESCRIPTION: SEQ ID NO:54: NCNACGAGAN GTC.AANGTGN AANCTGNCGA TGATNAAAAN AACCGANCTT AGGGTGC4CAA NGGGTTACCC AGGANGGGGN CAAAGCAAGN TCCAGGCCCA TNANGGACCT GCTGGTNCAT NGCCNGNAAA NACCTACTTA TCCTNGAANA GCCCGAAANG TCCGCTNNGA CCANNTAAGT NCANNNCAAN ANGNACCACN CCNTTAACAC CACCGTATGA NCCCNAANT INFORMATION FOR SEQ ID 140:55: SEQUENCE CHARACTERISTICS: LENGTH: 465 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genoinic) 4~~a (xi) SEQUENCE DESCRIPTION: SEQ ID CCCCTTTCGN NGGCCTCAAT NANTN4ATTGN CTACCCNANA GTGGCGGTCT CAAATAAJANC AGCCTTCATG AAATACGATG GCGGGGGGAT TAGAGGNNTT GCTGAAGOGG CTTGCAACCC CATAAGAACA ACAATGCCAA CCACCCAGAG ATTAAAACAC TACTGAAAGA CTATACATGG ACTGACCCTG GNCTCCAACT CAGAGCAAGA GCCTNGTTGG NGCACCAGTG GAAGGGGAAG CCCTTGNTCC GGNCTCCCAG NCCAGGGGTA ATNTNGGGGG CGGNGGAGCA GTAAGGGAGG GGGCTACCCA TATNGNGTGG CGGAGGAGAT CGNNGCTNAT GGACAGGAAA GGAATNACAT TGGANATCT C NATAAAGNNN NCATTTCTTA TTCNA INFORMATION FO0R SEQ ID NO:56: SEQUENCE CHARACTERISTICS: LENGTH: 564 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:56: TTGGGGCCGN TNAACTCTGN GTNNNAGTAT NCCCNANAGG GGGGGTCTCA CACCNCATNT GNGGGN4GCCC NTTCNCNACA ACACATTTTG TCNGGNGGTT CACANATTTT GAGAGTC1NCC NGANAGGGGA GAGAGACNCA CACNAGTCTC GTTCGCGAGN GNACNCTTCT CTNCACATCT ANAGTATANC CCAGNGTCAC GGGGGGTNGT GTCAGNNACA GNGTTTCCCC CNCCNGTNTT TCCCCCTNCC GGGNAGACAA NGTNNTAGAG AGAACAGGGG TTATCCACAC ATCNCACTGN AGGANNANAN TTGTGCTNAG AGCCCCTGCN CTTCTGGTGG TANCTCTGGG TCTNCTCTGG GTCCCCCCCG GGGGGGTGTN NCCCTCNCCG GGAGAGAGTN

NNCATCATGA

TNTTGAAAGA

CTTCNAGGGC

GCATAT GTAG

TGCCAAGGTT

GTGGATGGCG

CTGGNAAACG

CAN4CGGGTCN

ATAGNGAGAG

TTCTCCCCGT

ATATGTGGCG

CCCCCCNCAG

GNGGCACAGG

GCC CATATTC

TTAGAGANAA

120 180 240 300 360 420 465 120 180 240 300 360 420 480 71 ATCTCCATCN CANATGANAkA AATNTGNGGG 14GAGAANCCC GGGGGATATC ACTNTTTTAN AANNGACCCC ACCCCCCCCC CCCT INFORMATION FOR SEQ ID NO:57: SEQUENCE CHARACTERISTICS: LENGTH: 822 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:57: GATTTGCNCT CATATNTCNT TTACCAAACA GNGGGNGTCT GCCCCCCTGT NATAN'ACCTC a.

TTGTTNTCGC

GGGGGATTTC

CCCCTCNCCG

ATAT CT C TNG N CT CTNC CCA

CCTCTCNTCT

CTCTAAAACA

P.PAACCCCCG

TGNGTTTATA

CNNCGAGNAG

CNTTNACNCC

TC CCC CCGC C

GGGGTGCTNN

TCTCTGNTGT

AAAAAGANAC

NNATCTT CTC

GAAATATNAT

NCCCCNAATA

CAN GNNNCTT

TGTTCTCCAC

ATTTCCAAGG

GGCTCTTTTN

CNGNCCCNCC

CNCCCNNACC

TN GGGGC CC C

AGANCTNTNC

C CCN'AAAAA

TCTAANCTCG

ACANNNNGNG

CTCTTCCNCC

NTCTGTGCCG

ATCNC CTCTN

AGAATGTNCN

TATATTTTTN

CAACNNCCCG

CCAATNCCCT

CCNTGTAGAA

NCTGAGACAC

AAAAAAAAAN

CTTTTAINTC C

TTCCCCTNCC

CC'ITNATTCT

CAATNTNTTN

TNATATCTCT

CAGGGGGGCC

NTCNAP.ACCN

ANCGGGGGAA.

TTTTTCGCGT

CCCCCCTTTT

AAAGAACA1N ACAGNGC CCT

AGACCGCGNG

T CAGAAAACC CAAAACCC CA

CNTATCTCTN

TGTNACANGG

GCCCCCTTCC

CCAATCTCC C

CCNTTGTCCT

ACGTTCCCCA

TCCGGGGGCC

TT

NGNTGTGGGN

GTGTGGGGTC

GGGNNGAAAA

CCACCCCNCC

AAGGGNNTCC

NGGACTCANA

CNCCCTGAAA

NCTATATCNC

CCCCTNGTTT

TTTAAATNGG

NTTTTCCNTT

CTGTTTCCCT

AANCCCGGAA TNAANTNCNT TNTTCAANCC INFORMATION FOR SEQ ID NO:58: SEQUENCE CHARACTERISTICS: LENGTH: 553 base pairs TYPE: nucleic acid CC) STF~ANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:58: TTTGGGTGCG GTCTCCTCTG TGTTAGTGTA TCCCCCATAG GGGGGGTCTC ACAGGGAGCC CTTCTCTTTT GGGGGGTTAT ACACAGGGGA CACACATGTG AGTGGGAGAG TGGGGGGGTG GGTGGAAGTG AGAAACAGAG GTGGTGTAAA ATGTGTTGAA TCTCTGGTTT GATAAATTTT ATCCCTGATC TCTCTCCTAT CCCC.ATTCTC TTTCAGAGAT AGATTTTCTG CTCTCACATG TTTGGTCCCT TATGTTCTC.A GATACATGTG CTCTTCCCCC TTGGGTCTTC TCTCTGTCTC ATAGAGTGTG TTTTCTCCCC GGGGTTTCCC TTGTTCACAA TATCTTCTCA AGGGTATAGC CCCCCAGTCC CCAGGCCCTT GGTTCCCCAT TTT INFORMATION FOR SEQ ID 14:59: SEQUENCE CHARACTERISTICS: LENGTH: 904 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (qenornic)

ATATAGAGAG

AGAGAGACAC

ACACATT CCC GT CTCTCTCC

CTCTCTCTTC

TGTCTCCCCC

GAAGAGCTCT

TTTCTTCCAA

AACACATGAC

TTTATTTTTT

CTTTGTCTAC

ATTCTCAGAC

TTTATTCTCT

CC CAT GATAC

GGGGAATCTC

TTTTCGAGGC

1210 180 240 300 360 420 480 540 553

S*

0* (xi) SEQUENCE DESCRIPTION: SEQ ID NO:59: GCCATTTCCT CTCACATCCT ACTTTACGTA AACTCTCCCT GTCTTGCCTC

CATCTCCC

CCCCCCCGCG

TCTGCSCTC

GATCTTACTT

CTCT1TTTCTT

CTTTAGATTC

TTATTTCTCT

TCGCTCTCT

AAGCCCCTAA

TTTTCTTACT

CTTTTCAAAA

TTTTTCCGAA

CCTAAATAAA

CTTGCTAAAA

TTTCTCCCC

CT CCCCCCTC TGTGCC TG

TTTCCTCTCC

ACCCCCTCTC

TAT CCTTT CT

TCTCCCTCTG

TCTTAAATTT

ATCTTTTAAA

CCTCAGGCGC

AADATTTTTCA

CGCCCC CC C

AAGGCTCCCC

ATTTCGCCTT

CGTCCCTT

TGTTTTCTGT

GTCCCGGTCT

CCCTTCTCTC

TACTTTATAT

GCACTTTTTC

TCC.ACTGTCG

CATCTCTTCT

Al GTCTCAG

ATATAAACCC

ATCTAAATCC

CC CT CCTCTG

CCCTTCTCCC

TTGATGCTTT

TTCTC3TCCTC-

GCTCCTCCCC

CCTCCATACC

TTTCTTCCGT

TCACACTTAC

TATTCTCCTC

TCAAAAACAC

ACAGTCTCTC

ATCTCTTTTT

CCCTCTCCTT

AAATTTTTTT

CCCCCTCATT

C CC CTGGCC T TCC CCCC CC

CTCCTTCTTC

CAGATGCTCT

CTGCTTTTTT

ATACACCACA

TCTCTCTCTT

TAGATTTCTC

CCTTATTAAA

TCCTTTAC

TTTTTTTACA

TAATATTTCT

TTTTTTTTCC

GCCCCATTT

AALTTAATCAA

TTAACCCCTC

TCTCTCAAAA

ACTTCTTTCT

CCCTTCCGC

CTTTTCTCCA

TTCTCTCTCT

TTCTTTTTCT

CCCTTTTTCT

TTTACACTTC

ATATTTTTAC

CTCCTTTCTT

CACTCTCTTT

TCCCCCCTAA

TTTTAATTCC

CCATTTTACC

TTT-TTTTTTT

120 180 240 300 360 420 480 540 600 660 720 780 840 900

TTTT

INFORMA!TION FOR SEQ ID NO0:60: SEQUENCE CHARACTERISTICS: LENGTH: 698 base pairs TYPE: nucleic acid STRANDEDN4ESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genoraic) (xi) SEQUENCE DESCRIPTION: SEQ ID 140:60: CYCACCACTO AAAGAGATAG ATTAARAACA AYXACAAAACA ACAACCAAAA AAATACAAAC

AAACAAACAA

AAAAT GAGTT TGCCAnAG.AAT

TTCTCTGTGT

CT CTGNCTCC

CATTTTTCAG

GAAAAACAGG

NTGTGGCCTT

AAATHANTTT

CC GGNGGGGA

TTTTTCCCGN

AAAAAAAC CC

AAGGTTAGGG

GTTTGAGGAC

AGCCTTTGNT

CAGT GNCAGA

CTTATAGTCT

CCACNGNGGG

CCN4GGGGGGT

TTTNGGCCGG

NAAACCCCCC

CC CT NAAAAG

CAAACAAGTC

TTAGGTTAGG

CTAAGTTTGN

ATAGACCAAG

ATTAALAGGCA

TTTGGCAAGG

GGGAACGCT G

CTTTCCCCTT

GTTTNGGGGN

GGACTAAAAA

NAAAAATTT T

GCTCAACTGT

GTTAGGGTAT

CTTTTTTCTT

GCTGGCTTCG

TGTGCCATCA

GATGCCAGGG

CTTCCCCGGG

TCAAAATTNT

CCCCCCNNTT

AAAAAGGGGG

TNTTTTCC

CTTGAGTCAA

AGCTCAGGCA

TCTTTCTTNT

A.ACT CAGAGO

CTGTCCAGCT

NACGAACCAG

TTATTTTCTT

TT GGGNTTGG

TGGNTTTTTT

GGANCCCCCC

TAGATTTTAA

GTAAGGTACT

GAAACAGGGT

ATCCACCTGC

CTTAGGTATT

AGGCAGGGTT

GGGTCANATC

GGN4GGGGTCC

TTTAGAAGGC

NGGGGNGGAA

904 120 180 240 300 360 4120 480 540 600 660 698 INFORMATION FOR SEQ ID NO:61: Wi SEQUENCE CHARACTERISTICS: LENGTH: 851 base pairs TYPE: nucleic acid STRA14DEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (Xi) SEQUENCE DESCRIPTION: SEQ ID NO:61: GAAANAANTC GGGAGAAAAA NAAANNNCCN TTAAGAGCTT GCCCCCANAG AAAAANTANN AANTNAAAAA CTGNTAGACC ANNNGAAAAG GAAGCGCAGT NANAAAATGG TTCCTACGGG TTAANTAAGA AGCANGACNG AAAGANN4GNN TNNATNTAAC CGGGGNTAGN AAACGGCCCN CTTGTANNAG GACCNAATCG AANTAGTACG ATCATGNTAC ANAGGGAAGG GGACGTTACC

CNCGGANGAA

CAAGGAAATT

GANAAGGCAT

AGGNGGAATA

TCNGTANKNA

TTTC.AGATCA

GATTCAAGA

NNTATTCCCC

AACNATATGA

AATGCNTTTT

ACCCGGCACA

ACTGTGGANA

CGATA}JAANT

GTCATANAAC

ANAACNCCCG

CCCAGATCAT

NNGNTGACAT

CNGNATGNAN

TCCCATGAGG

TTTGTNTGNG

ALGATCTCNNA

CGGGAGGAAT

GAT OAT GGNT CAT GNAPAZkA

GTGGCCGTGA

CGNTGNAGAT

GGTGAAATGA

GGACNTCTTA

GNGGNNACCC

AACCCANTGC

AGGGAGAAGA

CNATNGTNAT

CAGGCGAAAG

ACNTTCAATA

TT CCTTTTTT 14CCATNGATG

TGTACAAATN

T GATGAANAC

AGGNAGTCAN

CC GAC CTNT C

TTCTGAACGN

NNAGNNNAGC

AGCATACGTA

AAAGATJJNCC

AACGGCAAAC

TTNTTGAAAC

ACAACANAGA.

CTTATACCAG

GAANAAATAC

AAA14AGAAGC 14ANNAANCCA

TGGNCACTTT

AAACCAAGCA

NGAATATTGA

AGCANNTTAG

TNANCTNGAG

NCGTCGAGAT

ACTCAAGTP.N

CNGAGAGTTA

ANAGCCCNAA

300 360 420 480 540 600 660 12 0 780 840

S.

0* S

S

AATTAATCCA

A

INFORMATION FOR SEQ ID NO:62: SEQUENCE CHARACTERISTICS: LENGTH: 936 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomxic) (xi) SEQUENCE DESCRIPTION: SEQ 11D NO:62:.

GGTTTTAGGA GGGAAAACCA ATAGGCCCTT GAGTTCT TAT TCTTAAGACA

CTAAGGAAAA

TTGTAAAGGA

CCGTTCTTCC

TAAATATATT

TGCTCCTTCC

CAGTCAATTT

AGTAAGTGAG

ACCAAGCACA

ATGCTAGGA

AGCAGCTGAG

GGGAGAGGTG

ATCATGGAGG

AAGGTTTAGG

ATAAAGGCCA

TTGAGGGGTT

CAGTGTTGGA

TAGGTTT TAT

TTCTTACAGA

CCAAGCAGCC

AATCTTCATG

ACCOPAACAGG

TOT GCTACAA

GGGACAGACG

GGAAAAATTA

GAGTTCACCA

CAT GGAATTG

TGCAGATATG

GGCAAZGCATT

GCAGAGAGAA

AAkTCCTTAGA

GCTCACGAAC

TATGGGTGGC

AGCCAGAGAG

ATTTGTCCCC

CCAGCCCGAT

TGAGTAACCA

GGTTOCCATT

CGCCCT OTTO

TATTCATCCC

GGAGCAATCT

AGGAAGAAGC

CTTGGGATTT

ATGTCGAGAC

AGGAACAGAT

AAGGAAAAGC-

CCATTAGGGT

GGATGTTTCT

T GGTAGTT GG GTTTTGAqTA

CACATTTTCT

GTGTTATCAA

AAACACTTG

CCCTGTCAGG

AGGAAAAGAA

AGGGAGGGGT

TCCCTTTATG

TCGGACCTTA

TAGCCTACCC

GTTTTGAGAT

GCCAGGGTGT

ATCAACTAGC

OTATCCTTCC

GTAGAATACA

CCTGTGTCTG

GTGCTGCACC

AGAGTTCTTA

120 280 240 300 360 420 480 540 600 660 '72 0 CTGAATTTGG GAATGACATG GGAGACCAAG GGcCAAAGTC CAGATGAGCA

GAGTGGGGAG

GAGGGTTGGA A.AGTTCCAAG GAGAGAGGCG TGGGGGTAAG GGAAGCTCGC AGGGCTCCGC CTCTGCCAGT GACCTTGGAC CGCTTTCTCT GAGGATCAGA GTTATCTGTA GGGGAGATGA GGTTGAAAGA TACCCACAAT AACTTTGGCAk AGTAGA INFORMATION FOR SEQ ID NO:63: SEQUENCE CHARACTERISTICS: LENGTH: 911 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (qenomic) (Al) SEQUENCE DESCRIPTION: SEQ ID NO:63: GGGAATTTAA GGGNGATTTG GAGACTTTNG AATTTTCGAA NGTTCCAAAA TAGANNTTNA 444.

.4.4 .4 4 4.

4444 4 4 4.

4.

4 4* 44 4 4 44 4 4.

GGNCAATGGG

AALACCCTGGG

AN GGTGNGAT

GGAATAGAAC

ATTAAGGAAA

ATTGTATTTC

AAAAGATAGT

TTATCAGGTT

GCATAGATCC

AAATGTTTGC

TGTGTGTGTG

ATT GCATTAG

TTGTGCTGTA

AGOCTAGACT

NTTGGGGCAG

GGTTCCAGTT

AGCAGCCNGA

AATGAZGAGTC

TATATCCATG

AGATAGAGAT

AATCTAATTT

TTACTTCT CA

CCAGAGAACA

GTAGACTCAA

TGTCCCGCAC

TAGAGATGTT

T GT GATAAGA

CACTACCAAA

NGGN4GCTTTT TA!ATCCCTT C

AACAGAGGTT

TTGGTAATAT

CATTCTGTAC

ANGACTATAC

CACATAACCA

GAAATTGCAG

GAGAGACTGG

GCTCGTATCA

ATGCTTGAGT

AAGGTTGAA.ZT

ATCAAT GTAA

AATAGNGCNA

TTAPATCANA

ATCATCTTGA

TTTATTATTA

TNTTCNGGAA

TY GCAPATTG

CTGTTATTTT

TTACTACTAA

CAT CTC CTAC

GAAATCATTG

GCTCATAAkGA, ATGCAT GT GT

GTATTTTCTG

CAAGGCTGGA

TCAGTGTGAA

NAAGTATTAG

AATATNACTT

CTGTTAGAGA

ACAACNGACA

CT CCAAGGAA

TTTCATTATA

AGTATATATG

AGAGCCTGTC

AAATTACACA

TCAGTGTGTG

GCATGCATGT

CTCATGGTCA

GAGATGACTT

14TTCCCCACA ATTTN4TATGG

GTTTATGGGA

NGAGGATT GG TA ATTGGAAC

CATGGAGAGT

GCAAZCATTAA

TANTCTTTGT

AAATGAGACN

ATCCTATCCC

TGTGTGTiTTG

GTGTATGTCT

TTGTAAGATA

CA'GCT GTTAA

GGAGCTTAGC

AAGN4TAATAG G INFORMATION FOR SEQ ID NO:64: SEQUEN4CE CHAR1ACTERISTICS: LENGTH: '781 base pairs TYPE: nucleic. acid STRAN4DEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DN4A (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID 140:64:

TTCAGGGGTA

AAAAATAAAA

ACGGAAAAAA

ATTTAACTGG

ACACTAATTA

TATCCCAAGT

CTATTAACTC

ATGTGAGAAA

CTGTGTCTGA

CAATCTACTA

TTGGTTTGTT

AAAGGCAGAG

TATTTCTTTC

ATCCTAAGGT AAACGGACAA AGTAAAGGGG AGGTTGGACC PATAAAGGGG

GATTAACCGG

AT GAACAAGT

CCTTATATTT

GATCATGTGT

GAGTTTAACC

CT GATTATTG

GGGAAAGTTG

CTCTTATCCA

AGTTTGAATA

AGGTCATTAG

AGAATACACC

TTTTTATTAA

ATGTTCCCTG

'PT CCTGTAAA

ACAAAGTCTA

GTACACCCAC

TTCCTTCTCC

Ar GAAZCTTT

AGGGACTGAG

ACATTCCAAT

TGATTTGTGC

GGTAGGGcTC CAcCCTAAAC

CTATTTGGTG

GAACGACAAA

GCAGGTAGCC

AAZCATTTTAC

AGTCTGACAG

ACATTTATTO

ATGAGACATA

TGTAATAG AG

TCTTCAAGTC

TCCTGGTGTC

TTATGATAGA

ATTTCTGCCA

ATAGTGACAA

TTGCCTTGGA

GC-AACGTTTC

TGGGGCATTA

ACAGGGTATT

CCATGTGCAA

AGAATGTACT

ACT GATAAGA

TAAAGGTGAA

TACAGAGTAT

ATTCTTGTGG

TT GTGCAATA

ACAACTAGAC

AGTTT CCTAT

TAGGCTATAA

CAATTTTATA

TTTTCCTTCT

TGCC-TAGCTT

TGACAACAGC

AATGAATGGG

GGGTCATTTT

TAGGAAATGT

CTTTACATGG

CAGTAAGGTA

TTCATATGTG

120 180 240 300 360 42 0 480 540 600 660 720 *780 INFORMATION FOR SEQ ID SEQUENCE CHARACTERISTICS: LENGTH: 389 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) t (xi) SEQUENCE DESCRIPTION: SEQ ID N0:65: TTGCTCTTAG GAGTTTCCTA ATACATCCCA AACTCAAATA

TATAAAGCAT

CTATGCC CTA GGGGGCGGGG GGAAGCT.AAG CCAGCTTTTT

TTAACATTTA

TCCATTTTAA AT GCACAGAT GT TTTTATTT CATAAGGGTT T CARZTGT OCA AATATTCCTG TTACCAAAGC TAGTATAAAT AAAJAATAGAT

AAACGTGG.AA

GTTTCTGTCA TTAACGTTTC CTTCCTCAGT TGACAACATA

AATGCGCTGC

GTTTGCATCT GTCAGGATCA ATTTCCCATT ATGCCAGTCA

TATTAATTAC

GTTGATTTTT ATTTTTGACA

TATACATOT

INFORMATION FOR SEQ ID NO:66:

TTGACTTGTT

AAATGTTAAT

TGAATGCTGC

ATTACTTAGA

TGAGAAGCCA

TAGTCAATTA

SEQUENCE CHARACTERISTICS: LENGTH: 340 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genornic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:66: AAATCGGGNT TNCGCGATTC GGTAATGACG NCNNATCCGT AAANNCATNC GCCGNNATNC NATTNGAAAA TNCCGGGNGC AANNCC-ATGT CTNATTGAGG TNNCAGANCC ATCCGGCACA GGCAATANGN AAAAAA.NGGG AGTTTCAC.AA TGTNTNTGAA TNTGNANCCA TTGGGCCCNA A-AM14TCCTN CGNTNNATGA ACCTTNNCGT NCAAAA-NTTT GGTNCC-ACNC AGCNGCTTTG CNAGCNTTNA ATAAACACCG GNr4TCCANAA TGNNACCAGN GNTGTTTNTN TCNANTN4GCA TNNCNNTTTG GAANCCCNCT TTTCCCAAAA CNTTNAAAAA INFORMATION FOR SEQ ID NO:67: SEQUENCE CHARACTERISTICS: LENGTH: 557 base oairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNJA (genornic) 4* a a a. a.

a (xi) SEQUENCE DESCRIPTION; SEQ ID NO:67: AGTC CGGGNA TGGTGGCANA TGCTTTTCAT NCCAGCACTT GGGAAGGCAA NACCTNAGGT TTANCCCAGN CTTTATTAGN ACCCCGTGTT CT14AAACACA NTTTGNGGGN NTTTAAGTGN AAACACTGTG TAAAACCTTG GCCCTGATGN TTTNGAACAG AAAATGTTTG AAGANTCCNA AAACATGTTG GGATGCCANA NGCATCCATC TCAACC-ANGT TTTGNGA.ATA AATGGCAGGT NAAACTAGTA TNGNANCCAC CGGGCNTGCA GATTTGTGGT GGGAACCAAG TCCTCCCATA CTGTGGTACN AACAGGGCTG GANCCACNGA ATCAGTGCAG NTCTGGACAC GGANGGNCTG GNCTAAGTNA ANNCAGGGGG C-GCAAGAGCA TNGGAN CNAA CGNCCCNCCC GGTGAGCTNT TCCATGCCTN4 NCCTCGNTTT ATTTGGCACT CAACTNAACT TAGGATG INFORMATION FOR SEQ ID NO:68: SEQUENCE CHARACTERISTICS:

AAAACAGTTA

AACNACAAAA

AGGGNTCTCC

CGN GTTNTTG

CATCATCAT,G

AAACAGGCTC

CTGTCTGGCC

CGNCAGAAAN

GGC-CATGT CC 12 0 IS0 240 300 360 420 480 540 557 LENGTH: 302 base pairs TYPE: nucleic acid STRANDEDNESSt double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (qenornic) 0@ee

S@

S S *0 5.55 *5@9

C.

G.e.

C. 59 *5 S S *5

C

Ge cc C C *9es 0 *9se 0@ 0 C C

S.

(xiJ) SEQUENCE DESCRI PTION: SEQ ID NO:68: GCCTATAAGT TTTGATTCCA TTCGTGAAAA TTTTTCCTAT ATCCCGAANA

GTCCACTTAT

TACTACTGCG GCCTATTTGG AAACTAACCG AAATTCAGTT AGTTCCCTAG

TAGCCTGCTC

TTGTA.ATATG TGTACTTTTC AATATTATAA AAAATTGGTC AGCAGATCTG

AGTAAA-ACAG

GTGkAATTCC GATCGGTAGT CCAATTTGGT TAAAGAACAG GATATCCAGT

GGTCCAAGGC

TCCAGTTTTG AACTCAAACA ATTATCAACC AGCTGNAAGC CCTATAGNAG

TACGNAGCCC

AT

INFORM1ATION FOR SEQ ID NO:63: SEQUENCE

CHARACTERISTICS:

LENGTH: 820 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genornic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:69: 120 180 240 300 302

GACTGCCTTT

AATAGGCAGC

GGTCCCCGAG

ATCACTGACC

CCGAGGACCA

AGCTGGCACT

CTGACAGACT

CC CTCTTTC C C-ACTTCT GTT

TACTCAAAGT

C CTCCAAGGA

GGGANCNAGT

TTTTTCTTCC

TT GGAGAAGA

AGAACCAAGC

GCTTCTGCGC

TAGTGAAC CT

GGATTCAGTC

TGCGTGCGAC

CTTCCAGCAC

GGCCGGTGTC

TTAACAGCAT

ACAGCGGGCC

AATCGGGNCT

CAAGGATACC CTGCAGCACC CAACAGTAAA AGACTTCATA

AGGCATTACC

TGATGACATG

CT GGCTAATC CTTAAT GTCA

TTTCATCCTT

TGT CCTCACA

ACATCCATTC

CGCCAAACCT

CT GAAAGACC ACAAGN4GGTN

GGCCCCAANT

ACT GAAGCCA

ACCAGCTTTG

AATACCTGGA

TGGGTGAGGC

CGCAzCAAAGT TCTcGATAAC C CAG CTAT CT TT GAGTT GAG

CCGCTGACGG

.AACTNAANAG

AAGGGTTTGG

TATTAAATTT

ACTGGAGGGA

GGTAAGAGGC

TAGAGACCTG

GGTAAGGGTG

TTCATGACTC

CCGGGCTGCC

CTCATTGATT

GTAGNAATCA

GGTTATTGNT

GCTTTATTNN

CTTC CCTAAC

TATATTCAAC

AGCA.ATCCAC

TTAGCCAGTC

CCATGGCCAT

CT CTGGCTC C AT TGCTC TAAT

GTGGACACTT

CTCAGAGGAN

AACGGC-NN CC

CNGGGACAAA

120 180 240 300 360 420 480 540 600 660 720 AACCGCAAAA AA.ANNAAACG CCTTN4TTGTA TTAAAANGCA NGNTTTTAGC CTTGGCCTGA AATGGNGNTA AGNTACGGCC CNCNGTCAAT TCCTACTATA INFORMATION FOR SEQ ID t40:70: SEQUENCE CHARACTERISTICS: LENGTH: 955 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genornic) (xi) SEQUENCE DESCRIPTION: SEQ ID AANCCGANAN TTTNAAAAAA CAANNANAAN S GGCCANGAN NTNAATANTT TCTNAAAAAA

S

0@@O 0e00

OS

SO S *5 *5@0

SO..

00 0005 0 0@ S

S

S.

0e 0 0@

S.

0055

S

555e

NGANTACANG

TTTTGAGCAG

AGGGGGNGGG

NGCCNTGATT

TNTTTTNTT S

TCAGATACGG

CAGAANGGAT

GCNTAGCATN

TATACANGAT

GGAACANGCN

CTCCCGTANA

ANGTCCCCTA

NNNTTATNGN

GAAGNGCATA

N4ACACGGCAG

GGTTTATNGG

AAGGGGTTNG

CAN GNCTTTN

TNTTGMGNAC

ATGAGAGTTT

TCAGTCGNGA

TAATGNNNAG

NTNTCGNTAN

GCGANTTTCT

CTTGTAGGNC

TAG CAG CAAA

GGACACGATG

GTAGAC CAT?

GGNNGTTTAG

NCTACGTTGA

GNTTTCCACA

CCTCCTTATT

AGGTGCACAA

CCGGGGA14AG

GGAGNCAGGG

AGAACACACA

AGGGTGAAGA

TACAGACCNA

AAGNAAATAtJ

NAGTTGNCAG

TCATCA"AGAG

CCCGTGTTC

TCAGAATANA

CCCAAGTCAC

GCNTTNAAGT

TCCNANCNTC

GT? TA GNANA

TATGNGGGCGA

ANGGGGT SN?

TNTTTTGGAT

CTGAAGAAAG

GGTTTCATA

TGCNNATTAT

AAANTCNCAC

GGAGTNNTGN

ACCNACANTC

CCACGCCTAG

ATNNACNCNN

ANTGCNTA-NCA

CAGAA-NTNGG

NCATTAANAN

GAG GAGACAN

TTTTCAGTCA

GGAGTTNACA

TTNAGAGACG

TGATGTCTCC

NAGS GAAAGT

GAGNCCGTTG

AGAGNTCCCC

ACTS? GACTC

AGCCNCTACC

TTTGCAAGTA

AAC CATTGNC

GACATNANNG

AGACACATTT

NAGAAAAGAG

TGTNTACAGA

GNNCACTACC

CCGANAGAC

NCCAAANCGC

AN CCANACN

CTATTCAAGC.

TTNTCAXACC

CGTCAGATNG

CAGTCCTGTT

AGCN GAAAGA

ATGAG

120 180 240 300 360 420 480 540 600 720 780 840 900 955 0@05

S

00 S 0e 00 GNAAAGGAGA GAGTTCGCAT ATGANAGACC INFORMATION FOR SEQ ID NO:71: SEQUENCE CHARACTERISTICS: LENGTH: 886 base pairs TYPE: nucleic acid STR.ANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DN4A (genomic) (xi) SEQUENCE DESCRIPTION! SEQ ID NO:7J.: AAA14NCCNAA AACCTCCAAA TTTGCTACCA NTCTTCNACG

NTNGAAGNAN

GTNGACTTTT1

GTTCCCNAGG

TTATTTNACC

TTCCCGTTCA

ACAACTGTAT

CTTCCAGACA

GCGCGCTGTA

CACGGAGCAA

TTAAGGNt~T

C

CGATTGGGTT

TTTGGGGACA

GGGGACCGGA

GGCAGCCGGG

AAPJTNGNAA

AP$ACAAAAGG

cAATTGTTTC

CNTTGAGTTT

AGACNACCCG

TCCCGGTT'TT

GTTTTGCCAG

NTCTTAGAAG

CGAGGAGAGC

GCcGCCATTT

TTGAAGGCAT

CTGAGGGGAA

ACTAGAC GTG

CTGGGTGTCC

AGGGGGGGGT

TTNTTTCANC

CCTGGCCGGN

GCGGTTAGTG

TTAGTATTTC

TNACGTGATT

GGCATTCTTC

GACGNTNTCT

TGTCCGTTCN

GGGTAGTGGC

GCCGNTTCTT

CCGGGCTGCG

CGGCGCCTCA

CCAGACCGTG

TCTTNTTCAA

NT'rCAACGGT

GCCTAGGGAC.

GNCAT GGGGA

CAAGCTTCCC

CGGTTCC GAG

CGCCCCACNT

CCACAGCCGT

TN GAGTTATT

TTGTAGACGC

GGGGTGTGTC

GCGCCCAGCG

CTCACATTTT

ATGGGCCCCT

TTTTGGGTTC

CTCCTT'rTTA

GATGGCCCCA

GCCAATTTTT

GCC CCAGCAC CCC GGTNTAG

GGCTTTTTTA

GTGTTGAGGG

ATGGCAGGAG

CCCTNGACGC

TGGGAGGACT

CATCCAACTT

CNTGGGCCLG

TGANTCCAAG

CTTCCTTCCG

CATGGAGANT

CCNGALAGGCC

TGGTTGGCAC

CAAGATCTTA

TTGGGATTCG

TGTTGTGGGT

CGCGCG GGCT 120 180 240 300 360 420 480 540 600 660 720 780 840 TTGCCACGAT TGTCGCCTGG CACGAGGAGT AGAAGC TTTGATTTCC cACCAATccc INFORMATION FOR SEQ ID NO:72: SEQUENCE

CHARACTERISTICS:

LENGTH: 900 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (mi) SEQUENCE DESCRIPTION: SEQ ID 140:72: GGGNGTTNGC. TCTCAGATGC NAGNTACNNN TCAGGGGGNG

TCTCACGAGA

TGTGGGGGNT ANTNTGTATC CCCTNNNCTC NCTCGAGANC

CCNNNTCTCG

GACCNGGGGC CGGGGCCCAG ANACTCNCCA CCCCATATGG

NGACCCTNTA

CCAGGGNNTG TTTTGGGNAA AATATANCNN ANAGNGGT GT NTNTNANATC ACAGACCCNN ATTTTTTTTT ATAAAGACCC GGGGCATNTT

CTCNGCCCCN

TACANGNNAC CCACACACAG TGTGTCTCCT CTCAGCCCCC

TGGCACACTT

C14GNGGGGAT ATGAGATTCN CNAGACTGGG NCCGCNNTAN

TANNCNCCCC.

CTCATAGTGT NGTGTCCCCC CCTCACCCN14 TNTTGNGGTN

CCCTACACCC

AAANCTNATG

ANATTTTGGN

TAAGTGTCNN

TCGGGGGGTG

TCTCCTCNGC

TNTNTNGANT

C14T GT CTCCT

ACACAATNTA

120 180 240 300 360 420 450

GACTCTNCCC

T GT NCT CCTC

AGGGACNCTT

GTTNCCCCCC

TCCGGGGCCC

CTNCCCCTAA

TNGGN4TNTTT NCCNt-CNGCT TCTNt~TACNG

TTCTATACAC.

NCTTTATNAT

CAACCCCAAA

ANTTTTGAAC

TCNCTAAAAA

NTGNGACNCA

GGNGGTCNCC

NCTTANTTTN

NTTTNTTTTN

ATCCC-ANTNT

CCCCTTTAAT

ATTTTTTGTN

CANCTG14AAA

CNCNNNNGAC

CCTCCTTTGT

TTCCCCAAAC

T CTTTT~nNT

TCCCCCCCCC

GCCCTCCCTG

TCCCGNNNCN

TCT4AAANGT

NTNGCAAAAA

TAANCTTTTA

TGGTT GGGGT

GGNTNAAGGC

GGAAATCCCC

CAAAAAGGGC

CCCTCNCAAA

ANNANCCTGT

GGN'NTNANCT

GTCAAAATTC

CCIACTTCCC

GGTATTCCTC

C

C. 2)INFORMATION FOR SEQ 1D NO:73: SEQUENCE CHARACTERISTICS: LENGTH: 1033 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:73:

CCTACGTTCA

CTGACCCCCA

AC CAGATCAC TAcTAACTCC

GACTCCATCA

GCTT CAT GTC

ACAGTAGGCC

TCATCTTTAG

CCCCTTTCTG

TCGTGCTGNA

AGCAGCTATA

T CAGTC CCTT

TCCCATCGC

AAT GTCCTCT

TGTTCCACAG

TATGTATTTT

AGCCGINACCA

CCTATGCGTA ACAGATCTGC TGTGTCAGGA GCCTCCTACC CTCGCGCATC

ACCACGTCCT

TCGTGGGGAT

TGCATCGTGG

GGAAkGCCACA CC CACAATAG

CTATGTGTTG,

NAAAGTTATC

AACTATT"TAT

GAGAAGACC C

CATAGGATGT

CATCTTTTCC

TGAACATCTT

GCTCCTCTTA

TGGCCCCACG

TTTTTTTCAG

CATTTCTTCC

CTTATCTGAT

CTCTAGGC CA

TAACCTCAAT

TGGGC-AGGTG

TGTCATCAAG

AAGACAGAAA

ACCAGAGATT

CACGGGCAGA

GAGTGGGCAG

CAGCAGCAAG

TAGAAGGGTT

TCTTCGAATG

ACCTCT GTGG

GTACTGGTTT

ACACTGTTCC

AGGTCAAAAA

C-ACTGGT CAT

CCTCCTGTGG

GGCTGATCTT

GCTGAATGCC

CANC GNTAT C CGTTCT14ATA

TCATCACATG

AAATNTACTG

CATGGNGATC

CCCTTCCCTG

T GTAATTTCT

TGACTCAAAG

CACACTCCTC

CAATATAGCT

TTTTGTATTC

CCATCTCTCC

CTTCCCAAGT

TACCCTAGGC

GAG GAT GCAG

ACAGGCACCT

TCCCTTTGTA

CTCAAAATAG

NCTNGGCTTA

ATTAT C CCT G

CAAGGAGACA

CCCACGTCAG

GTTGATTGTG

TGAGT GCAC C

CTAACACATG

TATGTATGAG

AACAACCTCC

AATTT GTTAT

CATACACCTC

CTTGGATCAC

TCTGGAGTTC

ACCACATAAT

CCT GNCTATC

CTACCTACTT

NGTATTTTAT

TATCATGACA

AGGGAAACCA

ACTAAACCCT

CACCAGCGCT

GAGTCTGGCT

TGTGTCGTCT

CAATAAGGGC

TCACATACT C

GAATTACTCC

120 IS0 240 300 360 420 480 540 600 660 '720 '780 840 900 960 1020 82 TNCAAGTTCA

COT

INFORMATION FOR SEQ ID NO:74: SEQUENCE CHARACTERISTICS: LENGTH: 883 base pairs (13) TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: 9SEQ ID NO:74: 1033 NAATTTCCCA AAAANNONNC GNCCCNTTTT TTATCCACTT TNNC-OTTGAA

S*

S*S*

S.

5

GCGCGGNNAA

NAT CT CNCCC

TTTGCCGGA

CAANTTTTTA

TTTCTAANAN

TCNCTAGCAO

AATAC CACAO

TTATAACAC

AAAAOAATAA

ACACACACAG

TTAAATAGT T

OCCACACCTT

NACACCPAAT

AT GTCCATAG

AATTAAAAAA

CGOTTTNAAA

CCCOOAAATT

COTTTCCCNN

OTTAAAAANA

ACCCACTTTT

CCAGCCTCCA

ACAGAGCAGC

GAACAGCAT N

CATTACCTAT

CTACOCCAAC

TCTTTCTOCT

TGCTTTACAA

TCACAOSACT

GAATTGTAAG

AC CCNCAAT C

TTTTTCCTTT

ANCT AATT TA ACGC-ANTT CC

CATTTTGACN

CCAGOCACAA

TTTACCAGOG

TCATCTCTCA

AAACTTCTTA

AGAFLATCAAC

TAOTTTCNTA

AATGCTAONT

TCCCTCCC-AG

GAGATCGACG

GCCAAAA'AGC

TTTTNTTTNN

TTT CAATCGA~

AANNTTNCTT

TGOTNCCNAA

TGOTATOTA

AC.AGGAAGCC

OCTCT CAC-AO

CATTAGITAT

AOAAATCACC

CTTCANTCTT

CTACTGTCCC

CTTCGCC-CTT

CACCGCGTCA

GCATTTTTC

CCATTTTT GO

TTCACTTTCC

AAGGNTT CCC

TTTAACACCA

AnAACAGCTG

TCGGTTTTA

TNTATTGCAG

TTATAACAC

ITCCACCOCAG

TCTCTATTCT

ATCTTTTGCA

GGG

CGTTCTCCCT

AGTTTCACCT

AACTATCTTC

TTTCAC CAAA

AATNTTAAAC

CACCACCACA

CATACAATAC

CACAOCTCTA

TCTGGT GAT

CAOCTTTGCA

GATCCATTGT

TACANCN CAT TNTTTATNGG 120 180 240 300 360 420 480 540 600 660 720 780 840 28 3 INFORMATION FOR SEQ ID SEQUENCE

CHARACTERISTICS:

LENGTH: 892 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID CCCCCCCCCT CCACGTCGAC COTATCATA ACCTTGATAT COAAkTTCACC

TCTTAGCAAT

CTGACAC CCT

CGTACATAGA

GGGAGTGCGG

TATTTACATT

TATAGCTGAG

TTGAGAAATA

TTTCTGTCTC

GTCTGAATCC

AAACGTGTGT

GTANTGGGTC

AAAACNCANG

AAGGTGNAAT

TCCNTTCCGG

C TTCT GG CCT

TAGTCAAAAT

TCAAATGACC

ATGATTCATA

AGTCACCACA

CTGGTCTAGA

CACACCACTA

A CT GAG GCAC

TTGGCACTGA

TTGAAGCACA

NTGTTCAACA

NCTTTGGGCN

AGTCATCCTT

cTTCAGGCAC

CTAGAGCACT

CTATCACAGG

GTAGTACCAG

ACATGCATAA

GCCATTCCTT

GCAAATTTTT

GGTCTGACTC

CTGTGTGNCC

GAT NCT CTAA

TNGGGNNCCN

NNTCGGTTTA

NCACTGGNGC

83

CTGCATGGTT

GTTTCTATAC

GGTCTCAAAT

AATTACAGTT

CTGTATTAAA

GT GCTGATAA TCT CTATATA

CAGAACAAAG

CAGGTTNTCT

CCTTACCCTG

CcCNGAAACA

GGAATTTTAA

CCNCTGGACC

GGGCNAAANG

CCACAGGACT

CTGTGAGTTG

GAGATATCCT

ATGAAGTTAC

ATGTTACAGC

AGGTGGCAGT

TAAACATGTA

GATCGTATTC

TTCTGNACTC

GNNGCT CA CT

GNGNTGTNGG

ACANNAACTG

C GGNGNANN G

CCCCTNNNNT

GT CACACCCA

CAACCCCTTT

GCATATCAAA

AAAATAATTT

ATTAGCAAGG

GAGCATTATC

ATATGAGACA

CTGAAAAGCA

CTAGAGGTCT

AGNATGCCCC

ATTTGGNAGA

GCTTNCNACG

GGCCANTTCG

TC

CCAGTTCGTN CCCCTGGNAC CCNTCNCCGG INFORMATION FOR SEQ ID rNO:76: SEQUENCE CHAJRACTERISTICS: LENGTH: 884 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SE-Q ID NO:76: TGGGCCCCCC TCGAGGTCGA CGGTATCGAT AAGCTTGAC-G GACCCACGTG ATGGAAAGGG

AGAAGCAATT

GGACTGTACA

C CCCTCAAGT

GGAGCACATC

GGCTCTTTCA

TCCTTGCCTC

ACATTCAAAC

ACTGGGCCAG

TAGTGTCCTT

CACACACACA

AACCGT GGAA

AGGGTGGTGC

GAACCAGGAG

CTGTTTTCCT

TGTAGTAAGT

TGCTGGTAAC

TGTCCTCTGA

CACACACACA

TAAAGGTCCG

TAAGCAGCAG

GGCATCGCCC

TCTGCCTACC

GTTTTAATTT

AGCAGACTGG

CCTCCACAAG

CACACACACA

ACCAGAAACC

AT C C CCTGT

CTCCAGCCAG

TTCCTTTGGC

TCTACTAAAC

GTGGAGTATC

TGCTGTGGCA

CACACACGCA

AC GCTGGAAC

AACTGGCAGC

ACTCTCCAGC

CTCAAACCAT

AATAA-AAC CT

ACAGAGGGTG

TGGGGACACA

CGCACACACA

GGGAGATGCT

AGAGGGGTGT

TTTCTTCCCC

AATGTGCAAC

TTAGATTTTC

TGGAGCAAGC

TGGCTACCCA GGGCTGGGCA CACTCAACAC TCTGGCATTC TGTGGAAGTT CTGGGCAGTA, 84 AAAACAGAAG CATACGTCAC GCACAGGTTC CATAGTGTTA GGCATCTTAA TCTATCTAGA 660 ATACCTGGTG TTTAGTTTGT TTACAAAATT GATTGTTGTA CTTGGACAGT GGTGTTTTTT 720 TCCCAGGGCT TccAGGATTT AG-GGGTATAC CAGGCCCATT ACATTGGGTA AACGTGTGTG 780 TTAATTTTTT CTTTTTAP.AC CTCCTTG-.TT GACTACTTGT TTTCCTTTTT AATGGTCCCA 840 GTTCCCC?1'G GGGGGTTTGT TTTGAAA GGCTTTCCGG TTTC 884 INFORYATION FOR SEQ ID NO:77: SEQUENCE

CHARACTERISTICS:

LENGTH: 326 base pairs TYPS: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genom.ic) xi) SEQUENCE DESCRIPTION: SEQ ID NO:77: AGCACACCAC AGAGAGGGGG TCTCCGTGCC CGAGAGGCAA AAGTCTCCCA CTGTGCTCC.T CTCCCCCCCT GG'FGGGGGTT AAGAGATGGG GGCTCTGGGG GGTGATAGPA CCCCTGGCGG 120 GACACCCCCC CGCTCTCGTG GAGAGAGACA GAGGGGGGTG CCCCTGATAT CTCACTAGAG 180 *GGGAGAGGTG AGAGGGCTCC ACAGTGTGGT GTGGTGGTGA GTGCTCTATC TCCAGGTGTC 240 TCACATATTT TCACAGCTCT TGACCACAGA. GAGATCTTGT TGACTCTGTG- CTCGCGGAAzT 300 CTAATGTGCC CCACATCATA TACACA 326 INF'ORMATIO14 FOR SEQ ID NO:78: SEQUENCE

CHARACTERISTICS:

LENGTH: 557 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomric) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:78: GGGGGGGTCT CACNNTANAN CACTCNGGNG TCTCCCATGT CTAGATCTCC CCCCNGCNCN NGNGANGAGT GTGNGGAGAT CCCTCTCTGN TCTCTACACT CTPAAGGGTA NGCGGGGAGA 120 GAGAGAGAGC ACANTCTATA GANCACANAG CACACNCGCT CNANGTGCCC NAN~TNACANG 180 N4NAGAGAGAN CCCCTCTCNC AGTATATNGG GGAGAGAGTN TGAGGGACNC TCCTCTTTTC 240 TCTCAACNCT GNGGGGGGAG N4GNGAGTGTT CTCTCTGNGG GGNGGAGNGG NACACTCNGN 300 TCTNCGTNTG NGTGCNCNNG TNTTCTGGGG GTCACANAGA AATCNCCTNT CTCAACACAA 360 CAACAACAAC CCCCCGCACG NGCACACACC ACAACAACAA NGGGAC.ANCG

CGNGGGGGNT

N4GNGCACACC CAGNGGAGAC ACTGTTTTCT GTTTNACACA CACACACACA

CACACACACA

CNCNCcCCCC ACANAGTTTT TNGGAAAANC GCNGGGGGGG GNGGGNCTTT TTGCCNCAAG CCTTTTTTNA NCN4CCCA INFORMATION FOR SEQ ID NOV'79: SEQUENCE

CHAPRACTERISTICS:

LENGTH: 376 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear ii) MOLECULE TYPEt DNA (genomic) SEQUENCE DESCRIPTION: SEQ ID NOV-79: CTCTCCCCCA AAGGGGGGGT CTCACCCTCC CGGACACCAC ACATCTCTCT TCTCTGACAC CCCACAGAGA TATATATAGO GACAACGCCG

CTGTCCCCAT

GAAGCGAGAC AAACTCTCAG GTACACATGA CACATGATCC

CCATGATCCC

TTCTAATATA GTT SAGAGAG TTGTGTCTCT CAAGTGTCTC

TGGTATTTTC

TTTTCTCTCA CAATGTCACA CGGGOGAGCT CGGAC5CGGT

GCACATGGGG

GTCTATGACA CACTAGTCTT GCCCCCGAAC CACAGAGACC

TCGACTCGGG

TCTGCCCCCC

CAGCTC-

INFORMATION FOSR SEQ ID SEQUENCE- CHAR-ACTERISTICS: LENGTH: 533 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE- TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID ATN4NCCCAAN ATCANATGNG GAANNNCCCA CATTTTNTAT

NTAC-AAANGN

TGTGNGTNNA ATTTGAGNTT TCACAGAGNT NACATTCTCT

GTGTCACAAN

CTACACTCCA CAGTGTGGTG NGAGATATAC TNTGA1NACAN ATGNGCTCTC CCNqNCATC-TT NTNCCCCACA GTNTACNNCN NCNATATATN GNNCNCNGNA NGNGNTGTNT TTNTTTAAAA AGATNTNANA NAGNGGGTAT

GCGTGNGGGG

CATATATGTN NNAGAGGGTC TCTCTGNGGC CCNATGGAGG

CA-NATCCC

GTCTCT CT GA

GATATAGAGA

CGGCACACTC

TAACC CCATG

GAGAGTTCGT

TTTAGTCTC C

GTTTTC-TGTG

CCCTTTCTCT

TCCTCNCCCC

GANNGGTATG

TATGTNNANA

CCNCTCNGAG

120 180 240 300 360 376 120 180 240 300 360 86 NNATATAGAA AAGAGTNTTT NANGGTGTTT GTGC-ACACAG ATAAGGGGAG

AGAGAGAGAG

AGAGANAGAG AGAGANAGAG AGAGAGAGAG, AGAGAGANAN GGNGTNTTNG GNTT CNTCCC CCCCNATATA CAGAAAAANC GGGGGGGGGT TAGGNGGNNG GGGGTTTNCT

TTA

INFORMATION FOR SEQ ID NO:81: SEQUENCE

CHARACTERISTICS:

LENGTH: 346 base pairs TYPE: nucleic acid STR.NDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genoznic) (xi) SEQUENCE DESCRIPTION; SEQ ID NO:8l: TTTCACACGA GAkTGTCGCGA. CTCTCGCGAG ACTCTCAGCG CGGAGATATA

GACCCACAAG

GGGAATCCCC CGGGTTTTTT GCCACAGGAG AGCGCGAGGA GAGAGATATT

CTTATTATGG

CTATAGACAC CCCCGTGGGT GGGGGACATT TGTGGTGTTT CCACAGGGGG

GGGGATGTAC

CCCGGATAT-C AGAGTATTCT CTAAAAAAGG TGAGAAGAGG TCTTCTCTTT

TGALGAGTPATG

GGGACACTCG AGGAGAGCTC TCTATCTATC TCTCACAGCG CCCCTGTGTG

GGCGGATCCT

CCACACCAGA TGTTAGTGTG NAGATCTCCC CATCTTCTAT

ATTGAA

INFORMATION FOR SEQ ID NO:82: (iJ) SEQUENCE

CHARACTERISTICS:

LENGTH: 461 base pairs TYPE: nucleic acid STRAINDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genormic) SEQUENCE DESCRIPTION: SEQ ID NO:82: GAANACCCAA AATTGNGCTN GTGGGCAAAN NTTTTNCCGT

TTCTTGTGCT

AGNNAAVAAAT TCAAAACCAA NACCACANAA GCGCGTTATC

CTGNCTNTCT

TGTCACACTG NGGCTGTACA GACATCNANC GCTTTCTAGA

GAGACGNGAG

CTCTTTCCCC CANNCGCATT ATANCCACAT ATTAGNGTAN

NANATTCAGC

TGGGNGTGT C TC CNTAGTGT GAAGCAACAC AGGGAkAACTN

TTCGCNCACA

TGTTCACAGA NATAAGNAGG CTCCTAGACC NNTATNACTG

TGGGNAGAGN

CCTATANNTC GGGGTCTATC TCTGTGAGAN AGAGN TTCCT TTCTCCCATN TGGGGTGNTA TNTACATCNC AGAGAGCAGA NAACTGTGAG

C

TGNGCGGCNA

GCCNTTNCCC

AGTCAGGGGA

TGTGNTNCAC

TGTCCTCTGG

ATGTTACCTC

CCTACCTCAG

120 240 300 360 420 461 87 INFORMATION FOR SEQ ID N~0:83: SEQUENCE CHARACTERISTICS: LENGTH: 367 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genoniic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:83: GGGGTNTCAC AGAGANAGGG CACANCTCTC CCNAGAANGG GNCNNCCCTC.

GTAACACcTC TCNCCGT GTC TCTTTCTTTC TTTTTTNTTT TTT GGGGGGC GGAGGNGGAG NNCGNCCGAG GGTCGGGCNN NNCNGNGGAN AGCTCTNTCN TCNCCNNANC CCCCCTGTNT CTTATAANNN ACATCTCTTC NTCNCAGGGT NTCTCNTTTC TACAACAACC CCCACACGCN AAAGCTCCCC ACNNNC-NGNG AAGAAKATCT CNGCGGAGAG GTGGNGGAGA GAGTGANATC TGNATNTCTG ANT GCCC

TTTTTNNGGN

T CTT TTCGN CANN GATATA CACAC CNAGA

GGGGTCTCNC

GNTTC CCC NC .0.

1.*

Claims (22)

1. An isolated nucleic acid comprising a nucleotide sequence set forth in SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:82, or SEQ ID NO:83.

2. An allelic variant or homolog of the nucleic acid of claim 1.

3. An isolated nucleic acid encoding the protein encoded by the gene comprising the nucleotide sequence set forth in SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:82 or SEQ ID NO:83.

4. A host cell containing the nucleic acid of claim 1, 2 or 3.

5. A nucleic acid that selectively hybridizes under stringent conditions with the nucleic acid of claim 1, 2 or 3.

6. A nucleic acid having a region within an exon wherein the region has at least homology with the nucleic acid of claim 1, 2, or 3.

7. A nucleic acid having a region within an exon wherein the region has at least homology with the nucleic acid of claim 1, 2, or 3.

8. A nucleic acid having a region within an exon wherein the region has at least homology with the nucleic acid of claim 1, 2 or 3.

9. A nucleic acid having a region within an exon wherein the region has at least homology with the nucleic acid of claim 1, 2 or 3.

10. A nucleic acid having a region within an exon wherein the region has at least homology with the nucleic acid of claim 1, 2 or 3.

11. A nucleic acid having a region within an exon wherein the region has at least homology with the nucleic acid of claim 1, 2 or 3. -89-

12. A protein encoded by the nucleic acid of claims 1, 2, 3, 5, 6, 7, 8, 9, 10 or 11.

13. A nucleic acid comprising a regulatory region of a gene comprising the nucleotide sequence set forth in SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:82, or SEQ ID NO:83.

14. A construct comprising a regulatory region of claim 13, wherein the regulatory region is functionally linked to a reporter gene. A method of identifying a cellular gene that can suppress a malignant phenotype in a cell, comprising: transferring into a cell culture incapable of growing well in soft agar a vector encoding a selective marker gene lacking a functional promoter, selecting cells expressing the marker gene, and isolating from selected cells which are capable of growing in agar a cellular gene within which the marker gene is inserted, thereby identifying a gene that can suppress a malignant phenotype in a cell.

S

16. A method of identifying a cellular gene that can suppress a malignant phenotype in a ~cell, comprising: transferring into a cell culture of non-transformed cells a vector encoding a o. °9 o selective marker gene lacking a functional promoter, selecting cells expressing the marker gene, and o(c) isolating from selected and transformed cells a cellular gene within which the marker gene is inserted, thereby identifying a gene that can suppress a malignant phenotype in a cell.

17. A method of screening for a compound suppressing a malignant phenotype in a cell comprising administering the compound to a cell containing a cellular gene functionally encoding a gene product involved in establishment of a malignant phenotype in the cell and detecting the level of the gene product produced, a decrease or elimination of the gene product indicating a compound effective for suppressing the malignant phenotype.

18. A method of suppressing a malignant phenotype in a cell in a subject, comprising administering to the subject an amount of a composition that inhibits expression or functioning of a gene product encoded by a gene comprising the nucleic acid set forth in SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79, SEQ ID SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83, or a homolog thereof, thereby suppressing a malignant phenotype.

19. The method of claim 18, wherein the composition comprises an antibody that binds a protein encoded by the gene.

The method of claim 18, wherein the composition comprises an antibody that binds a receptor for a protein encoded by the gene.

21. The method of claim 18, wherein the composition comprises an antisense RNA that binds an RNA encoded by the gene.

22. The method of claim 18, wherein the composition comprises a nucleic acid functionally encoding an antisense RNA that binds an RNA encoded by the gene. Dated this TWENTIETH day of DECEMBER 2004. Vanderbilt University Applicant Wray Associates Perth, Western Australia Patent Attorneys for the Applicant