WO1996033271A2 - Genetic markers for breast and ovarian cancer - Google Patents

Genetic markers for breast and ovarian cancer Download PDF

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WO1996033271A2
WO1996033271A2 PCT/US1996/005621 US9605621W WO9633271A2 WO 1996033271 A2 WO1996033271 A2 WO 1996033271A2 US 9605621 W US9605621 W US 9605621W WO 9633271 A2 WO9633271 A2 WO 9633271A2
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asn
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PCT/US1996/005621
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WO1996033271A3 (en
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Mary-Claire King
Lori Friedman
Beth Ostermeyer
Sarah Rowel
Eric Lynch
Csilla Szabo
Ming Lee
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The Regents Of The University Of California
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Priority to JP8531995A priority Critical patent/JPH11503915A/en
Priority to CA002217668A priority patent/CA2217668C/en
Priority to DE69633664T priority patent/DE69633664T2/en
Priority to EP96913045A priority patent/EP0821733B1/en
Priority to AT96913045T priority patent/ATE280226T1/en
Priority to AU55668/96A priority patent/AU698800B2/en
Publication of WO1996033271A2 publication Critical patent/WO1996033271A2/en
Publication of WO1996033271A3 publication Critical patent/WO1996033271A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/82—Translation products from oncogenes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/136—Screening for pharmacological compounds

Definitions

  • the field of the invention is genetic markers for inheritable breast cancer susceptibility.
  • the invention discloses methods and compositions useful in the diagnosis and treatment of breast and ovarian cancer associated with mutations and/or rare alleles of BRCAl, a breast cancer susceptibility gene.
  • Specific genetic probes diagnostic of inheritable breast cancer susceptibility and methods of use are provided.
  • Labelled nucleic acid probes comprising sequences complementary to specified BRCAl alleles are hybridized to clinical nucleic acid samples. Linkage analysis and inheritance patterns of the disclosed markers are used to diagnose genetic susceptibility.
  • BRCAl mutations and or rare alleles are directly identified by hybridization, polymorphism and or sequence analysis.
  • labeled binding agents such as antibodies, specific for peptides encoded by the subject nucleic acids are used to identify expression products of diagnostic mutations or alleles in patient derived fluid or tissue samples.
  • the invention provides compositions which can functionally interfere with the transcription or translation products of the breast and ovarian cancer susceptibility associated mutations and/or rare alleles within BRCAl .
  • Such products include anti- sense nucleic acids, competitive peptides encoded by the subject nucleic acids, and high affinity binding agents such as antibodies, specific for e.g. translation products of the disclosed BRCAl mutations and alleles.
  • Tumorigenic BRCAl alleles include BRCAl allele #5803 (SEQ ID NO:l), 9601 (SEQ ID NO:2), 9815 (SEQ ID NO:3), 8403 (SEQ ID NO:4), 8203 (SEQ ID NO:5), 388 (SEQ ID NO:6), 6401 (SEQ ID NO:7), 4406 (SEQ ID NO:8), 10201 (SEQ ID NO:9), 7408 (SEQ ID NO: 10), 582 (SEQ ID NO: 11) or 77 (SEQ ID NO: 12).
  • mutant and/or rare BRCAl alleles are used to generate specific binding compounds. Binding reagents are used diagnostically to distinguish non-tumorigenic wild-type and tumorigenic BRCAl translation products.
  • the subject nucleic acids may be single or double stranded and are isolated, partially purified, and/or recombinant.
  • An "isolated" nucleic acid is present as other than a naturally occurring chromosome or transcript in its natural state and isolated from
  • a partially pure nucleic acid constitutes at least about 10%, preferably at least about 30%, and more preferably at least about 90% by weight of total nucleic acid present in a given fraction; and a recombinant nucleic acid is joined in sequence to at least one nucleotide with which it is not normally associated on a natural chromosome.
  • Fragments of the disclosed alleles are sufficiently long for use as specific hybridization probes for detecting endogenous alleles, and particularly to distinguish the disclosed critical rare or mutant alleles which correlate with cancer susceptibility from other BRCAl alleles, including alleles encoding the BRCAl translation product displayed in Miki et al (1994) supra, under stringent conditions.
  • Preferred fragments are capable of hybridizing to the corresponding mutant allele under stringency conditions characterized by a hybridization buffer comprising 0% formamide in 0.9 M saline/0.09 M sodium citrate (SSC) buffer at a temperature of 37 °C and remaining bound when subject to washing at 42°C with the SSC buffer at 37°C.
  • SSC sodium citrate
  • fragments will hybridize in a hybridization buffer comprising 20% formamide in 0.9 M saline/0.09 M sodium citrate (SSC) buffer at a temperature of 42°C and remaining bound when subject to washing at 42°C with 2 X SSC buffer at 42°C.
  • SSC sodium citrate
  • the fragments are necessarily of length sufficient to be unique to the corresponding allele; i.e. has a nucleotide sequence at least long enough to define a novel oligonucleotide, usually at least about 14, 16, 18, 20, 22, or 24 bp in length, though such fragment may be joined in sequence to other nucleotides which may be nucleotides which naturally flank the fragment.
  • the nucleic acids are labelled with directly or indirectly detectable signals or means for amplifying a detectable signal.
  • Examples include radiolabels, luminescent (e.g. fluorescent) tags, components of amplified tags such antigen-labelled antibody, biotin-avidin combinations etc.
  • the nucleic acids can be subject to purification, synthesis, modification, sequencing, recombination, incorporation into a variety of vectors, expression, transfection, administration or methods of use disclosed in standard manuals such as Molecular Cloning, A
  • the subject nucleic acids are used in a wide variety of nucleic acid-based diagnostic method that are known to those in the art. Exemplary methods include their use as allele-specific oligonucleotide probes (ASOs), in ligase mediated methods for detecting mutations, as primers in PCR-based methods, direct sequencing methods wherein the clinical BRCAl nucleic acid sequence is compared with the disclosed mutations and rare alleles, etc.
  • ASOs allele-specific oligonucleotide probes
  • ligase mediated methods for detecting mutations
  • primers in PCR-based methods as primers in PCR-based methods
  • direct sequencing methods wherein the clinical BRCAl nucleic acid sequence is compared with the disclosed mutations and rare alleles, etc.
  • the subject nucleic acids are capable of detecting the presence of a critical mutant or rare BRCAl allele in a sample and distinguishing the mutant or rare allele from other BRCAl alleles.
  • the subject primer or probe comprises an oligonucleotide complementary to a strand of the mutant or rare allele of length sufficient to selectively hybridize with the mutant or rare allele.
  • these primers and probes comprise at least 16 bp to 24 bp complementary to the mutant or rare allele and may be as large as is convenient for the hybridizations conditions.
  • useful primers/probes require wild-type sequences flanking (both sides) the deletion with at least 2, usually at least 3, more usually at least 4, most usually at least 5 bases.
  • nucleic acid portions comprise and flank the substitution insertion with at least 2, preferably at least 3, more preferably at least 4, most preferably at least 5 bases.
  • substitutions or insertions from about 5 to about 20 bp it is usually necessary to include both the entire insertion/substitution and at least 2, usually at least 3, more usually at least 4, most usually at least 5 basis of wild-type sequence of at least one flank of the substitution/insertion.
  • BRCAl nucleic acids are used to effect a variety of gene-based therapies.
  • therapeutic nucleic acids are used to modulate cellular expression or intracellular concentration or availability of a tumorigenic BRCAl translation product by introducing into cells complements of the disclosed nucleic acids.
  • These nucleic acids are typically antisense: single-stranded sequences comprising complements of the disclosed relevant BRCAl mutant.
  • Antisense modulation of the expression of a given mutant may employ antisense nucleic acids operably linked to gene regulatory sequences.
  • Cell are transfected with a vector comprising such a sequence with a promoter sequence oriented such that transcription of the gene yields an antisense transcript capable of binding to the endogenous tumorigenic BRCAl allele or transcript.
  • Transcription of the antisense nucleic acid may be constitutive or inducible and the vector may provide for stable extrachromosomal maintenance or integration.
  • single-stranded antisense nucleic acids that bind to BRCAl genomic DNA or mRNA may be administered to the target cell, in or temporarily isolated from a host, at a concentration that results in a substantial reduction in expression of the targeted translation product.
  • nucleic acids may be introduced into viable cells.
  • the techniques vary depending upon whether one is using the subject compositions in culture or in vivo in a host.
  • Various techniques which have been found efficient include transfection with a retrovirus, viral coat protein-liposome mediated transfection, see Dzau et al., Trends in Biotech 11, 205-210 (1993).
  • an agent which targets the target cells such as an antibody specific for a surface membrane protein on the target cell, a ligand for a receptor on the target cell, etc.
  • proteins which bind to a surface membrane protein associated with endocytosis may be used for targeting and or to facilitate uptake, e.g.
  • capsid proteins or fragments thereof tropic for a particular cell type antibodies for proteins which undergo internalization in cycling, proteins that target intracellular localization and enhance intracellular half-life.
  • the decoy concentration in the lumen will generally be in the range of about 0.1 ⁇ M to 20 ⁇ M.
  • the application rate is determined empirically, using conventional techniques to determine desired ranges.
  • application of the subject therapeutics will be local, so as to be administered at the site of interest.
  • Various techniques can be used for providing the subject compositions at the site of interest, such as injection, use of catheters, trocars, projectiles, pluronic gel, stents, sustained drug release polymers or other device which provides for internal access.
  • Systemic administration of the nucleic acid using lipofection, liposomes with tissue targeting may also be employed.
  • the invention also provides isolated translation products of the disclosed BRCAl allele which distinguish the wild type BRCAl gene product. For example, for alleles which encode truncated tumorigenic translation product, the C-terminus is used to differentiate wild-type BRCAl. Accordingly, the invention provides the translation product of BRCAl allele #5803 (SEQ ID NO: 13), 9601 (SEQ ID NO: 14), 9815 (SEQ ID NO: 15), 8203 (SEQ ID NO: 17), 388 (SEQ ID NO: 18), 6401 (SEQ ID NO:19), 4406 (SEQ ID NO:20), 10201 (SEQ ID NO:21), 7408 (SEQ ID NO:22), 582 (SEQ ID NO:23) or 77 (SEQ ID NO:24), or a C-terminus fragment thereof; and that of #8403 (SEQ ID NO: 16), or a fragment thereof comprising Gly at position 61.
  • BRCAl allele #5803 SEQ ID NO: 13
  • 9601 SEQ ID
  • the subject mutant and/or rare allelic BRCAl translation products comprise an amino acid sequence which provides a target for distinguishing the product from that of other BRCAl alleles.
  • Preferred fragments are capable of eliciting the production of a peptide-specific antibody, in vivo or in vitro, capable of distinguishing a protein comprising the immunogenic peptide from a wild- type BRCAl translation product.
  • the fragments are necessarily unique to the disclosed allele translation product in that it is not found in any previously known protein and has a length at least long enough to define a novel peptide, from about 5 to about 25 residues, preferably from 6 to 10 residues in length, depending on the particular amino acid sequence.
  • the subject translation products are either isolated, i.e. unaccompanied by at least some of the material with which they are associated in their natural state); partially purified, i.e. constituting at least about 1%, preferably at least about 10%, and more preferably at least about 50% by weight of the total translation product in a given sample; or pure, Le. at least about 60%, preferably at least 80%, and more preferably at least about 90% by weight of total translation product. Included in the subject translation product weight are any atoms, molecules, groups, etc. covalently coupled to the subject translation products, such as detectable labels, glycosylations, phosphorylations, etc.
  • the subject translation products may be isolated, purified, modified or joined to other compounds in a variety of ways known to those skilled in the art depending on what other components are present in the sample and to what, if anything, the translation product is covalently linked.
  • Binding agents specific for the disclosed tumorigenic BRCAl genes and gene products find particular use in cancer diagnosis. The selected method of diagnosis will depend on the nature of the tumorigenic BRCAl mutants/rare allele and its transcription or translation product(s).
  • soluble secreted translation products of the disclosed alleles may be detected in a variety of physiologic fluids using a binding agent with a detectable label such as a radiolabel, fluorescer etc. Detection of membrane bound or intracellular products generally requires preliminary isolation of cells (e.g. blood cells) or tissue (e.g. breast biopsy tissue).
  • a wide variety of specific binding assays, e.g. ELISA may be used
  • BRCAl gene product-specific binding agents are produced in a variety of ways using the compositions disclosed herein.
  • structural x-ray crystallographic and/or NMR data of the mutant and/or rare allelic BRCAl translation products are used to rationally design binding molecules of determined structure or complementarity.
  • the disclosed mutant and/or rare allelic BRCAl translation products are used as immunogens to generate specific polyclonal or monoclonal antibodies. See, Harlow and Lane (1988) Antibodies, A Laboratory Manual, Cold Spring Harbor Laboratory, for general methods. Specific antibodies are readily modified to a monovalent form, such as Fab, Fab', or Fv.
  • mutant and or rare allelic BRCAl gene-product specific agents are screened from large libraries of synthetic or natural compounds. For example, numerous means are available for random and directed synthesis of saccharide, peptide, and nucleic acid based compounds. Alternatively, libraries of natural compounds in the form of bacterial, fungal, plant and animal extracts are available or readily producible. Additionally, natural and synthetically produced libraries and compounds are readily modified through conventional chemical, physical, and biochemical means. See, e.g. Houghten et al. and Lam et al (1991) Nature 354, 84 and 81, respectively and Blake and Litzi-Davis (1992), Bioconjugate Chem 3, 510.
  • Useful binding agents are identified with assays employing a compound comprising mutant and or rare allelic BRCAl peptides or encoding nucleic acids.
  • a wide variety of in vitro, cell-free binding assays, especially assays for specific binding to immobilized compounds comprising the subject nucleic acid or translation product find convenient use. See, e.g. Fodor et al (1991) Science 251, 767 for the light directed parallel synthesis method. Such assays are amenable to scale-up, high throughput usage suitable for volume drug screening.
  • Useful agents are typically those that bind the targeted mutant and/or rare allelic BRCAl gene product with high affinity and specificity and distinguish the tumorigenic BRCAl mutants/rare alleles from the wild-type BRCAl gene product.
  • Candidate agents comprise functional chemical groups necessary for structural interactions with proteins and/or DNA, and typically include at least an amine, carbonyl, hydroxyl or carboxyl group, preferably at least two of the functional chemical groups, more preferably at least three.
  • the candidate agents often comprise cyclical carbon or heterocyclic structures and/or aromatic or polyaromatic structures substituted with one or more of the forementioned functional groups.
  • Candidate agents are also found among biomolecules including peptides, saccharides, fatty acids, sterols, isoprenoids, purines, pyrimidines, derivatives, structural analogs or combinations thereof, and the like. Where the agent is or is encoded by a transfected nucleic acid, said nucleic acid is typically DNA or RNA.
  • Candidate agents are obtained from a wide variety of sources including libraries of synthetic or natural compounds. For example, numerous means are available for random and directed synthesis of a wide variety of organic compounds and biomolecules, including expression of randomized oligonucleotides. Alternatively, libraries of natural compounds in the form of bacteriaL fungaL plant and animal extracts are available or readily produced. Additionally, natural and synthetically produced libraries and compounds are readily modified through conventional chemical, physical, and biochemical means to enhance efficacy, stability, pharmaceutical compatibility, and the like. In addition, known pharmacological agents may be subject to directed or random chemical modifications, such as acylation, alkylation, esterification, amidification, etc., to produce structural analogs.
  • compositions and agents disclosed herein may be administered by any convenient way. Small organics are preferably administered orally; other compositions and agents are preferably administered parenterally, conveniently in a pharmaceutically or physiologically acceptable carrier, e.g., phosphate buffered saline, or the like. Typically, the compositions are added to a retained physiological fluid such as blood or synovial fluid. Generally, the amount administered will be empirically determined, typically in the range of about 10 to 1000 ⁇ g/kg of the recipient. For peptide agents, the concentration will generally be in the range of about 50 to 500 ⁇ g/ml in the dose administered. Other additives may be included, such as stabilizers, bactericides, etc. These additives will be present in conventional amounts.
  • Cosmids A gridded cosmid library of chromosome 17 was prepared. Alu-Alu PCR products of YACs were hybridized to the cosmid grids and positively hybridizing cosmids used for subsequent studies. Contigs were constructed in two ways. Cosmids with the same restriction patterns were aligned; and, the unique sequences flanking polymorphic markers and our sequenced cDNAs were used as STSes. Physical mapping by pulsed field gel electrophoresis. Physical distances were estimated by pulsed field gel electrophoresis, using DNA from lymphocyte cell lines of BRCAl -linked patients and of controls.
  • DNA samples were digested with NotI, Mlul, Rsrll, Nrul, Sac ⁇ , and EclXI. Filters were probed with single-copy sequences isolated from cosmids and later with cDNA clones. Multiple unrelated linked patients and controls were screened to detect large insertions or deletions associated with BRCAl. Results of PFGE were used to define the region first used to screen cDNA libraries as ⁇ 1 Mb and the current linked region as ⁇ 500 kb.
  • the fibroblast library was screened with YAC DNA isolated by PFGE. Pure YAC DNA (100 nanograms) was random primed with both aP32-dATP ( ⁇ OOOmCi/mmole) and 3 P-dCTP (3000 mCi/mmole), and used immediately after labelling. Filters from the library were prehybridized with human placental DNA for 24-48 hours. Labelled YAC DNA was hybridized to the filters for 48 hours at 65C. Approximately 250 transcripts were selected by screening with 7 YACs and then ross-hybridized. We also used pools of cosmids from the linked region to screen the fibroblast library. We selected 122 transcripts and cross-hybridized them to clones previously detected by the YACs.
  • RNA and polyA+ RNA from germline DNA (from lymphoblast lines) of 20 unrelated linked patients, from ovarian and breast tissues, from fibroblasts, from a HeLa cell line, and from breast cancer cell lines. Northern blots are screened with each gene.
  • cDNA From poly-A+ mRNA from lymphoblast cell lines of 20 unrelated linked patients and from controls. cDNA has also been made from 65 malignant ovarian cancers from patients not selected for family history.
  • Primers are constructed every -200 basepairs along the sequence and used to amplify these cDNAs.
  • Genomic DNA has also been prepared from cell lines from all family members (linked and unlinked), from malignant and normal cells from parafiBn blocks from their breast and ovarian surgeries, and from malignant and normal cells from 29 breast tumors not selected for family history. For sequences without introns, cDNA and gDNA lengths are equal, and the gDNA samples are amplified as well.
  • BRCAl mutations in chromosome 17q-linked families The series of families includes 20 large extended kindreds in which breast and ovarian cancer (and in one family prostatic cancer) are linked to 17q21, with individual lod scores > 1.5. Since linked patients in these families carry mutations in BRCAl, we have identified their mutations first.
  • Table 1 summarizes critical BRCAl mutations and rare alleles:
  • Germline mutations in BRCAl are identified using the approaches described above and by directly sequencing new mutations. Paraffin-embedded tumor specimens from the same patients are screened for alterations of p53, HER2, PRAD1, and ER. Germline BRCAl mutations are tested in the tumor blocks. A preliminary estimate of risk associated with different BRCAl mutations is obtained from relatives of patients with germline alterations.
  • Malignant cells are dissected from normal cells from paraffin blocks. By identifying BRCAl mutations in these series, we estimate the frequency of somatic BRCAl alterations, determine BRCAl mutations characteristic of any particular stage of tumor development, and evaluate their association with prognosis.
  • BRCAl Characterizing mutant and rare alleles of BRCAl. Mutant or rare BRCAl allele function and pattern of expression during development are characterized using transformed cells expressing the allele and knockout or transgenic mice. For example, phenotypic changes in the animal or cell line, such as growth rate and anchorage independence are determined. In addition, several methods are used to study loss-of-function mutations, including replacing normal genes with their mutant alleles (BRCAl - BRCA 1-) by homologous recombination in embryonic stem (ES) cells and replacing mutant alleles with their normal counterparts in differentiated cultured cells (Capecchi 1989 Science 244:1288-1292; Weissman et al. 1987 Science 236:175-180; Wang et al. 1993 Oncogene 8:279-288). Breast carcinoma cell lines are screened for mutation at the
  • BRCAl locus and a mutant BRCAl line is selected.
  • Normal and mutant cDNAs of BRCAl are subcloned into an expression vector carrying genes which confer resistance to ampicillin and geneticin (Baker et aL 1990 Nature 249:912-915).
  • Subclones are transfected into mutant BRCAl breast cancer cells
  • Geneticin-resistant colonies are isolated and examined for any change in tumorigenic phenotype, such as colony formation in soft agar, increased growth rate, and/or tumor formation in athymic nude mice.
  • In vivo functional demonstrations involve introducing the normal BCRA1 gene into a breast carcinoma cell line mutant at BRCAl and injecting these BRCAl + cells into nude mice. Changes observed in tumorigenic growth compared to nude mice injected with BRCAl mutant breast carcinoma cells are readily observed. For example, correcting the mutant gene decreases the ability of the breast carcinoma cells to form tumors in nude mice
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  • CAGTCAGGCA CAGCAGAAAC CTACAACTCA TGGAAGGTAA AGAACCTGCA ACTGGAGCCA 2100 AGAAGAGTAA CAAGCCAAAT GAACAGACAA GTAAAAGACA TGACAGCGAT ACTTTCCCAG 2160
  • GTAGTCATGC ATCTCAGGTT TGTTCTGAGA CACCTGATGA CCTGTTAGAT GATGGTGAAA 3540
  • AAAGCGTCCA GAAAGGAGAG CTTAGCAGGA GTCCTAGCCC TTTCACCCAT ACACATTTGG 660
  • AAAGTAGTGA ATACCCTATA AGCCAGAATC CAGAAGGCCT TTCTGCTGAC AAGTTTGAGG 4500
  • TGACAGCTTC AACAGAAAGG GTCAACAAAA GAATGTCCAT GGTGGTGTCT GGCCTGACCC 5040 CAGAAGAATT TATGCTCGTG TACAAGTTTG CCAGAAAACA CCACATCACT TTAACTAATC 5100
  • TGTAAAAGTG AAAGAGTTCA CTCCAAATCA GTAGAGAGTA ATATTGAAGA CAAAATATTT 1500 GGGAAAACCT ATCGGAAGAA GGCAAGCCTC CCCAACTTAA GCCATGTAAC TGAAAATCTA 1560
  • TGTGCAACAT TCTCTGCCCA CTCTGGGTCC TTAAAGAAAC AAAGTCCAAA AGTCACTTTT 2820 GAATGTGAAC AAAAGGAAGA AAATCAAGGA AAGAATGAGT CTAATATCAA GCCTGTACAG 2880
  • CTACCCTTCC ATCATAAGTG ACTCTTCTGC CCTTGAGGAC CTGCGAAATC CAGAACAAAG 4440
  • CAAGCAATAT TAATGAAGTA GGTTCCAGTA CTAATGAAGT GGGCTCCAGT ATTAATGAAA 3300 TAGGTTCCAG TGATGAAAAC ATTCAAGCAG AACTAGGTAG AAACAGAGGG CCAAAATTGA 3360
  • GTAATTGTAA GCATCCTGAA ATAAAAAAGC AAGAATATGA AGAAGTAGTT CAGACTGTTA 3480
  • CTACTAGGCA TAGCACCGTT GCTACCGAGT GTCTGTCTAA GAACACAGAG GAGAATTTAT 3900
  • TAACAAGCCA AATGAACAGA CAAGTAAAAG ACATGACAGC GATACTTTCC CAGAGCTGAA 2220 GTTAACAAAT GCACCTGGTT CTTTTACTAA GTGTTCAAAT ACCAGTGAAC TTAAAGAATT 2280
  • CAAGGTTTCA AAGCGCCAGT CATTTGCTCC GTTTTCAAAT CCAGGAAATG CAGAAGAGGA 2760
  • MOLECULE TYPE cDNA
  • SEQUENCE DESCRIPTION SEQ ID NO:7:
  • GGCACAGCAG AAACCTACAA CTCATGGAAG GTAAAGAACC TGCAACTGGA GCCAAGAAGA 2160 GTAACAAGCC AAATGAACAG ACAAGTAAAA GACATGACAG CGATACTTTC CCAGAGCTGA 2220
  • TGTGCAACAT TCTCTGCCCA CTCTGGGTCC TTAAAGAAAC AAAGTCCAAA AGTCACTTTT 2820
  • GGCACAGCAG AAACCTACAA CTCATGGAAG GTAAAGAACC TGCAACTGGA GCCAAGAAGA 2160 GTAACAAGCC AAATGAACAG ACAAGTAAAA GACATGACAG CGATACTTTC CCAGAGCTGA 2220
  • CTACTAGGCA TAGCACCGTT GCTACCGAGT GTCTGTCTAA GAACACAGAG GAGAATTTAT 3900
  • GTAATTGTAA GCATCCTGAA ATAAAAAAGC AAGAATATGA AGAAGTAGTT CAGACTGTTA 3480
  • CTACTAGGCA TAGCACCGTT GCTACCGAGT GTCTGTCTAA GAACACAGAG GAGAATTTAT 3900
  • CAAGCAATAT TAATGAAGTA GGTTCCAGTA CTAATGAAGT GGGCTCCAGT ATTAATGAAA 3300 TAGGTTCCAG TGATGAAAAC ATTCAAGCAG AACTAGGTAG AAACAGAGGG CCAAAATTGA 3360
  • GTAATTGTAA GCATCCTGAA ATAAAAAAGC AAGAATATGA AGAAGTAGTT CAGACTGTTA 3480
  • CTACTAGGCA TAGCACCGTT GCTACCGAGT GTCTGTCTAA GAACACAGAG GAGAATTTAT 3900 TATCATTGAA GAATAGCTTA AATGACTGCA GTAACCAGGT AATATTGGCA AAGGCATCTC 3960

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Abstract

Specific BRCA1 mutations, PCR primers and hybridization probes are used in nucleic acid-based methods for diagnostic of inheritable breast cancer susceptibility. Addtionally, binding agents, such as antibodies, specific for peptides encoded by the subject BRCA1 mutants are used to identify expression products of diagnostic mutations/rare alleles in patient derived fluid or tissue samples. Compositions with high binding affinity for transcription or translation products of the disclosed BRCA1 mutations and alleles are used in therapeutic intervention. Such products include anti-sense nucleic acids, peptides encoded by the subject nucleic acids, and binding agents such as antibodies, specific for such peptides.

Description

Genetic Markers for Breast and Ovarian Cancer
The research carried out in the subject application was supported in part by grants from the National Institutes of Health. The government may have rights in any patent issuing on this application.
INTRODUCTION Field of the Invention The field of the invention is genetic markers for inheritable breast cancer susceptibility.
Background
The largest proportion of inherited breast cancer described so far has been attributed to a genetic locus, the BRCAl locus, on chromosome 17q21 (Hall et al. 1990 Science 250:1684- 1689; Narod et al. 1991 Lancet 338:82-83; Easton et al. 1993 Am J Hum Genet 52:678-701). Background material on the genetic markers for breast cancer screening is found in the Jan 29,
1993 issue of Science, vol 259, especially pages 622-625; see also King et al., 1993 J Amer Med Assoc 269: 1975-198. Other relevant research papers include King (1992) Nature Genet 2: 125- 126; Merette et al. (1992) Amer J Human Genet 50:515-519; NIH CEPH Collaborative Mapping Group (1992) Science 258:67-86. Risks of breast cancer to women inheriting the locus are extremely high, exceeding 50% before age 50 and reaching 80% by age 65 (Newman et al. 1988 Proc Natl Acad Sci USA 85:3044-3048; Hall et al. 1992 Amer J Human Genet 50:1235-1242; Easton et al. 1993). Epidemiological evidence for inherited susceptibility to ovarian cancer is even stronger (Cramer et al. 1983 J Natl Cancer Inst 71:711-716; Schildkraut & Thompson 1988 Amer J Epidemiol 128:456-466; Schildkraut et al. 1989 Amer J Hum Genet 45:521-529). According to one study, more than 90% of families with multiple relatives with breast and ovarian cancer trace disease susceptibility to chromosome 17q21 (Easton et al. 1993).
The link between increasing risk of breast and ovarian cancer and inherited susceptibility to these diseases lies in the application of genetics to diagnosis and prevention. Creating molecular tools for earlier diagnosis and developing ways to reverse the first steps of tumorigenesis may be the most effective means of breast and ovarian cancer control.
Our laboratory previously mapped the heritable breast cancer susceptibility gene locus (BRCAl locus) to a 50 cM region of chromosome 17q (Hall et al. 1990). More recently, we developed new polymorphisms at ERBB2 (Hall and King 1991 Nucl Acids Res 19:2515), THRA1
(Bowcock et aL 1993 Amer J Human Genet 52:718-722), EDH17B (Friedman et al. 1993 Hum Molec Genet 2:821), and multiple anonymous loci (Anderson et al. 1993 Genomics 17:616-623), ultimately developing a high density map of 17ql2-q21 (Anderson et al. 1993; see also, Simard et al. 1993 Human Molec Genet 2:1193-1199). We also added families to the genetic study; there are now 100 families for whom transformed lymphocyte lines have been established and all informative relatives genotyped. We used our new markers and the many chromosome 17q polymorphisms developed in the past three years to test linkage in our families, refining the region first to 8 cM (Hall et al. 1992), then to 4 cM (Bowcock et al. 1993), then to 1 Mb based on polymorphisms from our high density map (Anderson et al. 1993; see also Flejter et al., 1993 Genomics 17:624-631). We disclose here a number of mutations in BRCAl which correlate with disease. Relevant Literature
The predicted amino acid sequence for a BRCAl cDNA and familial studies of this gene were described by Miki et al. (1994) Science 266, 66-71 and Futeal et al. (1994) Science 266, 120-122. A study of Canadian cancer families is described in Simard et al. (1994) Nature
Genetics 8, 392-398. A collaborative survey of BRCAl mutations is described in Shattuch- Eidens et al. (1995) JAMA 273, 535-541.
SUMMARY OF THE INVENTION The invention discloses methods and compositions useful in the diagnosis and treatment of breast and ovarian cancer associated with mutations and/or rare alleles of BRCAl, a breast cancer susceptibility gene. Specific genetic probes diagnostic of inheritable breast cancer susceptibility and methods of use are provided. Labelled nucleic acid probes comprising sequences complementary to specified BRCAl alleles are hybridized to clinical nucleic acid samples. Linkage analysis and inheritance patterns of the disclosed markers are used to diagnose genetic susceptibility. In addition, BRCAl mutations and or rare alleles are directly identified by hybridization, polymorphism and or sequence analysis. In another embodiment, labeled binding agents, such as antibodies, specific for peptides encoded by the subject nucleic acids are used to identify expression products of diagnostic mutations or alleles in patient derived fluid or tissue samples. For therapeutic intervention, the invention provides compositions which can functionally interfere with the transcription or translation products of the breast and ovarian cancer susceptibility associated mutations and/or rare alleles within BRCAl . Such products include anti- sense nucleic acids, competitive peptides encoded by the subject nucleic acids, and high affinity binding agents such as antibodies, specific for e.g. translation products of the disclosed BRCAl mutations and alleles.
DESCRIPTION OF SPECIFIC EMBODIMENTS We disclose here methods and compositions for determining the presence or absence of
BRCAl mutations and rare alleles or translation products thereof which are useful in the diagnosis of breast and ovarian cancer susceptibility. Tumorigenic BRCAl alleles include BRCAl allele #5803 (SEQ ID NO:l), 9601 (SEQ ID NO:2), 9815 (SEQ ID NO:3), 8403 (SEQ ID NO:4), 8203 (SEQ ID NO:5), 388 (SEQ ID NO:6), 6401 (SEQ ID NO:7), 4406 (SEQ ID NO:8), 10201 (SEQ ID NO:9), 7408 (SEQ ID NO: 10), 582 (SEQ ID NO: 11) or 77 (SEQ ID NO: 12). These nucleic acids or fragments capable of specifically hybridizing with the corresponding allele in the presence of other BRCAl alleles under stringent conditions find broad diagnostic and therapeutic application. Gene products of the disclosed mutant and/or rare BRCAl alleles also find a broad range of therapeutic and diagnostic applications. For example, mutant and/or rare allelic BRCAl peptides are used to generate specific binding compounds. Binding reagents are used diagnostically to distinguish non-tumorigenic wild-type and tumorigenic BRCAl translation products.
The subject nucleic acids (including fragments thereof) may be single or double stranded and are isolated, partially purified, and/or recombinant. An "isolated" nucleic acid is present as other than a naturally occurring chromosome or transcript in its natural state and isolated from
(not joined in sequence to) at least one nucleotide with which it is normally associated on a natural chromosome; a partially pure nucleic acid constitutes at least about 10%, preferably at least about 30%, and more preferably at least about 90% by weight of total nucleic acid present in a given fraction; and a recombinant nucleic acid is joined in sequence to at least one nucleotide with which it is not normally associated on a natural chromosome.
Fragments of the disclosed alleles are sufficiently long for use as specific hybridization probes for detecting endogenous alleles, and particularly to distinguish the disclosed critical rare or mutant alleles which correlate with cancer susceptibility from other BRCAl alleles, including alleles encoding the BRCAl translation product displayed in Miki et al (1994) supra, under stringent conditions. Preferred fragments are capable of hybridizing to the corresponding mutant allele under stringency conditions characterized by a hybridization buffer comprising 0% formamide in 0.9 M saline/0.09 M sodium citrate (SSC) buffer at a temperature of 37 °C and remaining bound when subject to washing at 42°C with the SSC buffer at 37°C. More preferred fragments will hybridize in a hybridization buffer comprising 20% formamide in 0.9 M saline/0.09 M sodium citrate (SSC) buffer at a temperature of 42°C and remaining bound when subject to washing at 42°C with 2 X SSC buffer at 42°C. In any event, the fragments are necessarily of length sufficient to be unique to the corresponding allele; i.e. has a nucleotide sequence at least long enough to define a novel oligonucleotide, usually at least about 14, 16, 18, 20, 22, or 24 bp in length, though such fragment may be joined in sequence to other nucleotides which may be nucleotides which naturally flank the fragment. In many applications, the nucleic acids are labelled with directly or indirectly detectable signals or means for amplifying a detectable signal. Examples include radiolabels, luminescent (e.g. fluorescent) tags, components of amplified tags such antigen-labelled antibody, biotin-avidin combinations etc. The nucleic acids can be subject to purification, synthesis, modification, sequencing, recombination, incorporation into a variety of vectors, expression, transfection, administration or methods of use disclosed in standard manuals such as Molecular Cloning, A
Laboratory Manual (2nd Ed., Sambrook, Fritsch and Maniatis, Cold Spring Harbor), Current
Protocols in Molecular Biology (Eds. Aufubel, Brent, Kingston, More, Feidman, Smith and Stuhl,
Greene Publ. Assoc, Wiley-Interscience, NY, NY, 1992) or that are otherwise known in the art.
The subject nucleic acids are used in a wide variety of nucleic acid-based diagnostic method that are known to those in the art. Exemplary methods include their use as allele-specific oligonucleotide probes (ASOs), in ligase mediated methods for detecting mutations, as primers in PCR-based methods, direct sequencing methods wherein the clinical BRCAl nucleic acid sequence is compared with the disclosed mutations and rare alleles, etc. The subject nucleic acids are capable of detecting the presence of a critical mutant or rare BRCAl allele in a sample and distinguishing the mutant or rare allele from other BRCAl alleles. For example, where the subject nucleic acids are used as PCR primers or hybridization probes the subject primer or probe comprises an oligonucleotide complementary to a strand of the mutant or rare allele of length sufficient to selectively hybridize with the mutant or rare allele. Generally, these primers and probes comprise at least 16 bp to 24 bp complementary to the mutant or rare allele and may be as large as is convenient for the hybridizations conditions. Where the critical mutation is a deletion of wild-type sequence, useful primers/probes require wild-type sequences flanking (both sides) the deletion with at least 2, usually at least 3, more usually at least 4, most usually at least 5 bases. Where the mutation is an insertion or substitution which exceeds about 20 bp, it is generally not necessary to include wild-type sequence in the probes/primers. For insertions or substitutions of fewer than 5 bp, preferred nucleic acid portions comprise and flank the substitution insertion with at least 2, preferably at least 3, more preferably at least 4, most preferably at least 5 bases. For substitutions or insertions from about 5 to about 20 bp, it is usually necessary to include both the entire insertion/substitution and at least 2, usually at least 3, more usually at least 4, most usually at least 5 basis of wild-type sequence of at least one flank of the substitution/insertion. In addition to their use as diagnostic genetic probes and primers, BRCAl nucleic acids are used to effect a variety of gene-based therapies. See, e.g. Zhu et al. (1993) Science 261, 209-211; Gutierrez et al. (1992) Lancet 339, 715-721; Gary Nabel lab (Dec 1993), Proc. Nat'l. Acad Sci USA. For example, therapeutic nucleic acids are used to modulate cellular expression or intracellular concentration or availability of a tumorigenic BRCAl translation product by introducing into cells complements of the disclosed nucleic acids. These nucleic acids are typically antisense: single-stranded sequences comprising complements of the disclosed relevant BRCAl mutant. Antisense modulation of the expression of a given mutant may employ antisense nucleic acids operably linked to gene regulatory sequences. Cell are transfected with a vector comprising such a sequence with a promoter sequence oriented such that transcription of the gene yields an antisense transcript capable of binding to the endogenous tumorigenic BRCAl allele or transcript. Transcription of the antisense nucleic acid may be constitutive or inducible and the vector may provide for stable extrachromosomal maintenance or integration. Alternatively, single-stranded antisense nucleic acids that bind to BRCAl genomic DNA or mRNA may be administered to the target cell, in or temporarily isolated from a host, at a concentration that results in a substantial reduction in expression of the targeted translation product.
Various techniques may be employed for introducing of the nucleic acids into viable cells. The techniques vary depending upon whether one is using the subject compositions in culture or in vivo in a host. Various techniques which have been found efficient include transfection with a retrovirus, viral coat protein-liposome mediated transfection, see Dzau et al., Trends in Biotech 11, 205-210 (1993). In some situations it is desirable to provide the nucleic acid source with an agent which targets the target cells, such as an antibody specific for a surface membrane protein on the target cell, a ligand for a receptor on the target cell, etc. Where liposomes are employed, proteins which bind to a surface membrane protein associated with endocytosis may be used for targeting and or to facilitate uptake, e.g. capsid proteins or fragments thereof tropic for a particular cell type, antibodies for proteins which undergo internalization in cycling, proteins that target intracellular localization and enhance intracellular half-life. In liposomes, the decoy concentration in the lumen will generally be in the range of about 0.1 μM to 20 μM. For other techniques, the application rate is determined empirically, using conventional techniques to determine desired ranges. Usually, application of the subject therapeutics will be local, so as to be administered at the site of interest. Various techniques can be used for providing the subject compositions at the site of interest, such as injection, use of catheters, trocars, projectiles, pluronic gel, stents, sustained drug release polymers or other device which provides for internal access. Systemic administration of the nucleic acid using lipofection, liposomes with tissue targeting (e.g. antibody) may also be employed.
The invention also provides isolated translation products of the disclosed BRCAl allele which distinguish the wild type BRCAl gene product. For example, for alleles which encode truncated tumorigenic translation product, the C-terminus is used to differentiate wild-type BRCAl. Accordingly, the invention provides the translation product of BRCAl allele #5803 (SEQ ID NO: 13), 9601 (SEQ ID NO: 14), 9815 (SEQ ID NO: 15), 8203 (SEQ ID NO: 17), 388 (SEQ ID NO: 18), 6401 (SEQ ID NO:19), 4406 (SEQ ID NO:20), 10201 (SEQ ID NO:21), 7408 (SEQ ID NO:22), 582 (SEQ ID NO:23) or 77 (SEQ ID NO:24), or a C-terminus fragment thereof; and that of #8403 (SEQ ID NO: 16), or a fragment thereof comprising Gly at position 61.
The subject mutant and/or rare allelic BRCAl translation products comprise an amino acid sequence which provides a target for distinguishing the product from that of other BRCAl alleles.
Preferred fragments are capable of eliciting the production of a peptide-specific antibody, in vivo or in vitro, capable of distinguishing a protein comprising the immunogenic peptide from a wild- type BRCAl translation product. The fragments are necessarily unique to the disclosed allele translation product in that it is not found in any previously known protein and has a length at least long enough to define a novel peptide, from about 5 to about 25 residues, preferably from 6 to 10 residues in length, depending on the particular amino acid sequence.
The subject translation products (including fragments) are either isolated, i.e. unaccompanied by at least some of the material with which they are associated in their natural state); partially purified, i.e. constituting at least about 1%, preferably at least about 10%, and more preferably at least about 50% by weight of the total translation product in a given sample; or pure, Le. at least about 60%, preferably at least 80%, and more preferably at least about 90% by weight of total translation product. Included in the subject translation product weight are any atoms, molecules, groups, etc. covalently coupled to the subject translation products, such as detectable labels, glycosylations, phosphorylations, etc. The subject translation products may be isolated, purified, modified or joined to other compounds in a variety of ways known to those skilled in the art depending on what other components are present in the sample and to what, if anything, the translation product is covalently linked. Binding agents specific for the disclosed tumorigenic BRCAl genes and gene products find particular use in cancer diagnosis. The selected method of diagnosis will depend on the nature of the tumorigenic BRCAl mutants/rare allele and its transcription or translation product(s). For example, soluble secreted translation products of the disclosed alleles may be detected in a variety of physiologic fluids using a binding agent with a detectable label such as a radiolabel, fluorescer etc. Detection of membrane bound or intracellular products generally requires preliminary isolation of cells (e.g. blood cells) or tissue (e.g. breast biopsy tissue). A wide variety of specific binding assays, e.g. ELISA, may be used
BRCAl gene product-specific binding agents are produced in a variety of ways using the compositions disclosed herein. For example, structural x-ray crystallographic and/or NMR data of the mutant and/or rare allelic BRCAl translation products are used to rationally design binding molecules of determined structure or complementarity. Also, the disclosed mutant and/or rare allelic BRCAl translation products are used as immunogens to generate specific polyclonal or monoclonal antibodies. See, Harlow and Lane (1988) Antibodies, A Laboratory Manual, Cold Spring Harbor Laboratory, for general methods. Specific antibodies are readily modified to a monovalent form, such as Fab, Fab', or Fv.
Other mutant and or rare allelic BRCAl gene-product specific agents are screened from large libraries of synthetic or natural compounds. For example, numerous means are available for random and directed synthesis of saccharide, peptide, and nucleic acid based compounds. Alternatively, libraries of natural compounds in the form of bacterial, fungal, plant and animal extracts are available or readily producible. Additionally, natural and synthetically produced libraries and compounds are readily modified through conventional chemical, physical, and biochemical means. See, e.g. Houghten et al. and Lam et al (1991) Nature 354, 84 and 81, respectively and Blake and Litzi-Davis (1992), Bioconjugate Chem 3, 510.
Useful binding agents are identified with assays employing a compound comprising mutant and or rare allelic BRCAl peptides or encoding nucleic acids. A wide variety of in vitro, cell-free binding assays, especially assays for specific binding to immobilized compounds comprising the subject nucleic acid or translation product find convenient use. See, e.g. Fodor et al (1991) Science 251, 767 for the light directed parallel synthesis method. Such assays are amenable to scale-up, high throughput usage suitable for volume drug screening.
Useful agents are typically those that bind the targeted mutant and/or rare allelic BRCAl gene product with high affinity and specificity and distinguish the tumorigenic BRCAl mutants/rare alleles from the wild-type BRCAl gene product. Candidate agents comprise functional chemical groups necessary for structural interactions with proteins and/or DNA, and typically include at least an amine, carbonyl, hydroxyl or carboxyl group, preferably at least two of the functional chemical groups, more preferably at least three. The candidate agents often comprise cyclical carbon or heterocyclic structures and/or aromatic or polyaromatic structures substituted with one or more of the forementioned functional groups. Candidate agents are also found among biomolecules including peptides, saccharides, fatty acids, sterols, isoprenoids, purines, pyrimidines, derivatives, structural analogs or combinations thereof, and the like. Where the agent is or is encoded by a transfected nucleic acid, said nucleic acid is typically DNA or RNA.
Candidate agents are obtained from a wide variety of sources including libraries of synthetic or natural compounds. For example, numerous means are available for random and directed synthesis of a wide variety of organic compounds and biomolecules, including expression of randomized oligonucleotides. Alternatively, libraries of natural compounds in the form of bacteriaL fungaL plant and animal extracts are available or readily produced. Additionally, natural and synthetically produced libraries and compounds are readily modified through conventional chemical, physical, and biochemical means to enhance efficacy, stability, pharmaceutical compatibility, and the like. In addition, known pharmacological agents may be subject to directed or random chemical modifications, such as acylation, alkylation, esterification, amidification, etc., to produce structural analogs. Therapeutic applications typically involve binding to and functional disruption of a tumorigenic BRCAl gene product by an administered high affinity binding agent. For therapeutic uses, the compositions and agents disclosed herein may be administered by any convenient way. Small organics are preferably administered orally; other compositions and agents are preferably administered parenterally, conveniently in a pharmaceutically or physiologically acceptable carrier, e.g., phosphate buffered saline, or the like. Typically, the compositions are added to a retained physiological fluid such as blood or synovial fluid. Generally, the amount administered will be empirically determined, typically in the range of about 10 to 1000 μg/kg of the recipient. For peptide agents, the concentration will generally be in the range of about 50 to 500 μg/ml in the dose administered. Other additives may be included, such as stabilizers, bactericides, etc. These additives will be present in conventional amounts.
The following examples are offered by way of illustration and not by way of limitation.
EXAMPLES Example 1 Positional cloning Contig construction.
______ Primers flanking polymorphic repeats in the 4 Mb region of linkage were used to amplify pools from the CEPH, Washington University, and CEPH megaYAC libraries available. 39 YACs were selected. Of these, 23 were tested for chimerism by FISH and 12 found to be chimeric. YACs were aligned to each other by attempting to amplify each YAC with primer pairs from known sequence tagged sites (STSes). More STSes were defined by sequencing the ends of
YACs, and these new STSes used for further alignment and YAC identification. Cosmids. A gridded cosmid library of chromosome 17 was prepared. Alu-Alu PCR products of YACs were hybridized to the cosmid grids and positively hybridizing cosmids used for subsequent studies. Contigs were constructed in two ways. Cosmids with the same restriction patterns were aligned; and, the unique sequences flanking polymorphic markers and our sequenced cDNAs were used as STSes. Physical mapping by pulsed field gel electrophoresis. Physical distances were estimated by pulsed field gel electrophoresis, using DNA from lymphocyte cell lines of BRCAl -linked patients and of controls. DNA samples were digested with NotI, Mlul, Rsrll, Nrul, Sacϋ, and EclXI. Filters were probed with single-copy sequences isolated from cosmids and later with cDNA clones. Multiple unrelated linked patients and controls were screened to detect large insertions or deletions associated with BRCAl. Results of PFGE were used to define the region first used to screen cDNA libraries as ~1 Mb and the current linked region as ≤ 500 kb.
Screening cDNA libraries. We began library screening when the linked region defined by meiotic recombination was -1 Mb. The first question was what library would optimize the length of cDNA clones, representation of both 5' and 3' ends of genes, and the chances that BRCAl would be expressed. We chose to use a random primed cDNA library cloned into lgtlO from cultured (not transformed) fibroblasts from a human female. This library was selected because it had inserts averaging 1.8 kb, with 80% of inserts between 1 and 4 kb, was contructed from cultured fibroblasts known to be "leaky" in gene expression, and was known to include 5' ends of genes. We simultaneously screened three other libraries (from ovary, fetal brain, and mouse mammary epithelium). With one exception (described below), all transcripts from these libraries cross-hybridized to transcripts from the fibroblast library.
The fibroblast library was screened with YAC DNA isolated by PFGE. Pure YAC DNA (100 nanograms) was random primed with both aP32-dATP (όOOOmCi/mmole) and 3 P-dCTP (3000 mCi/mmole), and used immediately after labelling. Filters from the library were prehybridized with human placental DNA for 24-48 hours. Labelled YAC DNA was hybridized to the filters for 48 hours at 65C. Approximately 250 transcripts were selected by screening with 7 YACs and then ross-hybridized. We also used pools of cosmids from the linked region to screen the fibroblast library. We selected 122 transcripts and cross-hybridized them to clones previously detected by the YACs.
Example 2. Cloning BRCAl and its characterization.
A. Screening for mutations in candidate genes. We initially identified 24 genes in the 1Mb BRCAl region defined by meiotic recombination, respective locations on the YAC contig, sizes of representative cDNA clones, numbers of replicates in the library, sizes of transcripts, homologies to known genes, and variants detected. Candidate gene were characterized in the following ways: (1) Cross-hybridi7ing clones. cDNA clones isolated from the library are hybridized against each other. Cross-hybridizing clones are considered "siblings" of the clone used as a probe and represent the same gene.
(2) Mapping back. At least one clone from each sibship is mapped back to total human genomic DNA, to cosmids, to YACs, and to somatic cell hybrid lines, some of which contain deletions of
17q and one of which has chromosome 17 as its only human chromosome.
(3) Subcloning and sequencing. One of the longest clones from each sibship is subcloned into M13 and sequenced manually by standard methods, constructing new primers at the end of each fragment to continue sequencing until the end of the clone is reached. (4) Extending sequences with sibs. In order to find clones that contain more of the gene, the last sequencing primer for the clone and primers made from λgtlO are used to amplify sibs of the first clone. Sibs that amplify the longest fragments are selected, subcloned, and sequenced. This process is continued until we reach the size of the transcript defined by Northern blot and/or until the 3' sequence is a polyA tail and the 5' sequence has features of the beginning of the coding region.
(5) Southerns. To identify insertion or deletion mutations, genomic DNA from 20 unrelated patients from families with breast cancer linked to 17q (i.e. "linked patients") and controls are digested with Baml/TaqI and independently with Hindm Hinfl. Each cDNA clone is used to screen Southern blots. Variants have been detected in two genes. Both of these variants are RFLPs, occuring in equal frequency in linked patients and in controls.
(6) Northerns. To identify splice mutations and/or length mutations, we prepared total RNA and polyA+ RNA from germline DNA (from lymphoblast lines) of 20 unrelated linked patients, from ovarian and breast tissues, from fibroblasts, from a HeLa cell line, and from breast cancer cell lines. Northern blots are screened with each gene. (7) Detection of small mutations. To screen for germline point mutations in patients without encountering introns, we prepared cDNA from poly-A+ mRNA from lymphoblast cell lines of 20 unrelated linked patients and from controls. cDNA has also been made from 65 malignant ovarian cancers from patients not selected for family history. Primers are constructed every -200 basepairs along the sequence and used to amplify these cDNAs. Genomic DNA has also been prepared from cell lines from all family members (linked and unlinked), from malignant and normal cells from parafiBn blocks from their breast and ovarian surgeries, and from malignant and normal cells from 29 breast tumors not selected for family history. For sequences without introns, cDNA and gDNA lengths are equal, and the gDNA samples are amplified as well.
Two mutation detection methods are used to screen each sequence. Amplified products are screened for SSCPs using modifications that enable electrophoresis to be done with only one set of running conditions (Keen et aL 1991 Trends Genet 7:5; Soto and Sukumar 1992 PCR Meth Appl 2:96-98). In order to screen longer segments of DNA (100-1500 bp) and to detect variants missed by SSCP, sequences are also screened for point mutations by CCM (Cotton 1993 Mutation Res 285:125-144) using essentially the protocol of Grompe et al. 1989 Proc Natl Acad Sci USA 86:5888-5892. An endonuclease developed for mismatch detection reduces the toxicity of the method (Youil et al. 1993 Amer J Hum Genet 53 (supplement): abstract 1257). (8) Polymorphism or mutation. Variants are screened in cases and controls to distinguish polymorphisms from a critical mutation. Linkage of breast cancer to each variant is tested in all informative families. Example 3. Characterize BRCAl mutations in germline DNA and breast cancer patients tumors.
A. BRCAl mutations in chromosome 17q-linked families. Our series of families includes 20 large extended kindreds in which breast and ovarian cancer (and in one family prostatic cancer) are linked to 17q21, with individual lod scores > 1.5. Since linked patients in these families carry mutations in BRCAl, we have identified their mutations first.
Table 1 summarizes critical BRCAl mutations and rare alleles:
Family Exon U 14680 nt Mutation Amino Acid Predicted change effect
5803 3 200-253 exon 3 deleted (54 bp) 27 Stop protein truncation
9601 3 230 deletion AA 39 Stop protein truncation
9815 Intron 5 splice donor, substitution G to A 64 Stop protein bp +1 ->22 bp deletion in RNA truncation
8403 5 300 substitution T to G Cys 61 Gly lose zinc- binding motif
8203 Intron 5 splice substitution T to G 81 Stop protein acceptor, bp ->59 bp insertion of truncation -11 intron into RNA 388 1048 deletion A 313 Stop protein truncation
6401 2415 deletion AG Ser 766 Stop protein truncation
4406 2800 deleiton AA 901 Stop protein truncation
10201 2863 deletion TC Ser 915 Stop protein truncation
7408 3726 substitution C to T Arg 1203 protein Stop truncation
582 4184 deletion TCAA 1364 Stop protein truncation
77 24 5677 Insertion A Tyr 1853 protein Stop truncation
B. Germline BRCAl mutations among breast cancer patients in the general population.
From each breast cancer patient, not selected for family history, a 30 ml sample of whole blood is drawn into acid citrate dextrose. DNA from the blood is extracted and stored at -70C in 3 aliquots. Germline mutations in BRCAl are identified using the approaches described above and by directly sequencing new mutations. Paraffin-embedded tumor specimens from the same patients are screened for alterations of p53, HER2, PRAD1, and ER. Germline BRCAl mutations are tested in the tumor blocks. A preliminary estimate of risk associated with different BRCAl mutations is obtained from relatives of patients with germline alterations. For each patient with a germline BRCAl mutation, each surviving sister and mother (and for older patients, brothers as well), DNA is extracted from a blood sample and tested for the presence of the proband's BRCA 1 mutation. To ascertain men at risk of prostatic cancer, brothers of breast cancer patients diagnosed after age 55 are also interviewed and sampled. Paraffin blocks from deceased relatives who had cancer are also screened. The frequency of breast, ovarian, or prostatic cancer among relatives carrying BRCAl mutations is a first estimate of risk of these cancers associated with different mutations. C .
Somatic alterations of BRCAl in breast tumors.
Malignant cells are dissected from normal cells from paraffin blocks. By identifying BRCAl mutations in these series, we estimate the frequency of somatic BRCAl alterations, determine BRCAl mutations characteristic of any particular stage of tumor development, and evaluate their association with prognosis.
P. Characterizing mutant and rare alleles of BRCAl. Mutant or rare BRCAl allele function and pattern of expression during development are characterized using transformed cells expressing the allele and knockout or transgenic mice. For example, phenotypic changes in the animal or cell line, such as growth rate and anchorage independence are determined. In addition, several methods are used to study loss-of-function mutations, including replacing normal genes with their mutant alleles (BRCAl - BRCA 1-) by homologous recombination in embryonic stem (ES) cells and replacing mutant alleles with their normal counterparts in differentiated cultured cells (Capecchi 1989 Science 244:1288-1292; Weissman et al. 1987 Science 236:175-180; Wang et al. 1993 Oncogene 8:279-288). Breast carcinoma cell lines are screened for mutation at the
BRCAl locus and a mutant BRCAl line is selected. Normal and mutant cDNAs of BRCAl are subcloned into an expression vector carrying genes which confer resistance to ampicillin and geneticin (Baker et aL 1990 Nature 249:912-915). Subclones are transfected into mutant BRCAl breast cancer cells Geneticin-resistant colonies are isolated and examined for any change in tumorigenic phenotype, such as colony formation in soft agar, increased growth rate, and/or tumor formation in athymic nude mice. In vivo functional demonstrations involve introducing the normal BCRA1 gene into a breast carcinoma cell line mutant at BRCAl and injecting these BRCAl + cells into nude mice. Changes observed in tumorigenic growth compared to nude mice injected with BRCAl mutant breast carcinoma cells are readily observed. For example, correcting the mutant gene decreases the ability of the breast carcinoma cells to form tumors in nude mice
(Weissman et al. 1987; Wang et al. 1993).
All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in fight of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims. SEQUENCE LISTING
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(xi) SEQUENCE DESCRIPTION: SEQ ID NO:1:
AGCTCGCTGA GACTTCCTGG ACCCCGCACC AGGCTGTGGG GTTTCTCAGA TAACTGGGCC 60 CCTGCGCTCA GGAGGCCTTC ACCCTCTGCT CTGGGTAAAG TTCATTGGAA CAGAAAGAAA 120
TGGATTTATC TGCTCTTCGC GTTGAAGAAG TACAAAATGT CATTAATGCT ATGCAGAAAA 180
TCTTAGAGTG TCCCATCTGA TTTTGCATGC TGAAACTTCT CAACCAGAAG AAAGGGCCTT 240
CACAGTGTCC TTTATGTAAG AATGATATAA CCAAAAGGAG CCTACAAGAA AGTACGAGAT 300
TTAGTCAACT TGTTGAAGAG CTATTGAAAA TCATTTGTGC TTTTCAGCTT GACACAGGTT 60 TGGAGTATGC AAACAGCTAT AATTTTGCAA AAAAGGAAAA TAACTCTCCT GAACATCTAA 420
AAGATGAAGT TTCTATCATC CAAAGTATGG GCTACAGAAA CCGTGCCAAA AGACTTCTAC 480 AGAGTGAACC CGAAAATCCT TCCTTGCAGG AAACCAGTCT CAGTGTCCAA CTCTCTAACC 540
TTGGAACTGT GAGAACTCTG AGGACAAAGC AGCGGATACA ACCTCAAAAG ACGTCTGTCT 600
ACATTGAATT GGGATCTGAT TCTTCTGAAG ATACCGTTAA TAAGGCAACT TATTGCAGTG 660
TGGGAGATCA AGAATTGTTA CAAATCACCC CTCAAGGAAC CAGGGATGAA ATCAGTTTGG 720
ATTCTGCAAA AAAGGCTGCT TGTGAATTTT CTGAGACGGA TGTAACAAAT ACTGAACATC 780
ATCAACCCAG TAATAATGAT TTGAACACCA CTGAGAAGCG TGCAGCTGAG AGGCATCCAG 840
AAAAGTATCA GGGTAGTTCT GTTTCAAACT TGCATGTGGA GCCATGTGGC ACAAATACTC 900 ATGCCAGCTC ATTACAGCAT GAGAACAGCA GTTTATTACT CACTAAAGAC AGAATGAATG 960
TAGAAAAGGC TGAATTCTGT AATAAAAGCA AACAGCCTGG CTTAGCAAGG AGCCAACATA 1020
ACAGATGGGC TGGAAGTAAG GAAACATGTA ATGATAGGCG GACTCCCAGC ACAGAAAAAA 1080
AGGTAGATCT GAATGCTGAT CCCCTGTGTG AGAGAAAAGA ATGGAATAAG CAGAAACTGC 1140
CATGCTCAGA GAATCCTAGA GATACTGAAG ATGTTCCTTG GATAACACTA AATAGCAGCA 1200 TTCAGAAAGT TAATGAGTGG TTTTCCAGAA GTGATGAACT GT AGGTTCT GATGACTCAC 1260
ATGATGGGGA GTCTGAATCA AATGCCAAAG TAGCTGATGT ATTGGACGTT CTAAATGAGG 1320
TAGATGAATA TTCTGGTTCT TCAGAGAAAA TAGACTTACT GGCCAGTGAT CCTCATGAGG 1380
CTTTAATATG TAAAAGTGAA AGAGTTCACT CCAAATCAGT AGAGAGTAAT ATTGAAGACA 14 0
AAATATTTGG GAAAACCTAT CGGAAGAAGG CAAGCCTCCC CAACTTAAGC CATGTAACTG 1500 AAAATCTAAT TATAGGAGCA TTTGTTACTG AGCCACAGAT AATACAAGAG CGTCCCCTCA 1560
CAAATAAATT AAAGCGTAAA AGGAGACCTA CATCAGGCCT TCATCCTGAG GATTTTATCA 1620
AGAAAGCAGA TTTGGCAGTT CAAAAGACTC CTGAAATGAT AAATCAGGGA ACTAACCAAA 1680
CGGAGCAGAA TGGTCAAGTG ATGAATATTA CTAATAGTGG TCATGAGAAT AAAACAAAAG 1740
GTGATTCTAT TCAGAATGAG AAAAATCCTA ACCCAATAGA ATCACTCGAA AAAGAATCTG 1800 CTTTCAAAAC GAAAGCTGAA CCTATAAGCA GCAGTATAAG CAATATGGAA CTCGAATTAA 1860
ATATCCACAA TTCAAAAGCA CCTAAAAAGA ATAGGCTGAG GAGGAAGTCT TCTACCAGGC 1920
ATATTCATGC GCTTGAACTA GTAGTCAGTA GAAATCTAAG CCCACCTAAT TGTACTGAAT 1980
TGCAAATTGA TAGTTGTTCT AGCAGTGAAG AGATAAAGAA AAAAAAGTAC AACCAAATGC 2040
CAGTCAGGCA CAGCAGAAAC CTACAACTCA TGGAAGGTAA AGAACCTGCA ACTGGAGCCA 2100 AGAAGAGTAA CAAGCCAAAT GAACAGACAA GTAAAAGACA TGACAGCGAT ACTTTCCCAG 2160
AGCTGAAGTT AACAAATGCA CCTGGTTCTT TTACTAAGTG TTCAAATACC AGTGAACTTA 2220
AAGAATTTGT CAATCCTAGC CTTCCAAGAG AAGAAAAAGA AGAGAAACTA GAAACAGTTA 2280
AAGTGTCTAA TAATGCTGAA GACCCCAAAG ATCTCATGTT AAGTGGAGAA AGGGTTTTGC 2340
AAACTGAAAG ATCTGTAGAG AGTAGCAGTA TTTCATTGGT ACCTGGTACT GATTATGGCA 2400 CTCAGGAAAG TATCTCGTTA CTGGAAGTTA GCACTCTAGG GAAGGCAAAA ACAGAACCAA 2460
ATAAATGTGT GAGTCAGTGT GCAGCATTTG AAAACCCCAA GGGACTAATT CATGGTTGTT 2520
CCAAAGATAA TAGAAATGAC ACAGAAGGCT TTAAGTATCC ATTGGGACAT GAAGTTAACC 2580
ACAGTCGGGA AACAAGCATA GAAATGGAAG AAAGTGAACT TGATGCTCAG TATTTGCAGA 2640
ATACATTCAA GGTTTCAAAG CGCCAGTCAT TTGCTCCGTT TTCAAATCCA GGAAATGCAG 2700
AAGAGGAATG TGCAACATTC TCTGCCCACT CTGGGTCCTT AAAGAAACAA AGTCCAAAAG 2760
TCACTTTTGA ATGTGAACAA AAGGAAGAAA ATCAAGGAAA GAATGAGTCT AATATCAAGC 2820 CTGTACAGAC AGTTAATATC ACTGCAGGCT TTCCTGTGGT TGGTCAGAAA GATAAGCCAG 2880
TTGATAATGC CAAATGTAGT ATCAAAGGAG GCTCTAGGTT TTGTCTATCA TCTCAGTTCA 2940
GAGGCAACGA AACTGGACTC ATTACTCCAA ATAAACATGG ACTTTTACAA AACCCATATC 3000
GTATACCACC ACTTTTTCCC ATCAAGTCAT TTGTTAAAAC TAAATGTAAG AAAAATCTGC 3060
TAGAGGAAAA CTTTGAGGAA CATTCAATGT CACCTGAAAG AGAAATGGGA AATGAGAACA 3120 TTCCAAGTAC AGTGAGCACA ATTAGCCGTA ATAACATTAG AGAAAATGTT TTTAAAGAAG 3180
CCAGCTCAAG CAATATTAAT GAAGTAGGTT CCAGTACTAA TGAAGTGGGC TCCAGTATTA 3240
ATGAAATAGG TTCCAGTGAT GAAAACATTC AAGCAGAACT AGGTAGAAAC AGAGGGCCAA 3300
AATTGAATGC TATGCTTAGA TTAGGGGTTT TGCAACCTGA GGTCTATAAA CAAAGTCTTC 3360
CTGGAAGTAA TTGTAAGCAT CCTGAAATAA AAAAGCAAGA ATATGAAGAA GTAGTTCAGA 3420 CTGTTAATAC AGATTTCTCT CCATATCTGA TTTCAGATAA CTTAGAACAG CCTATGGGAA 3480
GTAGTCATGC ATCTCAGGTT TGTTCTGAGA CACCTGATGA CCTGTTAGAT GATGGTGAAA 3540
TAAAGGAAGA TACTAGTTTT GCTGAAAATG ACATTAAGGA AAGTTCTGCT GTTTTTAGCA 3600
AAAGCGTCCA GAAAGGAGAG CTTAGCAGGA GTCCTAGCCC TTTCACCCAT ACACATTTGG 660
CTCAGGGTTA CCGAAGAGGG GCCAAGAAAT TAGAGTCCTC AGAAGAGAAC TTATCTAGTG 3720 AGGATGAAGA GCTTCCCTGC TTCCAACACT TGTTATTTGG TAAAGTAAAC AA ATACCTT 3780
CTCAGTCTAC TAGGCATAGC ACCGTTGCTA CCGAGTGTCT GTCTAAGAAC ACAGAGGAGA 38 0
ATTTATTATC ATTGAAGAAT AGCTTAAATG ACTGCAGTAA CCAGGTAATA TTGGCAAAGG 3900
CATCTCAGGA ACATCACCTT AGTGAGGAAA CAAAATGTTC TGCTAGCTTG TTTTCTTCAC 3960
AGTGCAGTGA ATTGGAAGAC TTGACTGCAA ATACAAACAC CCAGGATCCT TTCTTGATTG 4020 GTTCTTCCAA ACAAATGAGG CATCAGTCTG AAAGCCAGGG AGTTGGTCTG AGTGACAAGG 4080
AATTGGTTTC AGATGATGAA GAAAGAGGAA CGGGCTTGGA AGAAAATAAT CAAGAAGAGC 4140
AAAGCATGGA TTCAAACTTA GGTGAAGCAG CATCTGGGTG TGAGAGTGAA ACAAGCGTCT 4200
CTGAAGACTG CTCAGGGCTA TCCTCTCAGA GTGACATTTT AACCACTCAG CAGAGGGATA 4260
CCATGCAACA TAACCTGATA AAGCTCCAGC AGGAAATGGC TGAACTAGAA GCTGTGTTAG 4320 AACAGCATGG GAGCCAGCCT TCTAACAGCT ACCCTTCCAT CATAAGTGAC TCTTCTGCCC 4380
TTGAGGACCT GCGAAATCCA GAACAAAGCA CATCAGAAAA AGCAGTATTA ACTTCACAGA 4440
AAAGTAGTGA ATACCCTATA AGCCAGAATC CAGAAGGCCT TTCTGCTGAC AAGTTTGAGG 4500
TGTCTGCAGA TAGTTCTACC AGTAAAAATA AAGAACCAGG AGTGGAAAGG TCATCCCCTT 4560
CTAAATGCCC ATCATTAGAT GATAGGTGGT ACATGCACAG TTGCTCTGGG AGTCTTCAGA 4620
ATAGAAACTA CCCATCTCAA GAGGAGCTCA TTAAGGTTGT TGATGTGGAG GAGCAACAGC 4680 TGGAAGAGTC TGGGCCACAC GATTTGACGG AAACATCTTA CTTGCCAAGG CAAGATCTAG - 4740 AGGGAACCCC TTACCTGGAA TCTGGAATCA GCCTCTTCTC TGATGACCCT GAATCTGATC 4800
CTTCTGAAGA CAGAGCCCCA GAGTCAGCTC GTGTTGGCAA CATACCATCT TCAACCTCTG 4860
CATTGAAAGT TCCCCAATTG AAAGTTGCAG AATCTGCCCA GAGTCCAGCT GCTGCTCATA 4920
CTACTGATAC TGCTGGGTAT AATGCAATGG AAGAAAGTGT GAGCAGGGAG AAGCCAGAAT 4980
TGACAGCTTC AACAGAAAGG GTCAACAAAA GAATGTCCAT GGTGGTGTCT GGCCTGACCC 5040 CAGAAGAATT TATGCTCGTG TACAAGTTTG CCAGAAAACA CCACATCACT TTAACTAATC 5100
TAATTACTGA AGAGACTACT CATGTTGTTA TGAAAACAGA TGCTGAGTTT GTGTGTGAAC 5160
GGACACTGAA ATATTTTCTA GGAATTGCGG GAGGAAAATG GGTAGTTAGC TATTTCTGGG 5220
TGACCCAGTC TATTAAAGAA AGAAAAATGC TGAATGAGCA TGATTTTGAA GTCAGAGGAG 5280
ATGTGGTCAA TGGAAGAAAC CACCAAGGTC CAAAGCGAGC AAGAGAATCC CAGG CAGAA 5340 AGATCTTCAG GGGGCTAGAA ATCTGTTGCT ATGGGCCCTT CACCAACATG CCCACAGATC 5400
AACTGGAATG GATGGTACAG CTGTGTGGTG CTTCTGTGGT GAAGGAGCTT TCATCATTCA 5 60
CCCTTGGCAC AGGTGTCCAC CCAATTGTGG TTGTGCAGCC AGATGCCTGG ACAGAGGACA 5520
ATGGCTTCCA TGCAATTGGG CAGATGTGTG AGGCACCTGT GGTGACCCGA GAGTGGGTGT 5580
TGGACAGTGT AGCACTCTAC CAGTGCCAGG AGCTGGACAC CTACCTGATA CCCCAGATCC 5640 CCCACAGCCA CTACTG 5656
(2) INFORMATION FOR SEQ ID NO:2:
(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 5709 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: double
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: CDNA
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:2:
AGCTCGCTGA GACTTCCTGG ACCCCGCACC AGGCTGTGGG GTTTCTCAGA TAACTGGGCC 60
CCTGCGCTCA GGAGGCCTTC ACCCTCTGCT CTGGGTAAAG TTCATTGGAA CAGAAAGAAA 120
TGGATTTATC TGCTCTTCGC GTTGAAGAAG TACAAAATGT CATTAATGCT ATGCAGAAAA 180 TCTTAGAGTG TCCCATCTGT CTGGAGTTGA TCAAGGAACC TGTCTCCACA GTGTGACCAC 240
ATATTTTGCA AATTTTGCAT GCTGAAACTT CTCAACCAGA AGAAAGGGCC TTCACAGTGT 300
CCTTTATGTA AGAATGATAT AACCAAAAGG AGCCTACAAG AAAGTACGAG ATTTAGTCAA 360
CTTGTTGAAG AGCTATTGAA AATCATTTGT GCTTTTCAGC TTGACACAGG TTTGGAGTAT 420
GCAAACAGCT ATAATTTTGC AAAAAAGGAA AATAACTCTC CTGAACATCT AAAAGATGAA 480
GTTTCTATCA TCCAAAGTAT GGGCTACAGA AACCGTGCCA AAAGACTTCT ACAGAGTGAA 540
CCCGAAAATC CTTCCTTGCA GGAAACCAGT CTCAGTGTCC AACTCTCTAA CCTTGGAACT 600 GTGAGAACTC TGAGGACAAA GCAGCGGATA CAACCTCAAA AGACGTCTGT CTACATTGAA 660
TTGGGATCTG ATTCTTCTGA AGATACCGTT AATAAGGCAA CTTATTGCAG TGTGGGAGAT 720
CAAGAATTGT TACAAATCAC CCCTCAAGGA ACCAGGGATG AAATCAGTTT GGATTCTGCA 780
AAAAAGGCTG CTTGTGAATT TTCTGAGACG GATGTAACAA ATACTGAACA TCATCAACCC 840
AGTAATAATG ATTTGAACAC CACTGAGAAG CGTGCAGCTG AGAGGCATCC AGAAAAGTAT 900 CAGGGTAGTT CTGTTTCAAA CTTGCATGTG GAGCCATGTG GCACAAATAC TCATGCCAGC 960
TCATTACAGC ATGAGAACAG CAGTTTATTA CTCACTAAAG ACAGAATGAA TGTAGAAAAG 1020
GCTGAATTCT GTAATAAAAG CAAACAGCCT GGCTTAGCAA GGAGCCAACA TAACAGATGG 1080
GCTGGAAGTA AGGAAACATG TAATGATAGG CGGACTCCCA GCACAGAAAA AAAGGTAGAT 1140
CTGAATGCTG ATCCCCTGTG TGAGAGAAAA GAATGGAATA AGCAGAAACT GCCATGCTCA 1200 GAGAATCCTA GAGATACTGA AGATGTTCCT TGGATAACAC TAAATAGCAG CATTCAGAAA 1260
GTTAATGAGT GGTTTTCCAG AAGTGATGAA CTGTTAGGTT CTGATGACTC ACATGATGGG 1320
GAGTCTGAAT CAAATGCCAA AGTAGCTGAT GTATTGGACG TTCTAAATGA GGTAGATGAA 1380
TATTCTGGTT CTTCAGAGAA AATAGACTTA CTGGCCAGTG ATCCTCATGA GGCTTTAATA 1440
TGTAAAAGTG AAAGAGTTCA CTCCAAATCA GTAGAGAGTA ATATTGAAGA CAAAATATTT 1500 GGGAAAACCT ATCGGAAGAA GGCAAGCCTC CCCAACTTAA GCCATGTAAC TGAAAATCTA 1560
ATTATAGGAG CATTTGTTAC TGAGCCACAG ATAATACAAG AGCGTCCCCT CACAAATAAA 1620
TTAAAGCGTA AAAGGAGACC TACATCAGGC CTTCATCCTG AGGATTTTAT CAAGAAAGCA 1680
GATTTGGCAG TTCAAAAGAC TCCTGAAATG ATAAATCAGG GAACTAACCA AACGGAGCAG 1740
AATGGTCAAG TGATGAATAT TACTAATAGT GGTCATGAGA ATAAAACAAA AGGTGATTCT 1800 ATTCAGAATG AGAAAAATCC TAACCCAATA GAATCACTCG AAAAAGAATC TGCTTTCAAA 1860
ACGAAAGCTG AACCTATAAG CAGCAGTATA AGCAATATGG AACTCGAATT AAATATCCAC 1920
AATTCAAAAG CACCTAAAAA GAATAGGCTG AGGAGGAAGT CTTCTACCAG GCATATTCAT 1980
GCGCTTGAAC TAGTAGTCAG TAGAAATCTA AGCCCACCTA ATTGTACTGA ATTGCAAATT 2040
GATAGTTGTT CTAGCAGTGA AGAGATAAAG AAAAAAAAGT ACAACCAAAT GCCAGTCAGG 2100 CACAGCAGAA ACCTACAACT CATGGAAGGT AAAGAACCTG CAACTGGAGC CAAGAAGAGT 2160
AACAAGCCAA ATGAACAGAC AAGTAAAAGA CATGACAGCG ATACTTTCCC AGAGCTGAAG 2220
TTAACAAATG CACCTGGTTC TTTTACTAAG TGTTCAAATA CCAGTGAACT TAAAGAATTT 2280
GTCAATCCTA GCCTTCCAAG AGAAGAAAAA GAAGAGAAAC TAGAAACAGT TAAAGTGTCT 2340
AATAATGCTG AAGACCCCAA AGATCTCATG TTAAGTGGAG AAAGGGTTTT GCAAACTGAA 2400
AGATCTGTAG AGAGTAGCAG TATTTCATTG GTACCTGGTA CTGATTATGG CACTCAGGAA 2460
AGTATCTCGT TACTGGAAGT TAGCACTCTA GGGAAGGCAA AAACAGAACC AAATAAATGT 2520 GTGAGTCAGT GTGCAGCATT TGAAAACCCC AAGGGACTAA TTCATGGTTG TTCCAAAGAT 2580
AATAGAAATG ACACAGAAGG CTTTAAGTAT CCATTGGGAC ATGAAGTTAA CCACAGTCGG 2640
GAAACAAGCA TAGAAATGGA AGAAAGTGAA CTTGATGCTC AGTATTTGCA GAATACATTC 2700
AAGGTTTCAA AGCGCCAGTC ATTTGCTCCG TTTTCAAATC CAGGAAATGC AGAAGAGGAA 2760
TGTGCAACAT TCTCTGCCCA CTCTGGGTCC TTAAAGAAAC AAAGTCCAAA AGTCACTTTT 2820 GAATGTGAAC AAAAGGAAGA AAATCAAGGA AAGAATGAGT CTAATATCAA GCCTGTACAG 2880
ACAGTTAATA TCACTGCAGG CTTTCCTGTG GTTGGTCAGA AAGATAAGCC AGTTGATAAT 2940
GCCAAATGTA GTATCAAAGG AGGCTCTAGG TTTTGTCTAT CATCTCAGTT CAGAGGCAAC 3000
GAAACTGGAC TCATTACTCC AAATAAACAT GGACTTTTAC AAAACCCATA TCGTATACCA 3060
CCACTTTTTC CCATCAAGTC ATTTGTTAAA ACTAAATGTA AGAAAAATCT GCTAGAGGAA 3120 AACTTTGAGG AACATTCAAT GTCACCTGAA AGAGAAATGG GAAATGAGAA CATTCCAAGT 3180
ACAGTGAGCA CAATTAGCCG TAATAACATT AGAGAAAATG TTTTTAAAGA AGCCAGCTCA 3240
AGCAATATTA ATGAAGTAGG TTCCAGTACT AATGAAGTGG GCTCCAGTAT TAATGAAATA 3300
GGTTCCAGTG ATGAAAACAT TCAAGCAGAA CTAGGTAGAA ACAGAGGGCC AAAATTGAAT 3360
GCTATGCTTA GATTAGGGGT TTTGCAACCT GAGGTCTATA AACAAAGTCT TCCTGGAAGT 3420 AATTGTAAGC ATCCTGAAAT AAAAAAGCAA GAATATGAAG AAGTAGTTCA GACTGTTAAT 3480
ACAGATTTCT CTCCATATCT GATTTCAGAT AACTTAGAAC AGCCTATGGG AAGTAGTCAT 3540
GCATCTCAGG TTTGTTCTGA GACACCTGAT GACCTGTTAG ATGATGGTGA AATAAAGGAA 3600
GATACTAGTT TTGCTGAAAA TGACATTAAG GAAAGTTCTG CTGTTTTTAG CAAAAGCGTC 3660
CAGAAAGGAG AGCTTAGCAG GAGTCCTAGC CCTTTCACCC ATACACATTT GGCTCAGGGT 3720 TACCGAAGAG GGGCCAAGAA ATTAGAGTCC TCAGAAGAGA ACTTATCTAG TGAGGATGAA 3780
GAGCTTCCCT GCTTCCAACA CTTGTTATTT GGTAAAGTAA ACAATATACC TTCTCAGTCT 3840
ACTAGGCATA GCACCGTTGC TACCGAGTGT CTGTCTAAGA ACACAGAGGA GAATTTATTA 3900
TCATTGAAGA ATAGCTTAAA TGACTGCAGT AACCAGGTAA TATTGGCAAA GGCATCTCAG 3960
GAACATCACC TTAGTGAGGA AACAAAATGT TCTGCTAGCT TGTTTTCTTC ACAGTGCAGT 4020 GAATTGGAAG ACTTGACTGC AAATACAAAC ACCCAGGATC CTTTCTTGAT TGGTTCTTCC 4080
AAACAAATGA GGCATCAGTC TGAAAGCCAG GGAGTTGGTC TGAGTGACAA GGAATTGGTT 4140
TCAGATGATG AAGAAAGAGG AACGGGCTTG GAAGAAAATA ATCAAGAAGA GCAAAGCATG 4200
GATTCAAACT TAGGTGAAGC AGCATCTGGG TGTGAGAGTG AAACAAGCGT CTCTGAAGAC 4260
TGCTCAGGGC TATCCTCTCA GAGTGACATT TTAACCACTC AGCAGAGGGA TACCATGCAA 4320
CATAACCTGA TAAAGCTCCA GCAGGAAATG GCTGAACTAG AAGCTGTGTT AGAACAGCAT 4380
GGGAGCCAGC CTTCTAACAG CTACCCTTCC ATCATAAGTG ACTCTTCTGC CCTTGAGGAC 4440 CTGCGAAATC CAGAACAAAG CACATCAGAA AAAGCAGTAT TAACTTCACA GAAAAGTAGT 4500
GAATACCCTA TAAGCCAGAA TCCAGAAGGC CTTTCTGCTG ACAAGTTTGA GGTGTCTGCA 4560
GATAGTTCTA CCAGTAAAAA TAAAGAACCA GGAGTGGAAA GGTCATCCCC TTCTAAATGC 4620
CCATCATTAG ATGATAGGTG GTACATGCAC AGTTGCTCTG GGAGTCTTCA GAATAGAAAC 4680
TACCCATCTC AAGAGGAGCT CATTAAGGTT GTTGATGTGG AGGAGCAACA GCTGGAAGAG 4740 TCTGGGCCAC ACGATTTGAC GGAAACATCT TACTTGCCAA GGCAAGATCT AGAGGGAACC 4800
CCTTACCTGG AATCTGGAAT CAGCCTCTTC TCTGATGACC CTGAATCTGA TCCTTCTGAA 4860
GACAGAGCCC CAGAGTCAGC TCGTGTTGGC AACATACCAT CTTCAACCTC TGCATTGAAA 4920
GTTCCCCAAT TGAAAGTTGC AGAATCTGCC CAGAGTCCAG CTGCTGCTCA TACTACTGAT 4980
ACTGCTGGGT ATAATGCAAT GGAAGAAAGT GTGAGCAGGG AGAAGCCAGA ATTGACAGCT 5040 TCAACAGAAA GGGTCAACAA AAGAATGTCC ATGGTGGTGT CTGGCCTGAC CCCAGAAGAA 5100
TTTATGCTCG TGTACAAGTT TGCCAGAAAA CACCACATCA CTTTAACTAA TCTAATTACT 5160
GAAGAGACTA CTCATGTTGT TATGAAAACA GATGCTGAGT TTGTGTGTGA ACGGACACTG 5220
AAATATTTTC TAGGAATTGC GGGAGGAAAA TGGGTAGTTA GCTATTTCTG GGTGACCCAG 5280
TCTATTAAAG AAAGAAAAAT GCTGAATGAG CATGATTTTG AAGTCAGAGG AGATGTGGTC 5340 AATGGAAGAA ACCACCAAGG TCCAAAGCGA GCAAGAGAAT CCCAGGACAG AAAGATCTTC 5400
AGGGGGCTAG AAATCTGTTG CTATGGGCCC TTCACCAACA TGCCCACAGA TCAACTGGAA 5460
TGGATGGTAC AGCTGTGTGG TGCTTCTGTG GTGAAGGAGC TTTCATCATT CACCCTTGGC 5520
ACAGGTGTCC ACCCAATTGT GGTTGTGCAG CCAGATGCCT GGACAGAGGA CAATGGCTTC 5580
CATGCAATTG GGCAGATGTG TGAGGCACCT GTGGTGACCC GAGAGTGGGT GTTGGACAGT 5640 GTAGCACTCT ACCAGTGCCA GGAGCTGGAC ACCTACCTGA TACCCCAGAT CCCCCACAGC 5700
CACTACTGA 5709 (2) INFORMATION FOR SEQ ID NO:3:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 5689 base pairs
(B) TYPE: nucleic acid (C) STRANDEDNESS: double
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: cDNA
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:3 :
AGCTCGCTGA GACTTCCTGG ACCCCGCACC AGGCTGTGGG GTTTCTCAGA TAACTGGGCC 60 CCTGCGCTCA GGAGGCCTTC ACCCTCTGCT CTGGGTAAAG TTCATTGGAA CAGAAAGAAA 120
TGGATTTATC TGCTCTTCGC GTTGAAGAAG TACAAAATGT CATTAATGCT ATGCAGAAAA 180
TCTTAGAGTG TCCCATCTGT CTGGAGTTGA TCAAGGAACC TGTCTCCACA AAGTGTGACC 240
ACATATTTTG CAAATTTTGC ATGCTGAAAC TTCTCAACCA GAAGAAAGGG CCTTCACAGT 300
GTCCTTTATG AGCCTACAAG AAAGTACGAG ATTTAGTCAA CTTGTTGAAG AGCTATTGAA 360 AATCATTTGT GCTTTTCAGC TTGACACAGG TTTGGAGTAT GCAAACAGCT ATAATTTTGC 420
AAAAAAGGAA AATAACTCTC CTGAACATCT AAAAGATGAA GTTTCTATCA TCCAAAGTAT 480
GGGCTACAGA AACCGTGCCA AAAGACTTCT ACAGAGTGAA CCCGAAAATC CTTCCTTGCA 540
GGAAACCAGT CTCAGTGTCC AACTCTCTAA CCTTGGAACT GTGAGAACTC TGAGGACAAA 600
GCAGCGGATA CAACCTCAAA AGACGTCTGT CTACATTGAA TTGGGATCTG ATTCTTCTGA 660 AGATACCGTT AATAAGGCAA CTTATTGCAG TGTGGGAGAT CAAGAATTGT TACAAATCAC 720
CCCTCAAGGA ACCAGGGATG AAATCAGTTT GGATTCTGCA AAAAAGGCTG CTTGTGAATT 780
TTCTGAGACG GATGTAACAA ATACTGAACA TCATCAACCC AGTAATAATG ATTTGAACAC 840
CACTGAGAAG CGTGCAGCTG AGAGGCATCC AGAAAAGTAT CAGGGTAGTT CTGTTTCAAA 900
CTTGCATGTG GAGCCATGTG GCACAAATAC TCATGCCAGC TCATTACAGC ATGAGAACAG 960 CAGTTTATTA CTCACTAAAG ACAGAATGAA TGTAGAAAAG GCTGAATTCT GTAATAAAAG 1020
CAAACAGCCT GGCTTAGCAA GGAGCCAACA TAACAGATGG GCTGGAAGTA AGGAAACATG 1080
TAATGATAGG CGGACTCCCA GCACAGAAAA AAAGGTAGAT CTGAATGCTG ATCCCCTGTG 1140
TGAGAGAAAA GAATGGAATA AGCAGAAACT GCCATGCTCA GAGAATCCTA GAGATACTGA 1200
AGATGTTCCT TGGATAACAC TAAATAGCAG CATTCAGAAA GTTAATGAGT GGTTTTCCAG 1260 AAGTGATGAA CTGTTAGGTT CTGATGACTC ACATGATGGG GAGTCTGAAT CAAATGCCAA 1320
AGTAGCTGAT GTATTGGACG TTCTAAATGA GGTAGATGAA TATTCTGGTT CTTCAGAGAA 1380
AATAGACTTA CTGGCCAGTG ATCCTCATGA GGCTTTAATA TGTAAAAGTG AAAGAGTTCA 1440
CTCCAAATCA GTAGAGAGTA ATATTGAAGA CAAAATATTT GGGAAAACCT ATCGGAAGAA 1500
GGCAAGCCTC CCCAACTTAA GCCATGTAAC TGAAAATCTA ATTATAGGAG CATTTGTTAC 1560 TGAGCCACAG ATAATACAAG AGCGTCCCCT CACAAATAAA TTAAAGCGTA AAAGGAGACC 1620
TACATCAGGC CTTCATCCTG AGGATTTTAT CAAGAAAGCA GATTTGGCAG TTCAAAAGAC 1680 TCCTGAAATG ATAAATCAGG GAACTAACCA AACGGAGCAG AATGGTCAAG TGATGAATAT 1740
TACTAATAGT GGTCATGAGA ATAAAACAAA AGGTGATTCT ATTCAGAATG AGAAAAATCC 1800
TAACCCAATA GAATCACTCG AAAAAGAATC TGCTTTCAAA ACGAAAGCTG AACCTATAAG 1860
CAGCAGTATA AGCAATATGG AACTCGAATT AAATATCCAC AATTCAAAAG CACCTAAAAA 1920
GAATAGGCTG AGGAGGAAGT CTTCTACCAG GCATATTCAT GCGCTTGAAC TAGTAGTCAG 1980
TAGAAATCTA AGCCCACCTA ATTGTACTGA ATTGCAAATT GATAGTTGTT CTAGCAGTGA 2040
AGAGATAAAG AAAAAAAAGT ACAACCAAAT GCCAGTCAGG CACAGCAGAA ACCTACAACT 2100 CATGGAAGGT AAAGAACCTG CAACTGGAGC CAAGAAGAGT AACAAGCCAA ATGAACAGAC 2160
AAGTAAAAGA CATGACAGCG ATACTTTCCC AGAGCTGAAG TTAACAAATG CACCTGGTTC 2220
TTTTACTAAG TGTTCAAATA CCAGTGAACT TAAAGAATTT GTCAATCCTA GCCTTCCAAG 2280
AGAAGAAAAA GAAGAGAAAC TAGAAACAGT TAAAGTGTCT AATAATGCTG AAGACCCCAA 2340
AGATCTCATG TTAAGTGGAG AAAGGGTTTT GCAAACTGAA AGATCTGTAG AGAGTAGCAG 2400 TATTTCATTG GTACCTGGTA CTGATTATGG CACTCAGGAA AGTATCTCGT TACTGGAAGT 2460
TAGCACTCTA GGGAAGGCAA AAACAGAACC AAATAAATGT GTGAGTCAGT GTGCAGCATT 2520
TGAAAACCCC AAGGGACTAA TTCATGGTTG TTCCAAAGAT AATAGAAATG ACACAGAAGG 2580
CTTTAAGTAT CCATTGGGAC ATGAAGTTAA CCACAGTCGG GAAACAAGCA TAGAAATGGA 2640
AGAAAGTGAA CTTGATGCTC AGTATTTGCA GAATACATTC AAGGTTTCAA AGCGCCAGTC 2700 ATTTGCTCCG TTTTCAAATC CAGGAAATGC AGAAGAGGAA TGTGCAACAT TCTCTGCCCA 2760
CTCTGGGTCC TTAAAGAAAC AAAGTCCAAA AGTCACTTTT GAATGTGAAC AAAAGGAAGA 2820
AAATCAAGGA AAGAATGAGT CTAATATCAA GCCTGTACAG ACAGTTAATA TCACTGCAGG 2880
CTTTCCTGTG GTTGGTCAGA AAGATAAGCC AGTTGATAAT GCCAAATGTA GTATCAAAGG 2940
AGGCTCTAGG TTTTGTCTAT CATCTCAGTT CAGAGGCAAC GAAACTGGAC TCATTACTCC 3000 AAATAAACAT GGACTTTTAC AAAACCCATA TCGTATACCA CCACTTTTTC CCATCAAGTC 3060
ATTTGTTAAA ACTAAATGTA AGAAAAATCT GCTAGAGGAA AACTTTGAGG AACATTCAAT 3120
GTCACCTGAA AGAGAAATGG GAAATGAGAA CATTCCAAGT ACAGTGAGCA CAATTAGCCG 3180
TAATAACATT AGAGAAAATG TTTTTAAAGA AGCCAGCTCA AGCAATATTA ATGAAGTAGG 3240
TTCCAGTACT AATGAAGTGG GCTCCAGTAT TAATGAAATA GGTTCCAGTG ATGAAAACAT 3300 TCAAGCAGAA CTAGGTAGAA ACAGAGGGCC AAAATTGAAT GCTATGCTTA GATTAGGGGT 3360
TTTGCAACCT GAGGTCTATA AACAAAGTCT TCCTGGAAGT AATTGTAAGC ATCCTGAAAT 3420
AAAAAAGCAA GAATATGAAG AAGTAGTTCA GACTGTTAAT ACAGATTTCT CTCCATATCT 3480
GATTTCAGAT AACTTAGAAC AGCCTATGGG AAGTAGTCAT GCATCTCAGG TTTGTTCTGA 3540
GACACCTGAT GACCTGTTAG ATGATGGTGA AATAAAGGAA GATACTAGTT TTGCTGAAAA 3600 TGACATTAAG GAAAGTTCTG CTGTTTTTAG CAAAAGCGTC CAGAAAGGAG AGCTTAGCAG 3660
GAGTCCTAGC CCTTTCACCC ATACACATTT GGCTCAGGGT TACCGAAGAG GGGCCAAGAA 3720
ATTAGAGTCC TCAGAAGAGA ACTTATCTAG TGAGGATGAA GAGCTTCCCT GCTTCCAACA 3780
CTTGTTATTT GGTAAAGTAA ACAATATACC TTCTCAGTCT ACTAGGCATA GCACCGTTGC 3840
TACCGAGTGT CTGTCTAAGA ACACAGAGGA GAATTTATTA TCATTGAAGA ATAGCTTAAA 3900
TGACTGCAGT AACCAGGTAA TATTGGCAAA GGCATCTCAG GAACATCACC TTAGTGAGGA 3960
AACAAAATGT TCTGCTAGCT TGTTTTCTTC ACAGTGCAGT GAATTGGAAG ACTTGACTGC 4020 AAATACAAAC ACCCAGGATC CTTTCTTGAT TGGTTCTTCC AAACAAATGA GGCATCAGTC 4080
TGAAAGCCAG GGAGTTGGTC TGAGTGACAA GGAATTGGTT TCAGATGATG AAGAAAGAGG 4140
AACGGGCTTG GAAGAAAATA ATCAAGAAGA GCAAAGCATG GATTCAAACT TAGGTGAAGC 4200
AGCATCTGGG TGTGAGAGTG AAACAAGCGT CTCTGAAGAC TGCTCAGGGC TATCCTCTCA 4260
GAGTGACATT TTAACCACTC AGCAGAGGGA TACCATGCAA CATAACCTGA TAAAGCTCCA 4320 GCAGGAAATG GCTGAACTAG AAGCTGTGTT AGAACAGCAT GGGAGCCAGC CTTCTAACAG 4380
CTACCCTTCC ATCATAAGTG ACTCTTCTGC CCTTGAGGAC CTGCGAAATC CAGAACAAAG 4440
CACATCAGAA AAAGCAGTAT TAACTTCACA GAAAAGTAGT GAATACCCTA TAAGCCAGAA 4500
TCCAGAAGGC CTTTCTGCTG ACAAGTTTGA GGTGTCTGCA GATAGTTCTA CCAGTAAAAA 4560
TAAAGAACCA GGAGTGGAAA GGTCATCCCC TTCTAAATGC CCATCATTAG ATGATAGGTG 4620 GTACATGCAC AGTTGCTCTG GGAGTCTTCA GAATAGAAAC TACCCATCTC AAGAGGAGCT 4680
CATTAAGGTT GTTGATGTGG AGGAGCAACA GCTGGAAGAG TCTGGGCCAC ACGATTTGAC 4740
GGAAACATCT TACTTGCCAA GGCAAGATCT AGAGGGAACC CCTTACCTGG AATCTGGAAT 4800
CAGCCTCTTC TCTGATGACC CTGAATCTGA TCCTTCTGAA GACAGAGCCC CAGAGTCAGC 4860
TCGTGTTGGC AACATACCAT CTTCAACCTC TGCATTGAAA GTTCCCCAAT TGAAAGTTGC 4920 AGAATCTGCC CAGAGTCCAG CTGCTGCTCA TACTACTGAT ACTGCTGGGT ATAATGCAAT 4980
GGAAGAAAGT GTGAGCAGGG AGAAGCCAGA ATTGACAGCT TCAACAGAAA GGGTCAACAA 5040
AAGAATGTCC ATGGTGGTGT CTGGCCTGAC CCCAGAAGAA TTTATGCTCG TGTACAAGTT 5100
TGCCAGAAAA CACCACATCA CTTTAACTAA TCTAATTACT GAAGAGACTA CTCATGTTGT 5160
TATGAAAACA GATGCTGAGT TTGTGTGTGA ACGGACACTG AAATATTTTC TAGGAATTGC 5220 GGGAGGAAAA TGGGTAGTTA GCTATTTCTG GGTGACCCAG TCTATTAAAG AAAGAAAAAT 5280
GCTGAATGAG CATGATTTTG AAGTCAGAGG AGATGTGGTC AATGGAAGAA ACCACCAAGG 5340
TCCAAAGCGA GCAAGAGAAT CCCAGGACAG AAAGATCTTC AGGGGGCTAG AAATCTGTTG 5400
CTATGGGCCC TTCACCAACA TGCCCACAGA TCAACTGGAA TGGATGGTAC AGCTGTGTGG 5460
TGCTTCTGTG GTGAAGGAGC TTTCATCATT CACCCTTGGC ACAGGTGTCC ACCCAATTGT 5520 GGTTGTGCAG CCAGATGCCT GGACAGAGGA CAATGGCTTC CATGCAATTG GGCAGATGTG 5580
TGAGGCACCT GTGGTGACCC GAGAGTGGGT GTTGGACAGT GTAGCACTCT ACCAGTGCCA 5640 GGAGCTGGAC ACCTACCTGA TACCCCAGAT CCCCCACAGC CACTACTGA 5689
(2) INFORMATION FOR SEQ ID NO:4:
(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 5711 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: double
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:4:
AGCTCGCTGA GACTTCCTGG ACCCCGCACC AGGCTGTGGG GTTTCTCAGA TAACTGGGCC 60
CCTGCGCTCA GGAGGCCTTC ACCCTCTGCT CTGGGTAAAG TTCATTGGAA CAGAAAGAAA 120
TGGATTTATC TGCTCTTCGC GTTGAAGAAG TACAAAATGT CATTAATGCT ATGCAGAAAA 180 TCTTAGAGTG TCCCATCTGT CTGGAGTTGA TCAAGGAACC TGTCTCCACA AAGTGTGACC 240
ACATATTTTG CAAATTTTGC ATGCTGAAAC TTCTCAACCA GAAGAAAGGG CCTTCACAGG 300
GTCCTTTATG TAAGAATGAT ATAACCAAAA GGAGCCTACA AGAAAGTACG AGATTTAGTC 360
AACTTGTTGA AGAGCTATTG AAAATCATTT GTGCTTTTCA GCTTGACACA GGTTTGGAGT 420
ATGCAAACAG CTATAATTTT GCAAAAAAGG AAAATAACTC TCCTGAACAT CTAAAAGATG 480 AAGTTTCTAT CATCCAAAGT ATGGGCTACA GAAACCGTGC CAAAAGACTT CTACAGAGTG 540
AACCCGAAAA TCCTTCCTTG CAGGAAACCA GTCTCAGTGT CCAACTCTCT AACCTTGGAA 600
CTGTGAGAAC TCTGAGGACA AAGCAGCGGA TACAACCTCA AAAGACGTCT GTCTACATTG 660
AATTGGGATC TGATTCTTCT GAAGATACCG TTAATAAGGC AACTTATTGC AGTGTGGGAG 720
ATCAAGAATT GTTACAAATC ACCCCTCAAG GAACCAGGGA TGAAATCAGT TTGGATTCTG 780 CAAAAAAGGC TGCTTGTGAA TTTTCTGAGA CGGATGTAAC AAATACTGAA CATCATCAAC 840
CCAGTAATAA TGATTTGAAC ACCACTGAGA AGCGTGCAGC TGAGAGGCAT CCAGAAAAGT 900
ATCAGGGTAG TTCTGTTTCA AACTTGCATG TGGAGCCATG TGGCACAAAT ACTCATGCCA 960
GCTCATTACA GCATGAGAAC AGCAGTTTAT TACTCACTAA AGACAGAATG AATGTAGAAA 1020
AGGCTGAATT CTGTAATAAA AGCAAACAGC CTGGCTTAGC AAGGAGCCAA CATAACAGAT 1080 GGGCTGGAAG TAAGGAAACA TGTAATGATA GGCGGACTCC CAGCACAGAA AAAAAGGTAG 1140
ATCTGAATGC TGATCCCCTG TGTGAGAGAA AAGAATGGAA TAAGCAGAAA CTGCCATGCT 1200
CAGAGAATCC TAGAGATACT GAAGATGTTC CTTGGATAAC ACTAAATAGC AGCATTCAGA 1260
AAGTTAATGA GTGGTTTTCC AGAAGTGATG AACTGTTAGG TTCTGATGAC TCACATGATG 1320
GGGAGTCTGA ATCAAATGCC AAAGTAGCTG ATGTATTGGA CGTTCTAAAT GAGGTAGATG 1380 AATATTCTGG TTCTTCAGAG AAAATAGACT TACTGGCCAG TGATCCTCAT GAGGCTTTAA 1440
TATGTAAAAG TGAAAGAGTT CACTCCAAAT CAGTAGAGAG TAATATTGAA GACAAAATAT 1500
TTGGGAAAAC CTATCGGAAG AAGGCAAGCC TCCCCAACTT AAGCCATGTA ACTGAAAATC 1560
TAATTATAGG AGCATTTGTT ACTGAGCCAC AGATAATACA AGAGCGTCCC CTCACAAATA 1620
AATTAAAGCG TAAAAGGAGA CCTACATCAG GCCTTCATCC TGAGGATTTT ATCAAGAAAG 1680
CAGATTTGGC AGTTCAAAAG ACTCCTGAAA TGATAAATCA GGGAACTAAC CAAACGGAGC 1740
AGAATGGTCA AGTGATGAAT ATTACTAATA GTGGTCATGA GAATAAAACA AAAGGTGATT .1800 CTATTCAGAA TGAGAAAAAT CCTAACCCAA TAGAATCACT CGAAAAAGAA TCTGCTTTCA 1860
AAACGAAAGC TGAACCTATA AGCAGCAGTA TAAGCAATAT GGAACTCGAA TTAAATATCC 1920
ACAATTCAAA AGCACCTAAA AAGAATAGGC TGAGGAGGAA GTCTTCTACC AGGCATATTC 1980
ATGCGCTTGA ACTAGTAGTC AGTAGAAATC TAAGCCCACC TAATTGTACT GAATTGCAAA 2040
TTGATAGTTG TTCTAGCAGT GAAGAGATAA AGAAAAAAAA GTACAACCAA ATGCCAGTCA 2100 GGCACAGCAG AAACCTACAA CTCATGGAAG GTAAAGAACC TGCAACTGGA GCCAAGAAGA 2160
GTAACAAGCC AAATGAACAG ACAAGTAAAA GACATGACAG CGATACTTTC CCAGAGCTGA 2220
AGTTAACAAA TGCACCTGGT TCTTTTACTA AGTGTTCAAA TACCAGTGAA CTTAAAGAAT 2280
TTGTCAATCC TAGCCTTCCA AGAGAAGAAA AAGAAGAGAA ACTAGAAACA GTTAAAGTGT 2340
CTAATAATGC TGAAGACCCC AAAGATCTCA TGTTAAGTGG AGAAAGGGTT TTGCAAACTG 2400 AAAGATCTGT AGAGAGTAGC AGTATTTCAT TGGTACCTGG TACTGATTAT GGCACTCAGG 2460
AAAGTATCTC GTTACTGGAA GTTAGCACTC TAGGGAAGGC AAAAACAGAA CCAAATAAAT 2520
GTGTGAGTCA GTGTGCAGCA TTTGAAAACC CCAAGGGACT AATTCATGGT TGTTCCAAAG 2580
ATAATAGAAA TGACACAGAA GGCTTTAAGT ATCCATTGGG ACATGAAGTT AACCACAGTC 2640
GGGAAACAAG CATAGAAATG GAAGAAAGTG AACTTGATGC TCAGTATTTG CAGAATACAT 2700 TCAAGGTTTC AAAGCGCCAG TCATTTGCTC CGTTTTCAAA TCCAGGAAAT GCAGAAGAGG 2760
AATGTGCAAC ATTCTCTGCC CACTCTGGGT CCTTAAAGAA ACAAAGTCCA AAAGTCACTT 2820
TTGAATGTGA ACAAAAGGAA GAAAATCAAG GAAAGAATGA GTCTAATATC AAGCCTGTAC 2880
AGACAGTTAA TATCACTGCA GGCTTTCCTG TGGTTGGTCA GAAAGATAAG CCAGTTGATA 2940
ATGCCAAATG TAGTATCAAA GGAGGCTCTA GGTTTTGTCT ATCATCTCAG TTCAGAGGCA 3000 ACGAAACTGG ACTCATTACT CCAAATAAAC ATGGACTTTT ACAAAACCCA TATCGTATAC 3060
CACCACTTTT TCCCATCAAG TCATTTGTTA AAACTAAATG TAAGAAAAAT CTGCTAGAGG 3120
AAAACTTTGA GGAACATTCA ATGTCACCTG AAAGAGAAAT GGGAAATGAG AACATTCCAA 3180
GTACAGTGAG CACAATTAGC CGTAATAACA TTAGAGAAAA TGTTTTTAAA GAAGCCAGCT 3240
CAAGCAATAT TAATGAAGTA GGTTCCAGTA CTAATGAAGT GGGCTCCAGT ATTAATGAAA 3300 TAGGTTCCAG TGATGAAAAC ATTCAAGCAG AACTAGGTAG AAACAGAGGG CCAAAATTGA 3360
ATGCTATGCT TAGATTAGGG GTTTTGCAAC CTGAGGTCTA TAAACAAAGT CTTCCTGGAA 3420
GTAATTGTAA GCATCCTGAA ATAAAAAAGC AAGAATATGA AGAAGTAGTT CAGACTGTTA 3480
ATACAGATTT CTCTCCATAT CTGATTTCAG ATAACTTAGA ACAGCCTATG GGAAGTAGTC 3540
ATGCATCTCA GGTTTGTTCT GAGACACCTG ATGACCTGTT AGATGATGGT GAAATAAAGG 3600
AAGATACTAG TTTTGCTGAA AATGACATTA AGGAAAGTTC TGCTGTTTTT AGCAAAAGCG 3660
TCCAGAAAGG AGAGCTTAGC AGGAGTCCTA GCCCTTTCAC CCATACACAT TTGGCTCAGG 3720 GTTACCGAAG AGGGGCCAAG AAATTAGAGT CCTCAGAAGA GAACTTATCT AGTGAGGATG 3780
AAGAGCTTCC CTGCTTCCAA CACTTGTTAT TTGGTAAAGT AAACAATATA CCTTCTCAGT 3840
CTACTAGGCA TAGCACCGTT GCTACCGAGT GTCTGTCTAA GAACACAGAG GAGAATTTAT 3900
TATCATTGAA GAATAGCTTA AATGACTGCA GTAACCAGGT AATATTGGCA AAGGCATCTC 3960
AGGAACATCA CCTTAGTGAG GAAACAAAAT GTTCTGCTAG CTTGTTTTCT TCACAGTGCA 4020 GTGAATTGGA AGACTTGACT GCAAATACAA ACACCCAGGA TCCTTTCTTG ATTGGTTCTT 4080
CCAAACAAAT GAGGCATCAG TCTGAAAGCC AGGGAGTTGG TCTGAGTGAC AAGGAATTGG 4140
TTTCAGATGA TGAAGAAAGA GGAACGGGCT TGGAAGAAAA TAATCAAGAA GAGCAAAGCA 4200
TGGATTCAAA CTTAGGTGAA GCAGCATCTG GGTGTGAGAG TGAAACAAGC GTCTCTGAAG 4260
ACTGCTCAGG GCTATCCTCT CAGAGTGACA TTTTAACCAC TCAGCAGAGG GATACCATGC 4320 AACATAACCT GATAAAGCTC CAGCAGGAAA TGGCTGAACT AGAAGCTGTG TTAGAACAGC 4380
ATGGGAGCCA GCCTTCTAAC AGCTACCCTT CCATCATAAG TGACTCTTCT GCCCTTGAGG 4440
ACCTGCGAAA TCCAGAACAA AGCACATCAG AAAAAGCAGT ATTAACTTCA CAGAAAAGTA 4500
GTGAATACCC TATAAGCCAG AATCCAGAAG GCCTTTCTGC TGACAAGTTT GAGGTGTCTG 4560
CAGATAGTTC TACCAGTAAA AATAAAGAAC CAGGAGTGGA AAGGTCATCC CCTTCTAAAT 4620 GCCCATCATT AGATGATAGG TGGTACATGC ACAGTTGCTC TGGGAGTCTT CAGAATAGAA 4680
ACTACCCATC TCAAGAGGAG CTCATTAAGG TTGTTGATGT GGAGGAGCAA CAGCTGGAAG 4740
AGTCTGGGCC ACACGATTTG ACGGAAACAT CTTACTTGCC AAGGCAAGAT CTAGAGGGAA 4800
CCCCTTACCT GGAATCTGGA ATCAGCCTCT TCTCTGATGA CCCTGAATCT GATCCTTCTG 4860
AAGACAGAGC CCCAGAGTCA GCTCGTGTTG GCAACATACC ATCTTCAACC TCTGCATTGA 4920 AAGTTCCCCA ATTGAAAGTT GCAGAATCTG CCCAGAGTCC AGCTGCTGCT CATACTACTG 4980
ATACTGCTGG GTATAATGCA ATGGAAGAAA GTGTGAGCAG GGAGAAGCCA GAATTGACAG 5040
CTTCAACAGA AAGGGTCAAC AAAAGAATGT CCATGGTGGT GTCTGGCCTG ACCCCAGAAG 5100
AATTTATGCT CGTGTACAAG TTTGCCAGAA AACACCACAT CACTTTAACT AATCTAATTA 5160
CTGAAGAGAC TACTCATGTT GTTATGAAAA CAGATGCTGA GTTTGTGTGT GAACGGACAC 5220 TGAAATATTT TCTAGGAATT GCGGGAGGAA AATGGGTAGT TAGCTATTTC TGGGTGACCC 5280
AGTCTATTAA AGAAAGAAAA ATGCTGAATG AGCATGATTT TGAAGTCAGA GGAGATGTGG 5340
TCAATGGAAG AAACCACCAA GGTCCAAAGC GAGCAAGAGA ATCCCAGGAC AGAAAGATCT 5400
TCAGGGGGCT AGAAATCTGT TGCTATGGGC CCTTCACCAA CATGCCCACA GATCAACTGG 5460
AATGGATGGT ACAGCTGTGT GGTGCTTCTG TGGTGAAGGA GCTTTCATCA TTCACCCTTG 5520
GCACAGGTGT CCACCCAATT GTGGTTGTGC AGCCAGATGC CTGGACAGAG GACAATGGCT 5580
TCCATGCAAT TGGGCAGATG TGTGAGGCAC CTGTGGTGAC CCGAGAGTGG GTGTTGGACA 5640 GTGTAGCACT CTACCAGTGC CAGGAGCTGG ACACCTACCT GATACCCCAG ATCCCCCACA 5700
GCCACTACTG A 5711 (2) INFORMATION FOR SEQ ID NO:5:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 59 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: double (D) TOPOLOGY: linear
(ii) MOLECULE TYPE: cDNA
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:5 :
TGTCCTTAAA AGGTTGATAA TCACTTGCTG AGTGTGTTTC TCAAACAAGT TAATTTCAG 59 (2) INFORMATION FOR SEQ ID NO:6: (i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 5710 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: double
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: cDNA
(Xi) SEQUENCE DESCRIPTION: SEQ ID NO:6: AGCTCGCTGA GACTTCCTGG ACCCCGCACC AGGCTGTGGG GTTTCTCAGA TAACTGGGCC 60
CCTGCGCTCA GGAGGCCTTC ACCCTCTGCT CTGGGTAAAG TTCATTGGAA CAGAAAGAAA 120
TGGATTTATC TGCTCTTCGC GTTGAAGAAG TACAAAATGT CATTAATGCT ATGCAGAAAA 180
TCTTAGAGTG TCCCATCTGT CTGGAGTTGA TCAAGGAACC TGTCTCCACA AAGTGTGACC 240
ACATATTTTG CAAATTTTGC ATGCTGAAAC TTCTCAACCA GAAGAAAGGG CCTTCACAGT 300 GTCCTTTATG TAAGAATGAT ATAACCAAAA GGAGCCTACA AGAAAGTACG AGATTTAGTC 360
AACTTGTTGA AGAGCTATTG AAAATCATTT GTGCTTTTCA GCTTGACACA GGTTTGGAGT 420
ATGCAAACAG CTATAATTTT GCAAAAAAGG AAAATAACTC TCCTGAACAT CTAAAAGATG 480
AAGTTTCTAT CATCCAAAGT ATGGGCTACA GAAACCGTGC CAAAAGACTT CTACAGAGTG 540
AACCCGAAAA TCCTTCCTTG CAGGAAACCA GTCTCAGTGT CCAACTCTCT AACCTTGGAA 600 CTGTGAGAAC TCTGAGGACA AAGCAGCGGA TACAACCTCA AAAGACGTCT GTCTACATTG 660
AATTGGGATC TGATTCTTCT GAAGATACCG TTAATAAGGC AACTTATTGC AGTGTGGGAG 720
ATCAAGAATT GTTACAAATC ACCCCTCAAG GAACCAGGGA TGAAATCAGT TTGGATTCTG 780
CAAAAAAGGC TGCTTGTGAA TTTTCTGAGA CGGATGTAAC AAATACTGAA CATCATCAAC 840
CCAGTAATAA TGATTTGAAC ACCACTGAGA AGCGTGCAGC TGAGAGGCAT CCAGAAAAGT 900
ATCAGGGTAG TTCTGTTTCA AACTTGCATG TGGAGCCATG TGGCACAAAT ACTCATGCCA 960
GCTCATTACA GCATGAGAAC AGCAGTTTAT TACTCACTAA AGACAGAATG AATGTAGAAA 1020 AGGCTGAATT CTGTAATAAA AGCAAACGCC TGGCTTAGCA AGGAGCCAAC ATAACAGATG 1080
GGCTGGAAGT AAGGAAACAT GTAATGATAG GCGGACTCCC AGCACAGAAA AAAAGGTAGA 1140
TCTGAATGCT GATCCCCTGT GTGAGAGAAA AGAATGGAAT AAGCAGAAAC TGCCATGCTC 1200
AGAGAATCCT AGAGATACTG AAGATGTTCC TTGGATAACA CTAAATAGCA GCATTCAGAA 1260
AGTTAATGAG TGGTTTTCCA GAAGTGATGA ACTGTTAGGT TCTGATGACT CACATGATGG 1320 GGAGTCTGAA TCAAATGCCA AAGTAGCTGA TGTATTGGAC GTTCTAAATG AGGTAGATGA 1380
ATATTCTGGT TCTTCAGAGA AAATAGACTT ACTGGCCAGT GATCCTCATG AGGCTTTAAT 1440
ATGTAAAAGT GAAAGAGTTC ACTCCAAATC AGTAGAGAGT AATATTGAAG ACAAAATATT 1500
TGGGAAAACC TATCGGAAGA AGGCAAGCCT CCCCAACTTA AGCCATGTAA CTGAAAATCT 1560
AATTATAGGA GCATTTGTTA CTGAGCCACA GATAATACAA GAGCGTCCCC TCACAAATAA 1620 ATTAAAGCGT AAAAGGAGAC CTACATCAGG CCTTCATCCT GAGGATTTTA TCAAGAAAGC 1680
AGATTTGGCA GTTCAAAAGA CTCCTGAAAT GATAAATCAG GGAACTAACC AAACGGAGCA 1740
GAATGGTCAA GTGATGAATA TTACTAATAG TGGTCATGAG AATAAAACAA AAGGTGATTC 1800
TATTCAGAAT GAGAAAAATC CTAACCCAAT AGAATCACTC GAAAAAGAAT CTGCTTTCAA 1860
AACGAAAGCT GAACCTATAA GCAGCAGTAT AAGCAATATG GAACTCGAAT TAAATATCCA 1920 CAATTCAAAA GCACCTAAAA AGAATAGGCT GAGGAGGAAG TCTTCTACCA GGCATATTCA 1980
TGCGCTTGAA CTAGTAGTCA GTAGAAATCT AAGCCCACCT AATTGTACTG AATTGCAAAT 2040
TGATAGTTGT TCTAGCAGTG AAGAGATAAA GAAAAAAAAG TACAACCAAA TGCCAGTCAG 2100
GCACAGCAGA AACCTACAAC TCATGGAAGG TAAAGAACCT GCAACTGGAG CCAAGAAGAG 2160
TAACAAGCCA AATGAACAGA CAAGTAAAAG ACATGACAGC GATACTTTCC CAGAGCTGAA 2220 GTTAACAAAT GCACCTGGTT CTTTTACTAA GTGTTCAAAT ACCAGTGAAC TTAAAGAATT 2280
TGTCAATCCT AGCCTTCCAA GAGAAGAAAA AGAAGAGAAA CTAGAAACAG TTAAAGTGTC 2340
TAATAATGCT GAAGACCCCA AAGATCTCAT GTTAAGTGGA GAAAGGGTTT TGCAAACTGA 2400
AAGATCTGTA GAGAGTAGCA GTATTTCATT GGTACCTGGT ACTGATTATG GCACTCAGGA 2460
AAGTATCTCG TTACTGGAAG TTAGCACTCT AGGGAAGGCA AAAACAGAAC CAAATAAATG 2520 TGTGAGTCAG TGTGCAGCAT TTGAAAACCC CAAGGGACTA ATTCATGGTT GTTCCAAAGA 2580
TAATAGAAAT GACACAGAAG GCTTTAAGTA TCCATTGGGA CATGAAGTTA ACCACAGTCG 2640
GGAAACAAGC ATAGAAATGG AAGAAAGTGA ACTTGATGCT CAGTATTTGC AGAATACATT 2700
CAAGGTTTCA AAGCGCCAGT CATTTGCTCC GTTTTCAAAT CCAGGAAATG CAGAAGAGGA 2760
ATGTGCAACA TTCTCTGCCC ACTCTGGGTC CTTAAAGAAA CAAAGTCCAA AAGTCACTTT 2820
TGAATGTGAA CAAAAGGAAG AAAATCAAGG AAAGAATGAG TCTAATATCA AGCCTGTACA 2880
GACAGTTAAT ATCACTGCAG GCTTTCCTGT GGTTGGTCAG AAAGATAAGC CAGTTGATAA .2940 TGCCAAATGT AGTATCAAAG GAGGCTCTAG GTTTTGTCTA TCATCTCAGT TCAGAGGCAA 3000
CGAAACTGGA CTCATTACTC CAAATAAACA TGGACTTTTA CAAAACCCAT ATCGTATACC 3060
ACCACTTTTT CCCATCAAGT CATTTGTTAA AACTAAATGT AAGAAAAATC TGCTAGAGGA 3120
AAACTTTGAG GAACATTCAA TGTCACCTGA AAGAGAAATG GGAAATGAGA ACATTCCAAG 3180
TACAGTGAGC ACAATTAGCC GTAATAACAT TAGAGAAAAT GTTTTTAAAG AAGCCAGCTC 3240 AAGCAATATT AATGAAGTAG GTTCCAGTAC TAATGAAGTG GGCTCCAGTA TTAATGAAAT 3300
AGGTTCCAGT GATGAAAACA TTCAAGCAGA ACTAGGTAGA AACAGAGGGC CAAAATTGAA 3360
TGCTATGCTT AGATTAGGGG TTTTGCAACC TGAGGTCTAT AAACAAAGTC TTCCTGGAAG 3420
TAATTGTAAG CATCCTGAAA TAAAAAAGCA AGAATATGAA GAAGTAGTTC AGACTGTTAA 3480
TACAGATTTC TCTCCATATC TGATTTCAGA TAACTTAGAA CAGCCTATGG GAAGTAGTCA 3540 TGCATCTCAG GTTTGTTCTG AGACACCTGA TGACCTGTTA GATGATGGTG AAATAAAGGA 3600
AGATACTAGT TTTGCTGAAA ATGACATTAA GGAAAGTTCT GCTGTTTTTA GCAAAAGCGT 3660
CCAGAAAGGA GAGCTTAGCA GGAGTCCTAG CCCTTTCACC CATACACATT TGGCTCAGGG 3720
TTACCGAAGA GGGGCCAAGA AATTAGAGTC CTCAGAAGAG AACTTATCTA GTGAGGATGA 3780
AGAGCTTCCC TGCTTCCAAC ACTTGTTATT TGGTAAAGTA AACAATATAC CTTCTCAGTC 3840 TACTAGGCAT AGCACCGTTG CTACCGAGTG TCTGTCTAAG AACACAGAGG AGAATTTATT 3900
ATCATTGAAG AATAGCTTAA ATGACTGCAG TAACCAGGTA ATATTGGCAA AGGCATCTCA 3960
GGAACATCAC CTTAGTGAGG AAACAAAATG TTCTGCTAGC TTGTTTTCTT CACAGTGCAG 4020
TGAATTGGAA GACTTGACTG CAAATACAAA CACCCAGGAT CCTTTCTTGA TTGGTTCTTC 4080
CAAACAAATG AGGCATCAGT CTGAAAGCCA GGGAGTTGGT CTGAGTGACA AGGAATTGGT 4140 TTCAGATGAT GAAGAAAGAG GAACGGGCTT GGAAGAAAAT AATCAAGAAG AGCAAAGCAT 4200
GGATTCAAAC TTAGGTGAAG CAGCATCTGG GTGTGAGAGT GAAACAAGCG TCTCTGAAGA 4260
CTGCTCAGGG CTATCCTCTC AGAGTGACAT TTTAACCACT CAGCAGAGGG ATACCATGCA 4320
ACATAACCTG ATAAAGCTCC AGCAGGAAAT GGCTGAACTA GAAGCTGTGT TAGAACAGCA 4380
TGGGAGCCAG CCTTCTAACA GCTACCCTTC CATCATAAGT GACTCTTCTG CCCTTGAGGA 4440 CCTGCGAAAT CCAGAACAAA GCACATCAGA AAAAGCAGTA TTAACTTCAC AGAAAAGTAG 4500
TGAATACCCT ATAAGCCAGA ATCCAGAAGG CCTTTCTGCT GACAAGTTTG AGGTGTCTGC 4560
AGATAGTTCT ACCAGTAAAA ATAAAGAACC AGGAGTGGAA AGGTCATCCC CTTCTAAATG 4620
CCCATCATTA GATGATAGGT GG ACATGCA CAGTTGCTCT GGGAGTCTTC AGAATAGAAA 4680
CTACCCATCT CAAGAGGAGC TCATTAAGGT TGTTGATGTG GAGGAGCAAC AGCTGGAAGA 4740
GTCTGGGCCA CACGATTTGA CGGAAACATC TTACTTGCCA AGGCAAGATC TAGAGGGAAC 4800
CCCTTACCTG GAATCTGGAA TCAGCCTCTT CTCTGATGAC CCTGAATCTG ATCCTTCTGA 4860 AGACAGAGCC CCAGAGTCAG CTCGTGTTGG CAACATACCA TCTTCAACCT CTGCATTGAA 4920
AGTTCCCCAA TTGAAAGTTG CAGAATCTGC CCAGAGTCCA GCTGCTGCTC ATACTACTGA 4980
TACTGCTGGG TATAATGCAA TGGAAGAAAG TGTGAGCAGG GAGAAGCCAG AATTGACAGC 5040
TTCAACAGAA AGGGTCAACA AAAGAATGTC CATGGTGGTG TCTGGCCTGA CCCCAGAAGA 5100
ATTTATGCTC GTGTACAAGT TTGCCAGAAA ACACCACATC ACTTTAACTA ATCTAATTAC 5160 TGAAGAGACT ACTCATGTTG TTATGAAAAC AGATGCTGAG TTTGTGTGTG AACGGACACT 5220
GAAATATTTT CTAGGAATTG CGGGAGGAAA ATGGGTAGTT AGCTATTTCT GGGTGACCCA 5280
GTCTATTAAA GAAAGAAAAA TGCTGAATGA GCATGATTTT GAAGTCAGAG GAGATGTGGT 5340
CAATGGAAGA AACCACCAAG GTCCAAAGCG AGCAAGAGAA TCCCAGGACA GAAAGATCTT 5400
CAGGGGGCTA GAAATCTGTT GCTATGGGCC CTTCACCAAC ATGCCCACAG ATCAACTGGA 5460 ATGGATGGTA CAGCTGTGTG GTGCTTCTGT GGTGAAGGAG CTTTCATCAT TCACCCTTGG 5520
CACAGGTGTC CACCCAATTG TGGTTGTGCA GCCAGATGCC TGGACAGAGG ACAATGGCTT 5580
CCATGCAATT GGGCAGATGT GTGAGGCACC TGTGGTGACC CGAGAGTGGG TGTTGGACAG 5640
TGTAGCACTC TACCAGTGCC AGGAGCTGGA CACCTACCTG ATACCCCAGA TCCCCCACAG 5700
CCACTACTGA 5710 (2) INFORMATION FOR SEQ ID NO:7:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 5709 base pairs
(B) TYPE: nucleic acid (C) STRANDEDNESS: double
(D) TOPOLOGY: linear
.(ii) MOLECULE TYPE: cDNA ( i) SEQUENCE DESCRIPTION: SEQ ID NO:7:
AGCTCGCTGA GACTTCCTGG ACCCCGCACC AGGCTGTGGG GTTTCTCAGA TAACTGGGCC 60
CCTGCGCTCA GGAGGCCTTC ACCCTCTGCT CTGGGTAAAG TTCATTGGAA CAGAAAGAAA 120
TGGATTTATC TGCTCTTCGC GTTGAAGAAG TACAAAATGT CATTAATGCT ATGCAGAAAA 180
TCTTAGAGTG TCCCATCTGT CTGGAGTTGA TCAAGGAACC TGTCTCCACA AAGTGTGACC 240 ACATATTTTG CAAATTTTGC ATGCTGAAAC TTCTCAACCA GAAGAAAGGG CCTTCACAGT 300
GTCCTTTATG TAAGAATGAT ATAACCAAAA GGAGCCTACA AGAAAGTACG AGATTTAGTC 360
AACTTGTTGA AGAGCTATTG AAAATCATTT GTGCTTTTCA GCTTGACACA GGTTTGGAGT 420
ATGCAAACAG CTATAATTTT GCAAAAAAGG AAAATAACTC TCCTGAACAT CTAAAAGATG 480
AAGTTTCTAT CATCCAAAGT ATGGGCTACA GAAACCGTGC CAAAAGACTT CTACAGAGTG 540
AACCCGAAAA TCCTTCCTTG CAGGAAACCA GTCTCAGTGT CCAACTCTCT AACCTTGGAA 600
CTGTGAGAAC TCTGAGGACA AAGCAGCGGA TACAACCTCA AAAGACGTCT GTCTACATTG 660 AATTGGGATC TGATTCTTCT GAAGATACCG TTAATAAGGC AACTTATTGC AGTGTGGGAG 720
ATCAAGAATT GTTACAAATC ACCCCTCAAG GAACCAGGGA TGAAATCAGT TTGGATTCTG 780
CAAAAAAGGC TGCTTGTGAA TTTTCTGAGA CGGATGTAAC AAATACTGAA CATCATCAAC 840
CCAGTAATAA TGATTTGAAC ACCACTGAGA AGCGTGCAGC TGAGAGGCAT CCAGAAAAGT 900
ATCAGGGTAG TTCTGTTTCA AACTTGCATG TGGAGCCATG TGGCACAAAT ACTCATGCCA 960 GCTCATTACA GCATGAGAAC AGCAGTTTAT TACTCACTAA AGACAGAATG AATGTAGAAA 1020
AGGCTGAATT CTGTAATAAA AGCAAACAGC CTGGCTTAGC AAGGAGCCAA CATAACAGAT 1080
GGGCTGGAAG TAAGGAAACA TGTAATGATA GGCGGACTCC CAGCACAGAA AAAAAGGTAG 1140
ATCTGAATGC TGATCCCCTG TGTGAGAGAA AAGAATGGAA TAAGCAGAAA CTGCCATGCT 1200
CAGAGAATCC TAGAGATACT GAAGATGTTC CTTGGATAAC ACTAAATAGC AGCATTCAGA 1260 AAGTTAATGA GTGGTTTTCC AGAAGTGATG AACTGTTAGG TTCTGATGAC TCACATGATG 1320
GGGAGTCTGA ATCAAATGCC AAAGTAGCTG ATGTATTGGA CGTTCTAAAT GAGGTAGATG 1380
AATATTCTGG TTCTTCAGAG AAAATAGACT TACTGGCCAG TGATCCTCAT GAGGCTTTAA 1440
TATGTAAAAG TGAAAGAGTT CACTCCAAAT CAGTAGAGAG TAATATTGAA GACAAAATAT 1500
TTGGGAAAAC CTATCGGAAG AAGGCAAGCC TCCCCAACTT AAGCCATGTA ACTGAAAATC 1560 TAATTATAGG AGCATTTGTT ACTGAGCCAC AGATAATACA AGAGCGTCCC CTCACAAATA 1620
AATTAAAGCG TAAAAGGAGA CCTACATCAG GCCTTCATCC TGAGGATTTT ATCAAGAAAG 1680
CAGATTTGGC AGTTCAAAAG ACTCCTGAAA TGATAAATCA GGGAACTAAC CAAACGGAGC 1740
AGAATGGTCA AGTGATGAAT ATTACTAATA GTGGTCATGA GAATAAAACA AAAGGTGATT 1800
CTATTCAGAA TGAGAAAAAT CCTAACCCAA TAGAATCACT CGAAAAAGAA TCTGCTTTCA 1860 AAACGAAAGC TGAACCTATA AGCAGCAGTA TAAGCAATAT GGAACTCGAA TTAAATATCC 1920
ACAATTCAAA AGCACCTAAA AAGAATAGGC TGAGGAGGAA GTCTTCTACC AGGCATATTC 1980
ATGCGCTTGA ACTAGTAGTC AGTAGAAATC TAAGCCCACC TAATTGTACT GAATTGCAAA 2040
TTGATAGTTG TTCTAGCAGT GAAGAGATAA AGAAAAAAAA GTACAACCAA ATGCCAGTCA 2100
GGCACAGCAG AAACCTACAA CTCATGGAAG GTAAAGAACC TGCAACTGGA GCCAAGAAGA 2160 GTAACAAGCC AAATGAACAG ACAAGTAAAA GACATGACAG CGATACTTTC CCAGAGCTGA 2220
AGTTAACAAA TGCACCTGGT TCTTTTACTA AGTGTTCAAA TACCAGTGAA CTTAAAGAAT 2280
TTGTCAATCC TAGCCTTCCA AGAGAAGAAA AAGAAGAGAA ACTAGAAACA GTTAAAGTGT 2340
CTAATAATGC TGAAGACCCC AAAGATCTCA TGTTAAGTGG AGAAAGGGTT TTGCAAACTG 2400
AAAGATCTGT AGAGTAGCAG TATTTCATTG GTACCTGGTA CTGATTATGG CACTCAGGAA 2460
AGTATCTCGT TACTGGAAGT TAGCACTCTA GGGAAGGCAA AAACAGAACC AAATAAATGT 2520
GTGAGTCAGT GTGCAGCATT TGAAAACCCC AAGGGACTAA TTCATGGTTG TTCCAAAGAT 2580 AATAGAAATG ACACAGAAGG CTTTAAGTAT CCATTGGGAC ATGAAGTTAA CCACAGTCGG 2640
GAAACAAGCA TAGAAATGGA AGAAAGTGAA CTTGATGCTC AGTATTTGCA GAATACATTC 2700
AAGGTTTCAA AGCGCCAGTC ATTTGCTCCG TTTTCAAATC CAGGAAATGC AGAAGAGGAA 2760
TGTGCAACAT TCTCTGCCCA CTCTGGGTCC TTAAAGAAAC AAAGTCCAAA AGTCACTTTT 2820
GAATGTGAAC AAAAGGAAGA AAATCAAGGA AAGAATGAGT CTAATATCAA GCCTGTACAG 2880 ACAGTTAATA TCACTGCAGG CTTTCCTGTG GTTGGTCAGA AAGATAAGCC AGTTGATAAT 2940
GCCAAATGTA GTATCAAAGG AGGCTCTAGG TTTTGTCTAT CATCTCAGTT CAGAGGCAAC 3000
GAAACTGGAC TCATTACTCC AAATAAACAT GGACTTTTAC AAAACCCATA TCGTATACCA 3060
CCACTTTTTC CCATCAAGTC ATTTGTTAAA ACTAAATGTA AGAAAAATCT GCTAGAGGAA 3120
AACTTTGAGG AACATTCAAT GTCACCTGAA AGAGAAATGG GAAATGAGAA CATTCCAAGT 3180 ACAGTGAGCA CAATTAGCCG TAATAACATT AGAGAAAATG TTTTTAAAGA AGCCAGCTCA 3240
AGCAATATTA ATGAAGTAGG TTCCAGTACT AATGAAGTGG GCTCCAGTAT TAATGAAATA 3300
GGTTCCAGTG ATGAAAACAT TCAAGCAGAA CTAGGTAGAA ACAGAGGGCC AAAATTGAAT 3360
GCTATGCTTA GATTAGGGGT TTTGCAACCT GAGGTCTATA AACAAAGTCT TCCTGGAAGT 3420
AATTGTAAGC ATCCTGAAAT AAAAAAGCAA GAATATGAAG AAGTAGTTCA GACTGTTAAT 3480 ACAGATTTCT CTCCATATCT GATTTCAGAT AACTTAGAAC AGCCTATGGG AAGTAGTCAT 3540
GCATCTCAGG TTTGTTCTGA GACACCTGAT GACCTGTTAG ATGATGGTGA AATAAAGGAA 600
GATACTAGTT TTGCTGAAAA TGACATTAAG GAAAGTTCTG CTGTTTTTAG CAAAAGCGTC 3660
CAGAAAGGAG AGCTTAGCAG GAGTCCTAGC CCTTTCACCC ATACACATTT GGCTCAGGGT 3720
TACCGAAGAG GGGCCAAGAA ATTAGAGTCC TCAGAAGAGA ACTTATCTAG TGAGGATGAA 3780 GAGCTTCCCT GCTTCCAACA CTTGTTATTT GGTAAAGTAA ACAATATACC TTCTCAGTCT 3840
ACTAGGCATA GCACCGTTGC TACCGAGTGT CTGTCTAAGA ACACAGAGGA GAATTTATTA 3900
TCATTGAAGA ATAGCTTAAA TGACTGCAGT AACCAGGTAA TATTGGCAAA GGCATCTCAG 3960
GAACATCACC TTAGTGAGGA AACAAAATGT TCTGCTAGCT TGTTTTCTTC ACAGTGCAGT 4020
GAATTGGAAG ACTTGACTGC AAATACAAAC ACCCAGGATC CTTTCTTGAT TGGTTCTTCC 4080 AAACAAATGA GGCATCAGTC TGAAAGCCAG GGAGTTGGTC TGAGTGACAA GGAATTGGTT 4140
TCAGATGATG AAGAAAGAGG AACGGGCTTG GAAGAAAATA ATCAAGAAGA GCAAAGCATG 4200
GATTCAAACT TAGGTGAAGC AGCATCTGGG TGTGAGAGTG AAACAAGCGT CTCTGAAGAC 4260
TGCTCAGGGC TATCCTCTCA GAGTGACATT TTAACCACTC AGCAGAGGGA TACCATGCAA 4320
CATAACCTGA TAAAGCTCCA GCAGGAAATG GCTGAACTAG AAGCTGTGTT AGAACAGCAT 4380
GGGAGCCAGC CTTCTAACAG CTACCCTTCC ATCATAAGTG ACTCTTCTGC CCTTGAGGAC 4440
CTGCGAAATC CAGAACAAAG CACATCAGAA AAAGCAGTAT TAACTTCACA GAAAAGTAGT -4500 GAATACCCTA TAAGCCAGAA TCCAGAAGGC CTTTCTGCTG ACAAGTTTGA GGTGTCTGCA 4560
GATAGTTCTA CCAGTAAAAA TAAAGAACCA GGAGTGGAAA GGTCATCCCC TTCTAAATGC 4620
CCATCATTAG ATGATAGGTG GTACATGCAC AGTTGCTCTG GGAGTCTTCA GAATAGAAAC 4680
TACCCATCTC AAGAGGAGCT CATTAAGGTT GTTGATGTGG AGGAGCAACA GCTGGAAGAG 4740
TCTGGGCCAC ACGATTTGAC GGAAACATCT TACTTGCCAA GGCAAGATCT AGAGGGAACC 4800 CCTTACCTGG AATCTGGAAT CAGCCTCTTC TCTGATGACC CTGAATCTGA TCCTTCTGAA 4860
GACAGAGCCC CAGAGTCAGC TCGTGTTGGC AACATACCAT CTTCAACCTC TGCATTGAAA 4920
GTTCCCCAAT TGAAAGTTGC AGAATCTGCC CAGAGTCCAG CTGCTGCTCA TACTACTGAT 4980
ACTGCTGGGT ATAATGCAAT GGAAGAAAGT GTGAGCAGGG AGAAGCCAGA ATTGACAGCT 5040
TCAACAGAAA GGGTCAACAA AAGAATGTCC ATGGTGGTGT CTGGCCTGAC CCCAGAAGAA 5100 TTTATGCTCG TGTACAAGTT TGCCAGAAAA CACCACATCA CTTTAACTAA TCTAATTACT 5160
GAAGAGACTA CTCATGTTGT TATGAAAACA GATGCTGAGT TTGTGTGTGA ACGGACACTG 5220
AAATATTTTC TAGGAATTGC GGGAGGAAAA TGGGTAGTTA GCTATTTCTG GGTGACCCAG 5280
TCTATTAAAG AAAGAAAAAT GCTGAATGAG CATGATTTTG AAGTCAGAGG AGATGTGGTC 5340
AATGGAAGAA ACCACCAAGG TCCAAAGCGA GCAAGAGAAT CCCAGGACAG AAAGATCTTC 5400 AGGGGGCTAG AAATCTGTTG CTATGGGCCC TTCACCAACA TGCCCACAGA TCAACTGGAA 5460
TGGATGGTAC AGCTGTGTGG TGCTTCTGTG GTGAAGGAGC TTTCATCATT CACCCTTGGC 5520
ACAGGTGTCC ACCCAATTGT GGTTGTGCAG CCAGATGCCT GGACAGAGGA CAATGGCTTC 5580
CATGCAATTG GGCAGATGTG TGAGGCACCT GTGGTGACCC GAGAGTGGGT GTTGGACAGT 5640
GTAGCACTCT ACCAGTGCCA GGAGCTGGAC ACCTACCTGA TACCCCAGAT CCCCCACAGC 5700 CACTACTGA 5709
(2) INFORMATION FOR SEQ ID NO:8:
(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 5709 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: double
(D) TOPOLOGY: linear (ll) MOLECULE TYPE: cDNA
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:8:
AGCTCGCTGA GACTTCCTGG ACCCCGCACC AGGCTGTGGG GTTTCTCAGA TAACTGGGCC 60
CCTGCGCTCA GGAGGCCTTC ACCCTCTGCT CTGGGTAAAG TTCATTGGAA CAGAAAGAAA 120
TGGATTTATC TGCTCTTCGC GTTGAAGAAG TACAAAATGT CATTAATGCT ATGCAGAAAA 180
TCTTAGAGTG TCCCATCTGT CTGGAGTTGA TCAAGGAACC TGTCTCCACA AAGTGTGACC 240
ACATATTTTG CAAATTTTGC ATGCTGAAAC TTCTCAACCA GAAGAAAGGG CCTTCACAGT 300 GTCCTTTATG TAAGAATGAT ATAACCAAAA GGAGCCTACA AGAAAGTACG AGATTTAGTC 360
AACTTGTTGA AGAGCTATTG AAAATCATTT GTGCTTTTCA GCTTGACACA GGTTTGGAGT 420
ATGCAAACAG CTATAATTTT GCAAAAAAGG AAAATAACTC TCCTGAACAT CTAAAAGATG 480
AAGTTTCTAT CATCCAAAGT ATGGGCTACA GAAACCGTGC CAAAAGACTT CTACAGAGTG 540
AACCCGAAAA TCCTTCCTTG CAGGAAACCA GTCTCAGTGT CCAACTCTCT AACCTTGGAA 600 CTGTGAGAAC TCTGAGGACA AAGCAGCGGA TACAACCTCA AAAGACGTCT GTCTACATTG 660
AATTGGGATC TGATTCTTCT GAAGATACCG TTAATAAGGC AACTTATTGC AGTGTGGGAG 720
ATCAAGAATT GTTACAAATC ACCCCTCAAG GAACCAGGGA TGAAATCAGT TTGGATTCTG 780
CAAAAAAGGC TGCTTGTGAA TTTTCTGAGA CGGATGTAAC AAATACTGAA CATCATCAAC 840
CCAGTAATAA TGATTTGAAC ACCACTGAGA AGCGTGCAGC TGAGAGGCAT CCAGAAAAGT 900 ATCAGGGTAG TTCTGTTTCA AACTTGCATG TGGAGCCATG TGGCACAAAT ACTCATGCCA 960
GCTCATTACA GCATGAGAAC AGCAGTTTAT TACTCACTAA AGACAGAATG AATGTAGAAA 1020
AGGCTGAATT CTGTAATAAA AGCAAACAGC CTGGCTTAGC AAGGAGCCAA CATAACAGAT 1080
GGGCTGGAAG TAAGGAAACA TGTAATGATA GGCGGACTCC CAGCACAGAA AAAAAGGTAG 1140
ATCTGAATGC TGATCCCCTG TGTGAGAGAA AAGAATGGAA TAAGCAGAAA CTGCCATGCT 1200 CAGAGAATCC TAGAGATACT GAAGATGTTC CTTGGATAAC ACTAAATAGC AGCATTCAGA 1260
AAGTTAATGA GTGGTTTTCC AGAAGTGATG AACTGTTAGG TTCTGATGAC TCACATGATG 1320
GGGAGTCTGA ATCAAATGCC AAAGTAGCTG ATGTATTGGA CGTTCTAAAT GAGGTAGATG 1380
AATATTCTGG TTCTTCAGAG AAAATAGACT TACTGGCCAG TGATCCTCAT GAGGCTTTAA 1440
TATGTAAAAG TGAAAGAGTT CACTCCAAAT CAGTAGAGAG TAATATTGAA GACAAAATAT 1500 TTGGGAAAAC CTATCGGAAG AAGGCAAGCC TCCCCAACTT AAGCCATGTA ACTGAAAATC 1560
TAATTATAGG AGCATTTGTT ACTGAGCCAC AGATAATACA AGAGCGTCCC CTCACAAATA 1620
AATTAAAGCG TAAAAGGAGA CCTACATCAG GCCTTCATCC TGAGGATTTT ATCAAGAAAG 1680
CAGATTTGGC AGTTCAAAAG ACTCCTGAAA TGATAAATCA GGGAACTAAC CAAACGGAGC 1740
AGAATGGTCA AGTGATGAAT ATTACTAATA GTGGTCATGA GAATAAAACA AAAGGTGATT 1800 CTATTCAGAA TGAGAAAAAT CCTAACCCAA TAGAATCACT CGAAAAAGAA TCTGCTTTCA 1860
AAACGAAAGC TGAACCTATA AGCAGCAGTA TAAGCAATAT GGAACTCGAA TTAAATATCC 1920
ACAATTCAAA AGCACCTAAA AAGAATAGGC TGAGGAGGAA GTCTTCTACC AGGCATATTC 1980
ATGCGCTTGA ACTAGTAGTC AGTAGAAATC TAAGCCCACC TAATTGTACT GAATTGCAAA 2040
TTGATAGTTG TTCTAGCAGT GAAGAGATAA AGAAAAAAAA GTACAACCAA ATGCCAGTCA 2100
GGCACAGCAG AAACCTACAA CTCATGGAAG GTAAAGAACC TGCAACTGGA GCCAAGAAGA 2160
GTAACAAGCC AAATGAACAG ACAAGTAAAA GACATGACAG CGATACTTTC CCAGAGCTGA 2220 AGTTAACAAA TGCACCTGGT TCTTTTACTA AGTGTTCAAA TACCAGTGAA CTTAAAGAAT 2280
TTGTCAATCC TAGCCTTCCA AGAGAAGAAA AAGAAGAGAA ACTAGAAACA GTTAAAGTGT 2340
CTAATAATGC TGAAGACCCC AAAGATCTCA TGTTAAGTGG AGAAAGGGTT TTGCAAACTG 2400
AAAGATCTGT AGAGAGTAGC AGTATTTCAT TGGTACCTGG TACTGATTAT GGCACTCAGG 2460
AAAGTATCTC GTTACTGGAA GTTAGCACTC TAGGGAAGGC AAAAACAGAA CCAAATAAAT 2520 GTGTGAGTCA GTGTGCAGCA TTTGAAAACC CCAAGGGACT AATTCATGGT TGTTCCAAAG 2580
ATAATAGAAA TGACACAGAA GGCTTTAAGT ATCCATTGGG ACATGAAGTT AACCACAGTC 2640
GGGAAACAAG CATAGAAATG GAAGAAAGTG AACTTGATGC TCAGTATTTG CAGAATACAT 2700
TCAAGGTTTC AAAGCGCCAG TCATTTGCTC CGTTTTCAAA TCCAGGAAAT GCAGAAGAGG 2760
AATGTGCAAC ATTCTCTGCC CACTCTGGGT CCTTAAAGAC AAAGTCCAAA AGTCACTTTT 2820 GAATGTGAAC AAAAGGAAGA AAATCAAGGA AAGAATGAGT CTAATATCAA GCCTGTACAG 2880
ACAGTTAATA TCACTGCAGG CTTTCCTGTG GTTGGTCAGA AAGATAAGCC AGTTGATAAT 2940
GCCAAATGTA GTATCAAAGG AGGCTCTAGG TTTTGTCTAT CATCTCAGTT CAGAGGCAAC 3000
GAAACTGGAC TCATTACTCC AAATAAACAT GGACTTTTAC AAAACCCATA TCGTATACCA 3060
CCACTTTTTC CCATCAAGTC ATTTGTTAAA ACTAAATGTA AGAAAAATCT GCTAGAGGAA 3120 AACTTTGAGG AACATTCAAT GTCACCTGAA AGAGAAATGG GAAATGAGAA CATTCCAAGT 3180
ACAGTGAGCA CAATTAGCCG TAATAACATT AGAGAAAATG TTTTTAAAGA AGCCAGCTCA 3240
AGCAATATTA ATGAAGTAGG TTCCAGTACT AATGAAGTGG GCTCCAGTAT TAATGAAATA 3300
GGTTCCAGTG ATGAAAACAT TCAAGCAGAA CTAGGTAGAA ACAGAGGGCC AAAATTGAAT 3360
GCTATGCTTA GATTAGGGGT TTTGCAACCT GAGGTCTATA AACAAAGTCT TCCTGGAAGT 3420 AATTGTAAGC ATCCTGAAAT AAAAAAGCAA GAATATGAAG AAGTAGTTCA GACTGTTAAT 3480
ACAGATTTCT CTCCATATCT GATTTCAGAT AACTTAGAAC AGCCTATGGG AAGTAGTCAT 3540
GCATCTCAGG TTTGTTCTGA GACACCTGAT GACCTGTTAG ATGATGGTGA AATAAAGGAA 3600
GATACTAGTT TTGCTGAAAA TGACATTAAG GAAAGTTCTG CTGTTTTTAG CAAAAGCGTC 3660
CAGAAAGGAG AGCTTAGCAG GAGTCCTAGC CCTTTCACCC ATACACATTT GGCTCAGGGT 3720 TACCGAAGAG GGGCCAAGAA ATTAGAGTCC TCAGAAGAGA ACTTATCTAG TGAGGATGAA 3780
GAGCTTCCCT GCTTCCAACA CTTGTTATTT GGTAAAGTAA ACAATATACC TTCTCAGTCT 3840
ACTAGGCATA GCACCGTTGC TACCGAGTGT CTGTCTAAGA ACACAGAGGA GAATTTATTA 3900
TCATTGAAGA ATAGCTTAAA TGACTGCAGT AACCAGGTAA TATTGGCAAA GGCATCTCAG 3960
GAACATCACC TTAGTGAGGA AACAAAATGT TCTGCTAGCT TGTTTTCTTC ACAGTGCAGT 4020
GAATTGGAAG ACTTGACTGC AAATACAAAC ACCCAGGATC CTTTCTTGAT TGGTTCTTCC 4080
AAACAAATGA GGCATCAGTC TGAAAGCCAG GGAGTTGGTC TGAGTGACAA GGAATTGGTT 4140 TCAGATGATG AAGAAAGAGG AACGGGCTTG GAAGAAAATA ATCAAGAAGA GCAAAGCATG 4200
GATTCAAACT TAGGTGAAGC AGCATCTGGG TGTGAGAGTG AAACAAGCGT CTCTGAAGAC 4260
TGCTCAGGGC TATCCTCTCA GAGTGACATT TTAACCACTC AGCAGAGGGA TACCATGCAA 4320
CATAACCTGA TAAAGCTCCA GCAGGAAATG GCTGAACTAG AAGCTGTGTT AGAACAGCAT 4380
GGGAGCCAGC CTTCTAACAG CTACCCTTCC ATCATAAGTG ACTCTTCTGC CCTTGAGGAC 4440 CTGCGAAATC CAGAACAAAG CACATCAGAA AAAGCAGTAT TAACTTCACA GAAAAGTAGT 4500
GAATACCCTA TAAGCCAGAA TCCAGAAGGC CTTTCTGCTG ACAAGTTTGA GGTGTCTGCA 4560
GATAGTTCTA CCAGTAAAAA TAAAGAACCA GGAGTGGAAA GGTCATCCCC TTCTAAATGC 4620
CCATCATTAG ATGATAGGTG GTACATGCAC AGTTGCTCTG GGAGTCTTCA GAATAGAAAC 4680
TACCCATCTC AAGAGGAGCT CATTAAGGTT GTTGATGTGG AGGAGCAACA GCTGGAAGAG 4740 TCTGGGCCAC ACGATTTGAC GGAAACATCT TACTTGCCAA GGCAAGATCT AGAGGGAACC 4800
CCTTACCTGG AATCTGGAAT CAGCCTCTTC TCTGATGACC CTGAATCTGA TCCTTCTGAA 4860
GACAGAGCCC CAGAGTCAGC TCGTGTTGGC AACATACCAT CTTCAACCTC TGCATTGAAA 4920
GTTCCCCAAT TGAAAGTTGC AGAATCTGCC CAGAGTCCAG CTGCTGCTCA TACTACTGAT 4980
ACTGCTGGGT ATAATGCAAT GGAAGAAAGT GTGAGCAGGG AGAAGCCAGA ATTGACAGCT 5040 TCAACAGAAA GGGTCAACAA AAGAATGTCC ATGGTGGTGT CTGGCCTGAC CCCAGAAGAA 5100
TTTATGCTCG TGTACAAGTT TGCCAGAAAA CACCACATCA CTTTAACTAA TCTAATTACT 5160
GAAGAGACTA CTCATGTTGT TATGAAAACA GATGCTGAGT TTGTGTGTGA ACGGACACTG 5220
AAATATTTTC TAGGAATTGC GGGAGGAAAA TGGGTAGTTA GCTATTTCTG GGTGACCCAG 5280
TCTATTAAAG AAAGAAAAAT GCTGAATGAG CATGATTTTG AAGTCAGAGG AGATGTGGTC 5340 AATGGAAGAA ACCACCAAGG TCCAAAGCGA GCAAGAGAAT CCCAGGACAG AAAGATCTTC 5400
AGGGGGCTAG AAATCTGTTG CTATGGGCCC TTCACCAACA TGCCCACAGA TCAACTGGAA 5460
TGGATGGTAC AGCTGTGTGG TGCTTCTGTG GTGAAGGAGC TTTCATCATT CACCCTTGGC 5520
ACAGGTGTCC ACCCAATTGT GGTTGTGCAG CCAGATGCCT GGACAGAGGA CAATGGCTTC 5580
CATGCAATTG GGCAGATGTG TGAGGCACCT GTGGTGACCC GAGAGTGGGT GTTGGACAGT 5640 GTAGCACTCT ACCAGTGCCA GGAGCTGGAC ACCTACCTGA TACCCCAGAT CCCCCACAGC 5700
CACTACTGA 5709 (2) INFORMATION FOR SEQ ID NO:9:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 5709 base pairs
(B) TYPE: nucleic acid (C) STRANDEDNESS: double
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:9:
AGCTCGCTGA GACTTCCTGG ACCCCGCACC AGGCTGTGGG GTTTCTCAGA TAACTGGGCC 60
CCTGCGCTCA GGAGGCCTTC ACCCTCTGCT CTGGGTAAAG TTCATTGGAA CAGAAAGAAA 120
TGGATTTATC TGCTCTTCGC GTTGAAGAAG TACAAAATGT CATTAATGCT ATGCAGAAAA 180
TCTTAGAGTG TCCCATCTGT CTGGAGTTGA TCAAGGAACC TGTCTCCACA AAGTGTGACC 240 ACATATTTTG CAAATTTTGC ATGCTGAAAC TTCTCAACCA GAAGAAAGGG CCTTCACAGT 300
GTCCTTTATG TAAGAATGAT ATAACCAAAA GGAGCCTACA AGAAAGTACG AGATTTAGTC 360
AACTTGTTGA AGAGCTATTG AAAATCATTT GTGCTTTTCA GCTTGACACA GGTTTGGAGT 420
ATGCAAACAG CTATAATTTT GCAAAAAAGG AAAATAACTC TCCTGAACAT CTAAAAGATG 480
AAGTTTCTAT CATCCAAAGT ATGGGCTACA GAAACCGTGC CAAAAGACTT CTACAGAGTG 540 AACCCGAAAA TCCTTCCTTG CAGGAAACCA GTCTCAGTGT CCAACTCTCT AACCTTGGAA 600
CTGTGAGAAC TCTGAGGACA AAGCAGCGGA TACAACCTCA AAAGACGTCT GTCTACATTG 660
AATTGGGATC TGATTCTTCT GAAGATACCG TTAATAAGGC AACTTATTGC AGTGTGGGAG 720
ATCAAGAATT GTTACAAATC ACCCCTCAAG GAACCAGGGA TGAAATCAGT TTGGATTCTG 780
CAAAAAAGGC TGCTTGTGAA TTTTCTGAGA CGGATGTAAC AAATACTGAA CATCATCAAC 840 CCAGTAATAA TGATTTGAAC ACCACTGAGA AGCGTGCAGC TGAGAGGCAT CCAGAAAAGT 900
ATCAGGGTAG TTCTGTTTCA AACTTGCATG TGGAGCCATG TGGCACAAAT ACTCATGCCA 960
GCTCATTACA GCATGAGAAC AGCAGTTTAT TACTCACTAA AGACAGAATG AATGTAGAAA 1020
AGGCTGAATT CTGTAATAAA AGCAAACAGC CTGGCTTAGC AAGGAGCCAA CATAACAGAT 1080
GGGCTGGAAG TAAGGAAACA TGTAATGATA GGCGGACTCC CAGCACAGAA AAAAAGGTAG 1140 ATCTGAATGC TGATCCCCTG TGTGAGAGAA AAGAATGGAA TAAGCAGAAA CTGCCATGCT 1200
CAGAGAATCC TAGAGATACT GAAGATGTTC CTTGGATAAC ACTAAATAGC AGCATTCAGA 1260
AAGTTAATGA GTGGTTTTCC AGAAGTGATG AACTGTTAGG TTCTGATGAC TCACATGATG 1320
GGGAGTCTGA ATCAAATGCC AAAGTAGCTG ATGTATTGGA CGTTCTAAAT GAGGTAGATG 1380
AATATTCTGG TTCTTCAGAG AAAATAGACT TACTGGCCAG TGATCCTCAT GAGGCTTTAA 1440 TATGTAAAAG TGAAAGAGTT CACTCCAAAT CAGTAGAGAG TAATATTGAA GACAAAATAT 1500
TTGGGAAAAC CTATCGGAAG AAGGCAAGCC TCCCCAACTT AAGCCATGTA ACTGAAAATC 1560
TAATTATAGG AGCATTTGTT ACTGAGCCAC AGATAATACA AGAGCGTCCC CTCACAAATA 1620
AATTAAAGCG TAAAAGGAGA CCTACATCAG GCCTTCATCC TGAGGATTTT ATCAAGAAAG 1680
CAGATTTGGC AGTTCAAAAG ACTCCTGAAA TGATAAATCA GGGAACTAAC CAAACGGAGC 1740
AGAATGGTCA AGTGATGAAT ATTACTAATA GTGGTCATGA GAATAAAACA AAAGGTGATT 1800
CTATTCAGAA TGAGAAAAAT CCTAACCCAA TAGAATCACT CGAAAAAGAA TCTGCTTTCA 1860 AAACGAAAGC TGAACCTATA AGCAGCAGTA TAAGCAATAT GGAACTCGAA TTAAATATCC 1920
ACAATTCAAA AGCACCTAAA AAGAATAGGC TGAGGAGGAA GTCTTCTACC AGGCATATTC 1980
ATGCGCTTGA ACTAGTAGTC AGTAGAAATC TAAGCCCACC TAATTGTACT GAATTGCAAA 2040
TTGATAGTTG TTCTAGCAGT GAAGAGATAA AGAAAAAAAA GTACAACCAA ATGCCAGTCA 2100
GGCACAGCAG AAACCTACAA CTCATGGAAG GTAAAGAACC TGCAACTGGA GCCAAGAAGA 2160 GTAACAAGCC AAATGAACAG ACAAGTAAAA GACATGACAG CGATACTTTC CCAGAGCTGA 2220
AGTTAACAAA TGCACCTGGT TCTTTTACTA AGTGTTCAAA TACCAGTGAA CTTAAAGAAT 2280
TTGTCAATCC TAGCCTTCCA AGAGAAGAAA AAGAAGAGAA ACTAGAAACA GTTAAAGTGT 2340
CTAATAATGC TGAAGACCCC AAAGATCTCA TGTTAAGTGG AGAAAGGGTT TTGCAAACTG 2400
AAAGATCTGT AGAGAGTAGC AGTATTTCAT TGGTACCTGG TACTGATTAT GGCACTCAGG 2460 AAAGTATCTC GTTACTGGAA GTTAGCACTC TAGGGAAGGC AAAAACAGAA CCAAATAAAT 2520
GTGTGAGTCA GTGTGCAGCA TTTGAAAACC CCAAGGGACT AATTCATGGT TGTTCCAAAG 2580
ATAATAGAAA TGACACAGAA GGCTTTAAGT ATCCATTGGG ACATGAAGTT AACCACAGTC 2640
GGGAAACAAG CATAGAAATG GAAGAAAGTG AACTTGATGC TCAGTATTTG CAGAATACAT 2700
TCAAGGTTTC AAAGCGCCAG TCATTTGCTC CGTTTTCAAA TCCAGGAAAT GCAGAAGAGG 2760 AATGTGCAAC ATTCTCTGCC CACTCTGGGT CCTTAAAGAA ACAAAGTCCA AAAGTCACTT 2820
TTGAATGTGA ACAAAAGGAA GAAAATCAAG GAAAGAATGA GTAATATCAA GCCTGTACAG 2880
ACAGTTAATA TCACTGCAGG CTTTCCTGTG GTTGGTCAGA AAGATAAGCC AGTTGATAAT 2940
GCCAAATGTA GTATCAAAGG AGGCTCTAGG TTTTGTCTAT CATCTCAGTT CAGAGGCAAC 3000
GAAACTGGAC TCATTACTCC AAATAAACAT GGACTTTTAC AAAACCCATA TCGTATACCA 3060 CCACTTTTTC CCATCAAGTC ATTTGTTAAA ACTAAATGTA AGAAAAATCT GCTAGAGGAA 3120
AACTTTGAGG AACATTCAAT GTCACCTGAA AGAGAAATGG GAAATGAGAA CATTCCAAGT 3180
ACAGTGAGCA CAATTAGCCG TAATAACATT AGAGAAAATG TTTTTAAAGA AGCCAGCTCA 3240
AGCAATATTA ATGAAGTAGG TTCCAGTACT AATGAAGTGG GCTCCAGTAT TAATGAAATA 3300
GGTTCCAGTG ATGAAAACAT TCAAGCAGAA CTAGGTAGAA ACAGAGGGCC AAAATTGAAT 3360 GCTATGCTTA GATTAGGGGT TTTGCAACCT GAGGTCTATA AACAAAGTCT TCCTGGAAGT 3420
AATTGTAAGC ATCCTGAAAT AAAAAAGCAA GAATATGAAG AAGTAGTTCA GACTGTTAAT 3480
ACAGATTTCT CTCCATATCT GATTTCAGAT AACTTAGAAC AGCCTATGGG AAGTAGTCAT 3540
GCATCTCAGG TTTGTTCTGA GACACCTGAT GACCTGTTAG ATGATGGTGA AATAAAGGAA 3600
GATACTAGTT TTGCTGAAAA TGACATTAAG GAAAGTTCTG CTGTTTTTAG CAAAAGCGTC 3660
CAGAAAGGAG AGCTTAGCAG GAGTCCTAGC CCTTTCACCC ATACACATTT GGCTCAGGGT 3720
TACCGAAGAG GGGCCAAGAA ATTAGAGTCC TCAGAAGAGA ACTTATCTAG TGAGGATGAA 3780 GAGCTTCCCT GCTTCCAACA CTTGTTATTT GGTAAAGTAA ACAATATACC TTCTCAGTCT 3840
ACTAGGCATA GCACCGTTGC TACCGAGTGT CTGTCTAAGA ACACAGAGGA GAATTTATTA 3900
TCATTGAAGA ATAGCTTAAA TGACTGCAGT AACCAGGTAA TATTGGCAAA GGCATCTCAG 3960
GAACATCACC TTAGTGAGGA AACAAAATGT TCTGCTAGCT TGTTTTCTTC ACAGTGCAGT 4020
GAATTGGAAG ACTTGACTGC AAATACAAAC ACCCAGGATC CTTTCTTGAT TGGTTCTTCC 4080 AAACAAATGA GGCATCAGTC TGAAAGCCAG GGAGTTGGTC TGAGTGACAA GGAATTGGTT 4140
TCAGATGATG AAGAAAGAGG AACGGGCTTG GAAGAAAATA ATCAAGAAGA GCAAAGCATG 4200
GATTCAAACT TAGGTGAAGC AGCATCTGGG TGTGAGAGTG AAACAAGCGT CTCTGAAGAC 4260
TGCTCAGGGC TATCCTCTCA GAGTGACATT TTAACCACTC AGCAGAGGGA TACCATGCAA 4320
CATAACCTGA TAAAGCTCCA GCAGGAAATG GCTGAACTAG AAGCTGTGTT AGAACAGCAT 4380 GGGAGCCAGC CTTCTAACAG CTACCCTTCC ATCATAAGTG ACTCTTCTGC CCTTGAGGAC 4440
CTGCGAAATC CAGAACAAAG CACATCAGAA AAAGCAGTAT TAACTTCACA GAAAAGTAGT 4500
GAATACCCTA TAAGCCAGAA TCCAGAAGGC CTTTCTGCTG ACAAGTTTGA GGTGTCTGCA 4560
GATAGTTCTA CCAGTAAAAA TAAAGAACCA GGAGTGGAAA GGTCATCCCC TTCTAAATGC 4620
CCATCATTAG ATGATAGGTG GTACATGCAC AGTTGCTCTG GGAGTCTTCA GAATAGAAAC 4680 TACCCATCTC AAGAGGAGCT CATTAAGGTT GTTGATGTGG AGGAGCAACA GCTGGAAGAG 4740
TCTGGGCCAC ACGATTTGAC GGAAACATCT TACTTGCCAA GGCAAGATCT AGAGGGAACC 4800
CCTTACCTGG AATCTGGAAT CAGCCTCTTC TCTGATGACC CTGAATCTGA TCCTTCTGAA 4860
GACAGAGCCC CAGAGTCAGC TCGTGTTGGC AACATACCAT CTTCAACCTC TGCATTGAAA 4920
GTTCCCCAAT TGAAAGTTGC AGAATCTGCC CAGAGTCCAG CTGCTGCTCA TACTACTGAT 4980 ACTGCTGGGT ATAATGCAAT GGAAGAAAGT GTGAGCAGGG AGAAGCCAGA ATTGACAGCT 5040
TCAACAGAAA GGGTCAACAA AAGAATGTCC ATGGTGGTGT CTGGCCTGAC CCCAGAAGAA 5100
TTTATGCTCG TGTACAAGTT TGCCAGAAAA CACCACATCA CTTTAACTAA TCTAATTACT 5160
GAAGAGACTA CTCATGTTGT TATGAAAACA GATGCTGAGT TTGTGTGTGA ACGGACACTG 5220
AAATATTTTC TAGGAATTGC GGGAGGAAAA TGGGTAGTTA GCTATTTCTG GGTGACCCAG 5280 TCTATTAAAG AAAGAAAAAT GCTGAATGAG CATGATTTTG AAGTCAGAGG AGATGTGGTC 5340
AATGGAAGAA ACCACCAAGG TCCAAAGCGA GCAAGAGAAT CCCAGGACAG AAAGATCTTC 5400
AGGGGGCTAG AAATCTGTTG CTATGGGCCC TTCACCAACA TGCCCACAGA TCAACTGGAA 5460
TGGATGGTAC AGCTGTGTGG TGCTTCTGTG GTGAAGGAGC TTTCATCATT CACCCTTGGC 5520
ACAGGTGTCC ACCCAATTGT GGTTGTGCAG CCAGATGCCT GGACAGAGGA CAATGGCTTC 5580
CATGCAATTG GGCAGATGTG TGAGGCACCT GTGGTGACCC GAGAGTGGGT GTTGGACAGT 5640
GTAGCACTCT ACCAGTGCCA GGAGCTGGAC ACCTACCTGA TACCCCAGAT CCCCCACAGC 5700 CACTACTGA 5709
(2) INFORMATION FOR SEQ ID NO:10:
(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 5711 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: double
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 10:
AGCTCGCTGA GACTTCCTGG ACCCCGCACC AGGCTGTGGG GTTTCTCAGA TAACTGGGCC 60
CCTGCGCTCA GGAGGCCTTC ACCCTCTGCT CTGGGTAAAG TTCATTGGAA CAGAAAGAAA 120
TGGATTTATC TGCTCTTCGC GTTGAAGAAG TACAAAATGT CATTAATGCT ATGCAGAAAA 180 TCTTAGAGTG TCCCATCTGT CTGGAGTTGA TCAAGGAACC TGTCTCCACA AAGTGTGACC 240
ACATATTTTG CAAATTTTGC ATGCTGAAAC TTCTCAACCA GAAGAAAGGG CCTTCACAGT 300
GTCCTTTATG TAAGAATGAT ATAACCAAAA GGAGCCTACA AGAAAGTACG AGATTTAGTC 360
AACTTGTTGA AGAGCTATTG AAAATCATTT GTGCTTTTCA GCTTGACACA GGTTTGGAGT 420
ATGCAAACAG CTATAATTTT GCAAAAAAGG AAAATAACTC TCCTGAACAT CTAAAAGATG 480 AAGTTTCTAT CATCCAAAGT ATGGGCTACA GAAACCGTGC CAAAAGACTT CTACAGAGTG 540
AACCCGAAAA TCCTTCCTTG CAGGAAACCA GTCTCAGTGT CCAACTCTCT AACCTTGGAA 600
CTGTGAGAAC TCTGAGGACA AAGCAGCGGA TACAACCTCA AAAGACGTCT GTCTACATTG 660
AATTGGGATC TGATTCTTCT GAAGATACCG TTAATAAGGC AACTTATTGC AGTGTGGGAG 720
ATCAAGAATT GTTACAAATC ACCCCTCAAG GAACCAGGGA TGAAATCAGT TTGGATTCTG 780 CAAAAAAGGC TGCTTGTGAA TTTTCTGAGA CGGATGTAAC AAATACTGAA CATCATCAAC 840
CCAGTAATAA TGATTTGAAC ACCACTGAGA AGCGTGCAGC TGAGAGGCAT CCAGAAAAGT 900
ATCAGGGTAG TTCTGTTTCA AACTTGCATG TGGAGCCATG TGGCACAAAT ACTCATGCCA 960
GCTCATTACA GCATGAGAAC AGCAGTTTAT TACTCACTAA AGACAGAATG AATGTAGAAA 1020
AGGCTGAATT CTGTAATAAA AGCAAACAGC CTGGCTTAGC AAGGAGCCAA CATAACAGAT 1080 GGGCTGGAAG TAAGGAAACA TGTAATGATA GGCGGACTCC CAGCACAGAA AAAAAGGTAG 1140
ATCTGAATGC TGATCCCCTG TGTGAGAGAA AAGAATGGAA TAAGCAGAAA CTGCCATGCT 1200
CAGAGAATCC TAGAGATACT GAAGATGTTC CTTGGATAAC ACTAAATAGC AGCATTCAGA 1260
AAGTTAATGA GTGGTTTTCC AGAAGTGATG AACTGTTAGG TTCTGATGAC TCACATGATG 1320
GGGAGTCTGA ATCAAATGCC AAAGTAGCTG ATGTATTGGA CGTTCTAAAT GAGGTAGATG 1380
AATATTCTGG TTCTTCAGAG AAAATAGACT TACTGGCCAG TGATCCTCAT GAGGCTTTAA 1440
TATGTAAAAG TGAAAGAGTT CACTCCAAAT CAGTAGAGAG TAATATTGAA GACAAAATAT _1500 TTGGGAAAAC CTATCGGAAG AAGGCAAGCC TCCCCAACTT AAGCCATGTA ACTGAAAATC 1560
TAATTATAGG AGCATTTGTT ACTGAGCCAC AGATAATACA AGAGCGTCCC CTCACAAATA 1620
AATTAAAGCG TAAAAGGAGA CCTACATCAG GCCTTCATCC TGAGGATTTT ATCAAGAAAG 1680
CAGATTTGGC AGTTCAAAAG ACTCCTGAAA TGATAAATCA GGGAACTAAC CAAACGGAGC 1740
AGAATGGTCA AGTGATGAAT ATTACTAATA GTGGTCATGA GAATAAAACA AAAGGTGATT 1800 CTATTCAGAA TGAGAAAAAT CCTAACCCAA TAGAATCACT CGAAAAAGAA TCTGCTTTCA 1860
AAACGAAAGC TGAACCTATA AGCAGCAGTA TAAGCAATAT GGAACTCGAA TTAAATATCC 1920
ACAATTCAAA AGCACCTAAA AAGAATAGGC TGAGGAGGAA GTCTTCTACC AGGCATATTC 1980
ATGCGCTTGA ACTAGTAGTC AGTAGAAATC TAAGCCCACC TAATTGTACT GAATTGCAAA 2040
TTGATAGTTG TTCTAGCAGT GAAGAGATAA AGAAAAAAAA GTACAACCAA ATGCCAGTCA 2100 GGCACAGCAG AAACCTACAA CTCATGGAAG GTAAAGAACC TGCAACTGGA GCCAAGAAGA 2160
GTAACAAGCC AAATGAACAG ACAAGTAAAA GACATGACAG CGATACTTTC CCAGAGCTGA 2220
AGTTAACAAA TGCACCTGGT TCTTTTACTA AGTGTTCAAA TACCAGTGAA CTTAAAGAAT 2280
TTGTCAATCC TAGCCTTCCA AGAGAAGAAA AAGAAGAGAA ACTAGAAACA GTTAAAGTGT 2340
CTAATAATGC TGAAGACCCC AAAGATCTCA TGTTAAGTGG AGAAAGGGTT TTGCAAACTG 2400 AAAGATCTGT AGAGAGTAGC AGTATTTCAT TGGTACCTGG TACTGATTAT GGCACTCAGG 2460
AAAGTATCTC GTTACTGGAA GTTAGCACTC TAGGGAAGGC AAAAACAGAA CCAAATAAAT 2520
GTGTGAGTCA GTGTGCAGCA TTTGAAAACC CCAAGGGACT AATTCATGGT TGTTCCAAAG 2580
ATAATAGAAA TGACACAGAA GGCTTTAAGT ATCCATTGGG ACATGAAGTT AACCACAGTC 2640
GGGAAACAAG CATAGAAATG GAAGAAAGTG AACTTGATGC TCAGTATTTG CAGAATACAT 2700 TCAAGGTTTC AAAGCGCCAG TCATTTGCTC CGTTTTCAAA TCCAGGAAAT GCAGAAGAGG 2760
AATGTGCAAC ATTCTCTGCC CACTCTGGGT CCTTAAAGAA ACAAAGTCCA AAAGTCACTT 2820
TTGAATGTGA ACAAAAGGAA GAAAATCAAG GAAAGAATGA GTCTAATATC AAGCCTGTAC 2880
AGACAGTTAA TATCACTGCA GGCTTTCCTG TGGTTGGTCA GAAAGATAAG CCAGTTGATA 2940
ATGCCAAATG TAGTATCAAA GGAGGCTCTA GGTTTTGTCT ATCATCTCAG TTCAGAGGCA 3000 ACGAAACTGG ACTCATTACT CCAAATAAAC ATGGACTTTT ACAAAACCCA TATCGTATAC 3060
CACCACTTTT TCCCATCAAG TCATTTGTTA AAACTAAATG TAAGAAAAAT CTGCTAGAGG 3120
AAAACTTTGA GGAACATTCA ATGTCACCTG AAAGAGAAAT GGGAAATGAG AACATTCCAA 3180
GTACAGTGAG CACAATTAGC CGTAATAACA TTAGAGAAAA TGTTTTTAAA GAAGCCAGCT 3240
CAAGCAATAT TAATGAAGTA GGTTCCAGTA CTAATGAAGT GGGCTCCAGT ATTAATGAAA 3300
TAGGTTCCAG TGATGAAAAC ATTCAAGCAG AACTAGGTAG AAACAGAGGG CCAAAATTGA 3360
ATGCTATGCT TAGATTAGGG GTTTTGCAAC CTGAGGTCTA TAAACAAAGT CTTCCTGGAA 3420 GTAATTGTAA GCATCCTGAA ATAAAAAAGC AAGAATATGA AGAAGTAGTT CAGACTGTTA 3480
ATACAGATTT CTCTCCATAT CTGATTTCAG ATAACTTAGA ACAGCCTATG GGAAGTAGTC 3540
ATGCATCTCA GGTTTGTTCT GAGACACCTG ATGACCTGTT AGATGATGGT GAAATAAAGG 3600
AAGATACTAG TTTTGCTGAA AATGACATTA AGGAAAGTTC TGCTGTTTTT AGCAAAAGCG 3660
TCCAGAAAGG AGAGCTTAGC AGGAGTCCTA GCCCTTTCAC CCATACACAT TTGGCTCAGG 3720 GTTACTGAAG AGGGGCCAAG AAATTAGAGT CCTCAGAAGA GAACTTATCT AGTGAGGATG 3780
AAGAGCTTCC CTGCTTCCAA CACTTGTTAT TTGGTAAAGT AAACAA ATA CCTTCTCAGT 3840
CTACTAGGCA TAGCACCGTT GCTACCGAGT GTCTGTCTAA GAACACAGAG GAGAATTTAT 3900
TATCATTGAA GAATAGCTTA AATGACTGCA GTAACCAGGT AATATTGGCA AAGGCATCTC 3960
AGGAACATCA CCTTAGTGAG GAAACAAAAT GTTCTGCTAG CTTGTTTTCT TCACAGTGCA 4020 GTGAATTGGA AGACTTGACT GCAAATACAA ACACCCAGGA TCCTTTCTTG ATTGGTTCTT 4080
CCAAACAAAT GAGGCATCAG TCTGAAAGCC AGGGAGTTGG TCTGAGTGAC AAGGAATTGG 4140
TTTCAGATGA TGAAGAAAGA GGAACGGGCT TGGAAGAAAA TAATCAAGAA GAGCAAAGCA 4200
TGGATTCAAA CTTAGGTGAA GCAGCATCTG GGTGTGAGAG TGAAACAAGC GTCTCTGAAG 4260
ACTGCTCAGG GCTATCCTCT CAGAGTGACA TTTTAACCAC TCAGCAGAGG GATACCATGC 4320 AACATAACCT GATAAAGCTC CAGCAGGAAA TGGCTGAACT AGAAGCTGTG TTAGAACAGC 4380
ATGGGAGCCA GCCTTCTAAC AGCTACCCTT CCATCATAAG TGACTCTTCT GCCCTTGAGG 4440
ACCTGCGAAA TCCAGAACAA AGCACATCAG AAAAAGCAGT ATTAACTTCA CAGAAAAGTA 4500
GTGAATACCC TATAAGCCAG AATCCAGAAG GCCTTTCTGC TGACAAGTTT GAGGTGTCTG 4560
CAGATAGTTC TACCAGTAAA AATAAAGAAC CAGGAGTGGA AAGGTCATCC CCTTCTAAAT 4620 GCCCATCATT AGATGATAGG TGGTACATGC ACAGTTGCTC TGGGAGTCTT CAGAATAGAA 4680
ACTACCCATC TCAAGAGGAG CTCATTAAGG TTGTTGATGT GGAGGAGCAA CAGCTGGAAG 4740
AGTCTGGGCC ACACGATTTG ACGGAAACAT CTTACTTGCC AAGGCAAGAT CTAGAGGGAA 4800
CCCCTTACCT GGAATCTGGA ATCAGCCTCT TCTCTGATGA CCCTGAATCT GATCCTTCTG 4860
AAGACAGAGC CCCAGAGTCA GCTCGTGTTG GCAACATACC ATCTTCAACC TCTGCATTGA 4920 AAGTTCCCCA ATTGAAAGTT GCAGAATCTG CCCAGAGTCC AGCTGCTGCT CATACTACTG 4980
ATACTGCTGG GTATAATGCA ATGGAAGAAA GTGTGAGCAG GGAGAAGCCA GAATTGACAG 5040
CTTCAACAGA AAGGGTCAAC AAAAGAATGT CCATGGTGGT GTCTGGCCTG ACCCCAGAAG 5100
AATTTATGCT CGTGTACAAG TTTGCCAGAA AACACCACAT CACTTTAACT AATCTAATTA 5160
CTGAAGAGAC TACTCATGTT GTTATGAAAA CAGATGCTGA GTTTGTGTGT GAACGGACAC 5220
TGAAATATTT TCTAGGAATT GCGGGAGGAA AATGGGTAGT TAGCTATTTC TGGGTGACCC 5280
AGTCTATTAA AGAAAGAAAA ATGCTGAATG AGCATGATTT TGAAGTCAGA GGAGATGTGG 5340 TCAATGGAAG AAACCACCAA GGTCCAAAGC GAGCAAGAGA ATCCCAGGAC AGAAAGATCT 5400
TCAGGGGGCT AGAAATCTGT TGCTATGGGC CCTTCACCAA CATGCCCACA GATCAACTGG 5460
AATGGATGGT ACAGCTGTGT GGTGCTTCTG TGGTGAAGGA GCTTTCATCA TTCACCCTTG 5520
GCACAGGTGT CCACCCAATT GTGGTTGTGC AGCCAGATGC CTGGACAGAG GACAATGGCT 5580
TCCATGCAAT TGGGCAGATG TGTGAGGCAC CTGTGGTGAC CCGAGAGTGG GTGTTGGACA 5640 GTGTAGCACT CTACCAGTGC CAGGAGCTGG ACACCTACCT GATACCCCAG ATCCCCCACA 5700
GCCACTACTG A 5711 (2) INFORMATION FOR SEQ ID NO:11:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 5707 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: double (D) TOPOLOGY: linear
(ii) MOLECULE TYPE: cDNA
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 11:
AGCTCGCTGA GACTTCCTGG ACCCCGCACC AGGCTGTGGG GTTTCTCAGA TAACTGGGCC 60
CCTGCGCTCA GGAGGCCTTC ACCCTCTGCT CTGGGTAAAG TTCATTGGAA CAGAAAGAAA 120 TGGATTTATC TGCTCTTCGC GTTGAAGAAG TACAAAATGT CATTAATGCT ATGCAGAAAA 180
TCTTAGAGTG TCCCATCTGT CTGGAGTTGA TCAAGGAACC TGTCTCCACA AAGTGTGACC 240
ACATATTTTG CAAATTTTGC ATGCTGAAAC TTCTCAACCA GAAGAAAGGG CCTTCACAGT 300
GTCCTTTATG TAAGAATGAT ATAACCAAAA GGAGCCTACA AGAAAGTACG AGATTTAGTC 360
AACTTGTTGA AGAGCTATTG AAAATCATTT GTGCTTTTCA GCTTGACACA GGTTTGGAGT 420 ATGCAAACAG CTATAATTTT GCAAAAAAGG AAAATAACTC TCCTGAACAT CTAAAAGATG 480
AAGTTTCTAT CATCCAAAGT ATGGGCTACA GAAACCGTGC CAAAAGACTT CTACAGAGTG 540
AACCCGAAAA TCCTTCCTTG CAGGAAACCA GTCTCAGTGT CCAACTCTCT AACCTTGGAA 600
CTGTGAGAAC TCTGAGGACA AAGCAGCGGA TACAACCTCA AAAGACGTCT GTCTACATTG 660
AATTGGGATC TGATTCTTCT GAAGATACCG TTAATAAGGC AACTTATTGC AGTGTGGGAG 720 ATCAAGAATT GTTACAAATC ACCCCTCAAG GAACCAGGGA TGAAATCAGT TTGGATTCTG 780
CAAAAAAGGC TGCTTGTGAA TTTTCTGAGA CGGATGTAAC AAATACTGAA CATCATCAAC 840
CCAGTAATAA TGATTTGAAC ACCACTGAGA AGCGTGCAGC TGAGAGGCAT CCAGAAAAGT 900
ATCAGGGTAG TTCTGTTTCA AACTTGCATG TGGAGCCATG TGGCACAAAT ACTCATGCCA 960
GCTCATTACA GCATGAGAAC AGCAGTTTAT TACTCACTAA AGACAGAATG AATGTAGAAA 1020
AGGCTGAATT CTGTAATAAA AGCAAACAGC CTGGCTTAGC AAGGAGCCAA CATAACAGAT 1080
GGGCTGGAAG TAAGGAAACA TGTAATGATA GGCGGACTCC CAGCACAGAA AAAAAGGTAG 1140 ATCTGAATGC TGATCCCCTG TGTGAGAGAA AAGAATGGAA TAAGCAGAAA CTGCCATGCT 1200
CAGAGAATCC TAGAGATACT GAAGATGTTC CTTGGATAAC ACTAAATAGC AGCATTCAGA 1260
AAGTTAATGA GTGGTTTTCC AGAAGTGATG AACTGTTAGG TTCTGATGAC TCACATGATG 1320
GGGAGTCTGA ATCAAATGCC AAAGTAGCTG ATGTATTGGA CGTTCTAAAT GAGGTAGATG 1380
AATATTCTGG TTCTTCAGAG AAAATAGACT TACTGGCCAG TGATCCTCAT GAGGCTTTAA 1440 TATGTAAAAG TGAAAGAGTT CACTCCAAAT CAGTAGAGAG TAATATTGAA GACAAAATAT 1500
TTGGGAAAAC CTATCGGAAG AAGGCAAGCC TCCCCAACTT AAGCCATGTA ACTGAAAATC 1560
TAATTATAGG AGCATTTGTT ACTGAGCCAC AGATAATACA AGAGCGTCCC CTCACAAATA 1620
AATTAAAGCG TAAAAGGAGA CCTACATCAG GCCTTCATCC TGAGGATTTT ATCAAGAAAG 1680
CAGATTTGGC AGTTCAAAAG ACTCCTGAAA TGATAAATCA GGGAACTAAC CAAACGGAGC 1740 AGAATGGTCA AGTGATGAAT ATTACTAATA GTGGTCATGA GAATAAAACA AAAGGTGATT 1800
CTATTCAGAA TGAGAAAAAT CCTAACCCAA TAGAATCACT CGAAAAAGAA TCTGCTTTCA 1860
AAACGAAAGC TGAACCTATA AGCAGCAGTA TAAGCAATAT GGAACTCGAA TTAAATATCC 1920
ACAATTCAAA AGCACCTAAA AAGAATAGGC TGAGGAGGAA GTCTTCTACC AGGCATATTC 1980
ATGCGCTTGA ACTAGTAGTC AGTAGAAATC TAAGCCCACC TAATTGTACT GAATTGCAAA 2040 TTGATAGTTG TTCTAGCAGT GAAGAGATAA AGAAAAAAAA GTACAACCAA ATGCCAGTCA 2100
GGCACAGCAG AAACCTACAA CTCATGGAAG GTAAAGAACC TGCAACTGGA GCCAAGAAGA 2160
GTAACAAGCC AAATGAACAG ACAAGTAAAA GACATGACAG CGATACTTTC CCAGAGCTGA 2220
AGTTAACAAA TGCACCTGGT TCTTTTACTA AGTGTTCAAA TACCAGTGAA CTTAAAGAAT 2280
TTGTCAATCC TAGCCTTCCA AGAGAAGAAA AAGAAGAGAA ACTAGAAACA GTTAAAGTGT 2340 CTAATAATGC TGAAGACCCC AAAGATCTCA TGTTAAGTGG AGAAAGGGTT TTGCAAACTG 2400
AAAGATCTGT AGAGAGTAGC AGTATTTCAT TGGTACCTGG TACTGATTAT GGCACTCAGG 2460
AAAGTATCTC GTTACTGGAA GTTAGCACTC TAGGGAAGGC AAAAACAGAA CCAAATAAAT 2520
GTGTGAGTCA GTGTGCAGCA TTTGAAAACC CCAAGGGACT AATTCATGGT TGTTCCAAAG 2580
ATAATAGAAA TGACACAGAA GGCTTTAAGT ATCCATTGGG ACATGAAGTT AACCACAGTC 2640 GGGAAACAAG CATAGAAATG GAAGAAAGTG AACTTGATGC TCAGTATTTG CAGAATACAT 2700
TCAAGGTTTC AAAGCGCCAG TCATTTGCTC CGTTTTCAAA TCCAGGAAAT GCAGAAGAGG 2760
AATGTGCAAC ATTCTCTGCC CACTCTGGGT CCTTAAAGAA ACAAAGTCCA AAAGTCACTT 2820
TTGAATGTGA ACAAAAGGAA GAAAATCAAG GAAAGAATGA GTCTAATATC AAGCCTGTAC 2880
AGACAGTTAA TATCACTGCA GGCTTTCCTG TGGTTGGTCA GAAAGATAAG CCAGTTGATA 2940
ATGCCAAATG TAGTATCAAA GGAGGCTCTA GGTTTTGTCT ATCATCTCAG TTCAGAGGCA 3000
ACGAAACTGG ACTCATTACT CCAAATAAAC ATGGACTTTT ACAAAACCCA TATCGTATAC .3060 CACCACTTTT TCCCATCAAG TCATTTGTTA AAACTAAATG TAAGAAAAAT CTGCTAGAGG 3120
AAAACTTTGA GGAACATTCA ATGTCACCTG AAAGAGAAAT GGGAAATGAG AACATTCCAA 3180
GTACAGTGAG CACAATTAGC CGTAATAACA TTAGAGAAAA TGTTTTTAAA GAAGCCAGCT 3240
CAAGCAATAT TAATGAAGTA GGTTCCAGTA CTAATGAAGT GGGCTCCAGT ATTAATGAAA 3300
TAGGTTCCAG TGATGAAAAC ATTCAAGCAG AACTAGGTAG AAACAGAGGG CCAAAATTGA 3360 ATGCTATGCT TAGATTAGGG GTTTTGCAAC CTGAGGTCTA TAAACAAAGT CTTCCTGGAA 3420
GTAATTGTAA GCATCCTGAA ATAAAAAAGC AAGAATATGA AGAAGTAGTT CAGACTGTTA 3480
ATACAGATTT CTCTCCATAT CTGATTTCAG ATAACTTAGA ACAGCCTATG GGAAGTAGTC 3540
ATGCATCTCA GGTTTGTTCT GAGACACCTG ATGACCTGTT AGATGATGGT GAAATAAAGG 3600
AAGATACTAG TTTTGCTGAA AATGACATTA AGGAAAGTTC TGCTGTTTTT AGCAAAAGCG 3660 TCCAGAAAGG AGAGCTTAGC AGGAGTCCTA GCCCTTTCAC CCATACACAT TTGGCTCAGG 3720
GTTACCGAAG AGGGGCCAAG AAATTAGAGT CCTCAGAAGA GAACTTATCT AGTGAGGATG 3780
AAGAGCTTCC CTGCTTCCAA CACTTGTTAT TTGGTAAAGT AAACAATATA CCTTCTCAGT 3840
CTACTAGGCA TAGCACCGTT GCTACCGAGT GTCTGTCTAA GAACACAGAG GAGAATTTAT 3900
TATCATTGAA GAATAGCTTA AATGACTGCA GTAACCAGGT AATATTGGCA AAGGCATCTC 3960 AGGAACATCA CCTTAGTGAG GAAACAAAAT GTTCTGCTAG CTTGTTTTCT TCACAGTGCA 4020
GTGAATTGGA AGACTTGACT GCAAATACAA ACACCCAGGA TCCTTTCTTG ATTGGTTCTT 4080
CCAAACAAAT GAGGCATCAG TCTGAAAGCC AGGGAGTTGG TCTGAGTGAC AAGGAATTGG 4140
TTTCAGATGA TGAAGAAAGA GGAACGGGCT TGGAAGAAAA TAAGAAGAGC AAAGCATGGA 4200
TTCAAACTTA GGTGAAGCAG CATCTGGGTG TGAGAGTGAA ACAAGCGTCT CTGAAGACTG 4260 CTCAGGGCTA TCCTCTCAGA GTGACATTTT AACCACTCAG CAGAGGGATA CCATGCAACA 4320
TAACCTGATA AAGCTCCAGC AGGAAATGGC TGAACTAGAA GCTGTGTTAG AACAGCATGG 4380
GAGCCAGCCT TCTAACAGCT ACCCTTCCAT CATAAGTGAC TCTTCTGCCC TTGAGGACCT 4440
GCGAAATCCA GAACAAAGCA CATCAGAAAA AGCAGTATTA ACTTCACAGA AAAGTAGTGA 4500
ATACCCTATA AGCCAGAATC CAGAAGGCCT TTCTGCTGAC AAGTTTGAGG TGTCTGCAGA 4560 TAGTTCTACC AG AAAAATA AAGAACCAGG AGTGGAAAGG TCATCCCCTT CTAAATGCCC 4620
ATCATTAGAT GATAGGTGGT ACATGCACAG TTGCTCTGGG AGTCTTCAGA ATAGAAACTA 4680
CCCATCTCAA GAGGAGCTCA TTAAGGTTGT TGATGTGGAG GAGCAACAGC TGGAAGAGTC 4740
TGGGCCACAC GATTTGACGG AAACATCTTA CTTGCCAAGG CAAGATCTAG AGGGAACCCC 4800
TTACCTGGAA TCTGGAATCA GCCTCTTCTC TGATGACCCT GAATCTGATC CTTCTGAAGA 4860
CAGAGCCCCA GAGTCAGCTC GTGTTGGCAA CATACCATCT TCAACCTCTG CATTGAAAGT 4920
TCCCCAATTG AAAGTTGCAG AATCTGCCCA GAGTCCAGCT GCTGCTCATA CTACTGATAC 4980 TGCTGGGTAT AATGCAATGG AAGAAAGTGT GAGCAGGGAG AAGCCAGAAT TGACAGCTTC 5040
AACAGAAAGG GTCAACAAAA GAATGTCCAT GGTGGTGTCT GGCCTGACCC CAGAAGAATT 5100
TATGCTCGTG TACAAGTTTG CCAGAAAACA CCACATCACT TTAACTAATC TAATTACTGA 5160
AGAGACTACT CATGTTGTTA TGAAAACAGA TGCTGAGTTT GTGTGTGAAC GGACACTGAA 5220
ATATTTTCTA GGAATTGCGG GAGGAAAATG GGTAGTTAGC TATTTCTGGG TGACCCAGTC 5280 TATTAAAGAA AGAAAAATGC TGAATGAGCA TGATTTTGAA GTCAGAGGAG ATGTGGTCAA 5340
TGGAAGAAAC CACCAAGGTC CAAAGCGAGC AAGAGAATCC CAGGACAGAA AGATCTTCAG 5400
GGGGCTAGAA ATCTGTTGCT ATGGGCCCTT CACCAACATG CCCACAGATC AACTGGAATG 5460
GATGGTACAG CTGTGTGGTG CTTCTGTGGT GAAGGAGCTT TCATCATTCA CCCTTGGCAC 5520
AGGTGTCCAC CCAATTGTGG TTGTGCAGCC AGATGCCTGG ACAGAGGACA ATGGCTTCCA 5580 TGCAATTGGG CAGATGTGTG AGGCACCTGT GGTGACCCGA GAGTGGGTGT TGGACAGTGT 5640
AGCACTCTAC CAGTGCCAGG AGCTGGACAC CTACCTGATA CCCCAGATCC CCCACAGCCA 5700
CTACTGA 5707 (2) INFORMATION FOR SEQ ID NO:12:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 5712 base pairs (B) TYPE: nucleic acid
(C) STRANDEDNESS: double
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: cDNA
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:12:
AGCTCGCTGA GACTTCCTGG ACCCCGCACC AGGCTGTGGG GTTTCTCAGA TAACTGGGCC 60 CCTGCGCTCA GGAGGCCTTC ACCCTCTGCT CTGGGTAAAG TTCATTGGAA CAGAAAGAAA 120
TGGATTTATC TGCTCTTCGC GTTGAAGAAG TACAAAATGT CATTAATGCT ATGCAGAAAA 180
TCTTAGAGTG TCCCATCTGT CTGGAGTTGA TCAAGGAACC TGTCTCCACA AAGTGTGACC 240
ACATATTTTG CAAATTTTGC ATGCTGAAAC TTCTCAACCA GAAGAAAGGG CCTTCACAGT 300
GTCCTTTATG TAAGAATGAT ATAACCAAAA GGAGCCTACA AGAAAGTACG AGATTTAGTC 360 AACTTGTTGA AGAGCTATTG AAAATCATTT GTGCTTTTCA GCTTGACACA GGTTTGGAGT 420
ATGCAAACAG CTATAATTTT GCAAAAAAGG AAAATAACTC TCCTGAACAT CTAAAAGATG 480
AAGTTTCTAT CATCCAAAGT ATGGGCTACA GAAACCGTGC CAAAAGACTT CTACAGAGTG 540
AACCCGAAAA TCCTTCCTTG CAGGAAACCA GTCTCAGTGT CCAACTCTCT AACCTTGGAA 600
CTGTGAGAAC TCTGAGGACA AAGCAGCGGA TACAACCTCA AAAGACGTCT GTCTACATTG 660
AATTGGGATC TGATTCTTCT GAAGATACCG TTAATAAGGC AACTTATTGC AGTGTGGGAG 720
ATCAAGAATT GTTACAAATC ACCCCTCAAG GAACCAGGGA TGAAATCAGT TTGGATTCTG 780 CAAAAAAGGC TGCTTGTGAA TTTTCTGAGA CGGATGTAAC AAATACTGAA CATCATCAAC 840
CCAGTAATAA TGATTTGAAC ACCACTGAGA AGCGTGCAGC TGAGAGGCAT CCAGAAAAGT 900
ATCAGGGTAG TTCTGTTTCA AACTTGCATG TGGAGCCATG TGGCACAAAT ACTCATGCCA 960
GCTCATTACA GCATGAGAAC AGCAGTTTAT TACTCACTAA AGACAGAATG AATGTAGAAA 1020
AGGCTGAATT CTGTAATAAA AGCAAACAGC CTGGCTTAGC AAGGAGCCAA CATAACAGAT 1080 GGGCTGGAAG TAAGGAAACA TGTAATGATA GGCGGACTCC CAGCACAGAA AAAAAGGTAG 1140
ATCTGAATGC TGATCCCCTG TGTGAGAGAA AAGAATGGAA TAAGCAGAAA CTGCCATGCT 1200
CAGAGAATCC TAGAGATACT GAAGATGTTC CTTGGATAAC ACTAAATAGC AGCATTCAGA 1260
AAGTTAATGA GTGGTTTTCC AGAAGTGATG AACTGTTAGG TTCTGATGAC TCACATGATG 1320
GGGAGTCTGA ATCAAATGCC AAAGTAGCTG ATGTATTGGA CGTTCTAAAT GAGGTAGATG 1380 AATATTCTGG TTCTTCAGAG AAAATAGACT TACTGGCCAG TGATCCTCAT GAGGCTTTAA 1440
TATGTAAAAG TGAAAGAGTT CACTCCAAAT CAGTAGAGAG TAATATTGAA GACAAAATAT 1500
TTGGGAAAAC CTATCGGAAG AAGGCAAGCC TCCCCAACTT AAGCCATGTA ACTGAAAATC 1560
TAATTATAGG AGCATTTGTT ACTGAGCCAC AGATAATACA AGAGCGTCCC CTCACAAATA 1620
AATTAAAGCG TAAAAGGAGA CCTACATCAG GCCTTCATCC TGAGGATTTT ATCAAGAAAG 1680 CAGATTTGGC AGTTCAAAAG ACTCCTGAAA TGATAAATCA GGGAACTAAC CAAACGGAGC 1740
AGAATGGTCA AGTGATGAAT ATTACTAATA GTGGTCATGA GAATAAAACA AAAGGTGATT 1800
CTATTCAGAA TGAGAAAAAT CCTAACCCAA TAGAATCACT CGAAAAAGAA TCTGCTTTCA 1860
AAACGAAAGC TGAACCTATA AGCAGCAGTA TAAGCAATAT GGAACTCGAA TTAAATATCC 1920
ACAATTCAAA AGCACCTAAA AAGAATAGGC TGAGGAGGAA GTCTTCTACC AGGCATATTC 1980 ATGCGCTTGA ACTAGTAGTC AGTAGAAATC TAAGCCCACC TAATTGTACT GAATTGCAAA 2040
TTGATAGTTG TTCTAGCAGT GAAGAGATAA AGAAAAAAAA GTACAACCAA ATGCCAGTCA 2100
GGCACAGCAG AAACCTACAA CTCATGGAAG GTAAAGAACC TGCAACTGGA GCCAAGAAGA 2160
GTAACAAGCC AAATGAACAG ACAAGTAAAA GACATGACAG CGATACTTTC CCAGAGCTGA 2220
AGTTAACAAA TGCACCTGGT TCTTTTACTA AGTGTTCAAA TACCAGTGAA CTTAAAGAAT 2280 TTGTCAATCC TAGCCTTCCA AGAGAAGAAA AAGAAGAGAA ACTAGAAACA GTTAAAGTGT 2340
CTAATAATGC TGAAGACCCC AAAGATCTCA TGTTAAGTGG AGAAAGGGTT TTGCAAACTG 2400
AAAGATCTGT AGAGAGTAGC AGTATTTCAT TGGTACCTGG TACTGATTAT GGCACTCAGG 2460
AAAGTATCTC GTTACTGGAA GTTAGCACTC TAGGGAAGGC AAAAACAGAA CCAAATAAAT 2520
GTGTGAGTCA GTGTGCAGCA TTTGAAAACC CCAAGGGACT. AATTCATGGT TGTTCCAAAG 2580
ATAATAGAAA TGACACAGAA GGCTTTAAGT ATCCATTGGG ACATGAAGTT AACCACAGTC 2640
GGGAAACAAG CATAGAAATG GAAGAAAGTG AACTTGATGC TCAGTATTTG CAGAATACAT 2700 TCAAGGTTTC AAAGCGCCAG TCATTTGCTC CGTTTTCAAA TCCAGGAAAT GCAGAAGAGG 2760
AATGTGCAAC ATTCTCTGCC CACTCTGGGT CCTTAAAGAA ACAAAGTCCA AAAGTCACTT 2820
TTGAATGTGA ACAAAAGGAA GAAAATCAAG GAAAGAATGA GTCTAATATC AAGCCTGTAC 2880
AGACAGTTAA TATCACTGCA GGCTTTCCTG TGGTTGGTCA GAAAGATAAG CCAGTTGATA 2940
ATGCCAAATG TAGTATCAAA GGAGGCTCTA GGTTTTGTCT ATCATCTCAG TTCAGAGGCA 3000 ACGAAACTGG ACTCATTACT CCAAATAAAC ATGGACTTTT ACAAAACCCA TATCGTATAC 3060
CACCACTTTT TCCCATCAAG TCATTTGTTA AAACTAAATG TAAGAAAAAT CTGCTAGAGG 3120
AAAACTTTGA GGAACATTCA ATGTCACCTG AAAGAGAAAT GGGAAATGAG AACATTCCAA 3180
GTACAGTGAG CACAATTAGC CGTAATAACA TTAGAGAAAA TGTTTTTAAA GAAGCCAGCT 3240
CAAGCAATAT TAATGAAGTA GGTTCCAGTA CTAATGAAGT GGGCTCCAGT ATTAATGAAA 3300 TAGGTTCCAG TGATGAAAAC ATTCAAGCAG AACTAGGTAG AAACAGAGGG CCAAAATTGA 3360
ATGCTATGCT TAGATTAGGG GTTTTGCAAC CTGAGGTCTA TAAACAAAGT CTTCCTGGAA 3420
GTAATTGTAA GCATCCTGAA ATAAAAAAGC AAGAATATGA AGAAGTAGTT CAGACTGTTA 3480
ATACAGATTT CTCTCCATAT CTGATTTCAG ATAACTTAGA ACAGCCTATG GGAAGTAGTC 3540
ATGCATCTCA GGTTTGTTCT GAGACACCTG ATGACCTGTT AGATGATGGT GAAATAAAGG 3600 AAGATACTAG TTTTGCTGAA AATGACATTA AGGAAAGTTC TGCTGTTTTT AGCAAAAGCG 3660
TCCAGAAAGG AGAGCTTAGC AGGAGTCCTA GCCCTTTCAC CCATACACAT TTGGCTCAGG 3720
GTTACCGAAG AGGGGCCAAG AAATTAGAGT CCTCAGAAGA GAACTTATCT AGTGAGGATG 3780
AAGAGCTTCC CTGCTTCCAA CACTTGTTAT TTGGTAAAGT AAACAATATA CCTTCTCAGT 3840
CTACTAGGCA TAGCACCGTT GCTACCGAGT GTCTGTCTAA GAACACAGAG GAGAATTTAT 3900 TATCATTGAA GAATAGCTTA AATGACTGCA GTAACCAGGT AATATTGGCA AAGGCATCTC 3960
AGGAACATCA CCTTAGTGAG GAAACAAAAT GTTCTGCTAG CTTGTTTTCT TCACAGTGCA 4020
GTGAATTGGA AGACTTGACT GCAAATACAA ACACCCAGGA TCCTTTCTTG ATTGGTTCTT 4080
CCAAACAAAT GAGGCATCAG TCTGAAAGCC AGGGAGTTGG TCTGAGTGAC AAGGAATTGG 4140
TTTCAGATGA TGAAGAAAGA GGAACGGGCT TGGAAGAAAA TAATCAAGAA GAGCAAAGCA 4200 TGGATTCAAA CTTAGGTGAA GCAGCATCTG GGTGTGAGAG TGAAACAAGC GTCTCTGAAG 4260
ACTGCTCAGG GCTATCCTCT CAGAGTGACA TTTTAACCAC TCAGCAGAGG GATACCATGC 4320
AACATAACCT GATAAAGCTC CAGCAGGAAA TGGCTGAACT AGAAGCTGTG TTAGAACAGC 4380
ATGGGAGCCA GCCTTCTAAC AGCTACCCTT CCATCATAAG TGACTCTTCT GCCCTTGAGG 4440
ACCTGCGAAA TCCAGAACAA AGCACATCAG AAAAAGCAGT ATTAACTTCA CAGAAAAGTA 4500
GTGAATACCC TATAAGCCAG AATCCAGAAG GCCTTTCTGC TGACAAGTTT GAGGTGTCTG 4560
CAGATAGTTC TACCAGTAAA AATAAAGAAC CAGGAGTGGA AAGGTCATCC CCTTCTAAAT -4620 GCCCATCATT AGATGATAGG TGGTACATGC ACAGTTGCTC TGGGAGTCTT CAGAATAGAA 4680
ACTACCCATC TCAAGAGGAG CTCATTAAGG TTGTTGATGT GGAGGAGCAA CAGCTGGAAG 4740
AGTCTGGGCC ACACGATTTG ACGGAAACAT CTTACTTGCC AAGGCAAGAT CTAGAGGGAA 4800
CCCCTTACCT GGAATCTGGA ATCAGCCTCT TCTCTGATGA CCCTGAATCT GATCCTTCTG 4860
AAGACAGAGC CCCAGAGTCA GCTCGTGTTG GCAACATACC ATCTTCAACC TCTGCATTGA 4920 AAGTTCCCCA ATTGAAAGTT GCAGAATCTG CCCAGAGTCC AGCTGCTGCT CATACTACTG 4980
ATACTGCTGG GTATAATGCA ATGGAAGAAA GTGTGAGCAG GGAGAAGCCA GAATTGACAG 5040
CTTCAACAGA AAGGGTCAAC AAAAGAATGT CCATGGTGGT GTCTGGCCTG ACCCCAGAAG 5100
AATTTATGCT CGTGTACAAG TTTGCCAGAA AACACCACAT CACTTTAACT AATCTAATTA 5160
CTGAAGAGAC TACTCATGTT GTTATGAAAA CAGATGCTGA GTTTGTGTGT GAACGGACAC 5220 TGAAATATTT TCTAGGAATT GCGGGAGGAA AATGGGTAGT TAGCTATTTC TGGGTGACCC 5280
AGTCTATTAA AGAAAGAAAA ATGCTGAATG AGCATGATTT TGAAGTCAGA GGAGATGTGG 5340
TCAATGGAAG AAACCACCAA GGTCCAAAGC GAGCAAGAGA ATCCCAGGAC AGAAAGATCT 5400
TCAGGGGGCT AGAAATCTGT TGCTATGGGC CCTTCACCAA CATGCCCACA GATCAACTGG 5460
AATGGATGGT ACAGCTGTGT GGTGCTTCTG TGGTGAAGGA GCTTTCATCA TTCACCCTTG 5520 GCACAGGTGT CCACCCAATT GTGGTTGTGC AGCCAGATGC CTGGACAGAG GACAATGGCT 5580
TCCATGCAAT TGGGCAGATG TGTGAGGCAC CTGTGGTGAC CCGAGAGTGG GTGTTGGACA 5640
GTGTAGCACT CTACCAGTGC CAGGAGCTGG ACACCTAACC TGATACCCCA GATCCCCCAC 5700
AGCCACTACT GA 5712 (2) INFORMATION FOR SEQ ID NO:13: (i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 26 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: protein
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:13 Met Asp Leu Ser Ala Leu Arg Val Glu Glu Val Gin Asn Val l ie Asn 1 5 10 15
Ala Met Gin Lys lie Leu Glu Cys Pro lie 20 25
( 2 ) INFORMATION FOR SEQ ID NO : 14 :
( i ) SEQUENCE CHARACTERISTICS : ( A) LENGTH : 38 amino acids
( B ) TYPE : amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 14:
Met Asp Leu Ser Ala Leu Arg Val Glu Glu Val Gin Asn Val lie Asn 1 5 10 15
Ala Met Gin Lys lie Leu Glu Cys Pro lie Cys Leu Glu Leu lie Lys 20 25 30 Glu Pro Val Ser Thr Val
35
(2) INFORMATION FOR SEQ ID NO:15: (i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 63 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: protein
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 15: Met Asp Leu Ser Ala Leu Arg Val Glu Glu Val Gin Asn Val lie Asn 1 5 10 15
Ala Met Gin Lys lie Leu Glu Cys Pro lie Cys Leu Glu Leu lie Lys 20 25 30
Glu Pro Val Ser Thr Lys Cys Asp His lie Phe Cys Lys Phe Cys Met 35 40 45
Leu Lys Leu Leu Asn Gin Lys Lys Gly Pro Ser Gin Cys Pro Leu 50 55 60
(2) INFORMATION FOR SEQ ID NO:16:
(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1863 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 16: Met Asp Leu Ser Ala Leu Arg Val Glu Glu Val Gin Asn Val lie Asn 1 5 10 15
Ala Met Gin Lys lie Leu Glu Cys Pro lie Cys Leu Glu Leu lie Lys 20 25 30
Glu Pro Val Ser Thr Lys Cys Asp His lie Phe Cys Lys Phe Cys Met 35 40 45 Leu Lys Leu Leu Asn Gin Lys Lys Gly Pro Ser Gin Gly Pro Leu Cys
50 55 60
Lys Asn Asp lie Thr Lys Arg Ser Leu Gin Glu Ser Thr Arg Phe Ser 65 70 75 80
Gin Leu Val Glu Glu Leu Leu Lys lie lie Cys Ala Phe Gin Leu Asp 85 90 95
Thr Gly Leu Glu Tyr Ala Asn Ser Tyr Asn Phe Ala Lys Lys Glu Asn 100 105 110
Asn Ser Pro Glu His Leu Lys Asp Glu Val Ser lie lie Gin Ser Met 115 120 125 Gly Tyr Arg Asn Arg Ala Lys Arg Leu Leu Gin Ser Glu Pro Glu Asn
130 135 140
Pro Ser Leu Gin Glu Thr Ser Leu Ser Val Gin Leu Ser Asn Leu Gly 145 150 155 160
Thr Val Arg Thr Leu Arg Thr Lys Gin Arg lie Gin Pro Gin Lys Thr 165 170 175
Ser Val Tyr lie Glu Leu Gly Ser Asp Ser Ser Glu Asp Thr Val Asn 180 185 190
Lys Ala Thr Tyr Cys Ser Val Gly Asp Gin Glu Leu Leu Gin lie Thr 195 200 205
Pro Gin Gly Thr Arg Asp Glu lie Ser Leu Asp Ser Ala Lys Lys Ala 210 215 220
Ala Cys Glu Phe Ser Glu Thr Asp Val Thr Asn Thr Glu His His Gin 225 230 235 240
Pro Ser Asn Asn Asp Leu Asn Thr Thr Glu Lys Arg Ala Ala Glu Arg 245 250 255
His Pro Glu Lys Tyr Gin Gly Ser Ser Val Ser Asn Leu His Val Glu 260 265 270
Pro Cys Gly Thr Asn Thr His Ala Ser Ser Leu Gin His Glu Asn Ser 275 280 285 Ser Leu Leu Leu Thr Lys Asp Arg Met Asn Val Glu Lys Ala Glu Phe
290 295 300
Cys Asn Lys Ser Lys Gin Pro Gly Leu Ala Arg Ser Gin His Asn Arg 305 310 315 320
Trp Ala Gly Ser Lys Glu Thr Cys Asn Asp Arg Arg Thr Pro Ser Thr
325 330 335 Glu Lys Lys Val Asp Leu Asn Ala Asp Pro Leu Cys Glu Arg Lys Glu
340 345 350
Trp Asn Lys Gin Lys Leu Pro Cys Ser Glu Asn Pro Arg Asp Thr Glu 355 360 365
Asp Val Pro Trp lie Thr Leu Asn Ser Ser lie Gin Lys Val Asn Glu
370 375 380 Trp Phe Ser Arg Ser Asp Glu Leu Leu Gly Ser Asp Asp Ser His Asp
385 390 395 400
Gly Glu Ser Glu Ser Asn Ala Lys Val Ala Asp Val Leu Asp Val Leu 405 410 415
Asn Glu Val Asp Glu Tyr Ser Gly Ser Ser Glu Lys lie Asp Leu Leu 420 425 430
Ala Ser Asp Pro His Glu Ala Leu lie Cys Lys Ser Glu Arg Val His 435 440 445
Ser Lys Ser Val Glu Ser Asn lie Glu Asp Lys lie Phe Gly Lys Thr 450 455 460
Tyr Arg Lys Lys Ala Ser Leu Pro Asn Leu Ser His Val Thr Glu Asn 465 470 475 480
Leu lie lie Gly Ala Phe Val Thr Glu Pro Gin He He Gin Glu Arg 485 490 495
Pro Leu Thr Asn Lys Leu Lys Arg Lys Arg Arg Pro Thr Ser Gly Leu 500 505 510
His Pro Glu Asp Phe He Lys Lys Ala Asp Leu Ala Val Gin Lys Thr 515 520 525
Pro Glu Met He Asn Gin Gly Thr Asn Gin Thr Glu Gin Asn Gly Gin 530 535 540 Val Met Asn He Thr Asn Ser Gly His Glu Asn Lys Thr Lys Gly Asp
545 550 555 560
Ser He Gin Asn Glu Lys Asn Pro Asn Pro He Glu Ser Leu Glu Lys 565 570 575
Glu Ser Ala Phe Lys Thr Lys Ala Glu Pro He Ser Ser Ser He Ser 580 585 590
Asn Met Glu Leu Glu Leu Asn He His Asn Ser Lys Ala Pro Lys Lys 595 600 605
Asn Arg Leu Arg Arg Lys Ser Ser Thr Arg His He His Ala Leu Glu 610 615 620 Leu Val Val Ser Arg Asn Leu Ser Pro Pro Asn Cys Thr Glu Leu Gin
625 630 635 640
He Asp Ser Cys Ser Ser Ser Glu Glu He Lys Lys Lys Lys Tyr Asn
645 650 655
Gin Met Pro Val Arg His Ser Arg Asn Leu Gin Leu Met Glu Gly Lys
660 665 670 Glu Pro Ala Thr Gly Ala Lys Lys Ser Asn Lys Pro Asn Glu Gin Thr
675 680 685
Ser Lys Arg His Asp Ser Asp Thr Phe Pro Glu Leu Lys Leu Thr Asn 690 695 700
Ala Pro Gly Ser Phe Thr Lys Cys Ser Asn Thr Ser Glu Leu Lys Glu
705 710 715 720 Phe Val Asn Pro Ser Leu Pro Arg Glu Glu Lys Glu Glu Lys Leu Glu
725 730 735
Thr Val Lys Val Ser Asn Asn Ala Glu Asp Pro Lys Asp Leu Met Leu" 740 745 750
Ser Gly Glu Arg Val Leu Gin Thr Glu Arg Ser Val Glu Ser Ser Ser 755 760 765
He Ser Leu Val Pro Gly Thr Asp Tyr Gly Thr Gin Glu Ser He Ser 770 775 780
Leu Leu Glu Val Ser Thr Leu Gly Lys Ala Lys Thr Glu Pro Asn Lys 785 790 795 800
Cys Val Ser Gin Cys Ala Ala Phe Glu Asn Pro Lys Gly Leu He His 805 810 815
Gly Cys Ser Lys Asp Asn Arg Asn Asp Thr Glu Gly Phe Lys Tyr Pro 820 825 830
Leu Gly His Glu Val Asn His Ser Arg Glu Thr Ser He Glu Met Glu 835 840 845
Glu Ser Glu Leu Asp Ala Gin Tyr Leu Gin Asn Thr Phe Lys Val Ser 850 855 860
Lys Arg Gin Ser Phe Ala Pro Phe Ser Asn Pro Gly Asn Ala Glu Glu
865 870 875 880 Glu Cys Ala Thr Phe Ser Ala His Ser Gly Ser Leu Lys Lys Gin Ser
885 890 895
Pro Lys Val Thr Phe Glu Cys Glu Gin Lys Glu Glu Asn Gin Gly Lys 900 905 910
Asn Glu Ser Asn He Lys Pro Val Gin Thr Val Asn He Thr Ala Gly 915 920 925
Phe Pro Val Val Gly Gin Lys Asp Lys Pro Val Asp Asn Ala Lys Cys 930 935 940
Ser He Lys Gly Gly Ser Arg Phe Cys Leu Ser Ser Gin Phe Arg Gly 945 950 955 960 Asn Glu Thr Gly Leu He Thr Pro Asn Lys His Gly Leu Leu Gin Asn
965 970 975
Pro Tyr Arg He Pro Pro Leu Phe Pro He Lys Ser Phe Val Lys Thr 980 985 990
Lys Cys Lys Lys Asn Leu Leu Glu Glu Asn Phe Glu Glu His Ser Met 995 1000 1005 Ser Pro Glu Arg Glu Met Gly Asn Glu Asn He Pro Ser Thr Val Ser 1010 1015 1020
Thr He Ser Arg Asn Asn He Arg Glu Asn Val Phe Lys Glu Ala Ser 1025 1030 1035 1040
Ser Ser Asn He Asn Glu Val Gly Ser Ser Thr Asn Glu Val Gly Ser 1045 1050 1055 Ser He Asn Glu He Gly Ser Ser Asp Glu Asn He Gin Ala Glu Leu
1060 1065 1070
Gly Arg Asn Arg Gly Pro Lys Leu Asn Ala Met Leu Arg Leu Gly Val 1075 1080 1085
Leu Gin Pro Glu Val Tyr Lys Gin Ser Leu Pro Gly Ser Asn Cys Lys 1090 1095 1100
His Pro Glu He Lys Lys Gin Glu Tyr Glu Glu Val Val Gin Thr Val 1105 1110 1115 1120
Asn Thr Asp Phe Ser Pro Tyr Leu He Ser Asp Asn Leu Glu Gin Pro 1125 1130 1135 Met Gly Ser Ser His Ala Ser Gin Val Cys Ser Glu Thr Pro Asp Asp
1140 1145 1150
Leu Leu Asp Asp Gly Glu He Lys Glu Asp Thr Ser Phe Ala Glu Asn 1155 1160 1165
Asp He Lys Glu Ser Ser Ala Val Phe Ser Lys Ser Val Gin Lys Gly 1170 1175 1180
Glu Leu Ser Arg Ser Pro Ser Pro Phe Thr His Thr His Leu Ala Gin 1185 1190 1195 1200
Gly Tyr Arg Arg Gly Ala Lys Lys Leu Glu Ser Ser Glu Glu Asn Leu 1205 1210 1215 Ser Ser Glu Asp Glu Glu Leu Pro Cys Phe Gin His Leu Leu Phe Gly
1220 1225 1230
Lys Val Asn Asn He Pro Ser Gin Ser Thr Arg His Ser Thr Val Ala 1235 1240 1245
Thr Glu Cys Leu Ser Lys Asn Thr Glu Glu Asn Leu Leu Ser Leu Lys 1250 1255 1260
Asn Ser Leu Asn Asp Cys Ser Asn Gin Val He Leu Ala Lys Ala Ser 1265 1270 1275 1280
Gin Glu His His Leu Ser Glu Glu Thr Lys Cys Ser Ala Ser Leu Phe 1285 1290 1295
Ser Ser Gin Cys Ser Glu Leu Glu Asp Leu Thr Ala Asn Thr Asn Thr 1300 1305 1310
Gin Asp Pro Phe Leu He Gly Ser Ser Lys Gin Met Arg His Gin Ser 1315 1320 1325
Glu Ser Gin Gly Val Gly Leu Ser Asp Lys Glu Leu Val Ser Asp Asp 1330 1335 1340 Glu Glu Arg Gly Thr Gly Leu Glu Glu Asn Asn Gin Glu Glu Gin Ser 1345 1350 1355 1360
Met Asp Ser Asn Leu Gly Glu Ala Ala Ser Gly Cys Glu Ser Glu Thr 1365 1370 1375
Ser Val Ser Glu Asp Cys Ser Gly Leu Ser Ser Gin Ser Asp He Leu 1380 1385 1390 Thr Thr Gin Gin Arg Asp Thr Met Gin His Asn Leu He Lys Leu Gin
1395 1400 1405
Gin Glu Met Ala Glu Leu Glu Ala Val Leu Glu Gin His Gly Ser Gin 1410 1415 1420
Pro Ser Asn Ser Tyr Pro Ser He He Ser Asp Ser Ser Ala Leu Glu 1425 1430 1435 1440
Asp Leu Arg Asn Pro Glu Gin Ser Thr Ser Glu Lys Ala Val Leu Thr 1445 1450 1455
Ser Gin Lys Ser Ser Glu Tyr Pro He Ser Gin Asn Pro Glu Gly Leu 1460 1465 1470 Ser Ala Asp Lys Phe Glu Val Ser Ala Asp Ser Ser Thr Ser Lys Asn
1475 1480 1485
Lys Glu Pro Gly Val Glu Arg Ser Ser Pro Ser Lys Cys Pro Ser Leu 1490 1495 1500
Asp Asp Arg Trp Tyr Met His Ser Cys Ser Gly Ser Leu Gin Asn Arg 1505 1510 1515 1520
Asn Tyr Pro Ser Gin Glu Glu Leu He Lys Val Val Asp Val Glu Glu 1525 1530 1535
Gin Gin Leu Glu Glu Ser Gly Pro His Asp Leu Thr Glu Thr Ser Tyr 1540 1545 1550 Leu Pro Arg Gin Asp Leu Glu Gly Thr Pro Tyr Leu Glu Ser Gly He
1555 1560 1565
Ser Leu Phe Ser Asp Asp Pro Glu Ser Asp Pro Ser Glu Asp Arg Ala 1570 1575 1580
Pro Glu Ser Ala Arg Val Gly Asn He Pro Ser Ser Thr Ser Ala Leu 1585 1590 1595 1600
Lys Val Pro Gin Leu Lys Val Ala Glu Ser Ala Gin Ser Pro Ala Ala 1605 1610 1615
Ala His Thr Thr Asp Thr Ala Gly Tyr Asn Ala Met Glu Glu Ser Val 1620 1625 1630
Ser Arg Glu Lys Pro Glu Leu Thr Ala Ser Thr Glu Arg Val Asn Lys 1635 1640 1645
Arg Met Ser Met Val Val Ser Gly Leu Thr Pro Glu Glu Phe Met Leu 1650 1655 1660
Val Tyr Lys Phe Ala Arg Lys His His He Thr Leu Thr Asn Leu He
1665 1670 1675 1680 Thr Glu Glu Thr Thr His Val Val Met Lys Thr Asp Ala Glu Phe Val 1685 1690 1695
Cys Glu Arg Thr Leu Lys Tyr Phe Leu Gly He Ala Gly Gly Lys Trp 1700 1705 1710
Val Val Ser Tyr Phe Trp Val Thr Gin Ser He Lys Glu Arg Lys Met 1715 1720 1725 Leu Asn Glu His Asp Phe Glu Val Arg Gly Asp Val Val Asn Gly Arg
1730 1735 1740
Asn His Gin Gly Pro Lys Arg Ala Arg Glu Ser Gin Asp Arg Lys He 1745 1750 1755 1760
Phe Arg Gly Leu Glu He Cys Cys Tyr Gly Pro Phe Thr Asn Met Pro 1765 1770 1775
Thr Asp Gin Leu Glu Trp Met Val Gin Leu Cys Gly Ala Ser Val Val 1780 1785 1790
Lys Glu Leu Ser Ser Phe Thr Leu Gly Thr Gly Val His Pro He Val 1795 1800 1805
Val Val Gin Pro Asp Ala Trp Thr Glu Asp Asn Gly Phe His Ala He 1810 1815 1820
Gly Gin Met Cys Glu Ala Pro Val Val Thr Arg Glu Trp Val Leu Asp 1825 1830 1835 1840
Ser Val Ala Leu Tyr Gin Cys Gin Glu Leu Asp Thr Tyr Leu He Pro 1845 1850 1855
Gin He Pro His Ser His Tyr I860
(2) INFORMATION FOR SEQ ID NO:17:
(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 80 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:17:
Met Asp Leu Ser Ala Leu Arg Val Glu Glu Val Gin Asn Val He Asn 1 5 10 15
Ala Met Gin Lys He Leu Glu Cys Pro He Cys Leu Glu Leu He Lys 20 25 30 Glu Pro Val Ser Thr Lys Cys Asp His He Phe Cys Lys Phe Cys Met
35 40 45
Leu Lys Leu Leu Asn Gin Lys Lys Gly Pro Ser Gin Cys Pro Leu Cys 50 55 60
Lys Asn Asp He Thr Lys Ser Val Leu Lys Arg Leu He He Thr Cys 65 70 75 80 (2) INFORMATION FOR SEQ ID NO:18:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 312 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: protein
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:18:
Met Asp Leu Ser Ala Leu Arg Val Glu Glu Val Gin Asn Val He Asn
1 5 10 15
Ala Met Gin Lys He Leu Glu Cys Pro He Cys Leu Glu Leu He Lys 20 25 30
Glu Pro Val Ser Thr Lys Cys Asp His He Phe Cys Lys Phe Cys Met 35 40 45
Leu Lys Leu Leu Asn Gin Lys Lys Gly Pro Ser Gin Cys Pro Leu Cys 50 55 60
Lys Asn Asp He Thr Lys Arg Ser Leu Gin Glu Ser Thr Arg Phe Ser 65 70 75 80
Gin Leu Val Glu Glu Leu Leu Lys He He Cys Ala Phe Gin Leu Asp 85 90 95
Thr Gly Leu Glu Tyr Ala Asn Ser Tyr Asn Phe Ala Lys Lys Glu Asn 100 105 110
Asn Ser Pro Glu His Leu Lys Asp Glu Val Ser He He Gin Ser Met 115 120 125
Gly Tyr Arg Asn Arg Ala Lys Arg Leu Leu Gin Ser Glu Pro Glu Asn
130 135 140 Pro Ser Leu Gin Glu Thr Ser Leu Ser Val Gin Leu Ser Asn Leu Gly
145 150 155 160
Thr Val Arg Thr Leu Arg Thr Lys Gin Arg He Gin Pro Gin Lys Thr 165 170 175
Ser Val Tyr He Glu Leu Gly Ser Asp Ser Ser Glu Asp Thr Val Asn 180 185 190
Lys Ala Thr Tyr Cys Ser Val Gly Asp Gin Glu Leu Leu Gin He Thr 195 200 205
Pro Gin Gly Thr Arg Asp Glu He Ser Leu Asp Ser Ala Lys Lys Ala
210 215 220 Ala Cys Glu Phe Ser Glu Thr Asp Val Thr Asn Thr Glu His His Gin 225 230 235 240
Pro Ser Asn Asn Asp Leu Asn Thr Thr Glu Lys Arg Ala Ala Glu Arg 245 250 255
His Pro Glu Lys Tyr Gin Gly Ser Ser Val Ser Asn Leu His Val Glu 260 265 270 Pro Cys Gly Thr Asn Thr His Ala Ser Ser Leu Gin His Glu Asn Ser 275 280 285
Ser Leu Leu Leu Thr Lys Asp Arg Met Asn Val Glu Lys Ala Glu Phe 290 295 300
Cys Asn Lys Ser Lys Arg Leu Ala 305 310 (2) INFORMATION FOR SEQ ID NO:19:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 765 amino acids
(B) TYPE: amino acid (C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:19:
Met Asp Leu Ser Ala Leu Arg Val Glu Glu Val Gin Asn Val He Asn
1 5 10 15 Ala Met Gin Lys He Leu Glu Cys Pro He Cys Leu Glu Leu He Lys
20 25 30
Glu Pro Val Ser Thr Lys Cys Asp His He Phe Cys Lys Phe Cys Met 35 40 45
Leu Lys Leu Leu Asn Gin Lys Lys Gly Pro Ser Gin Cys Pro Leu Cys 50 55 60
Lys Asn Asp He Thr Lys Arg Ser Leu Gin Glu Ser Thr Arg Phe Ser 65 70 75 80
Gin Leu Val Glu Glu Leu Leu Lys He He Cys Ala Phe Gin Leu Asp 85 90 95
Thr Gly Leu Glu Tyr Ala Asn Ser Tyr Asn Phe Ala Lys Lys Glu Asn
100 105 110
Asn Ser Pro Glu His Leu Lys Asp Glu Val Ser He He Gin Ser Met
115 120 125
Gly Tyr Arg Asn Arg Ala Lys Arg Leu Leu Gin Ser Glu Pro Glu Asn
130 135 140
Pro Ser Leu Gin Glu Thr Ser Leu Ser Val Gin Leu Ser Asn Leu Gly 145 150 155 160
Thr Val Arg Thr Leu Arg Thr Lys Gin Arg He Gin Pro Gin Lys Thr 165 170 175 Ser Val Tyr He Glu Leu Gly Ser Asp Ser Ser Glu Asp Thr Val Asn
180 185 190
Lys Ala Thr Tyr Cys Ser Val Gly Asp Gin Glu Leu Leu Gin He Thr 195 200 205
Pro Gin Gly Thr Arg Asp Glu He Ser Leu Asp Ser Ala Lys Lys Ala 210 215 220 Ala Cys Glu Phe Ser Glu Thr Asp Val Thr Asn Thr Glu His His Gin
225 230 235 240
Pro Ser Asn Asn Asp Leu Asn Thr Thr Glu Lys Arg Ala Ala Glu Arg 245 250 255
His Pro Glu Lys Tyr Gin Gly Ser Ser Val Ser Asn Leu His Val Glu
260 265 270 Pro Cys Gly Thr Asn Thr His Ala Ser Ser Leu Gin His Glu Asn Ser
275 280 285
Ser Leu Leu Leu Thr Lys Asp Arg Met Asn Val Glu Lys Ala Glu Phe 290 295 300
Cys Asn Lys Ser Lys Gin Pro Gly Leu Ala Arg Ser Gin His Asn Arg 305 310 315 320
Trp Ala Gly Ser Lys Glu Thr Cys Asn Asp Arg Arg Thr Pro Ser Thr 325 330 335
Glu Lys Lys Val Asp Leu Asn Ala Asp Pro Leu Cys Glu Arg Lys Glu 340 345 350 Trp Asn Lys Gin Lys Leu Pro Cys Ser Glu Asn Pro Arg Asp Thr Glu
355 360 365
Asp Val Pro Trp He Thr Leu Asn Ser Ser He Gin Lys Val Asn Glu 370 375 380
Trp Phe Ser Arg Ser Asp Glu Leu Leu Gly Ser Asp Asp Ser His Asp 385 390 395 400
Gly Glu Ser Glu Ser Asn Ala Lys Val Ala Asp Val Leu Asp Val Leu 405 410 415
Asn Glu Val Asp Glu Tyr Ser Gly Ser Ser Glu Lys He Asp Leu Leu 420 425 430
Ala Ser Asp Pro His Glu Ala Leu He Cys Lys Ser Glu Arg Val His 435 440 445
Ser Lys Ser Val Glu Ser Asn He Glu Asp Lys He Phe Gly Lys Thr
450 455 460
Tyr Arg Lys Lys Ala Ser Leu Pro Asn Leu Ser His Val Thr Glu Asn
465 470 475 480
Leu He He Gly Ala Phe Val Thr Glu Pro Gin He He Gin Glu Arg 485 490 495
Pro Leu Thr Asn Lys Leu Lys Arg Lys Arg Arg Pro Thr Ser Gly Leu
500 505 510 His Pro Glu Asp Phe He Lys Lys Ala Asp Leu Ala Val Gin Lys Thr
515 520 525
Pro Glu Met He Asn Gin Gly Thr Asn Gin Thr Glu Gin Asn Gly Gin
530 535 540
Val Met Asn He Thr Asn Ser Gly His Glu Asn Lys Thr Lys Gly Asp
545 550 555 560 Ser He Gin Asn Glu Lys Asn Pro Asn Pro He Glu Ser Leu Glu Lys
565 570 575
Glu Ser Ala Phe Lys Thr Lys Ala Glu Pro He Ser Ser Ser He Ser 580 585 590
Asn Met Glu Leu Glu Leu Asn He His Asn Ser Lys Ala Pro Lys Lys 595 600 605 Asn Arg Leu Arg Arg Lys Ser Ser Thr Arg His He His Ala Leu Glu
610 615 620
Leu Val Val Ser Arg Asn Leu Ser Pro Pro Asn Cys Thr Glu Leu Gin
625 630 635 640
He Asp Ser Cys Ser Ser Ser Glu Glu He Lys Lys Lys Lys Tyr Asn
645 650 655
Gin Met Pro Val Arg His Ser Arg Asn Leu Gin Leu Met Glu Gly Lys 660 665 670
Glu Pro Ala Thr Gly Ala Lys Lys Ser Asn Lys Pro Asn Glu Gin Thr 675 680 685
Ser Lys Arg His Asp Ser Asp Thr Phe Pro Glu Leu Lys Leu Thr Asn 690 695 700
Ala Pro Gly Ser Phe Thr Lys Cys Ser Asn Thr Ser Glu Leu Lys Glu 705 710 715 720
Phe Val Asn Pro Ser Leu Pro Arg Glu Glu Lys Glu Glu Lys Leu Glu 725 730 735
Thr Val Lys Val Ser Asn Asn Ala Glu Asp Pro Lys Asp Leu Met Leu 740 745 750
Ser Gly Glu Arg Val Leu Gin Thr Glu Arg Ser Val Glu 755 760 765 (2) INFORMATION FOR SEQ ID NO:20:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 900 amino acids
(B) TYPE: amino acid (C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:20:
Met Asp Leu Ser Ala Leu Arg Val Glu Glu Val Gin Asn Val He Asn 1 5 10 15 Ala Met Gin Lys He Leu Glu Cys Pro He Cys Leu Glu Leu He Lys
20 25 30
Glu Pro Val Ser Thr Lys Cys Asp His He Phe Cys Lys Phe Cys Met 35 40 45
Leu Lys Leu Leu Asn Gin Lys Lys Gly Pro Ser Gin Cys Pro Leu Cys 50 55 60 Lys Asn Asp He Thr Lys Arg Ser Leu Gin Glu Ser Thr Arg Phe Ser
65 70 75 80
Gin Leu Val Glu Glu Leu Leu Lys He He Cys Ala Phe Gin Leu Asp 85 90 95
Thr Gly Leu Glu Tyr Ala Asn Ser Tyr Asn Phe Ala Lys Lys Glu Asn 100 105 110 Asn Ser Pro Glu His Leu Lys Asp Glu Val Ser He He Gin Ser Met
115 120 125
Gly Tyr Arg Asn Arg Ala Lys Arg Leu Leu Gin Ser Glu Pro Glu Asn- 130 135 140
Pro Ser Leu Gin Glu Thr Ser Leu Ser Val Gin Leu Ser Asn Leu Gly 145 150 155 160
Thr Val Arg Thr Leu Arg Thr Lys Gin Arg He Gin Pro Gin Lys Thr 165 170 175
Ser Val Tyr He Glu Leu Gly Ser Asp Ser Ser Glu Asp Thr Val Asn 180 185 190 Lys Ala Thr Tyr Cys Ser Val Gly Asp Gin Glu Leu Leu Gin He Thr
195 200 205
Pro Gin Gly Thr Arg Asp Glu He Ser Leu Asp Ser Ala Lys Lys Ala 210 215 220
Ala Cys Glu Phe Ser Glu Thr Asp Val Thr Asn Thr Glu His His Gin 225 230 235 240
Pro Ser Asn Asn Asp Leu Asn Thr Thr Glu Lys Arg Ala Ala Glu Arg 245 250 255
His Pro Glu Lys Tyr Gin Gly Ser Ser Val Ser Asn Leu His Val Glu
260 265 270 Pro Cys Gly Thr Asn Thr His Ala Ser Ser Leu Gin His Glu Asn Ser
275 280 285
Ser Leu Leu Leu Thr Lys Asp Arg Met Asn Val Glu Lys Ala Glu Phe 290 295 300
Cys Asn Lys Ser Lys Gin Pro Gly Leu Ala Arg Ser Gin His Asn Arg 305 310 315 320
Trp Ala Gly Ser Lys Glu Thr Cys Asn Asp Arg Arg Thr Pro Ser Thr 325 330 335
Glu Lys Lys Val Asp Leu Asn Ala Asp Pro Leu Cys Glu Arg Lys Glu 340 345 350 Trp Asn Lys Gin Lys Leu Pro Cys Ser Glu Asn Pro Arg Asp Thr Glu
355 360 365
Asp Val Pro Trp He Thr Leu Asn Ser Ser He Gin Lys Val Asn Glu 370 375 380
Trp Phe Ser Arg Ser Asp Glu Leu Leu Gly Ser Asp Asp Ser His Asp
385 390 395 400 Gly Glu Ser Glu Ser Asn Ala Lys Val Ala Asp Val Leu Asp Val Leu
405 410 415
Asn Glu Val Asp Glu Tyr Ser Gly Ser Ser Glu Lys He Asp Leu Leu 420 425 430
Ala Ser Asp Pro His Glu Ala Leu He Cys Lys Ser Glu Arg Val His
435 440 445 Ser Lys Ser Val Glu Ser Asn He Glu Asp Lys He Phe Gly Lys Thr
450 455 460
Tyr Arg Lys Lys Ala Ser Leu Pro Asn Leu Ser His Val Thr Glu Asn 465 470 475 480
Leu He He Gly Ala Phe Val Thr Glu Pro Gin He He Gin Glu Arg 485 490 495
Pro Leu Thr Asn Lys Leu Lys Arg Lys Arg Arg Pro Thr Ser Gly Leu 500 505 510
His Pro Glu Asp Phe He Lys Lys Ala Asp Leu Ala Val Gin Lys Thr 515 520 525
Pro Glu Met He Asn Gin Gly Thr Asn Gin Thr Glu Gin Asn Gly Gin 530 535 540
Val Met Asn He Thr Asn Ser Gly His Glu Asn Lys Thr Lys Gly Asp 545 550 555 560
Ser He Gin Asn Glu Lys Asn Pro Asn Pro He Glu Ser Leu Glu Lys 565 570 575
Glu Ser Ala Phe Lys Thr Lys Ala Glu Pro He Ser Ser Ser He Ser 580 585 590
Asn Met Glu Leu Glu Leu Asn He His Asn Ser Lys Ala Pro Lys Lys 595 600 605 Asn Arg Leu Arg Arg Lys Ser Ser Thr Arg His He His Ala Leu Glu
610 615 620
Leu Val Val Ser Arg Asn Leu Ser Pro Pro Asn Cys Thr Glu Leu Gin 625 630 635 640
He Asp Ser Cys Ser Ser Ser Glu Glu He Lys Lys Lys Lys Tyr Asn 645 650 655
Gin Met Pro Val Arg His Ser Arg Asn Leu Gin Leu Met Glu Gly Lys 660 665 670
Glu Pro Ala Thr Gly Ala Lys Lys Ser Asn Lys Pro Asn Glu Gin Thr 675 680 685 Ser Lys Arg His Asp Ser Asp Thr Phe Pro Glu Leu Lys Leu Thr Asn
690 695 700
Ala Pro Gly Ser Phe Thr Lys Cys Ser Asn Thr Ser Glu Leu Lys Glu 705 710 715 720
Phe Val Asn Pro Ser Leu Pro Arg Glu Glu Lys Glu Glu Lys Leu Glu 725 730 735 Thr Val Lys Val Ser Asn Asn Ala Glu Asp Pro Lys Asp Leu Met Leu
740 745 750
Ser Gly Glu Arg Val Leu Gin Thr Glu Arg Ser Val Glu Ser Ser Ser 755 760 765
He Ser Leu Val Pro Gly Thr Asp Tyr Gly Thr Gin Glu Ser He Ser 770 775 780 Leu Leu Glu Val Ser Thr Leu Gly Lys Ala Lys Thr Glu Pro Asn Lys
785 790 795 800
Cys Val Ser Gin Cys Ala Ala Phe Glu Asn Pro Lys Gly Leu He His
805 810 815
Gly Cys Ser Lys Asp Asn Arg Asn Asp Thr Glu Gly Phe Lys Tyr Pro
820 825 830
Leu Gly His Glu Val Asn His Ser Arg Glu Thr Ser He Glu Met Glu 835 840 845
Glu Ser Glu Leu Asp Ala Gin Tyr Leu Gin Asn Thr Phe Lys Val Ser 850 855 860
Lys Arg Gin Ser Phe Ala Pro Phe Ser Asn Pro Gly Asn Ala Glu Glu 865 870 875 880
Glu Cys Ala Thr Phe Ser Ala His Ser Gly Ser Leu Lys Thr Lys Ser 885 890 895
Lys Ser His Phe 900
(2) INFORMATION FOR SEQ ID NO:21:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 914 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single (D) TOPOLOGY: linear
(ii) MOLECULE TYPE: protein
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:21:
Met Asp Leu Ser Ala Leu Arg Val Glu Glu Val Gin Asn Val He Asn 1 5 10 15
Ala Met Gin Lys He Leu Glu Cys Pro He Cys Leu Glu Leu He Lys 20 25 30
Glu Pro Val Ser Thr Lys Cys Asp His He Phe Cys Lys Phe Cys Met 35 40 45 Leu Lys Leu Leu Asn Gin Lys Lys Gly Pro Ser Gin Cys Pro Leu Cys
50 55 60
Lys Asn Asp He Thr Lys Arg Ser Leu Gin Glu Ser Thr Arg Phe Ser
65 70 75 80
Gin Leu Val Glu Glu Leu Leu Lys He He Cys Ala Phe Gin Leu Asp
85 90 95 Thr Gly Leu Glu Tyr Ala Asn Ser Tyr Asn Phe Ala Lys Lys Glu Asn
100 105 110
Asn Ser Pro Glu His Leu Lys Asp Glu Val Ser He He Gin Ser Met 115 120 125
Gly Tyr Arg Asn Arg Ala Lys Arg Leu Leu Gin Ser Glu Pro Glu Asn
130 135 140 Pro Ser Leu Gin Glu Thr Ser Leu Ser Val Gin Leu Ser Asn Leu Gly
145 150 155 160
Thr Val Arg Thr Leu Arg Thr Lys Gin Arg He Gin Pro Gin Lys Thr 165 170 175
Ser Val Tyr He Glu Leu Gly Ser Asp Ser Ser Glu Asp Thr Val Asn 180 185 190
Lys Ala Thr Tyr Cys Ser Val Gly Asp Gin Glu Leu Leu Gin He Thr 195 200 205
Pro Gin Gly Thr Arg Asp Glu He Ser Leu Asp Ser Ala Lys Lys Ala 210 215 220 Ala Cys Glu Phe Ser Glu Thr Asp Val Thr Asn Thr Glu His His Gin
225 230 235 240
Pro Ser Asn Asn Asp Leu Asn Thr Thr Glu Lys Arg Ala Ala Glu Arg 245 250 255
His Pro Glu Lys Tyr Gin Gly Ser Ser Val Ser Asn Leu His Val Glu 260 265 270
Pro Cys Gly Thr Asn Thr His Ala Ser Ser Leu Gin His Glu Asn Ser 275 280 285
Ser Leu Leu Leu Thr Lys Asp Arg Met Asn Val Glu Lys Ala Glu Phe 290 295 300 Cys Asn Lys Ser Lys Gin Pro Gly Leu Ala Arg Ser Gin His Asn Arg
305 310 315 320
Trp Ala Gly Ser Lys Glu Thr Cys Asn Asp Arg Arg Thr Pro Ser Thr 325 330 335
Glu Lys Lys Val Asp Leu Asn Ala Asp Pro Leu Cys Glu Arg Lys Glu 340 345 350
Trp Asn Lys Gin Lys Leu Pro Cys Ser Glu Asn Pro Arg Asp Thr Glu 355 360 365
Asp Val Pro Trp He Thr Leu Asn Ser Ser He Gin Lys Val Asn Glu 370 375 380
Trp Phe Ser Arg Ser Asp Glu Leu Leu Gly Ser Asp Asp Ser His Asp 385 390 395 400
Gly Glu Ser Glu Ser Asn Ala Lys Val Ala Asp Val Leu Asp Val Leu 405 410 415
Asn Glu Val Asp Glu Tyr Ser Gly Ser Ser Glu Lys He Asp Leu Leu 420 425 430 Ala Ser Asp Pro His Glu Ala Leu He Cys Lys Ser Glu Arg Val His 435 440 445
Ser Lys Ser Val Glu Ser Asn He Glu Asp Lys He Phe Gly Lys Thr 450 455 460
Tyr Arg Lys Lys Ala Ser Leu Pro Asn Leu Ser His Val Thr Glu Asn
465 470 475 480 Leu He He Gly Ala Phe Val Thr Glu Pro Gin He He Gin Glu Arg
485 490 495
Pro Leu Thr Asn Lys Leu Lys Arg Lys Arg Arg Pro Thr Ser Gly Leu- 500 505 510
His Pro Glu Asp Phe He Lys Lys Ala Asp Leu Ala Val Gin Lys Thr 515 520 525
Pro Glu Met He Asn Gin Gly Thr Asn Gin Thr Glu Gin Asn Gly Gin 530 535 540
Val Met Asn He Thr Asn Ser Gly His Glu Asn Lys Thr Lys Gly Asp 545 550 555 560 Ser He Gin Asn Glu Lys Asn Pro Asn Pro He Glu Ser Leu Glu Lys
565 570 575
Glu Ser Ala Phe Lys Thr Lys Ala Glu Pro He Ser Ser Ser He Ser 580 585 590
Asn Met Glu Leu Glu Leu Asn He His Asn Ser Lys Ala Pro Lys Lys 595 600 605
Asn Arg Leu Arg Arg Lys Ser Ser Thr Arg His He His Ala Leu Glu 610 615 620
Leu Val Val Ser Arg Asn Leu Ser Pro Pro Asn Cys Thr Glu Leu Gin
625 630 635 640 He Asp Ser Cys Ser Ser Ser Glu Glu He Lys Lys Lys Lys Tyr Asn
645 650 655
Gin Met Pro Val Arg His Ser Arg Asn Leu Gin Leu Met Glu Gly Lys 660 665 670
Glu Pro Ala Thr Gly Ala Lys Lys Ser Asn Lys Pro Asn Glu Gin Thr 675 680 685
Ser Lys Arg His Asp Ser Asp Thr Phe Pro Glu Leu Lys Leu Thr Asn 690 695 700
Ala Pro Gly Ser Phe Thr Lys Cys Ser Asn Thr Ser Glu Leu Lys Glu 705 710 715 720
Phe Val Asn Pro Ser Leu Pro Arg Glu Glu Lys Glu Glu Lys Leu Glu 725 730 735
Thr Val Lys Val Ser Asn Asn Ala Glu Asp Pro Lys Asp Leu Met Leu 740 745 750
Ser Gly Glu Arg Val Leu Gin Thr Glu Arg Ser Val Glu Ser Ser Ser 755 760 765 He Ser Leu Val Pro Gly Thr Asp Tyr Gly Thr Gin Glu Ser He Ser 770 775 780
Leu Leu Glu Val Ser Thr Leu Gly Lys Ala Lys Thr Glu Pro Asn Lys 785 790 795 800
Cys Val Ser Gin Cys Ala Ala Phe Glu Asn Pro Lys Gly Leu He His 805 810 815 Gly Cys Ser Lys Asp Asn Arg Asn Asp Thr Glu Gly Phe Lys Tyr Pro
820 825 830
Leu Gly His Glu Val Asn His Ser Arg Glu Thr Ser He Glu Met Glu
835 840 845
Glu Ser Glu Leu Asp Ala Gin Tyr Leu Gin Asn Thr Phe Lys Val Ser 850 855 860
Lys Arg Gin Ser Phe Ala Pro Phe Ser Asn Pro Gly Asn Ala Glu Glu 865 870 875 880
Glu Cys Ala Thr Phe Ser Ala His Ser Gly Ser Leu Lys Lys Gin Ser 885 890 895 Pro Lys Val Thr Phe Glu Cys Glu Gin Lys Glu Glu Asn Gin Gly Lys
900 905 910
Asn Glu
(2) INFORMATION FOR SEQ ID NO:22:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 1202 amino acids (B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: protein
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:22:
Met Asp Leu Ser Ala Leu Arg Val Glu Glu Val Gin Asn Val He Asn 1 5 10 15
Ala Met Gin Lys He Leu Glu Cys Pro He Cys Leu Glu Leu He Lys 20 25 30
Glu Pro Val Ser Thr Lys Cys Asp His He Phe Cys Lys Phe Cys Met 35 40 45
Leu Lys Leu Leu Asn Gin Lys Lys Gly Pro Ser Gin Cys Pro Leu Cys 50 55 60 Lys Asn Asp He Thr Lys Arg Ser Leu Gin Glu Ser Thr Arg Phe Ser
65 70 75 80
Gin Leu Val Glu Glu Leu Leu Lys He He Cys Ala Phe Gin Leu Asp 85 90 95
Thr Gly Leu Glu Tyr Ala Asn Ser Tyr Asn Phe Ala Lys Lys Glu Asn 100 105 110 Asn Ser Pro Glu His Leu Lys Asp Glu Val Ser He He Gin Ser Met 115 120 125
Gly Tyr Arg Asn Arg Ala Lys Arg Leu Leu Gin Ser Glu Pro Glu Asn 130 135 140
Pro Ser Leu Gin Glu Thr Ser Leu Ser Val Gin Leu Ser Asn Leu Gly
145 150 155 160 Thr Val Arg Thr Leu Arg Thr Lys Gin Arg He Gin Pro Gin Lys Thr
165 170 175
Ser Val Tyr He Glu Leu Gly Ser Asp Ser Ser Glu Asp Thr Val Asn 180 185 190
Lys Ala Thr Tyr Cys Ser Val Gly Asp Gin Glu Leu Leu Gin He Thr 195 200 205
Pro Gin Gly Thr Arg Asp Glu He Ser Leu Asp Ser Ala Lys Lys Ala 210 215 220
Ala Cys Glu Phe Ser Glu Thr Asp Val Thr Asn Thr Glu His His Gin 225 230 235 240
Pro Ser Asn Asn Asp Leu Asn Thr Thr Glu Lys Arg Ala Ala Glu Arg 245 250 255
His Pro Glu Lys Tyr Gin Gly Ser Ser Val Ser Asn Leu His Val Glu 260 265 270
Pro Cys Gly Thr Asn Thr His Ala Ser Ser Leu Gin His Glu Asn Ser 275 280 285
Ser Leu Leu Leu Thr Lys Asp Arg Met Asn Val Glu Lys Ala Glu Phe 290 295 300
Cys Asn Lys Ser Lys Gin Pro Gly Leu Ala Arg Ser Gin His Asn Arg 305 310 315 320 Trp Ala Gly Ser Lys Glu Thr Cys Asn Asp Arg Arg Thr Pro Ser Thr
325 330 335
Glu Lys Lys Val Asp Leu Asn Ala Asp Pro Leu Cys Glu Arg Lys Glu 340 345 350
Trp Asn Lys Gin Lys Leu Pro Cys Ser Glu Asn Pro Arg Asp Thr Glu 355 360 365
Asp Val Pro Trp He Thr Leu Asn Ser Ser He Gin Lys Val Asn Glu 370 375 380
Trp Phe Ser Arg Ser Asp Glu Leu Leu Gly Ser Asp Asp Ser His Asp 385 390 395 400 Gly Glu Ser Glu Ser Asn Ala Lys Val Ala Asp Val Leu Asp Val Leu
405 410 415
Asn Glu Val Asp Glu Tyr Ser Gly Ser Ser Glu Lys He Asp Leu Leu 420 425 430
Ala Ser Asp Pro His Glu Ala Leu He Cys Lys Ser Glu Arg Val His 435 440 445 Ser Lys Ser Val Glu Ser Asn He Glu Asp Lys He Phe Gly Lys Thr 450 455 460
Tyr Arg Lys Lys Ala Ser Leu Pro Asn Leu Ser His Val Thr Glu Asn 465 470 475 480
Leu He He Gly Ala Phe Val Thr Glu Pro Gin He He Gin Glu Arg
485 490 495 Pro Leu Thr Asn Lys Leu Lys Arg Lys Arg Arg Pro Thr Ser Gly Leu
500 505 510
His Pro Glu Asp Phe He Lys Lys Ala Asp Leu Ala Val Gin Lys Thr 515 520 525
Pro Glu Met He Asn Gin Gly Thr Asn Gin Thr Glu Gin Asn Gly Gin 530 535 540
Val Met Asn He Thr Asn Ser Gly His Glu Asn Lys Thr Lys Gly Asp 545 550 555 560
Ser He Gin Asn Glu Lys Asn Pro Asn Pro He Glu Ser Leu Glu Lys 565 570 575 Glu Ser Ala Phe Lys Thr Lys Ala Glu Pro He Ser Ser Ser He Ser
580 585 590
Asn Met Glu Leu Glu Leu Asn He His Asn Ser Lys Ala Pro Lys Lys
595 600 605
Asn Arg Leu Arg Arg Lys Ser Ser Thr Arg His He His Ala Leu Glu
610 615 620
Leu Val Val Ser Arg Asn Leu Ser Pro Pro Asn Cys Thr Glu Leu Gin 625 630 635 640
He Asp Ser Cys Ser Ser Ser Glu Glu He Lys Lys Lys Lys Tyr Asn 645 650 655 Gin Met Pro Val Arg His Ser Arg Asn Leu Gin Leu Met Glu Gly Lys
660 665 670
Glu Pro Ala Thr Gly Ala Lys Lys Ser Asn Lys Pro Asn Glu Gin Thr
675 680 685
Ser Lys Arg His Asp Ser Asp Thr Phe Pro Glu Leu Lys Leu Thr Asn
690 695 700
Ala Pro Gly Ser Phe Thr Lys Cys Ser Asn Thr Ser Glu Leu Lys Glu 705 710 715 720
Phe Val Asn Pro Ser Leu Pro Arg Glu Glu Lys Glu Glu Lys Leu Glu 725 730 735 Thr Val Lys Val Ser Asn Asn Ala Glu Asp Pro Lys Asp Leu Met Leu
740 745 750
Ser Gly Glu Arg Val Leu Gin Thr Glu Arg Ser Val Glu Ser Ser Ser 755 760 765
He Ser Leu Val Pro Gly Thr Asp Tyr Gly Thr Gin Glu Ser He Ser 770 775 780 Leu Leu Glu Val Ser Thr Leu Gly Lys Ala Lys Thr Glu Pro Asn Lys
785 790 795 800
Cys Val Ser Gin Cys Ala Ala Phe Glu Asn Pro Lys Gly Leu He His 805 810 815
Gly Cys Ser Lys Asp Asn Arg Asn Asp Thr Glu Gly Phe Lys Tyr Pro
820 825 830 Leu Gly His Glu Val Asn His Ser Arg Glu Thr Ser He Glu Met Glu
835 840 845
Glu Ser Glu Leu Asp Ala Gin Tyr Leu Gin Asn Thr Phe Lys Val Ser. 850 855 860
Lys Arg Gin Ser Phe Ala Pro Phe Ser Asn Pro Gly Asn Ala Glu Glu 865 870 875 880
Glu Cys Ala Thr Phe Ser Ala His Ser Gly Ser Leu Lys Lys Gin Ser 885 890 895
Pro Lys Val Thr Phe Glu Cys Glu Gin Lys Glu Glu Asn Gin Gly Lys 900 905 910 Asn Glu Ser Asn He Lys Pro Val Gin Thr Val Asn He Thr Ala Gly
915 920 925
Phe Pro Val Val Gly Gin Lys Asp Lys Pro Val Asp Asn Ala Lys Cys 930 935 940
Ser He Lys Gly Gly Ser Arg Phe Cys Leu Ser Ser Gin Phe Arg Gly 945 950 955 960
Asn Glu Thr Gly Leu He Thr Pro Asn Lys His Gly Leu Leu Gin Asn 965 970 975
Pro Tyr Arg He Pro Pro Leu Phe Pro He Lys Ser Phe Val Lys Thr
980 985 990 Lys Cys Lys Lys Asn Leu Leu Glu Glu Asn Phe Glu Glu His Ser Met
995 1000 1005
Ser Pro Glu Arg Glu Met Gly Asn Glu Asn He Pro Ser Thr Val Ser 1010 1015 1020
Thr He Ser Arg Asn Asn He Arg Glu Asn Val Phe Lys Glu Ala Ser 1025 1030 1035 1040
Ser Ser Asn He Asn Glu Val Gly Ser Ser Thr Asn Glu Val Gly Ser 1045 1050 1055
Ser He Asn Glu He Gly Ser Ser Asp Glu Asn He Gin Ala Glu Leu 1060 1065 1070 Gly Arg Asn Arg Gly Pro Lys Leu Asn Ala Met Leu Arg Leu Gly Val
1075 1080 1085
Leu Gin Pro Glu Val Tyr Lys Gin Ser Leu Pro Gly Ser Asn Cys Lys 1090 1095 1100
His Pro Glu He Lys Lys Gin Glu Tyr Glu Glu Val Val Gin Thr Val 1105 1110 1115 1120 Asn Thr Asp Phe Ser Pro Tyr Leu He Ser Asp Asn Leu Glu Gin Pro 1125 1130 1135
Met Gly Ser Ser His Ala Ser Gin Val Cys Ser Glu Thr Pro Asp Asp 1140 1145 1150
Leu Leu Asp Asp Gly Glu He Lys Glu Asp Thr Ser Phe Ala Glu Asn 1155 1160 1165 Asp He Lys Glu Ser Ser Ala Val Phe Ser Lys Ser Val Gin Lys Gly
1170 1175 1180
Glu Leu Ser Arg Ser Pro Ser Pro Phe Thr His Thr His Leu Ala Gin 1185 1190 1195 1200
Gly Tyr
(2) INFORMATION FOR SEQ ID NO:23:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 1363 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single (D) TOPOLOGY: linear
(ii) MOLECULE TYPE: protein
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:23:
Met Asp Leu Ser Ala Leu Arg Val Glu Glu Val Gin Asn Val He Asn 1 5 10 15
Ala Met Gin Lys He Leu Glu Cys Pro He Cys Leu Glu Leu He Lys 20 25 30
Glu Pro Val Ser Thr Lys Cys Asp His He Phe Cys Lys Phe Cys Met 35 40 45
Leu Lys Leu Leu Asn Gin Lys Lys Gly Pro Ser Gin Cys Pro Leu Cys 50 55 60
Lys Asn Asp He Thr Lys Arg Ser Leu Gin Glu Ser Thr Arg Phe Ser 65 70 75 80
Gin Leu Val Glu Glu Leu Leu Lys He He Cys Ala Phe Gin Leu Asp 85 90 95
Thr Gly Leu Glu Tyr Ala Asn Ser Tyr Asn Phe Ala Lys Lys Glu Asn 100 105 110
Asn Ser Pro Glu His Leu Lys Asp Glu Val Ser He He Gin Ser Met 115 120 125 Gly Tyr Arg Asn Arg Ala Lys Arg Leu Leu Gin Ser Glu Pro Glu Asn
130 135 140
Pro Ser Leu Gin Glu Thr Ser Leu Ser Val Gin Leu Ser Asn Leu Gly 145 150 155 160
Thr Val Arg Thr Leu Arg Thr Lys Gin Arg He Gin Pro Gin Lys Thr 165 170 175 Ser Val Tyr He Glu Leu Gly Ser Asp Ser Ser Glu Asp Thr Val Asn
180 185 190
Lys Ala Thr Tyr Cys Ser Val Gly Asp Gin Glu Leu Leu Gin He Thr 195 200 205
Pro Gin Gly Thr Arg Asp Glu He Ser Leu Asp Ser Ala Lys Lys Ala
210 215 220 Ala Cys Glu Phe Ser Glu Thr Asp Val Thr Asn Thr Glu His His Gin
225 230 235 240
Pro Ser Asn Asn Asp Leu Asn Thr Thr Glu Lys Arg Ala Ala Glu Arg 245 250 255
His Pro Glu Lys Tyr Gin Gly Ser Ser Val Ser Asn Leu His Val Glu 260 265 270
Pro Cys Gly Thr Asn Thr His Ala Ser Ser Leu Gin His Glu Asn Ser 275 280 285
Ser Leu Leu Leu Thr Lys Asp Arg Met Asn Val Glu Lys Ala Glu Phe
290 295 300 Cys Asn Lys Ser Lys Gin Pro Gly Leu Ala Arg Ser Gin His Asn Arg
305 310 315 320
Trp Ala Gly Ser Lys Glu Thr Cys Asn Asp Arg Arg Thr Pro Ser Thr 325 330 335
Glu Lys Lys Val Asp Leu Asn Ala Asp Pro Leu Cys Glu Arg Lys Glu 340 345 350
Trp Asn Lys Gin Lys Leu Pro Cys Ser Glu Asn Pro Arg Asp Thr Glu 355 360 365
Asp Val Pro Trp He Thr Leu Asn Ser Ser He Gin Lys Val Asn Glu 370 375 380
Trp Phe Ser Arg Ser Asp Glu Leu Leu Gly Ser Asp Asp Ser His Asp 385 390 395 400
Gly Glu Ser Glu Ser Asn Ala Lys Val Ala Asp Val Leu Asp Val Leu 405 410 415
Asn Glu Val Asp Glu Tyr Ser Gly Ser Ser Glu Lys He Asp Leu Leu 420 425 430
Ala Ser Asp Pro His Glu Ala Leu He Cys Lys Ser Glu Arg Val His 435 440 445
Ser Lys Ser Val Glu Ser Asn He Glu Asp Lys He Phe Gly Lys Thr 450 455 460 Tyr Arg Lys Lys Ala Ser Leu Pro Asn Leu Ser His Val Thr Glu Asn
465 470 475 480
Leu He He Gly Ala Phe Val Thr Glu Pro Gin He He Gin Glu Arg 485 490 495
Pro Leu Thr Asn Lys Leu Lys Arg Lys Arg Arg Pro Thr Ser Gly Leu 500 505 510 His Pro Glu Asp Phe He Lys Lys Ala Asp Leu Ala Val Gin Lys Thr
515 520 525
Pro Glu Met He Asn Gin Gly Thr Asn Gin Thr Glu Gin Asn Gly Gin 530 535 540
Val Met Asn He Thr Asn Ser Gly His Glu Asn Lys Thr Lys Gly Asp
545 550 555 560 Ser He Gin Asn Glu Lys Asn Pro Asn Pro He Glu Ser Leu Glu Lys
565 570 575
Glu Ser Ala Phe Lys Thr Lys Ala Glu Pro He Ser Ser Ser He Ser
580 585 590
Asn Met Glu Leu Glu Leu Asn He His Asn Ser Lys Ala Pro Lys Lys
595 600 605
Asn Arg Leu Arg Arg Lys Ser Ser Thr Arg His He His Ala Leu Glu 610 615 620
Leu Val Val Ser Arg Asn Leu Ser Pro Pro Asn Cys Thr Glu Leu Gin 625 630 635 640
He Asp Ser Cys Ser Ser Ser Glu Glu He Lys Lys Lys Lys Tyr Asn 645 650 655
Gin Met Pro Val Arg His Ser Arg Asn Leu Gin Leu Met Glu Gly Lys 660 665 670
Glu Pro Ala Thr Gly Ala Lys Lys Ser Asn Lys Pro Asn Glu Gin Thr 675 680 685
Ser Lys Arg His Asp Ser Asp Thr Phe Pro Glu Leu Lys Leu Thr Asn 690 695 700
Ala Pro Gly Ser Phe Thr Lys Cys Ser Asn Thr Ser Glu Leu Lys Glu 705 710 715 720 Phe Val Asn Pro Ser Leu Pro Arg Glu Glu Lys Glu Glu Lys Leu Glu
725 730 735
Thr Val Lys Val Ser Asn Asn Ala Glu Asp Pro Lys Asp Leu Met Leu 740 745 750
Ser Gly Glu Arg Val Leu Gin Thr Glu Arg Ser Val Glu Ser Ser Ser
755 760 765
He Ser Leu Val Pro Gly Thr Asp Tyr Gly Thr Gin Glu Ser He Ser 770 775 780
Leu Leu Glu Val Ser Thr Leu Gly Lys Ala Lys Thr Glu Pro Asn Lys 785 790 795 800 Cys Val Ser Gin Cys Ala Ala Phe Glu Asn Pro Lys Gly Leu He His
805 810 815
Gly Cys Ser Lys Asp Asn Arg Asn Asp Thr Glu Gly Phe Lys Tyr Pro 820 825 830
Leu Gly His Glu Val Asn His Ser Arg Glu Thr Ser He Glu Met Glu 835 840 845 Glu Ser Glu Leu Asp Ala Gin Tyr Leu Gin Asn Thr Phe Lys Val Ser
850 855 860
Lys Arg Gin Ser Phe Ala Pro Phe Ser Asn Pro Gly Asn Ala Glu Glu 865 870 875 880
Glu Cys Ala Thr Phe Ser Ala His Ser Gly Ser Leu Lys Lys Gin Ser 885 890 895 Pro Lys Val Thr Phe Glu Cys Glu Gin Lys Glu Glu Asn Gin Gly Lys
900 905 910
Asn Glu Ser Asn He Lys Pro Val Gin Thr Val Asn He Thr Ala Gly 915 920 925
Phe Pro Val Val Gly Gin Lys Asp Lys Pro Val Asp Asn Ala Lys Cys 930 935 940
Ser He Lys Gly Gly Ser Arg Phe Cys Leu Ser Ser Gin Phe Arg Gly 945 950 955 960
Asn Glu Thr Gly Leu He Thr Pro Asn Lys His Gly Leu Leu Gin Asn
965 970 975 Pro Tyr Arg He Pro Pro Leu Phe Pro He Lys Ser Phe Val Lys Thr
980 985 990
Lys Cys Lys Lys Asn Leu Leu Glu Glu Asn Phe Glu Glu His Ser Met 995 1000 1005
Ser Pro Glu Arg Glu Met Gly Asn Glu Asn He Pro Ser Thr Val Ser 1010 1015 1020
Thr He Ser Arg Asn Asn He Arg Glu Asn Val Phe Lys Glu Ala Ser 1025 1030 1035 1040
Ser Ser Asn He Asn Glu Val Gly Ser Ser Thr Asn Glu Val Gly Ser 1045 1050 1055 Ser He Asn Glu He Gly Ser Ser Asp Glu Asn He Gin Ala Glu Leu
1060 1065 1070
Gly Arg Asn Arg Gly Pro Lys Leu Asn Ala Met Leu Arg Leu Gly Val 1075 1080 1085
Leu Gin Pro Glu Val Tyr Lys Gin Ser Leu Pro Gly Ser Asn Cys Lys 1090 1095 1100
His Pro Glu He Lys Lys Gin Glu Tyr Glu Glu Val Val Gin Thr Val 1105 1110 1115 1120
Asn Thr Asp Phe Ser Pro Tyr Leu He Ser Asp Asn Leu Glu Gin Pro 1125 1130 1135
Met Gly Ser Ser His Ala Ser Gin Val Cys Ser Glu Thr Pro Asp Asp 1140 1145 1150
Leu Leu Asp Asp Gly Glu He Lys Glu Asp Thr Ser Phe Ala Glu Asn 1155 1160 1165
Asp He Lys Glu Ser Ser Ala Val Phe Ser Lys Ser Val Gin Lys Gly 1170 1175 1180 Glu Leu Ser Arg Ser Pro Ser Pro Phe Thr His Thr His Leu Ala Gin
1185 1190 1195 1200
Gly Tyr Arg Arg Gly Ala Lys Lys Leu Glu Ser Ser Glu Glu Asn Leu 1205 1210 1215
Ser Ser Glu Asp Glu Glu Leu Pro Cys Phe Gin His Leu Leu Phe Gly 1220 1225 1230 Lys Val Asn Asn He Pro Ser Gin Ser Thr Arg His Ser Thr Val Ala
1235 1240 1245
Thr Glu Cys Leu Ser Lys Asn Thr Glu Glu Asn Leu Leu Ser Leu Lys 1250 1255 1260
Asn Ser Leu Asn Asp Cys Ser Asn Gin Val He Leu Ala Lys Ala Ser
1265 1270 1275 1280
Gin Glu His His Leu Ser Glu Glu Thr Lys Cys Ser Ala Ser Leu Phe 1285 1290 1295
Ser Ser Gin Cys Ser Glu Leu Glu Asp Leu Thr Ala Asn Thr Asn Thr 1300 1305 1310
Gin Asp Pro Phe Leu He Gly Ser Ser Lys Gin Met Arg His Gin Ser 1315 1320 1325
Glu Ser Gin Gly Val Gly Leu Ser Asp Lys Glu Leu Val Ser Asp Asp 1330 1335 1340
Glu Glu Arg Gly Thr Gly Leu Glu Glu Asn Lys Lys Ser Lys Ala Trp
1345 1350 1355 1360
He Gin Thr
(2) INFORMATION FOR SEQ ID NO:24:
(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1852 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:24:
Met Asp Leu Ser Ala Leu Arg Val Glu Glu Val Gin Asn Val He Asn 1 5 10 15
Ala Met Gin Lys He Leu Glu Cys Pro He Cys Leu Glu Leu He Lys 20 25 30 Glu Pro Val Ser Thr Lys Cys Asp His He Phe Cys Lys Phe Cys Met
35 40 45
Leu Lys Leu Leu Asn Gin Lys Lys Gly Pro Ser Gin Cys Pro Leu Cys 50 55 60
Lys Asn Asp He Thr Lys Arg Ser Leu Gin Glu Ser Thr Arg Phe Ser 65 70 75 80 Gin Leu Val Glu Glu Leu Leu Lys He He Cys Ala Phe Gin Leu Asp 85 90 95
Thr Gly Leu Glu Tyr Ala Asn Ser Tyr Asn Phe Ala Lys Lys Glu Asn 100 105 110
Asn Ser Pro Glu His Leu Lys Asp Glu Val Ser He He Gin Ser Met 115 120 125 Gly Tyr Arg Asn Arg Ala Lys Arg Leu Leu Gin Ser Glu Pro Glu Asn
130 135 140
Pro Ser Leu Gin Glu Thr Ser Leu Ser Val Gin Leu Ser Asn Leu Gly 145 150 155 160
Thr Val Arg Thr Leu Arg Thr Lys Gin Arg He Gin Pro Gin Lys Thr 165 170 175
Ser Val Tyr He Glu Leu Gly Ser Asp Ser Ser Glu Asp Thr Val Asn 180 185 190
Lys Ala Thr Tyr Cys Ser Val Gly Asp Gin Glu Leu Leu Gin He Thr 195 200 205
Pro Gin Gly Thr Arg Asp Glu He Ser Leu Asp Ser Ala Lys Lys Ala 210 215 220
Ala Cys Glu Phe Ser Glu Thr Asp Val Thr Asn Thr Glu His His Gin 225 230 235 240
Pro Ser Asn Asn Asp Leu Asn Thr Thr Glu Lys Arg Ala Ala Glu Arg 245 250 255
His Pro Glu Lys Tyr Gin Gly Ser Ser Val Ser Asn Leu His Val Glu 260 265 270
Pro Cys Gly Thr Asn Thr His Ala Ser Ser Leu Gin His Glu Asn Ser 275 280 285 Ser Leu Leu Leu Thr Lys Asp Arg Met Asn Val Glu Lys Ala Glu Phe
290 295 300
Cys Asn Lys Ser Lys Gin Pro Gly Leu Ala Arg Ser Gin His Asn Arg 305 310 315 320
Trp Ala Gly Ser Lys Glu Thr Cys Asn Asp Arg Arg Thr Pro Ser Thr 325 330 335
Glu Lys Lys Val Asp Leu Asn Ala Asp Pro Leu Cys Glu Arg Lys Glu 340 345 350
Trp Asn Lys Gin Lys Leu Pro Cys Ser Glu Asn Pro Arg Asp Thr Glu 355 360 365 Asp Val Pro Trp He Thr Leu Asn Ser Ser He Gin Lys Val Asn Glu
370 375 380
Trp Phe Ser Arg Ser Asp Glu Leu Leu Gly Ser Asp Asp Ser His Asp 385 390 395 400
Gly Glu Ser Glu Ser Asn Ala Lys Val Ala Asp Val Leu Asp Val Leu 405 410 415 Asn Glu Val Asp Glu Tyr Ser Gly Ser Ser Glu Lys He Asp Leu Leu
420 425 430
Ala Ser Asp Pro His Glu Ala Leu He Cys Lys Ser Glu Arg Val His 435 440 445
Ser Lys Ser Val Glu Ser Asn He Glu Asp Lys He Phe Gly Lys Thr
450 455 460 Tyr Arg Lys Lys Ala Ser Leu Pro Asn Leu Ser His Val Thr Glu Asn
465 470 475 480
Leu He He Gly Ala Phe Val Thr Glu Pro Gin He He Gin Glu Arg 485 490 495
Pro Leu Thr Asn Lys Leu Lys Arg Lys Arg Arg Pro Thr Ser Gly Leu 500 505 510
His Pro Glu Asp Phe He Lys Lys Ala Asp Leu Ala Val Gin Lys Thr 515 520 525
Pro Glu Met He Asn Gin Gly Thr Asn Gin Thr Glu Gin Asn Gly Gin 530 535 540 Val Met Asn He Thr Asn Ser Gly His Glu Asn Lys Thr Lys Gly Asp
545 550 555 560
Ser He Gin Asn Glu Lys Asn Pro Asn Pro He Glu Ser Leu Glu Lys 565 570 575
Glu Ser Ala Phe Lys Thr Lys Ala Glu Pro He Ser Ser Ser He Ser 580 585 590
Asn Met Glu Leu Glu Leu Asn He His Asn Ser Lys Ala Pro Lys Lys 595 600 605
Asn Arg Leu Arg Arg Lys Ser Ser Thr Arg His He His Ala Leu Glu 610 615 620 Leu Val Val Ser Arg Asn Leu Ser Pro Pro Asn Cys Thr Glu Leu Gin
625 630 635 640
He Asp Ser Cys Ser Ser Ser Glu Glu He Lys Lys Lys Lys Tyr Asn 645 650 655
Gin Met Pro Val Arg His Ser Arg Asn Leu Gin Leu Met Glu Gly Lys 660 665 670
Glu Pro Ala Thr Gly Ala Lys Lys Ser Asn Lys Pro Asn Glu Gin Thr 675 680 685
Ser Lys Arg His Asp Ser Asp Thr Phe Pro Glu Leu Lys Leu Thr Asn 690 695 700 Ala Pro Gly Ser Phe Thr Lys Cys Ser Asn Thr Ser Glu Leu Lys Glu
705 710 715 720
Phe Val Asn Pro Ser Leu Pro Arg Glu Glu Lys Glu Glu Lys Leu Glu 725 730 735
Thr Val Lys Val Ser Asn Asn Ala Glu Asp Pro Lys Asp Leu Met Leu 740 745 750 Ser Gly Glu Arg Val Leu Gin Thr Glu Arg Ser Val Glu Ser Ser Ser
755 760 765
He Ser Leu Val Pro Gly Thr Asp Tyr Gly Thr Gin Glu Ser He Ser 770 775 780
Leu Leu Glu Val Ser Thr Leu Gly Lys Ala Lys Thr Glu Pro Asn Lys
785 790 795 800 Cys Val Ser Gin Cys Ala Ala Phe Glu Asn Pro Lys Gly Leu He His
805 810 815
Gly Cys Ser Lys Asp Asn Arg Asn Asp Thr Glu Gly Phe Lys Tyr Pro- 820 825 830
Leu Gly His Glu Val Asn His Ser Arg Glu Thr Ser He Glu Met Glu 835 840 845
Glu Ser Glu Leu Asp Ala Gin Tyr Leu Gin Asn Thr Phe Lys Val Ser 850 855 860
Lys Arg Gin Ser Phe Ala Pro Phe Ser Asn Pro Gly Asn Ala Glu Glu
865 870 875 880 Glu Cys Ala Thr Phe Ser Ala His Ser Gly Ser Leu Lys Lys Gin Ser
885 890 895
Pro Lys Val Thr Phe Glu Cys Glu Gin Lys Glu Glu Asn Gin Gly Lys 900 905 910
Asn Glu Ser Asn He Lys Pro Val Gin Thr Val Asn He Thr Ala Gly 915 920 925
Phe Pro Val Val Gly Gin Lys Asp Lys Pro Val Asp Asn Ala Lys Cys 930 935 940
Ser He Lys Gly Gly Ser Arg Phe Cys Leu Ser Ser Gin Phe Arg Gly 945 950 955 960 Asn Glu Thr Gly Leu He Thr Pro Asn Lys His Gly Leu Leu Gin Asn
965 970 975
Pro Tyr Arg He Pro Pro Leu Phe Pro He Lys Ser Phe Val Lys Thr 980 985 990
Lys Cys Lys Lys Asn Leu Leu Glu Glu Asn Phe Glu Glu His Ser Met 995 1000 1005
Ser Pro Glu Arg Glu Met Gly Asn Glu Asn He Pro Ser Thr Val Ser 1010 1015 1020
Thr He Ser Arg Asn Asn He Arg Glu Asn Val Phe Lys Glu Ala Ser 1025 1030 1035 1040 Ser Ser Asn He Asn Glu Val Gly Ser Ser Thr Asn Glu Val Gly Ser
1045 1050 1055
Ser He Asn Glu He Gly Ser Ser Asp Glu Asn He Gin Ala Glu Leu 1060 1065 1070
Gly Arg Asn Arg Gly Pro Lys Leu Asn Ala Met Leu Arg Leu Gly Val 1075 1080 1085 Leu Gin Pro Glu Val Tyr Lys Gin Ser Leu Pro Gly Ser Asn Cys Lys
1090 1095 1100
His Pro Glu He Lys Lys Gin Glu Tyr Glu Glu Val Val Gin Thr Val 1105 1110 1115 1120
Asn Thr Asp Phe Ser Pro Tyr Leu He Ser Asp Asn Leu Glu Gin Pro 1125 1130 1135 Met Gly Ser Ser His Ala Ser Gin Val Cys Ser Glu Thr Pro Asp Asp
1140 1145 1150
Leu Leu Asp Asp Gly Glu He Lys Glu Asp Thr Ser Phe Ala Glu Asn 1155 1160 1165
Asp He Lys Glu Ser Ser Ala Val Phe Ser Lys Ser Val Gin Lys Gly 1170 1175 1180
Glu Leu Ser Arg Ser Pro Ser Pro Phe Thr His Thr His Leu Ala Gin 1185 1190 1195 1200
Gly Tyr Arg Arg Gly Ala Lys Lys Leu Glu Ser Ser Glu Glu Asn Leu 1205 1210 1215 Ser Ser Glu Asp Glu Glu Leu Pro Cys Phe Gin His Leu Leu Phe Gly
1220 1225 1230
Lys Val Asn Asn He Pro Ser Gin Ser Thr Arg His Ser Thr Val Ala 1235 1240 1245
Thr Glu Cys Leu Ser Lys Asn Thr Glu Glu Asn Leu Leu Ser Leu Lys 1250 1255 1260
Asn Ser Leu Asn Asp Cys Ser Asn Gin Val He Leu Ala Lys Ala Ser 1265 1270 1275 1280
Gin Glu His His Leu Ser Glu Glu Thr Lys Cys Ser Ala Ser Leu Phe 1285 1290 1295 Ser Ser Gin Cys Ser Glu Leu Glu Asp Leu Thr Ala Asn Thr Asn Thr
1300 1305 1310
Gin Asp Pro Phe Leu He Gly Ser Ser Lys Gin Met Arg His Gin Ser 1315 1320 1325
Glu Ser Gin Gly Val Gly Leu Ser Asp Lys Glu Leu Val Ser Asp Asp 1330 1335 1340
Glu Glu Arg Gly Thr Gly Leu Glu Glu Asn Asn Gin Glu Glu Gin Ser 1345 1350 1355 1360
Met Asp Ser Asn Leu Gly Glu Ala Ala Ser Gly Cys Glu Ser Glu Thr 1365 1370 1375
Ser Val Ser Glu Asp Cys Ser Gly Leu Ser Ser Gin Ser Asp He Leu 1380 1385 1390
Thr Thr Gin Gin Arg Asp Thr Met Gin His Asn Leu He Lys Leu Gin 1395 1400 1405
Gin Glu Met Ala Glu Leu Glu Ala Val Leu Glu Gin His Gly Ser Gin 1410 1415 1420 Pro Ser Asn Ser Tyr Pro Ser He He Ser Asp Ser Ser Ala Leu Glu 1425 1430 1435 1440
Asp Leu Arg Asn Pro Glu Gin Ser Thr Ser Glu Lys Ala Val Leu Thr 1445 1450 1455
Ser Gin Lys Ser Ser Glu Tyr Pro He Ser Gin Asn Pro Glu Gly Leu 1460 1465 1470 Ser Ala Asp Lys Phe Glu Val Ser Ala Asp Ser Ser Thr Ser Lys Asn
1475 1480 1485
Lys Glu Pro Gly Val Glu Arg Ser Ser Pro Ser Lys Cys Pro Ser Leu 1490 1495 1500
Asp Asp Arg Trp Tyr Met His Ser Cys Ser Gly Ser Leu Gin Asn Arg 1505 1510 1515 1520
Asn Tyr Pro Ser Gin Glu Glu Leu He Lys Val Val Asp Val Glu Glu 1525 1530 1535
Gin Gin Leu Glu Glu Ser Gly Pro His Asp Leu Thr Glu Thr Ser Tyr 1540 1545 1550
Leu Pro Arg Gin Asp Leu Glu Gly Thr Pro Tyr Leu Glu Ser Gly He 1555 1560 1565
Ser Leu Phe Ser Asp Asp Pro Glu Ser Asp Pro Ser Glu Asp Arg Ala 1570 1575 1580
Pro Glu Ser Ala Arg Val Gly Asn He Pro Ser Ser Thr Ser Ala Leu 1585 1590 1595 1600
Lys Val Pro Gin Leu Lys Val Ala Glu Ser Ala Gin Ser Pro Ala Ala 1605 1610 1615
Ala His Thr Thr Asp Thr Ala Gly Tyr Asn Ala Met Glu Glu Ser Val 1620 1625 1630 Ser Arg Glu Lys Pro Glu Leu Thr Ala Ser Thr Glu Arg Val Asn Lys
1635 1640 1645
Arg Met Ser Met Val Val Ser Gly Leu Thr Pro Glu Glu Phe Met Leu 1650 1655 1660
Val Tyr Lys Phe Ala Arg Lys His His He Thr Leu Thr Asn Leu He 1665 1670 1675 1680
Thr Glu Glu Thr Thr His Val Val Met Lys Thr Asp Ala Glu Phe Val 1685 1690 1695
Cys Glu Arg Thr Leu Lys Tyr Phe Leu Gly He Ala Gly Gly Lys Trp 1700 1705 1710 Val Val Ser Tyr Phe Trp Val Thr Gin Ser He Lys Glu Arg Lys Met
1715 1720 1725
Leu Asn Glu His Asp Phe Glu Val Arg Gly Asp Val Val Asn Gly Arg 1730 1735 1740
Asn His Gin Gly Pro Lys Arg Ala Arg Glu Ser Gin Asp Arg Lys He
1745 1750 1755 1760 Phe Arg Gly Leu Glu He Cys Cys Tyr Gly Pro Phe Thr Asn Met Pro 1765 1770 1775
Thr Asp Gin Leu Glu Trp Met Val Gin Leu Cys Gly Ala Ser Val Val 1780 1785 1790
Lys Glu Leu Ser Ser Phe Thr Leu Gly Thr Gly Val His Pro He Val 1795 1800 1805 Val Val Gin Pro Asp Ala Trp Thr Glu Asp Asn Gly Phe His Ala He
1810 1815 1820
Gly Gin Met Cys Glu Ala Pro Val Val Thr Arg Glu Trp Val Leu Asp 1825 1830 1835 1840
Ser Val Ala Leu Tyr Gin Cys Gin Glu Leu Asp Thr 1845 1850

Claims

WHAT IS C ATMFT) TS:
1. An isolated nucleic acid comprising BRCAl allele #5803 (SEQ ID NO:l), 9601 (SEQ ID NO:2), 9815 (SEQ ID NO:3), 8403 (SEQ ID NO:4), 8203 (SEQ ID NO:5), 388 (SEQUENCE ID NO:6), 6401 (SEQ ID NO:7), 4406 (SEQ ID NO:8), 10201 (SEQ ID NO:9), 7408 (SEQ ID NO: 10), 582 (SEQ ID NO: 11) or 77 (SEQ ID NO: 12), or a fragment thereof, wherein said fragment is capable of specifically hybridizing with said allele in the presence of wild-type BRCAl under stringent conditions.
2. An isolated translation product of BRCAl allele #5803 (SEQ ID NO: 13), 9601 (SEQ ID NO: 14), 9815 (SEQ ID NO: 15), 8203 (SEQ ID NO:17), 388 (SEQ ID NO: 18), 6401
(SEQ ID NO: 19), 4406 (SEQ ID NO:20), 10201 (SEQ ID NO:21), 7408 (SEQ ID NO:22), 582 (SEQ ID NO:23) or 77 (SEQ ID NO:24), or a C-terminus fragment thereof, or #8403 (SEQ ID NO: 16), or a fragment thereof comprising Gly at position 61.
3. A method of diagnosing a patient for a cancer susceptibility, said method comprising the steps of: isolating from said patient a first nucleic acid comprising at least one BRCAl allele or fragment thereof; contacting said sample with a second nucleic acid according to claim 1 under conditions whereby said second nucleic acid is capable of specifically hybridizing with said first nucleic acid; detecting the presence or absence of specific hybridization of said second nucleic acid with said first nucleic acid; wherein the presence of specific hybridization of said second nucleic acid to said first nucleic acid is diagnostic of a cancer susceptibility.
4. A method of diagnosing a patient for a cancer susceptibility, said method comprising the steps of: isolating from said patient a composition comprising a first translation product of at least one BRCAl allele; contacting said first translation product with a reagent specific for a protein or C- terminal fragment thereof according to claim 2 under conditions wherein said reagent is capable of specifically binding said second translation product; detecting the presence or absence of specifically bound complexes of said reagent and said first translation product; wherein the presence of said complexes correlates with a cancer susceptibility.
PCT/US1996/005621 1995-04-19 1996-04-19 Genetic markers for breast and ovarian cancer WO1996033271A2 (en)

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CA002217668A CA2217668C (en) 1995-04-19 1996-04-19 Genetic markers for breast and ovarian cancer
DE69633664T DE69633664T2 (en) 1995-04-19 1996-04-19 GENETIC MARKERS FOR CHEST AND EGG CANCER
EP96913045A EP0821733B1 (en) 1995-04-19 1996-04-19 Genetic markers for breast and ovarian cancer
AT96913045T ATE280226T1 (en) 1995-04-19 1996-04-19 GENETIC MARKERS FOR BREAST AND Ovarian CANCER
AU55668/96A AU698800B2 (en) 1995-04-19 1996-04-19 Genetic markers for breast and ovarian cancer

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JPH11503915A (en) 1999-04-06
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CA2217668C (en) 1999-11-16
ATE280226T1 (en) 2004-11-15
US5821328A (en) 1998-10-13
CA2217668A1 (en) 1996-10-24
US5622829A (en) 1997-04-22
WO1996033271A3 (en) 1997-03-20
DE69633664D1 (en) 2004-11-25
EP0821733A2 (en) 1998-02-04
EP0821733B1 (en) 2004-10-20
DE69633664T2 (en) 2006-02-23
ES2231808T3 (en) 2005-05-16
AU5566896A (en) 1996-11-07

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