AU5417201A - Polycystic kidney disease gene - Google Patents

Description

Regulation 3.2

AUSTRALIA

Patents Act 1990 DIVISIONAL APPLICATION r e Name of Applicant: Actual Inventor(s): Address for Service: Invention Title: Genzyme Corporation AND Johns Hopkins University KLINGER, Katherine; BURN, Timothy; CONNORS, Timothy; DACKOWSKI, William; GERMINO, Gregory and QIAN,Feng C. c- cO DAVIES COLLISON CAVE, Patent Attorneys, Level 3, 303 Coronation Drive, Milton, Queensland, 4064, Australia "Polycystic kidney disease gene" Details of Parent Application No: 32119/97 The following statement is a full description of this invention, including the best method of performing it known to me/us: Q:\opcr\Vpa\July 2001\2432061 divisional Genzym.183.doc 2/7/01 POLYCYSTIC KIDNEY DISEASE

GENE

This application is a continuation-in-part of U.S.

patent application Serial No. 08/381,520, filed January 31, 1995.

FIELD OF THE INVENTION The present invention pertains to the diagnosis and treatment of polycystic kidney disease in humans, using DNA sequences derived from the human PKD1 gene and the protein or proteins encoded by that gene.

BACKGROUND OF THE INVENTION Autosomal dominant polycystic kidney disease (APKD), also called adult-onset polycystic kidney disease, is one of the most common hereditary disorders in humans, 20 affecting approximately one individual in a thousand. The prevalence in the United States is greater than 500,000, with 6,000 to 7,000 new cases detected yearly (Striker et al., Am.

*T

J. Nephrol., 6:161-164, 1986; Iglesias et al., Am. J. Kid.

Dis., 2:630-639, 1983). The disease is considered to be a systemic disorder, characterized by cyst formation in the ductal organs such as kidney, liver, and pancreas, as well as by gastrointestinal, cardiovascular, and musculoskeletal abnormalities, including colonic diverticulitis, berry aneurysms, hernias, and mitral valve prolapse (Gabow et al., 30 Adv. Nephrol., 18:19-32, 1989; Gabow, New Eng. J. Med., 329:332-342, 1993).

The most prevalent and obvious symptom of APKD, however, is the formation of kidney cysts, which result in grossly enlarged kidneys and a decrease in renalconcentrating ability. Hypertension and endocrine abnormalities are also common in APKD patients, appearing even before symptoms of renal insufficiency. In approximately half of APKD patients, the disease progresses to end-stage renal disease; accordingly, APKD is responsible for 4-8% of the renal dialysis and transplantation cases in the United States and Europe (Proc. European Dialysis and Transplant Assn., Robinson and Hawkins, eds., 17:20, 1981).

Thus, there is a need in the art for diagnostic and therapeutic tools to reduce the incidence and severity of this disease.

APKD exhibits a transmission pattern typical of autosomal dominant inheritance, each offspring of an affected individual has a 50% chance of inheriting the causative gene. Linkage studies indicated that a causative gene is present on the short arm of chromosome 16, near the a-globin cluster; this locus was designated PKD1 (Reeders et S 20 al., Nature, 317:542, 1985). Though other PKD-associated genes exist, such as, for example, PKD2, PKD1 defects appear to cause APKD in about 85-90% of affected families (Parfrey et al., New Eng. J. Med., 323:1085-1090, 1990; Peters et al., Contrib. Nephrol., 97:128-139, 1992).

SThe PKD1 gene has been localized to chromosomal position 16p13.3. Using extensive linkage analysis, in conjunction with the identification of new markers and restriction enzyme analysis, the gene has been further localized to an interval of approximately 700 kb between the markers ATPL (ATP6C) and CMM65 (D16S84). The region is rich in CpG islands that are thought to flank transcribed sequences, and it has been estimated that this interval contains at least 20 genes. The precise location of the PKD1 gene was pinpointed by the finding of a PKD family whose affected members carry a translocation that disrupts a 14 kb RNA transcript associated with this region, as reported in the European PKD Consortium (EPKDC), Cell, 77:881, 1994, describing approximately 5631 bp of DNA sequence corresponding to the 3' end of the putative PKD1 cDNA sequence.

Notwithstanding knowledge of the partial PKD1 3' cDNA sequence, several significant impediments stand in the way of determining the complete sequence of the PKD1 gene.

For the most part, these impediments arise from the complex organization of the PKD1 locus. One serious obstacle is that sequences related to the PKD1 transcript are duplicated at least three times on chromosome 16 proximal to the PKD1 locus, forming PKD1 homologues. Another obstacle is that the PKD1 genomic interval also contains repeat elements that are present in other genomic regions. Both of these types of sequence duplications interfere with "chromosome walking" 20 techniques that are widely used for identification of genomic DNA. This is because these techniques rely on hybridization to identify clones containing overlapping fragments of genomic DNA; thus, there is a high likelihood of "walking" into clones derived from PKD1 homologues instead of clones derived from the authentic PKD1 gene. In a similar manner, the PKD1 duplications and chromosome 1 6 -specific repeats also interfere with the unambiguous determination of a complete cDNA sequence that encodes the PKD1 protein. Thus, there is a need in the art for genomic and cDNA sequences corresponding to the authentic PKD1 gene. This includes identification of segments of these sequences that are unique to the expressed PKD1 and not are present in the duplicated homologous sequences also present on chromosome 16.

SUMMARY OF THE INVENTION The present invention involves an isolated normal human PKD1 gene having the sequence set forth in Figure 1, sequences derived therefrom such as the sequence set forth in Figure 2, an isolated nucleic acid having the PKD1 cDNA sequence set forth in Figure 3, and sequences derived therefrom. The PKD1 gene is a genomic DNA sequence whose altered, defective, or non-functional expression leads to adult-onset polycystic kidney disease. The invention also encompasses DNA vectors comprising these nucleic acids, cells transformed with the vectors, and methods for producing PKD1 protein or fragments thereof.

In another aspect, the invention involves isolated oligonucleotides that hybridize only to the authentic expressed PKD1 gene, and not to PKD1 homologues.

20 In yet another aspect, the invention involves isolated mutant PKD1 genes, and their cDNA cognates, which contain alterations in nucleotide sequence relative to the normal PKD1 gene, and whose presence in one or more copies in the genome of a human individual is associated with adultonset polycystic kidney disease.

In still another aspect, the invention involves isolated oligonucleotides that discriminate between normal and mutant versions of the PKD1 gene.

In still another aspect, the invention involves methods for identifying a human subject carrying a mutant PKD1 gene in a human subject, comprising: a) obtaining a sample of biological material from the subject, and b) detecting the presence of the mutant gene or its protein product.

In still another aspect, the invention involves methods and compositions for treating APKD or disease conditions having the characteristics of APKD. Such methods encompass administering an isolated human PKD1 gene, or fragments of the gene, under conditions that result in expression of therapeutically effective amounts of all, or part of, the PKD1 protein. The invention also encompasses compositions for treating APKD that comprise all or part of the PKD1 DNA of Figures 1, 2 and 3, or the PKD1 protein encoded by the DNA of Figures 1, 2 or 3.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1A shows the DNA sequence of the human PKD1 locus between chromosomal markers ATPL (ATP6C) and D16S84.

(SEQ ID NO:1).

Figure 1B shows the DNA sequence of 53,526 bases comprising the normal human PKD1 gene. (SEQ ID NO:2).

Figure 2 shows a partial DNA sequence of 894 bases within the 5' region of normal human PKD1 DNA. (SEQ ID NO:3) Figure 3 shows the full-length sequence of normal human PKD1 cDNA and corresponding amino acid sequence.

(SEQ

ID Figure 4A shows a comparison of the DNA sequence of the 5' region of DNAs derived from the authentic PKD1 gene (SEQ ID NO:19) and PKD1 homologues (SEQ ID NO:18). A 2 9 -base pair gap must be introduced into the sequence of the authentic gene to align the two sequences. In addition, the authentic PKD1 and the PKD1 homologue differ at position 418 of this figure.

Figure 4B shows the DNA sequence of an oligonucleotide that can be used to discriminate between the authentic PKD1 sequence and PKD1 homologues. The star denotes a polymerization-blocking modification. (SEQ ID Figure 5 shows the region of chromosome 16 containing the PKD1 locus. The upper panel shows NotI restriction sites, as well as previously identified genetic markers in this region. The bottom panel shows P1 clones covering this region.

20 Figure 6 shows the restriction map of the 91.8B P1 clone containing the PKD1 gene and flanking regions with only the relevant sites indicated (B=BamHI, C=SacI, E=EcoRI, N=NotI, S=SalI, X=XhoI and V=EcoRV). The NotI site in parenthesis is methylated in genomic DNA. The position of 25 the 1.9 kb BamHI-BamHI fragment is shown by the shaded box, the striped box denotes the location of the 2.5 kb polypurine/polypyrimidine tract. The arrows indicate the position and orientation of the next most centromeric transcript (NCT), TSC-2 and PKD1 genes. The location of relevant cosmid clones is shown by open boxes. Restriction fragments used to generate sequencing templates are shown at the bottom with quotation marks denoting that the site is vector derived. Pools used in fluorescence in situ hybridization (FISH) are indicated by brackets at the bottom.

Figure 7 shows a comparison between the previously reported (EPKDC) partial PKD1 cDNA (SEQ ID NOS:20, 21, 24, 25,28 and 29) sequence and the sequence reported herein (SEQ ID NOS: 22,23,26, 27, 30 and 31). The upper sequence is that reported for the cDNA (EPKDC), while the lower sequence is the genomic sequence of the present invention. Discrepancies are highlighted by lower case in the cDNA (EPKDC) sequence and by boxes in the genomic sequence with the corresponding changes in amino acids denoted with X's. The altered carboxy-terminal residues resulting from the frame shift are shown above the genomic sequence and the previously predicted residues are shown in lowercase. An in-frame termination codon is indicated by an underline in the genomic sequence.

Figure 8 shows an illustration of the PKD1 genomic structure as predicted by GRAIL2. The predicted exons are represented as boxes along the genomic sequence. The reported cDNA is at the top right. The position of the 20 kb GC-rich region is indicated by the striped box at the bottom. The stippled box above exons 3 and 4 in the gene model indicate the position of the predicted LRR and carboxy-flanking region. The extent of the published cDNA is shown by the open (coding region) and cross hatched boxes (3' untranslated region). The filled black box indicates the e. relative position of the exon which was absent in the o" predicted gene model, while the asterisk designates the exon which contains an unspliced intron. The position of the kb GC-rich region is marked by the striped box below the 30 GC-content bar.

Figure 9 shows a schematic structure of the predicted PKD1 protein. Multiple domains are depicted based on sequence homology including two copies of a leucine-rich repeat (LRR) near the N-terminal which is flanked by a cysteine-rich cluster Three perfect copies and 12 related copies of a domain of unknown function (Pmel-17 or Ig-like repeat) are shown. The predicted 7 (or more) membrane-spanning domains are indicated. The exons encoding the various domains are listed.

Figure 10 shows the RT-PCR and cDNA products comprising the PKD1 cDNA. The EPKDC 3' cDNA sequence is shown by the striped box. The full-length cDNA is shown in black. Shaded boxes denote individual cDNAs and RT-PCR products. The cross hatched box denotes the RT-PCR products containing alternatively spliced exons and an unspliced exon which do not maintain the open reading frame. Alternatively spliced exons and insertions are designated by thin lines and inverted triangles, respectively. Open boxes designate the position of open reading frames. The stippled box denotes the 5' untranslated region.

20 Figure 11 shows a schematic structure of the full length PKD1 cDNA in pCMV-SPORT vector. Thin line represents PKD1 cDNA with restriction sites used to assemble individual ScDNA clones. Thick line represents pCMV-SPORT vector which :contains SP6 and T7 RNA polymerase promoters to generate

RNA

for in vitro translations, CMV promoter, SV40 origin of replication and polyadenylation signal for expression in mammalian cells.

Figure 12 shows a schematic of the full-length PKD1 30 product and its truncated products. Black box represents signal peptide Leucine rich repeat (LRR) and Ig-like (Ig-like) domains are indicated by shaded boxes. The eleven predicted transmembrane regions are also indicated by black bars and numbered.

Figure 13 shows regions of homology in the PKD1 gene between sequences encoded by GRAIL2-predicted exons and proteins present in SwissProt and PIR databases. (SEQ ID NOS: 32-55). Positions where the PKD1 sequence matches the consensus sequence are shaded.

Figure 14 shows the results of exon trapping within the PKD1 locus.

Figure 15 shows the regions of PKD1 protein used as fusion proteins for generation of domain specific polyclonal antibodies. The predicted structure of the PKD1 protein is shown above. Each fusion protein consists of the carrier glutathione-S-transferase (GST) or maltose binding protein (MBP) and the indicated region of PKD1 polypeptide. PKD1 corresponding residues of each fusion protein are shown.

Figure 16 shows the two constructs used for 20 immunoprecipitation, SrfIA, which corresponds to the N-terminal half of the PKD1 protein and BRASH 7, which corresponds to the C-terminal half of the PKD1 protein as shown. Epitopes for anti-fusion proteins FP-LRR, FP-46-lc and FP-46-2 polyclonal antibodies used for immunoprecipitations are also indicated.

DETAILED DESCRIPTION OF THE INVENTION All patent applications, patents, and literature references cited in this specification are hereby incorporated by reference in their entirety. In case of conflict or inconsistency, the present description, including definitions, will control.

Definitions: 1. "APKD" as used herein denotes adult-onset polycystic kidney disease, which is characterized by the development of renal cysts and, ultimately, renal failure, and may alternatively or in addition involve cysts in other organs including liver and spleen, as well as gastrointestinal, cardiovascular, and musculoskeletal abnormalities.

2. The term "PKDI gene" refers to a genomic

DNA

sequence which maps to chromosomal position 16p13.3 and gives rise to a messenger RNA molecule encoding the PKDl protein.

The PKDI gene encompasses the sequences shown in Figures 1 and 2, which includes introns and putative.regulatory sequences. The term "authentic" is used herein to denote the 20 genomic sequence at this location, as well as sequences derived therefrom, and serves to distinguish these authentic sequences from "PKDI homologues" (see below).

3. "PKDI complementary DNA (cDNA)" is defined herein as a single-stranded or double-stranded intronless

DNA

molecule encompassing the sequence shown in Figure 3, that is derived from the authentic PKDI gene and whose sequence, or complement thereof, encodes the PKDl protein shown in Figure 3.

4. A "normal" PKDI gene is defined herein as a PKD1 gene whose altered, defective, or non-functional expression leads to adult-onset polycystic kidney disease.

A

normal PKDI gene is not associated with disease and thus is considered to be a wild-type version of the gene. Included in this category are allelic variants in the PKD1 gene, also denoted allelic polymorphisms, i.e. alternate versions of the PKD1 gene, not associated with disease, that may be represented at any frequency in the population. Also included are alterations in DNA sequence, whether recombinant or naturally occurring, that have no apparent effect on expression or function of the PKD1 gene product.

5. A "mutant" PKD1 gene is defined herein as a PKD1 gene whose sequence has been modified by transitions, transversions, deletions, insertions, or other modifications relative to the normal PKD1 gene, which modifications cause detectable changes in the expression or function of the PKD1 gene product, including causing disease. The modifications may involve from one to as many as several thousand nucleotides, and result in one or more of a variety of changes in PKD1 gene expression, such as, for example, decreased or increased rates of expression, or expression of 20 a defective RNA transcript or protein product. Mutant PKD1 genes encompass those genes whose presence in one or more copies in the genome of a human individual is associated with

APKD.

6. A "PKD1 homologue" is a sequence which is o* closely related to PKD1, but which does not encode the authentic expressed PKD1 gene product. Several examples of such homologues that map to chromosomal location 16p13.1 have been identified and sequenced by the present inventors.

7. A "PKD 1 carrier" is defined herein as an individual who carries at least one copy of a diseaseproducing mutant PKD1 gene. Since the disease generally exhibits an autosomal dominant pattern of transmission, PKD1 carriers have a high probability of developing some symptom of PKD. Thus, a PKD1 carrier is likely to be a "PKD patient." 8. As referred to herein, a "contig" is a continuous stretch of DNA or DNA sequence, which may be represented by multiple, overlapping, clones or sequences.

9. As referred to herein, a "cosmid" is a DNA plasmid that can replicate in bacterial cells and that accommodates large DNA inserts from about 30 to about 45 kb in length.

The term "P1 clones" refers to genomic DNAs cloned into vectors based on the P1 phage replication mechanisms. These vectors generally accommodate inserts of about 70 to about 105 kb (Pierce et al., Proc. Natl. Acad.

Sci., USA, 89:2056-2060, 1992).

20 11. As used herein, the term "exon trapping" refers to a method for isolating genomic DNA sequences that are flanked by donor and acceptor splice sites for RNA processing.

12. The term "single-strand conformational polymorphism analysis" (SSCP) refers to a method for detecting sequence differences between two DNAs, comprising hybridization of the two species with subsequent mismatch *o detection by gel electrophoresis. (Ravnik-Glavac et al., Hum.

30 Mol. Genet., 3:801, 1994).

13. "HOT cleavage" is defined herein as a method for detecting sequence differences between two DNAs, comprising hybridization of the two species with subsequent mismatch detection by chemical cleavage (Cotton, et al., Proc. Natl. Acad. Sci., USA, 85:4397, 1988).

14. "Denaturing gradient gel electrophoresis" (DDGE) refers to a method for resolving two DNA fragments of identical length on the basis of sequence differences as small as a single base pair change, using electrophoresis through a gel containing varying concentrations of denaturant (Guldberg et al., Nuc. Acids Res., 22:880, 1994).

As used herein, "sequence-specific oligonucleotides" refers to related sets of oligonucleotides that can be used to detect allelic variations or mutations in the PKD1 gene.

16. As used herein, "PKD1-specific oligonucleotides" refers to oligonucleotides that hybridize to sequences present in the authentic expressed PKD1 gene and not to PKD1 homologues or other sequences.

17. "Amplification" of DNA as used herein denotes a reaction that serves to increase the concentration of a particular DNA sequence within a mixture of DNA sequences.

Amplification may be carried out using polymerase chain 25 reaction (PCR) (Saiki et al., Science, 239:487, 1988), ligase chain reaction (LCR), nucleic acid-specific based amplification (NSBA), or any method known in the art.

18. "RT-PCR" as used herein refers to coupled 30 reverse transcription and polymerase chain reaction. This method of amplification uses an initial step in which a specific oligonucleotide, oligo dT, or a mixture of random primers is used to prime reverse transcription of RNA into single-stranded cDNA; this cDNA is then amplified using standard amplification techniques e.g. PCR.

19. A PKDl gene or PKDI cDNA, whether normal or mutant, corresponding to a particular sequence is understood to include alterations in the particular sequence that do not change the inherent properties of the sequence. It will be understood that additional nucleotides may be added to the and/or terminus of the PKDI gene shown in Figure

IB,

or the PKD1 cDNA shown in Figure 3, as part of routine recombinant DNA manipulations. Furthermore, conservative

DNA

substitutions, i.e. changes in the sequence of the proteincoding region that do not change the encoded amino acid sequence, may also be accommodated.

The present invention encompasses the human gene for PKD1. Mutations in this gene are associated with the occurrence of adult-onset polycystic kidney disease.

A

"normal" version of the genomic sequence, corresponding to 20 53,526 bases of the PKD1 gene is shown in Figure lB.

The PKDl gene sequence was determined using the ."strategy described in Example 1. Briefly, a series of cosmid and P1 DNA clones was assembled containing overlapping human 25 genomic DNA sequences that collectively cover a 700 kilobase segment of chromosome 16 known to contain the PKDI locus. To identify transcribed sequences within this 700 kb segment, including those sequences encoding PKD1, both exon trapping and cDNA selection techniques were employed. At the same time, direct DNA sequencing of the human DNA sequences contained in the genomic clones was performed, using techniques that are well-known in the art. These included the isolation of subclones from particular cosmid or P1 clones. Nested deletions were created from selected subclones, and the nested deletions were then subjected to direct DNA sequencing using the ALFm automated sequencer (Pharmacia, Uppsala, Sweden).

The full-length sequence of PKD1 cDNA is shown in Figure 3.

The present invention encompasses isolated oligonucleotides corresponding to sequences within the PKD1 gene, or within PKD1 cDNA, which, alone or together, can be used to discriminate between the authentic expressed PKD1 gene and PKD1 homologues or other repeated sequences. These oligonucleotides may be from about 12 to about 60 nucleotides in length, preferably about 18 nucleotides, may be single- or double-stranded, and may be labelled or modified as described below. An example of an oligonucleotide that can be used in this manner is shown in Figure 4B. The discrimination function of this oligonucleotide is based on a comparison of the sequence of the authentic PKD1 gene with three cDNAs 20 derived from the PKD1 homologues, which revealed that o homologue cDNAs contain a 29 bp insertion relative to the e authentic PKD1 sequence (Figure 4A). The oligonucleotide shown in Figure 4B is modified at its 3' terminus so that it does not support polymerization reactions, and is designed to hybridize specifically to the homologue sequence and not to oo.*g the authentic PKD1 sequence. When this oligonucleotide is included in amplification reactions, it selectively prevents the amplification of PKD1 homologue sequences. In this *°oo manner, authentic PKD1 sequences are selectively amplified 30 and PKD1 homologues are not. These oligonucleotides or their functional equivalents thus provide a basis for testing for the presence of mutations in the authentic PKD1 gene in a human patient (see Example 5 below).

The present invention encompasses isolated DNA and RNA sequences, including sense and antisense sequences, derived from the sequences shown in Figures 1, 2, and 3. The particular sequences may represent "normal" alleles of PKD1, including allelic variants, or "mutant" alleles, which are associated with disease symptoms. PKD1-derived sequences may also be associated with heterologous sequences, including promoters, enhancers, response elements, signal sequences, polyadenylation sequences, and the like. Furthermore, the nucleic acids can be modified to alter stability, solubility, binding affinity, and specificity. For example, PKD1-derived sequences can be selectively methylated.

The DNA may comprise antisense oligonucleotides and may further include nuclease-resistant phosphorothioate, phosphoroamidate, and methylphosphonate derivatives, as well as "protein nucleic acid" (PNA) formed by conjugating bases to an amino acid backbone as described in Nielsen et al., Science, 254: 1497, 1991. The DNA may be derivatized by linkage of the a-anomer nucleotide, or by formation of a methyl or ethyl phosphotriester or an alkyl phosphoramidate linkage. Furthermore, the nucleic acid sequences of the present invention may also be modified with a label capable of providing a detectable signal, either directly or 25 indirectly. Exemplary labels include radioisotopes, fluorescent molecules, biotin, and the like.

In general, nucleic acid manipulations according to the present invention use methods that are well known in the 30 art, as disclosed in, for example, Molecular Cloning,

A

.Laboratory Manual (2nd Ed., Sambrook, Fritsch and Maniatis, Cold Spring Harbor), or Current Protocols in Molecular Biology (Eds. Ausubel, Brent, Kingston, More, Feidman, Smith and Struhl, Greene Publ. Assoc., Wiley-Interscience, NY, NY, 1992).

The invention also provides vectors comprising nucleic acids having PKDI or PKDl-related sequences A large number of vectors, including plasmid, phage, viral and fungal vectors, have been described for expression in a variety of eukaryotic and prokaryotic hosts, and may be used for gene therapy as well as for simple protein expression.

Advantageously, vectors may also include a promoter operably linked to the PKDI- encoding portion, particularly when the PKDl-encoding portion comprises the cDNA shown in Figure 3 or derivatives or fragments thereof. The encoded PKDI may be expressed by using any suitable vectors, such as pREP4, pREPS, or pCEP4 (InVitrogen, San Diego, CA), and any suitable host cells, using methods disclosed or cited herein.or otherwise known to those skilled in the relevant art. The particular choice of vector/host is not critical to the operation of the invention.

Recombinant cloning vectors will often include one or more replication systems for cloning or expression, one or more markers for selection in the host, e.g. antibiotic resistance,, and one or more expression cassettes. The inserted PKDI coding sequences may be synthesized, isolated 00. from natural sources, or prepared as hybrids, for example.

Ligation of the PKDI coding sequences to transcriptional regulatory elements and/or to other amino acid coding sequences may be achieved by known methods. Suitable host 30 cells may be transformed/transfected/infected by any suitable method including electroporation, CaCI 2 mediated DNA uptake, fungal infection, microinjection, microprojectile, or other established methods.

Appropriate host cells included bacteria, archebacteria, fungi, especially yeast, and plant and animal cells, especially mammalian cells. Of particular interest are E. coli, B. Subtilis, Saccharomyces cerevisiae, SF9 cells, C129 cells, 293 cells, Neurospora, and CHO cells,

COS

cells, HeLa cells, and immortalized mammalian myeloid and lymphoid cell lines. Preferred replication systems include M13, ColE1, SV40, baculovirus, lambda, adenovirus, artificial chromosomes, and the like. A large number of transcription initiation and termination regulatory regions have been isolated and shown to be effective in the transcription and translation of heterologous proteins in the various hosts.

Examples of these regions, methods of isolation, manner of manipulation, and the like, are known in the art. Under appropriate expression conditions, host cells can be used as a source of recombinantly produced PKD1.

This invention also contemplates the use of unicellular or multicellular organisms whose genome has been transfected or transformed by the introduction of PKD1 coding sequences through any suitable method, in order to obtain recombinantly produced PKqE protein or peptides derived therefrom.

25 Nucleic acids encoding PKD1 polypeptides may also be incorporated into the genome of recipient cells by recombination events. For example, such a sequence can be microinjected into a cell, and thereby effect homologous recombination at the site of an endogenous gene encoding 30 PKD1, an analog or pseudogene thereof, or a sequence with substantial identity to a PKD1-encoding gene. Other recombination-based methods such as nonhomologous recombinations or deletion of endogenous gene by homologous recombination, especially in pluripotent cells, may also be used.

The present invention also encompasses an isolated polypeptide having a sequence encoded by the authentic PKD1 gene, as well as peptides of six or more amino acids derived therefrom. The polypeptide(s) may be isolated from human tissues obtained by biopsy or autopsy, or may be produced in a heterologous cell by recombinant DNA methods as described above. Standard protein purification methods may be used to isolate PKD1-related polypeptides, including but not limited to detergent extraction, and chromatographic methods including molecular sieve, ion-exchange, and affinity chromatography using e.g. PKD1-specific antibodies or ligands. When the PKD1 polypeptide to be purified is produced in a recombinant system, the recombinant expression vector may comprise additional sequences that encode additional amino-terminal or carboxy-terminal amino acids; these extra amino acids act as "tags" for immunoaffinity purification using immobilized antibodies or for affinity purification using immobilized ligands.

Peptides comprising PKDl-specific sequences may be derived from isolated larger PKD1 polypeptides described 25 above, using proteolytic cleavages by e.g. proteases such as trypsin and chemical treatments such as cyanogen bromide that are well-known in the art. Alternatively, peptides up to residues in length can be routinely synthesized in milligram quantities using commercially available peptide synthesizers.

The present invention encompasses antibodies that specifically recognize the PKD1 polypeptide(s) encoded by the ene shown in Figures 1 and 2 or the cDNA shown in Figure 3, and/or fragments or portions thereof. The antibodies may be polyclonal or monoclonal, may be produced in response to the native PKD1 polypeptide or to synthetic peptides as described above. Such antibodies are conveniently made using the methods and compositions disclosed in Harlow and Lane, Antibodies, A Laboratory Manual, Cold Spring Harbor Laboratory, 1988, other references cited herein, as well as immunological and hybridoma technologies known to those in the art. Where natural or synthetic PKD1-derived peptides are used to induce a PKD-specific immune response, the peptides may be conveniently coupled to an suitable carrier such as KLH and administered in a suitable adjuvant such as Freund's. Preferably, selected peptides are coupled to a lysine core carrier substantially according to the methods of Tam, Proc.Natl.Acad.Sci,USA 85:5409-5413, 1988. The resulting antibodies may be modified to a monovalent form, such as, for example, Fab, Fab 2 FAB', or FV. Anti-idiotypic antibodies may also be prepared using known methods.

In one embodiment, normal or mutant PKD1 polypeptides are used to immunize mice, after which their spleens are removed, and splenocytes used to form cell hybrids with myeloma cells and obtain clones of antibodysecreted cells according to techniques that are standard in -the art. The resulting monoclonal antibodies are screened 25 for specific binding to PKD1 proteins or PKD1-related peptides.

In another embodiment, antibodies are screened for selective binding to normal or mutant PKD1 sequences.

30 Antibodies that distinguish between normal and mutant forms *of PKD1 may be used in diagnostic tests (see below) employing ELISA, EMIT, CEDIA, SLIFA, and the like. Anti-PKD1 antibodies may also be used to perform subcellular and histochemical localization studies. Finally, antibodies may be used to block the function of the PKD1 polypeptide, whether normal or mutant, or to perform rational drug design studies to identify and test inhibitors of the function using an anti-idiotypic antibody approach).

Identification of Disease-CausinQ Mutations in PKDQ In one mode of practice of the present invention, the isolated and sequenced PKD1 gene is utilized to identify previously unknown or mutant versions of the PKD1 gene.

First, human subjects with inherited polycystic kidney disease are identified by clinical testing, pedigree analysis, and linkage analysis, using standard diagnostic criteria and interview procedures, and DNA or RNA samples are obtained from the subjects (see below).

A variety of techniques are then employed to pinpoint new mutant sequences. First, PKD1 DNA may be subjected to direct DNA sequencing, using methods that are standard in the art. Furthermore, deletions may be detected using a PCR-based assay, in which pairs of oligonucleotides are used to prime amplification reactions and the sizes of the amplification products are compared with those of control products. Other useful techniques include Single-Strand 25 Conformation Polymorphism analysis (SSCP), HOT cleavage, denaturing gradient gel electrophoresis, and two-dimensional gel electrophoresis.

A confounding and complicating factor in the 30 detection of a PKD1 mutation is the presence of PKD1 homologues at several sites on chromosome 16 proximal to the transcribed gene. In analysis of mutations in PKD1, it is critical to distinguish between sequences derived from the authentic PKD1 gene and sequences derived from any of the homologues. Thus, an important feature of the present invention is the provision of oligonucleotide primers that discriminate between authentic PKD1 and the homologues.

A

detailed comparison of the sequences of the authentic PKD1 gene and the homologues enables the design of primers that discriminate between the authentic PKD1 gene or cDNA and the homologues. Primers that conform to this criterion, such as those disclosed in Figure 4B, may be used in conjunction with any of the analytical methods described below.

For SSCP, primers are designed that amplify

DNA

products of about 250-300 bp in length across non-duplicated segments of the PKD1 gene. For each amplification product, one gel system and two running conditions are used. Each amplification product is applied to a 10% polyacrylamide gel containing 10% glycerol. Separate aliquots of each amplimer are subjected to electrophoresis at 8W at room temperature for 16 hours and at 30W at 4°C for 5.4 hours. These conditions were previously shown to identify 98% of the known mutations in the CFTR gene (Ravnik-Glavac et al., Hum. Mol.

Genet., 3:801, 1994).

For "HOT" cleavage, amplification reactions are performed using radiolabelled PKD1-specific primers. 'Each 25 radiolabelled amplification product is then mixed with a fold to 100-fold molar excess of unlabelled amplification products produced using the identical primers and DNA from APKD-affected or -unaffected subjects. Heteroduplex formation, chemical cleavage, and gel analysis are then performed as described (Cotton, et al., Proc. Natl. Acad.

Sci., USA, 85:4397, 1988). Bands on the gel that are smaller than the homoduplex result from chemical cleavage of heteroduplexes at base pair mismatches involving cytidine or thymidine. Once a mutation has been identified by this procedure, the exact location of the mismatch(es) is determined by direct DNA sequencing.

Mutations are also identified by "broad range" DDGE (Guldberg et al., Nuc. Acids Res., 22:880, 1994). The use of GC-clamped PCR primers and a very broad denaturant gradient enables the efficient detection of mutant sequences. This method can also be combined with non-denaturing size fractionation in a two-dimensional system. An apparatus is used that permits automated two-dimensional electrophoresis, and the second dimension considerably increases the resolution of mutations.

After the presence of a mutation is detected by any of the above techniques, the specific nucleic acid alteration comprising the mutation is identified by direct DNA sequence analysis. In this manner, previously unidentified PKD1 mutations may be defined.

Once a previously unidentified PKD1 mutation is defined, methods for detecting the particular mutation in other affected individuals can be devised, using a variety of methods that are standard in the art. For example, oligonucleotide probes may be prepared that allow the detection and discrimination of the particular mutation. It will be understood that such probes may comprise either the mutant sequence itself, or, alternatively, may flank the mutant sequence. Furthermore, the oligonucleotide sequence can be used to design a peptide immunogen comprising the 30 mutant amino acid sequence. These peptides are then used to elicit antibodies that distinguish between normal and mutant PKD1 polypeptides.

Diagnostic Tests for PKDI Mutations Mutant PKD1 genes, whether identified by the methods described above or by other means, find use in the design and operation of diagnostic tests. Tests that detect the presence of mutant PKD1 genes, including those described below and in Example 5, can be applied in the following ways: 1 0 To determine donor suitability for kidney transplants. In general, it is desirable to use a close relative of the transplant recipient. When the recipient is a patient suffering from familial APKD, it is important to ascertain that the donor relative does not also carry the familial mutant PKD1 gene.

To screen for at-risk individuals in APKDaffected families. Presymptomatic individuals who have a high probability of developing APKD can be identified, allowing them to be monitored and to avail themselves of preventive therapies.

To target hypertensive patients for antihypertensive treatment. Hypertension is also linked to 25 APKD. Screening of hypertensive patients for the presence of mutant PKD 1 genes can be used to identify patients for preemptive regulation of blood pressure to prevent later kidney damage.

30 To perform prenatal screening. Most PKD1linked PKD is of the adult-onset type. In a small subset of families carrying a mutation in PKD1 genes, however, juvenile onset is common and signifies a more severe form of the disease. In these families, prenatal screening can be useful for genetic counselling purposes.

In general, the diagnostic tests according to the present invention involve obtaining a biological sample from a subject, and screening the sample, using all or part of the PKDl gene of this invention, for the presence of one or more mutant versions of the PKDI gene or its protein product. The subject may be a fetus in utero, or a human patient of any age.

In one embodiment, a sample of genomic DNA is obtained from a human subject and assayed for the presence of one or more disease-associated PKD1 mutations. This DNA may be obtained from any cell source or body fluid. Non-limiting examples of cell sources available in clinical practice include blood cells, buccal cells, cervicovaginal cells, epithelial cells from urine, fetal cells, or any cells present in tissue obtained by biopsy. Body fluids include blood, urine, cerebrospinal fluid, amniotic fluid, and tissue exudates at the site of infection or inflammation. DNA is extracted from the cell source or body fluid using any of the numerous methods that are standard in the art. It will be understood that the particular method used to extract DNA 25 will depend on the nature -of the source. The minimum amount of DNA to be extracted for use in the present invention is about 25 pg (corresponding to about 5 cell equivalents of a genome size of 3 x 109 base pairs).

30 In this embodiment, the assay used to detect the presence of mutations may comprise restriction enzyme digestion, direct DNA sequencing, hybridization with sequence-specific oligonucleotides, amplification by PCR, single-stranded conformational polymorphism analysis, denaturating gradient gel electrophoresis (DDGE), twodimensional gel electrophoresis, in situ hybridization, and combinations thereof.

In a preferred embodiment; RNA is isolated from a PKD1-expressing cell or tissue, preferably lymphocytes, using standard techniques including automated systems such as that marketed by Applied Biosystems, Inc. (Foster City, CA). The RNA is then subjected to coupled reverse-transcription and PCR amplification (RT-PCR). The resulting DNA may then be screened for the presence of mutant sequences by any of the methods outlined above (see Example 5 below).

As discussed above, any nucleic-acid-based screening method for PKD1 mutations must be able to discriminate between the authentic PKD1 gene present at chromosome location 1 6 p13.3 and PKD1 homologues present at 16p13.1 and other locations. The oligonucleotides

SEQ

ID Nos:10 and 13-15) are examples of primers that discriminate between the authentic and homologue sequences, and these oligonucleotides or their equivalents form an important part of any such diagnostic test. Furthermore, nucleotides 43,823 through 52,887 of the PKD1 sequence of Figure 1B represent a sequence that is unique to the 25 authentic PKD1 gene and is not present in the homologues.

Thus, oligonucleotides derived from this region can be used in a screening method to insure that the authentic PKD1 gene, and not the homologues, are detected.

30 In another embodiment, the assay used to detect the presence of a mutant PKD1 gene involves testing for mutant gene products by an immunological assay, using one of many methods known in the art, such as, for example, radioimmunoassay, ELISA, immunofluorescence, and the like. In this embodiment, the biological sample is preferably derived from a PKD1-expressing tissue such as kidney. The PKD1 polypeptide may be extracted from the sample. Alternatively, the sample may be treated to allow detection or visualization of specifically bound antibodies in situ as occurs in, for example, cryosectioning followed by immunofluorescent staining.

The antibodies may be monoclonal or polyclonal, may be raised against intact PKD1 protein, or natural or synthetic peptides derived from PKD1. In a preferred embodiment, the antibodies discriminate between "normal" and "mutant" PKD1 sequences, and possess a sufficiently high affinity for PKD1 polypeptides so that they can be used in routine assays.

It will be understood that the particular method or combination of methods used will depend on the particular application. For example, high-throughput screening methods preferably involve extraction of DNA or RNA from an easily available tissue, followed by amplification of particular SI"" PKD1 sequences and hybridization of the amplification products with a panel of specific oligonucleotides.

25 Therapeutic Applications The present invention encompasses the treatment of PKD using the methods and compositions disclosed herein. All or part of the normal PKD1 gene disclosed above can be 30 delivered to kidney cells or other affected cells using a variety of known methods, including e.g. liposomes, viral vectors, recombinant viruses, and the like. The gene can be incorporated into DNA'vectors that additionally comprise tissue-specific regulatory elements, allowing PKD1 expression in a tissue-specific manner. This approach is feasible if a particular mutant PKD1 allele, when present in a single copy, merely causes the level of the PKD1 protein to diminish below a threshold level necessary for normal function; in this case, increasing the gene dosage by supplementing with additional normal copies of the PKD1 gene should correct the functional defect. In another embodiment, a mixture of isolated nucleic acids, such as that set forth in Figure 2 and at least a portion of the normal PKD1 gene, may be delivered to kidney or other affected cells in order to treat APKD. Alternatively, it may be desired to limit the expression of a mutant PKD1 gene, using, for example, antisense sequences. In this embodiment, antisense oligonucleotides may be delivered to kidney or other cells.

For therapeutic uses, PKD1-related DNA may be administered in any convenient way, for example, parenterally in a physiologically acceptable carrier such as phosphate buffered saline, saline, deionized water, or the like.

Typically, the compositions are added to a retained physiological fluid such as blood or synovial fluid. The amount administered will be empirically determined using routine experimentation. Other additives, such as :i stabilizers, bactericides, and the like, may be included in 25 conventional amounts.

This invention also encompasses the treatment of APKD by protein replacement. In one embodiment, protein produced by host cells transformed or transfected with DNA 30 encoding the PKD1 polypeptide of the present invention is o* introduced into the cells of an individual suffering from altered, defective, or non-functional expression of the PKD1 gene. This approach augments the absence of PKD1 protein, or the presence of a defective PKD1 protein, by adding functional PKD1 protein. The PKD1 protein used in augmentation may comprise a subcellular fragment or fraction, or may be partially or substantially purified. In any case, the PKD1 protein is formulated in an appropriate vehicle, such as, for example, liposomes, that may additionally include conventional carriers, excipients, stabilizers, and the like.

It will be understood that the therapeutic compositions of the present invention need not in themselves constitute an effective amount, since such effective amounts can be reached by administering a plurality of such therapeutic compositions.

The following examples are intended to illustrate the invention without limiting its scope thereof.

Example 1: Cloning and Seuencing of the Human PKD1 gene A. Methods: Employing an ordered sequencing approach, restriction fragments from cDEB11 and cGGG10.2 cosmids were subcloned into either pBLUESCRIPT (Stratagene, La Jolla, CA) 25 or pGEM (Promega, Madison, WI). Plasmids were purified by CsC1 density centrifugation in the presence of ethidium bromide. Nested deletions were generated from each plasmid using ExoIII (Henikoff, Methods Enzymol. 155: 156-165, 1987) and additional enzymatic reagents provided by the Erase-A-Base kit (Promega, Madison, WI). The resulting nested clones were analyzed electrophoretically after appropriate restriction enzyme digestion and were ordered into a nested set of templates for sequencing. A minimum tiling series of plasmids, each differing by approximately 250 bp from flanking clones, were identified and used for sequencing.

Plasmid DNAs were prepared for sequencing in one of two ways. Initially, all clones of interest were cultured in 2 mL of Super Broth (Tartof et al., BRL Focus 9: 12, 1987) for 20 hours at 37 0 C. Sets of 12-24 were processed simultaneously using a modified alkaline SDS procedure followed by ion-exchange chromatography as described by the manufacturer (Easy-Prep, Pharmacia, Piscataway, NJ). Plasmid DNA yields ranged from 2.5 to 25 gg. Poor growing clones, or those whose plasmids generated sequence of unacceptable quality, were recultured in 100 mL of Luria's Broth and the plasmid DNA isolated using Qiagen columns (Qiagen, San Diego,

CA).

Dideoxy sequencing reactions were performed on deletion clones using the Auto-Read Sequencing Kit (Pharmacia, Piscataway, NJ) and fluorescein-labeled vector primers (M13 universal, M13 reverse, T3, T7 and SP6).

Reaction products were separated on 6% denaturing acrylamide gels using the ALF m DNA Sequencer (Pharmacia, Piscataway,

NJ).

25 Second strand sequencing was performed using either an opposing set of nested deletions or primer walking. For .primer walking, custom 1 7-mers, staggered every 250 bp, were purchased from a commercial supplier (Protogene, Palo Alto, CA). Template DNAs prepared by Qiagen or CsCl density 30 gradients were sequenced using the unlabeled 17-mers by inclusion of fluor-dATP labeling mix in the sequencing reactions as described by the manufacturer (Pharmacia, Piscataway, NJ). In all cases, except the 2.5kb GC-rich region, single-stranded DNA was rescued from deletion clones using helper phage VCSM13 (Stratagene) as described by the manufacturer.

Single-stranded templates from the 2.5 kb GC-rich region were sequenced using fluorescein-labeled universal primer and the Sequitherm Long Read cycle sequencing kit (Epicentre Technologies, Madison, WI) (Zimmerman et al., Biotechniques 17: 303-307, 1994). All processed sequencing data was transferred to a Quadra 700 Macintosh computer and assembled using the SEQUENCHER (Gene Codes, Ann Arbor,

MI)

sequencing assembly program. For differences that would not be resolved by examining the chromatograms, templates were either resequenced or primers proximal to the ambiguity were designed and used for resolution of the sequence difference.

Cycle sequencing was performed using the Sequitherm cycle sequencing kit as described by the manufacturer (Epicentre Technologies, Madison, WI). Reaction products were separated on denaturing acrylamide gels and subsequently detected by autoradiography.

B. Sequencing Strategy: A 700 kb region of chromosome 16 containing the 25 PKD1 locus is shown in Figure 5 (top panel). A contig :covering this region was assembled from overlapping P1 clones (shown in the middle panel). The contig was assembled by unidirectional chromosomal walking from the ends of the interval (ATPL and D16S84) and bidirectional walking from several internal loci (D16S139 and KG8). One of the clones, 91.8B (ATCC Accession No. 98056), spans the entire PKD1 interval and includes cosmids cDEB11 (ATCC Accession No.

98057), cGGG10.2 (ATCC Accession No. 98058), and substantial portions of cosmids 2H2 and 325A11 (Stallings, R.L. et al., Genomics 13:1031, 1992). The P1 clone 91.8B (shown schematically in Figure 6) was used as a second genomic template to confirm discrepancies between the published cDNA sequence (EPKDC, Cell, 1994, supra) and the cosmid-derived genomic sequence.

Preliminary experiments revealed the presence of multiple repetitive elements in the cGGG10.2 cosmid.

Therefore, an ordered approach based on nested deletions, rather than random shotgun subcloning, was used to sequence the PKD1 gene. Restriction fragments derived from the inserts of both cGGG10.2 and cDEB11 were subcloned into highcopy number plasmids as a preliminary step to the generation of nested deletions. Unidirectional deletions were prepared and sequenced, using the ALF" automated sequencing system (Pharmacia, Uppsala, Sweden).

C. Primary Structure of the PKD1 Locus: The primary sequence of the locus encompassing the PKD1 gene is 53,577 bp in length. This locus is GC-rich with a CpG/GpC dinucleotide ratio of 0.485. The primary sequence of the PKD1 gene within this locus is 53,526 bp in length. The present sequence was analyzed for S. 25 transcriptional elements and CpG islands using GRAIL2 (Uberbacher, E.C. et al., Proc. Natl. Acad. Sci., USA 88:11261, 1991) and XGrail client server (Shah et al., User's Guide to GRAIL and GENQUEST, Client-Server Systems, available by anonymous ftp to arthur.epm.omi.gov (128.219.9.76) from directory pub/xgrail or pub/xgenquest, as file manual.grailgenquest, 1994). Ten CpG islands were identified (Figure 8).

Forty-eight exons were predicted on the coding strand by the GRAIL program. The quality of 39 of the 48 exons was "excellent", six were considered "good", and three were deemed "marginal". These data were analyzed using the gene model feature of GRAIL2. The final gene model contained 46 exons.

Comparison of the present genomic sequence with the previously reported partial cDNA sequence (EPKDC, Cell, 1994, supra) revealed several differences (Figure The first and most significant difference is the presence of two additional cytosine residues at position 4566 of the reported sequence. The presence of these two cytosine residues results in a frame shift in the predicted protein coding sequence, leading to the replacement of 92 carboxy-terminal amino acids with a novel 12-amino acid carboxy terminus.

Seven of the twelve amino acids of the new carboxy terminus are charged or polar. Additional sequence differences are located at positions 3639-3640 and 3708-3709 of the published EPKDC sequence (Figure A GC dinucleotide pair is present at each of these positions in the present sequence, while a CG pair is found in the reported sequence. In each case, histidine and valine residues would replace the previously predicted glutamine and leucine residues, respectively.

D. Identification of Protein Coding Regions: 25 Exons predicted by the GRAIL2 program with an "excellent" score were used to search the SwissProt and PIR databases (Bairoch and Boeckmann, Nuc. Acids Res. 20:2019- 2022, 1992) using the BLASTP program (Altschul et al., J.

Mol. Biol. 215:403-410, 1990). Exons 3 and 4 of the gene 30 model were predicted to encode peptides with homology to a number of leucine-rich repeat (LRR)-containing proteins involved in protein-protein interactions (Figure 13). In :addition to the LRR itself, sequences amino- and carboxyflanking to the LRR may also be conserved in proteins of the leucine-rich glycoprotein (LRG) family, either singly or together.

Exon 3 encodes residues homologous to the LRR from leucine-rich a2 glycoprotein, members of the GPlb.IX complex which comprise the von Willebrand factor receptor, as well as to the Drosophila proteins chaoptin, toll, and slit. The latter are involved in adhesion, dorsal-ventral polarity, and morphogenesis, respectively.

Sequences predicted by GRAIL2 to be encoded by exon 4 were found to have homology to the conserved region carboxy terminal to the LRR in all of the above proteins except chaoptin, which lacks this conserved region. Homology was also observed between the exon 4-encoded sequences and-the trk proto-oncogene, which encodes a receptor for nerve growth factor. Further examination of the predicted PKD1 peptide revealed additional regions of weaker homology with conserved regions of the trk tyrosine kinase domain. None of the more proximal exons in the gene model appear to encode a peptide with homology to the conserved amino-flanking region seen in a subset of the LRR-containing proteins.

Exon trapping, RT-PCR, and Northern blot analysis 25 revealed that GRAIL2-predicted exons 3 and 4 are present in expressed sequences. During initial exon trapping experiments using genomic P1 and cosmid clones from the PKD1 locus, an exon trap was identified that contained both of these exons. In separate experiments, the presence of the 30 LRR-carboxy-flanking motif in transcribed sequences was confirmed by RT-PCR using as a template RNA from fetal kidney and from adult brain. On a Northern blot, an RT-PCR fragment containing this motif detected the 14kb PKD1 transcript and several other transcripts of 21 kb, 17 kb, and 8.5 kb.

A region of homology was also observed between the GRAIL2-predicted peptide and the human gplO0O/Pmell7 gene products, as well as with bovine RPE1. Three copies of a 34 amino acid segment that is also present in the Pmel-17 and gpl00 gene products was deduced (Kwon et al, Proc. Natl.

Acad. Sci., USA 88:9228-9232, 1991; Adema et al., J. Biol.

Chem. 269:20126-33, 1994) within the larger context of immunoglobulin repeat motifs. The RPE1 gene product has significant homology to gplOO and may represent the bovine homolog (Kim and Wistow, Exp. Eye Res. 55:657-662, 1992).

GRAIL2-predicted exons 9, 22, and 28, upstream of the 3' cDNA, showed strong homology to EST T03080 255 bp), EST T04943 189 bp) and EST T05931 233 bp) In addition, nucleotides 10378-10625 of GRAIL-predicted intron 1 showed strong homology to a region of the Apo CII gene 263 bp).

The identification of a number of transmembrane domains and a leucine-rich repeat motif possessing conserved carboxy-flanking regions, raises interesting speculations about potential protein function. LRR motifs have been shown o to be involved in protein-protein interactions, while the 25 conserved carboxy-flanking region is associated with proteins which interact with the extracellular matrix. These data suggest that the PKD1 gene product may be a membrane oooo glycoprotein that functions in cell-matrix or cell-cell interactions. Less commonly, LRR motifs have been identified in receptors involved in signal transduction (McFarland et al., Science 245:494-499, 1989). Thus an alternative hypothesis is that the gene product is a receptor for a soluble factor(s). In either case, PKDI would function to mediate interactions with the extracellular environment. If so, ligands for the gene product as well as downstream intracellular effectors are obvious candidates for the non-chromosome 16-linked forms of the disease. A model of the predicted PKD1 protein structure is shown in Figure 9.

E. Repeated Sequences: The PKD1 locus was searched for known classes of repetitive DNA by FASTA comparison against the repeat database of Jurka et al., J.Mol.Evol. 35:286-291, 1992. This search identified 23 Alu repeats but no other repetitive elements. The Alu repeats are organized into three clusters of four or more Alu repeats, three clusters of two Alu repeats, and two singlet Alu repeats (Figure 8).

The PKD1 sequence interval contained two dinucleotide repeats and a single tetranucleotide repeat ((TTTA)6). The TG dinucleotide repeats are present at positions 209-224 and 52,698-52,715. The tetranucleotide repeat is located at position 7796-7819. No trinucleotide S. repeats >5 were identified. Only the most 3' TG8 repeat is known to be polymorphic.

In addition to the more usual repetitive elements, 25 the PKD1 gene contains several types of repeated sequences that either do not appear in existing data bases, or do not appear in the extreme form seen at this locus. The most striking repeat is a 2.5 kb segment within the 4 kb BamHI- SacI fragment. A significantly shorter C-T rich region is also found in the adjoining 1.8 kb SaCI-BamHI fragment.

These regions proved very difficult to sequence unambiguously due to the high GC content to the purine asymmetry S. with respect to each strand and to the length of the repeat.

The coding strand in this region has an extreme pyrimidine bias, being 96% C-T, and could not be sequenced using T7 DNA polymerase or Sequenase. This was true regardless of the template type (plasmid, single-stranded phage, or strandseparated single-stranded DNA). In both cases, the noncoding strand, which is G-A rich, was successfully sequenced with both T7 DNA polymerase and Sequenase, although run lengths were noticeably abbreviated compared to all other regions sequenced. Compressions on the non-coding strand were resolved by conventional and cycle sequencing using single-stranded template. The extreme purine asymmetry of strands in this segment may promote localized triple strand conformation under the appropriate conditions (pH, divalent cations, supercoiling), and may be a major cause of the difficulty in sequencing this segment.

The other unusual repeat was located in the 7.6 kb XhoI fragment. This repeat is 459 bp in length and consists of 17 tandem copies of a perfect 27 bp repeat.

Example 2: PKD1 cDNA Sequences Obtained Through Exon Trapping and cDNA Selection Techniques 25 The 700 kb interval of chromosome 16 that includes the PKD1 gene appears to be particularly rich in CpG islands and, by association, is most likely rich in expressed sequences as well. To purify and sequence expressed PKD1 sequences, an exon-rescue vector, pSPL3, was used to recover sequences from cosmids that contain both a splice acceptor and splice donor element; this method is designated "exon trapping." Exon trapping is a highly efficient method for isolating expressed sequences from genomic DNA. The procedure utilizes the pSPL3 plasmid, which contains rabbit i-globin coding sequences separated by a portion of the HIVtat gene, or improved derivatives of SPL3 lacking cryptic (interfering) splice sites. Fragments of cloned PKD1 genomic DNA were cloned into the intron of the tat gene, and the resulting subclones were transfected into COS-7 cells. sequences in the vector allow for both relaxed episomal replication of the transfected vectors, as well as transcription of the cloned genomic DNAS. Exons within the subcloned genomic DNAs spliced into the globin/tat transcript were recovered using RT-PCR, using primers containing tat splice donor and acceptor sequences. A major advantage of exon trapping is that expression of the cloned DNA is directed by a viral promoter; thus, developmental or tissuespecific expression of gene products is not a concern.

PKD1-containing genomic clones, in the form of either cosmid or P1 DNA, were either double digested with BamHI and BglII or partially digested with Sau3A and shotgun cloned into BamHI-digested and dephosphorylated pSPL3 (GIBCO BRL, Bethesda, MD) or its derivatives. Plasmid minipreps were electroporated into COS-7 cells, and trapped exons were S. 25 recovered by RT-PCR, followed by subcloning, using standard procedures.

Trapped exons from the PKD1 locus are shown in Figure 14 (bottom). The trapped exons were subjected to 30 automated DNA sequencing as above, allowing their alignment with the genomic PKD1 DNA.

Example 3: Construction of Full-length PKD1 cDNA In the case of PKD1, the identification of cDNAs which are specific for the 5' end of the PKD1 locus is particularly difficult since multiple transcribed copies of homologous sequences are also present at 16p13.1

(EPKDC,

Cell, 1994 supra). Regions of both genomic DNA and cDNA derived from the homologues were sequenced and compared with the present PKD1 sequence. In this data set, the PKD1 and homologous sequences were greater than 97% identical at the nucleotide level. Therefore, direct comparisons of potential PKD1 cDNAs and genomic sequence are required to definitively map a cDNA to the PKD1 locus, and to verify that the correct sequence is encoded by.the cDNA.

Multiple approaches were required to assemble the full-length PKD1 cDNA. Seven cDNAs were used to construct the full-length cDNA. Five of these cDNAs were recovered from screening cDNA libraries: the BRL Gene-Trapper brain library, and cDNA libraries constructed from fetal brain, and constructed from the somatic cell hybrid 145.19. The 145.19 cell line contains the PKD1 locus, but does not include the 25 PKD1 homologs in its human component.

A. cDNA Library Construction and Screening The somatic cell hybrid library was constructed 30 using both oligo(dT) and random hexamer priming and poly(A)-containing RNA from the 145.19 cell line. The duplex cDNA was linked and then ligated into lambda ZAP EXPRESS (Stratagene, La Jolla, CA) to yield a library consisting of several million independent plaques. Fourteen clones were positive by colony hybridization using a PKD1 specific probe, with inserts ranging in size from 2.6 to 9 kb. Consistent with the RT-PCR products derived from the 145.19 cell line, substantial alternative splicing or incomplete splicing was evident. Interestingly, the missing exons appeared to comprise one or more distinct protein domains.

Two additional libraries were constructed using fetal brain cDNA cloned into lambda ZAP EXPRESS and the replacement vector, lambda DASH (Stratagene, La Jolla,

CA).

Additionally, a variation of.the cDNA selection methodology was used to screen oligo(dT)-primed, unidirectional cDNA libraries (in phagemids). Briefly, single-stranded library DNA was prepared from cultures of the adult brain cDNA library. A single biotinylated 1 7 -mer derived from the sense-strand from the gene-specific portion of the predicted PKD1 cDNA was used for hybrid selection.

Hybrid-bound cDNAs released by denaturation were made double-stranded using the same oligonucleotide as a gene-specific primer and Klenow and then introduced into E.

coli by electroporation. Colony hybridization was used to identify the PKD1 clones from the enriched brain cDNA 25 population. The cloned brain inserts ranged in size from 0.7 to 2.5 kb. The sequence of the two largest cDNAs was virtually identical to each other as well as to the genomic S. sequence.

Example 4: Expression of Full-LenOth PKD1 cDNA Full-length PKD1 cDNA was cloned into three expression vectors, pCMV-SPORT, pcDNA3, and pCEP4 (total construct sizes ranging from 18-24.2 kb). The schematic structure of full-length PKD1 cDNA in pCMV-SPORT is shown in Figure 11.

pCMV-SPORT and pcDNA3 have small differences in cloning sites and some other small features, but share the basic features of flanking T7 and SP6 promoters, CMV enhancer-promoter sequences for high level transcription, and eukaryotic polyadenylation and transcription sequences which enhance RNA stability. The SV40 origin of replication allows growth in eukaryotic cells, while the ColE1 origin allows growth in E. coli. The vector pcDNA3 confers neomycin resistance in eukaryotes, while ampicillin resistance is used for selection in E. coli.

pCEP4 is an EBV-based vector which is maintained extrachromosomally in primate cells. Like pCMV-SPORT and pcDNA3, pCEP4 contains the CMV enhancer and promoter, and the ColEl origin of replication and ampicillin resistance are used for maintenance. However, hygromycin resistance is used e for selection in eukaryotic cells. The use of the EBV origin of replication and hygromycin resistance are important features for studies of PKD1 transformed cell lines, since as a function of the transformation procedure they already S 25 contain SV40 large T antigen, and are G418 resistant.

A. In vitro Expression The T7 promoter feature of pcDNA3 was used to 30 analyze the protein product encoded by the PKD1 cDNA employing the TNT Coupled Reticulocyte Lysate System, (Promega, Madison, WI). This system enables large amounts of RNA to be synthesized from the T7 promoter, and the RNA to be translated into protein in the rabbit reticulocyte lysate.

Since conventional molecular weight standards only extend up to -216 kD, the size estimates of in vitro synthesized polycystin, -462 kD (non-glycosylated), would be speculative at best. For this reason, a series of 3' deleted PKD1 cDNA plasmid templates encoding truncated proteins of predicted size were constructed (Figure 10). The protein products of these deletion clones as well as the full-length PKD1 cDNA were analyzed using the TNT system.

Newly synthesized protein was labeled by inclusion of radioactive amino acids, initially 35 S-methionine. The synthesized proteins were then resolved by electrophoresis on a 3-12% gradient SDS-PAGE gel. The mobility of the protein product produced from each of the truncated clones was consistent with its predicted molecular size. These results are consistent with assembled PKD1 cDNA expression vectors directing in vitro synthesis of polycystin.

20 B. In vivo Expression: PKD1 cDNA Transfection in Human Embryonic Kidney (HEK) 293 cells cDNA constructs containing full-length PKD1 cDNA or portions thereof were transfected into HEK 293 cells and assayed for PKD1 expression using Northern analysis, 48 hours post-transfection. An insertless vector, pcDNA3, was used in parallel as a control for transfection. A Northern blot was probed with a PKD1-specific probe and then subsequently re-probed with a g-actin cDNA to normalize the respective 30 lanes. The results showed that the PKD1 mRNA is increased at least two-fold in HEK 293 which received the PKD1 cDNA construct.

Example 5: Diagnostic Tests for PKD1 Mutations Whole blood samples collected in high glucose

ACD

Vacutainers T (yellow top) were centrifuged and the buffy coat collected. The white cells were lysed with two washed of a 10:1 mixture of 14mM NH 4 Cl and ImM NaHC03, their nuclei were resuspended in nuclei-lysis buffer (10mM Tris, pH 0.4M NaC1, 2mM EDTA, 0.5% SDS, 500 Jg/ml proteinase K) and incubated overnight at 37 0 C. Samples were then extracted with a one-fourth volume of saturated NaCl and the DNA was precipitated in ethanol. The DNA was then washed with ethanol, dried, and dissolved in TE buffer (10mM Tris-HCl, pH ImM EDTA).

A. Test I Long PCR conditions were used with a 4-part reaction mixture. Part 1 containing the following S 20 components: 3.3X XL Buffer 12 il dNTPs (2mM each) 8 Il Forward primer (20M) 1-5 pl 25 Reverse primer (20pM) 1-5 pl Blocking oligo (2mM) 1.5 p.

Mg(OAc)2, (25mM) 4.4 .l water to 40 p.

Part 1 can be assembled as a single reaction component or in batch (10, 50, 100 reaction equivalents) and then dispensed as 40pl aliquots into individual reaction tubes.

Part 2 comprises carefully adding 1 AmpliWaxPCR Gem 100 (or comparable product to each Part 1 reaction tube). The tubes were incubated at 75-80°C for 5 min.to melt the wax bead.

The reactions were cooled allowing the wax to solidify.

In Part 3, the following components were added to the cooled reaction mixture of Part 2: 3.3X XL Buffer 1811i rTth DNA Polymerase, XL 2Li In Part 4, the following components are added to the reaction mixture of Part 3: human DNA 0.2-1Ig water to The forward primer used in the reaction described above comprises an oligonucleotide that hybridizes to both 20 authentic PKD1 and PKD1 homologue sequences. An example of such a primer is: -CACGACCTGTCCCAGGCAT-3' (SEQ ID NO:6) (corresponding to nucleotides 4702-4720 of SEQ ID NO:1).

The reverse primer comprises a sequence derived from a 3' region of the authentic PKD1 gene, which may or may not be present in the PKD1 homologues. Examples of such 3' regions and corresponding reverse primers are: 3' seuence: reverse primer: 5'-CTGGCGGGCGAGGAGAT-3 5'-ATCTCCTCGCCCGCCAG-3 (SEQ ID NO:7) (SEQ ID NO:56) 5'-CTTTGACAAGCACATCT-3' (SEQ ID NO:8) 5'-CAACTGGCTGGACAACA-3' (SEQ ID NO:9) 5'-AGATGTGCTTGTCAAAG-3, (SEQ ID NO:57) 5'-TGTTGTCCAGCCAGTTG-3' (SEQ ID NO:58) The blocking oligonucleotide comprises: 5'-AGGACCTGTCCAGGCATC-3' (SEQ ID Importantly, this oligonucleotide must be incapable of supporting polymerization. One example is an oligonucleotide in which the 3' terminal nucleotide comprises a dideoxynucleotide. It will be understood that any modification that achieves this effect may be used in practicing the invention. Under appropriate conditions, the blocking oligonucleotide hybridizes efficiently to PKD1 homologues but inefficiently to the authentic PKD1 sequence.

Thus, the amplification products in this diagnostic test are 20 derived only from the authentic PKD1 gene.

Twenty-five to thirty-eight cycles of amplification were

S..

performed, using a standard DNA primer-dependent conditions for SEQ ID NO:56: 94°C, 30 seconds; 34 minutes.

SEQ ID NO:57: 94°C, 30 seconds; 30 37 minutes.

SEQ ID NO:58: 94°C, 30 seconds; minutes.

thermal cycler the following each cycle: 62 0 C, 30 seconds; and 72 0

C,

56°C, 30 seconds; and 72 0

C,

58 0 C, 30 seconds; and 72 0

C,

b The 72 0 C extension cycle was lengthened 5 seconds each subsequent cycle. The primary PCR product can be analyzed immediately for mutations or alternatively, can be used as a template for secondary PCR using a collection of paired amplimers to generate an overlapping set of smaller amplicons. The smaller amplicons can then be analyzed for mutations.

B. Test II Long PCR conditions were used with a 4-part reaction mixture. Part 1 containing the following components: 3.3X XL Buffer 12 .l dNTPs (2mM each) 8 1 Forward primer (20pM) 1-5 p.

Reverse primer (20pM) 1-5 p.

Mg(OAc)2, (25mM) 4.4 p.

S" 20 water to 40 ~I *P art 1 can be assembled as a single reaction component or in batch (10, 50, 100 reaction equivalents) and then dispensed as 40pl aliquots into individual reaction tubes.

Part. 2 comprises carefully adding 1 AmpliWaXPCR Gem 100 (or comparable product to each Part 1 reaction tube. The tubes were incubated at 75-80C for 5 min. To melt the wax bead.

The reactions were cooled allowing the wax to solidify.

In Part 3, the following components were added to the cooled S" reaction mixture of Part 2: 3.3X XL Buffer 18L1 rTth DNA Polymerase, XL 2pl In Part 4, the following components are added to the reaction mixture of Part 3: human DNA 0.

2 -lig water to Twenty-five to thirty-eight cycles of amplification were performed, using a standard DNA thermal cycler the following protocol for each cycle: 94C, 30 seconds; 61°C, 30 seconds; and 72 0 C, 11 minutes. The 72°C extension cycle was lengthened 5 seconds each subsequent cycle. The primary

PCR

product can be analyzed immediately for mutations or alternatively, can be used as a template for secondary

PCR

using a collection of paired amplimers to generate an overlapping set of smaller amplicons. The smaller amplicons can then be analyzed for mutations.

The forward primer used in the reaction described 20 above comprises an oligonucleotide that hybridizes to both authentic PKD1 and PKD1 homologue sequences. An Example of such a primer is: CTGCACTGACCTCACGCATGT (SEQ ID NO:11) The reverse primer comprises a sequence derived from the authentic PKD1 gene and is not present in the PKD1 homologues. Thus, the amplification product in this diagnostic test is derived only from the authentic PKD1 gene.

30 An example of a suitable reverse primer is: 5'-GCGCTTTGCAGACGGTAGGCG (SEQ ID NO:14) C. Test III Long PCR conditions were used with a 4 -part reaction mixture. Part 1 containing the following components: 3.3X XL Buffer 12 p.

dNTPs (2mM each) 8 il Forward primer (20pM) 1-5 ll Reverse primer (20pM) 1-5 .1 Mg(OAc)2, (25mM) 4.4 .1 water to 40 pll Part 1 can be assembled as a single reaction component or in batch (10, 50, 100 reaction equivalents) and then dispensed as 40.l aliquots into individual reaction tubes.

Part 2 comprises carefully adding 1 AmpliWaxPCR Gem 100 (or 20 comparable product to each Part 1 reaction tube. The tubes were incubated at 75-80°C for 5 min. To melt the wax bead.

The reactions were cooled allowing the wax to solidify.

In Part 3, the following components were added to the cooled reaction mixture of Part 2: 3.3X XL Buffer 18L1 rTth DNA Polymerase, XL 2.l 30 In Part 4, the following components are added to the reaction mixture of Part 3: human DNA 0.

2 -1gg water to 40 .l Twenty-five to thirty-eight cycles of amplification were performed, using a standard DNA thermal cycler the following protocol for each cycle: 94 0 C, 30 seconds; 65 0 C, 30 seconds; and 72 0 C, 11 minutes. The 72 0 C extension cycle was lengthened 5 seconds each subsequent cycle. The primary

PCR

product can be analyzed immediately for mutations or alternatively, can be used as a template for secondary

PCR

using a collection of paired amplimers to generate an overlapping set of smaller amplicons. The smaller amplicons can then be analyzed for mutations.

The forward primer used in the reaction described above comprises an oligonucleotide that hybridizes to both authentic PKD1 and PKD1 homologue sequences. An Example of such a primer is: ACGTTGGGCTCCTGGGCAACC (SEQ ID NO:12) The reverse primer comprises a sequence derived O 20 from the authentic PKD1 gene and is not present in the PKD1 homologues. Thus, the amplification product in this diagnostic test is derived only from the authentic PKD1 gene.

An example of a suitable reverse primer is: 5'-AGGTCAACGTGGGCCTCCAAGTAGT (SEQ ID NO:13) For RT-PCR, first strand cDNA synthesis is performed using the reverse primer (SEQ ID NO:14) and SuperscriptIIm according to manufacturer's recommended 30 conditions (Life Technologies, Inc., Gaithersburg, MD). PCR is then performed using 1-50% of the first strand reaction under the reaction conditions described above, with the modification that the extension cycle is conducted at 72 0

C

for only 6 min. (due to the smaller product size).

D. Test IV To analyze PKD1 mRNA for mutations, RNA is isolated from the white blood cells as a requisite template for RT- PCR. Whole blood samples collected in high glucose

ACD

Vacutainers (yellow top) were centrifuged and the buffy coat collected (4-20 x 106 cells/10 ml of blood). RNA can be isolated directly from white blood cells or after standard short-term culturing of white blood cells in the presence of a mitogen such as phytohemagglutinin (48-72 hours). RNA is isolated as described using standard conditions such as guanidium isothiocyanate:acid phenol extraction (Chomczynski and Sacchi, Anal. Biochem. 162:156-159, 1987).

For RT-PCR, first strand cDNA synthesis is performed using the reverse primer (below) and a commercially available reverse transcriptase, such as, for example, SuperscriptII

T

m according to manufacturer's recommended conditions (Life Technologies, Inc., Gaithersburg, MD).

PCR

20 is then performed using 1-50% of the first strand reaction under the reaction conditions described below.

The reverse primer comprises a sequence derived from both the authentic PKD1 gene and the PKD1 homologues.

In contrast, the forward primer is specific for the authentic PKD1 locus and will not allow amplification of cDNAs derived from the homologous loci. Thus, the resulting

RT-PCR

amplification product in this diagnostic test is derived only from authentic PKD1 RNA.

The forward primer used in this reaction comprises an oligonucleotide that hybridizes only to authentic PKD1 and not to homologue sequences. An example of such a primer is: AGCGCAACTACTTGGAGGCCC (SEQ ID An example of a suitable reverse primer is: GCCAAAGGGAAAGGGATTGGA (SEQ ID NO:16) The amplification aspect of the RT-PCR reactions was performed using standard conditions as described below including a "hot-start" step: Taq Buffer 8 a1 dNTPs (2mM each) 7 il Forward Primer (100M) 0.4-1.5 .1 Reverse Primer (100M) 0.4-1.5 g1 DNA 0.2-1.0 gg water to 80 .1 Amplification was initiated using a single "hotstart" step, followed by twenty-five to thirty-eight cycles 20 of amplification using a standard DNA thermal cycler. The single "hot-start" step consisted of 80°C for 3-5 minutes after which time 1 i 1 of Tag polymerase was added to each reaction tube. "Hot-start" was proceeded by 25-38 cycles with each cycle consisting of the following specifications: 94C, 20 seconds; 64°C, 30 seconds; and 72°C, 2 minutes.

The primary PCR product can be analyzed immediately for mutations or alternatively, can be used as a template for secondary PCR using a collection of paired amplimers to 30 generate an overlapping set of smaller amplicons. The smaller amplicons can then be analyzed for mutations.

The PCR and RT-PCR products obtained above were analyzed for the presence of specific PKD1 mutations as follows: 8 g1 of the amplified products were added to 50 il of a denaturing solution (0.5mM NaOH, 2.0M NaC1, 25mM

EDTA)

and spotted onto nylon membrane filters (INC Biotrans). The denatured DNA was then fixed to the nylon filters by baking the filters at 80 0 C for 15 minutes under vacuum.

Oligonucleotides that detect PKD1 mutations were chemically synthesized using an automated synthesizer and radiolabeled with y 2 p with polynucleotide kinase, using methods that are standard in the art.

Hybridizations were carried out in plastic bags containing the filters prepared above, to which one or more labeled oligonucleotides were added in a hybridization buffer Tetramethylammonium chloride (TMAC), 0.6% SDS, 1mM 20 EDTA, 10mM sodium phosphate pH 6.8, 5X Denhardt's Solution, and 40 pg/ml yeast RNA). Oligonucleotide concentrations in the pools ranged from 0.03 to 0.15 pmol/ml hybridization olution.

Hybridizations were allowed to proceed overnight at 52°C, with agitation. The filters were then removed from the bags and washed for 20 min. at room temperature with wash buffer (3.0M TMAC, 0.6% SDS, ImM EDTA, 10mM sodium phosphate H followed by a second wash in the same buffer for 30 min. at 52°C. The filters were dried and exposed to Kodak X-OMAT film.

It will be understood that the enzymes and nucleotides used in the above reactions may be obtained from any manufacturer, such as GIBCO-BRL, Promega, New England Biolabs, and the like.

Example 6: Antipolvcvstin Antibodies A. Production and Characterization of Polyclonal Antisera Against Synthetic C-Terminal Peptide.

A peptide (C)SRTPLRAKNKVHPSST (SEQ ID NO:17) representing the last 16 carboxy-terminal amino acids of the predicted PKD1 gene product was synthesized. A cysteine residue that is not predicted from the DNA sequence was appended to the amino terminus to facilitate coupling to KLH carrier protein. Two rabbits (A and B) were immunized with the peptide as described in Cheng et al., EMBO J. 7:3845- 3855, 1988.

Polyclonal anti-peptide antisera were diluted from 20 1:10 up to 1:10,000, and immunoreactivity was determined by ELISA according to conventional procedures (Cheng et al., EMBO 1988 supra.). Antisera produced by both rabbits were epitope mapped by the SPOTs method (Blankenmeyer-Menge and Frank, in INNOVATION AND PERSPECTIVES IN SOLID PHASE SYNTHESIS, Epton, R. Ed., Chapman and Hall Medical, London, 1990, pp. 1-10). Briefly, overlapping 8 amino acid long peptides were synthesized simultaneously on a cellulose membrane and assayed for immunological reactivity. Positive peptides were aligned and the epitope was identified by 30 determining sequence homologies. Interestingly, antisera

A

and B had at least 2 non-overlapping epitopes each, thus increasing the possibility that these antibodies will recognize the PKD1 gene product.

B. Domain Specific Fusion Proteins Four fusion clones were constructed to contain different domains of polycystin such that the correct open reading frame was maintained, as shown in Figure 15. Three of the expression constructs were cloned in the pGEX vectors designed for the expression of foreign sequences as glutathione S-transferase (GST) fusion proteins in E. coli.

These are FP-LRR, which contained the leucine-rich repeat (LRR); FP-46-lc, containing 83 C-terminal amino acids and.

FP46-2 which has 77 amino acids internal to the FP-46-1c.

The fourth fusion construct was cloned into a maltose binding protein (MBP) vector, and encoded 205 amino acids at the carboxy terminus, thus overlapping two of the GST fusion proteins. The overlapping carboxy-fusion products provide an additional layer of antibody reagent confirmation. They allow one to verify that positive antibody reactions are not artifactual, since similar, if not identical, patterns of antibody reactivity should be seen with antibodies raised 20 against these overlapping proteins. Two different 'carrier' fusion proteins also allows one to purify antibody raised against a fusion product using the alternate carrier protein -:as the affinity ligand. This helps to eliminate antibodies raised against the carrier protein itself.

GST fusion proteins were purified from extracts of transformed bacteria using glutathione-Sepharose (Pharmacia) as described in Smith and Johnson, Gene 67:31-40, 1988. MBP fusion proteins were purified on amylose resin (NEB, Beverly, 30 MA).

C. Generation and characterization of polyclonal antibodies to domain specific polycystin fusion proteins.

Antibodies against the fusion proteins were raised in rabbits using published procedures (Cheng et al., EMBO J.

1988 supra.) with 200 gg of protein. These respective antibodies specifically recognized PKD1 protein as part of the fusion protein construct used as immunogen

FP-LRR,

FP46-lc, FP46-2 and MAL-BD-3). Further, these antibodies did not bind the irrelevant antigens GST or MBP, nor cross-react -to polycystin domains not present in the immunogen included as controls after sufficient antibody purification.

In vitro synthesized polycystin protein was used to test the domain specific antibodies. In addition to the full-length PKD1 cDNA, two shorter clones which each expressed only a subset of the PKD1 domains were constructed 20 in expression vectors as shown in Figure 16. The BRASH 7 clone contains the carboxy terminal epitopes, as well as the oo.o. transmembrane domains, while SrfIA contains the amino terminus, the LRR, and the majority of the Ig-like domains.

Both are efficiently expressed in the TNT in vitro transcription/translation system.

D. Immunoprecipitation Antipolycystin antibodies were incubated with 30 either protein A Sepharose or Protein G Sepharose to generate antibody coupled beads. These beads were then incubated with 3 5 S-labeled protein synthesized in vitro from the expression clones. The void and retained fractions were collected and analyzed by SDS gel electrophoresis. Sepharose alone was included as a control against artifactual binding, a concern due to the large size of polycystin, the presence of the large number of Ig-like repeats, and the lectin domain.

Antibodies to irrelevant antigens were also included as controls. If the antibody specifically bound the antigen, a protein species of the correct molecular mass will be detected on the gel in the bead fraction. If not, the expressed protein will appear in the void volume on the gel.

1 0 Each of the anti-fusion protein antibodies coupled to Sepharose A specifically immunoprecipitated protein expressed by clones which contained the matching antigenic domain. The antibodies did not immunoprecipitate protein expressed from irrelevant domains of polycystin domains not used as immunogen to generate that particular antibody), nor did they recognize other irrelevant antigens luciferase). These results confirm that these polyclonal antibodies specifically recognize the carboxy terminus and LRR domains of polycystin.

Example 7: Identification of Proteins that Interact with PKDI Further characterization of the PKD1 protein can be accomplished through identification of other proteins which *normally interact with the PKD1 protein. Those of skill in the art are familiar with a variety of approaches useful for such purposes, including, but not limited to, 30 immunoprecipitation of protein complexes using antipolycystin antibodies, screening of expression libraries with labeled in vitro synthesized polycystin, and use of yeast systems that exploit the interaction of DNA binding and activation domains.

For example, one such approach is the two-hybrid yeast system (Fields and Song, Nature 340:245-6, 1989; Finley and Brent, Proc. Natl. Acad. Sci., USA 91:12980-84, 1994) which enables the identification of genes which encode proteins that interact with PKD1. This technique relies on the fact that eukaryotic transcriptional activators, such as GAL4, function utilizing two essential and discrete domains, an amino terminal DNA binding domain and a carboxy terminal transcriptional activation domain (Ma and Ptashne, Cell 51:113-119, 1987). The two-hybrid system exploits the observation that a functional transcriptional activator can be generated even when the two domains are encoded by different hybrid polypeptides, so long as the spatial relationship between the two essential domains is similar to the native transcriptional activator. The yeast two hybrid system has been used successfully to screen cDNA expression libraries in search of proteins that interact with Yin-Yang-1 (Shrivastava et al., Science 262:1889-92, 1993), E12 20 (Staudinger et al., J. Biol. Chem. 268:4608-11, 1993), H-Ras (Vojtek et al., Cell 74:205-214, 1993), Pr55gag (Luban et al., Cell 73:1067-78, 1993), pllORB (Durfee et al., Genes Dev. 7:555-69, 1993), and p53 (Iwabuchi et al., Oncogene 8:1693-96, 1993).

A. Hybrid Construction Several constructs of the PKD1 regions as fusion proteins with the GAL4 DNA binding domain were prepared. The *fo. 30 constructs were: a BD-3 fusion between the GAL4 DNA-binding domain and the cytoplasmic tail of the PKD1 protein (amino acid residues 4097-4302) using pGBT9 vector, a BD-1 clone containing a DNA-binding domain and the LRR region of polycystin (amino acid residues 27-360), and a BD-2 clone which contains DNA-binding domain and region of Ig-like repeats (amino acid residues 713-2324).

B. Transformation of constructs into yeast Competent yeast cells HF7c, containing the lacz reporter gene are obtained by the LiAc method. Briefly, overnight cultures are diluted to OD600 0.2 and continue to grow for an additional 3 hr. Cells are collected, washed in H20 and resuspended in 0.1M LiAc in TE. Competent cells (0.1 ml) are mixed with 0.1 mg of plasmid-construct DNA and 100 mg of carrier DNA. 50% PEG400 (0.6 ml) is added and incubated at 0 C for 1h. Following this incubation, the cells are heated to 42C for 10 min. and plated on minimal medium (Difco Yeast Nitrogen Base without amino acids, supplemented with auxotrophic requirements) Yeast transformants are selected after 3 days of culture.

B. Colony lift filter assay for E-galactosidase 9 99 9 2 VWR grade 410 filters are layered over agar plates containing transformants on selection medium and transferred to a pool of liquid nitrogen for 10 sec. Filters, colony side up are placed on another filter that is presoaked in 25 X-gal solution. After two hours, filters are analyzed for the presence of blue, E-galactosidase producing colonies (not shown). Alternatively, individual colonies from different transformations can be streaked onto the same plate and processed for E-galactosidase activity.

While the present invention has been described with respect to what are presently considered to be the preferred embodiments, it is to be understood that the invention is not limited to the disclosed embodiments. To the contrary, the -59invention is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the appended claims. The scope of the following claims is to be accorded the broadest interpretation so as to encompass all such modifications and equivalent structures and functions.

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

The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common 0 general knowledge in Australia.

see* o*oo oooo o 0 oeooo eeo Page(s)II- LTL+ are claims pages they appear after the sequence listing SEQUENCE LISTING GENERAL INFORMATION: APPLICANT: KLINGER, KATHERINE W LANDES, GREGORY M BURN, TIMOTHY C CONNORS, TIMOTHY D DACKOWSKI,

WILLIAM

GERMINO,

GREGORY

QIAN, FENG (ii) TITLE OF INVENTION: POLYCYSTIC KIDNEY DISEASE GENE (iii) NUMBER OF SEQUENCES: 58 (iv) CORRESPONDENCE

ADDRESS:

ADDRESSEE: GENZYME CORPORATION STREET: ONE MOUNTAIN ROAD CITY: FRAMINGHAM STATE: MASSACHUSETTS COUNTRY: USA ZIP: 01701 COMPUTER READABLE FORM: MEDIUM TYPE: Floppy disk COMPUTER: IBM PC compatible OPERATING SYSTEM:

PC-DOS/MS-DOS

SOFTWARE: PatentIn Release Version #1.25 (vi) CURRENT APPLICATION

DATA:

APPLICATION NUMBER: US FILING DATE:

CLASSIFICATION:

(viii) ATTORNEY/AGENT

INFORMATION:

NAME: LASSEN, ELIZABETH REGISTRATION NUMBER: 31,845 REFERENCE/DOCKET NUMBER: GEN4-17.8 (ix) TELECOMMUNICATION

INFORMATION:

TELEPHONE: 508-872-8400 TELEFAX: 508-872-5415 INFORMATION FOR SEQ ID NO:1: SEQUENCE CHARACTERISTICS: LENGTH: 53577 base pairs o TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear *O (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1: o*o TGTAAACTTT TTGAGACAGC ATCTCACCCT GTTCCCCAGG CTGGAGTGCA GTGGTGTGAT

CATGGCTC,

TGTAATAAj

TTCGTGGG)

TTGAGACAC

CTGCAAcT'I

GATTACAGG

TCCATATT(G

CCCAAAATG

AACACAACAI

CTCTTTTCC4

ACTTACTTT(

CTCACTC=G

CTCCTGGGT]

TGCCACCATC

CAGGATGGCIl

ATTACAGGCA

CTGTCACCCA

GGTTCCAGTG

CATGCCTGG4C

GGTCTCGAAC

ACAGGTGTGA

CCCCCTTTTA

AAGAAACATT

TTCTCTGTC

TCACTCTTGT

CTCCTGGGTT

TGGCACCACC

CAGGCTGGTC

GATTACAGGC

ATTTCCAGGT

CTAAACAATT

TGCAGCGTCA ACCTCCTGGG CCTCCTGCAA TGTCTTTGTT GATGTTCTAT TTTGTTTTTG GTCTTGCTCT TGTTGCCCAG CACCTCTTGG GTTCAAGAGA

TCTACTTGAT

TTTCAAAATc

TGTGTGTGTG

GCTGGAGTGC

TTCTCCTGCC

ATTTTGTATT

CTGTAAACTT CGAGGGAAGG TTTGTATTTC ACAGTTTAGC TGTGTGTTTT

GTGTTTTTTT

AATGGTGTGA TCTTGGCTCA TCAGCCTTCC

GAGTAGCTAG

TTTAGTAGAG ATG7GGGTTTC

CACCCCGCTA

C GCCGCCACC G TCAGGCTGG C TGGGATTAC.

3TTCATAATAJ 2 ATTTAACAC( 3TTTGCAGTT.

r' cAccAGGcJ

'CATGCGATTC

*CCCAGCCAA'I

CAATCTCTTG-

*TGAGCCACTG

GGCTGGAGTG

ATTCTCCTGC

TAATTTTTGT

TCTTGGCCTC

GCCACTGTGC

GGCTAACAAT

TCCCTCACGT

TCACCACATG

TGCCCAGGCT

CAAGCGATTC

CCCAGCTAAT

TCGAACTCCT

ATGAGCCACC

AACTAATTTG

GCATTTTATT

CTCAAACTCC CGACCTCAGG TGATCCGCCC

ACCTCAGCCT

A GGCGTGAGTC r ATTCTACATA

-TTTTGCCTTA

V CCTGTCTTTT r' GGAGTGAAGT

TCCTGCCTCA

lTrTGTATTT

ACCTCGTGAT

TGCCTGGCCT

CAGTGGGGTA.

CTCAGCCTCC

ATTTTTAGTA

ATGTGACCCG(

CTGGCCTGGC

IJ

TATTCACTGT

CTTCTTCCCTC

GATTTTGTTT1

GGAGTGCCATG

TCCTGTCTCAG

TTTTGTATTTT

GACCTTGTGAT

ACGCCCGGCC C CTTCTTTAAA

C.

CCACAACCGC C

ACCGCACCTG

GACCATACCT

GGTTTATTTT

TTTTTTTTTT

GGCGGGATCT

GCTTCCCGAA

TTAGTAGACA

CCACCTGCCT

TTTTTTTTCT

ACCTCAGGTC I

CGAGTAGCTG

3AGACGGGGT T CTGCCTTGG C ETTCTTGTTT

C

'AATAAAAAC

C

;AACCAAACAA

'TTTGTTTCT 1 GCACAATCT C CCTCCTGAG

T

TAGTAGAGA C( CTGCCCACC

T

CCATGGTIT

ATATGTCTT TJ 7'rCAAACAA T(

GCCAATGTTC

GTTATGTGTA

TCTGGTATCA

TTTTTTTTTT

CGG3CTCACTG3

TAGCTGAGAC

CGGGGTTTCA

CCGCCTCCCA

VTTTGAGATG

~CTGCGACCT(

;GATTACAGGC

TTGCCACGT

CTCCCAAAG

TTTTCTCCT C CTCAGGTCT G

GATCTCTGGC

TGTTTTTTGA

AkGCTCACTG C kGCTGGGAT T 3GGGTTTCA C4 PGG CCTCCC A [CAAATAGT T' rCTATTTAA G ATTGAGAC T

TATTTTTGAG

GATAAACAGA

ATACTGGCAC

GAGACAGAGT

CAACCTCTAC

CACAACTGTG

CCATAcTGGc

AAGTGCTGGG

3AGTCTCACT

CGCCTCCCG

'ACCCACCAC

.GCCAGGTT

IGCTGGGATT

TTCTAGTTT

TATTMATC

ACATTTTATT

GATGGAGTC

AACCTCCAC

k~CAGGCGCG

CAIGTTGGT

V ATGCTGG

I'AGAATTTC

!LAATCCT'T

rGGTTAATC 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920

TGTTTTGCTC

AATCTTAAGT

TACCATCCAC

GCTCTGTTGC

CTACTGCCTC

TTTITGTATT

TGATCTTGTG

CACTCCCAGC

ACTCTrTTTGcC

CTGGGCTCAC

CAGTTTGGCT GGTCTCCAAC

T

ACCGGAGTGA G

CTCATTTAAT

AATAAATAAG

G(

TCTTTCAATA AC CCCTCTGTCT

C]

GTCGGGAGGC

TC

AACCGCGGAA

GA

CTGGCCCACA

CC

ACGCACTTTA

GC

CTGCAGTGCG

AC

GCGTGGGGCG

GA(

AGCCTCCGGA

TGC

CCTGCACCCG

CC(

AGGAGCCGCG

C

GAGCGGCCTG

CC

CCATCCAGCC

CC

GCGGGCGGGC cT CGCCCGCC!CG

CCT

GCCCCGGGCG

CGG

ATTTGGC

CTGTCAT

CTGCTGn

CCAGGCT(

AGGCTCCC

TTTAGTAG

1TCTGCCC

AGTTCTT

~CAGGCGG4

CGCTCCT(

ATTTTGGC

CCTGGAC

CCACTGTG

AAGGGAAT

AATAAAT

CTCTCACi

.'CTCTCAG(

CGGGTAC

AGGATCAC

ACAGGAGA

CTGCAGCG

GGCGGTGC

~CTTCCGG

MCAGTCCC

CGCCCCC

G-GGCCCG

CCGAGCC

GCCGCC!

GGGACGG

GGCGCTG

TGCCGG

AGC AGTTTCTTGT GGCTGTq TTG ACTGCAATTA

AAAGCTG

~TG ACCTGGTAAA

TTTCTTT'

3GA GTGCAGTGGC

ACAACCT(

TA GTAGCTGGGA

TTATAGG

AG ATGAGGTTTC

ACCATGTJ

GC CTCGGCCTCC cAAAGTGC TT TTTCTTTTTT

CCATTTTT

3A GTGCAGTGGC

ACAATCAC

C GGCCTCAGCC

TCTCGAGT

~T AATTTTTGTA GAAAcGGG( 'C AAGGGATCCA

CCTTCCTCC

C CCTGCTGCA

AATTTCTT;

A ATTGTAGCAC

ACTTTTTC

GAATGGATGGG

GAATGAAGG

CATCAACCT~C

CATTGCCTG

SCAGGAAA~CCT

GGGGTAGGG.

P GACTCGGCC

GCGCACGGA(

GGTGGAGCCT

GTGGCTGCTC

AGGGCGGAGC

AGATGGCACC

GGGCGGAGCG

TGAAAAATAC

TTCCAGACGC

TCCGCCCCAC

ACGCCCCGCC

CTGCTGCCGA

TCATCGCTGG

CCCGGTCGCG

CCTCGCCCCG

TCC!GCCCCGC

C.ACTGCAGCG

CCAGCGTCCG

CCGAGCGGGC

GTCGCTCAGC

ATGCCGTCCG

CGGGCCCCG;C

CGGGGCCArG CGCGC GC=GC GCCCTGGGCC TGGGCCTOGrn -TCT TCCCTCCACT

GGAGTCCTTG

GGT TTGGAATACA

ATCGCAGCCT

TTT TTTTTTTGAG

ACGGAGTCTT

CTG CCTCCCAGGT

TCAAGCGATT

['CC CTGCCACCAT

GCCCAGCTGA

'CG CTAGGCTGGT

CTCGAACTTC

TG GGATTACAGG

CATGAGCCAC

TT TTTTTTCGAG

ACAGGATCTT

GG CTCAGCGCAG

CCACTGCCTA

kC CTGGGACTAC

AAGCGTCAGC

*T CTCGCCATGT TGCCCAGGcTr *C CCTCTCAjAjG

TTCTCGGATT

LACTGTCTGTG

CCTCAGTGAC

'A GACCTGTGA GATTcAATGG ATGTGGGTTTC

CTCCCTCTTG

T TCTCTCTC TT CCCCCTCTCT G~ GCTTC'GA#GC CA~cCGCTGC SATCGCGGGG

AAGGATCCAC

CAGGAGGAGG

AACCCGCCGC

CTGCCCACCG

CTTCCCGCCC

CTCGTGCTCC

TCGGCCGACT

CTCCCATCGc

CCCCGGGAAC

CCCTGTGCAG

CCCACCCTGA

CTGTGCCCAJA

GGGCGGAG

CCCGCGGG

GAGGAGGAGG

AGCGGCCGC

CGAGCTCCCG

AGCAGGTCGC

GGCCGCACC

CTGAGCTGCG

GCCTCCGC

CICTAACGA'rG

CCGCCCGCCG

GCTCCCGC CTrCCGc3G CTGCGGCCCA GCCCCCGGCG 1980 2040 2100 2160 2220 2280 2340 2400 2460 2520 2580 2640 2700 2760 2820 2880 2940 3000 3060 3120 3180 3240 3300 3360 3420 348 0 3540O 3600 3660 3720 3780 S

SSSSSS

S

SSSS

SSSS

S

S

5

CCCTGCGAC

CCCCCTGCCT

CCGCCTGCC(

TCCCCGCGG2

GGACGGGCGC

CGCTCCCAGG.

GAGCCGCGGT

CACCCGGGGG

GGACAAACAG

AGAGGTGGGG

ATTTGATGGA

AAGAAGGGGG

GTGAGGGGTA

TCAGGCGCTC

3CGTCAACTG( SCGCCACAGCc

;GCGTGGGCGC

GGCGAGGCTC

TGGCACGGCC

CTCTGCAGAC

TCGCTAATTG

ATGGCTGTAG

TGTGCAAGAA

GTGAACGGTG

GGGGCAGGGT

TGCTATTGGG

TCGGGCCGC(

CTGTGAGTAC

GTTCCCTGGc

CGGCGCGGC.P

CCGGGGAGCC

GCCAGCGGGG

GAGAGGAATT

GGGGCGGCAG

TTGGGCTGAT

TGAGCAkAAGA

GGGAGGTGGG

TTCCAAGGCT

3 GGCTGCGGCc GCTCGGTCCC

GCGCTGCGCA

CGGGCCCAGC GGCACCCGGG

AGAGGCCGCG

CCGGGACGG AAGCAGGACG

CGGGCCAGGA

CGGCGGG4CCC TGCTAAATAA

GGAACGCCTG

GAAAAACCCC GGGTCTGGAG

ACAGACGTCC

GCGGGGCGCG GAGGCCGCGC

TCAGCTGGGA

GGGATCGGCC TGGGGCTGCG

GGGTACCCGG

GGAAGAGTTC CAGGAGGGT CTGGAAjGG GCTTAGGAAG GGGCGATGAG

GTGGGTCCAG

CCGTGAGGCT GGAGGCTGGC

CACGGGAGGT

CTCGCGGGrG GGCTGGGGTC

ATGAAGGGCC

ATCCTGAGAA CAGGGGTGAG GGGGGATTc CGTGGGGGGT TAAAGCCTTG

TCATGTTCGC

TATGGAGAC(

AATCCTGACI

GAAACAGG71

CAGGGGTTTC

ACTAAGATAA

CTTGTATTTC

ATCCCTGGGG

GGTTTTGTAA

TGTCCTrTGGG

AATGGAGCCC

TGTCTCGCGG

TTGCATCAGA

CCAGGCCGGT

TGGTGTCCAT

TGAGCGGAGA

CTGCCTTGTG

GTTGGTGGCC

3CTGCCCAGA(

PCTGACCATC(

TGGAGAGGTC(

GAACTATGAC

GCAGACAGTI

CCAGGCTCCA

GACGTGGCAC

CGTITCTGGG

GCTTTCTGG

GTGCCCCTCG

CTGTCTCTGT

CCTACCCCAC

CACTG2GGGAC

GAGAGCAGCC

GCAAGGCCCG

TTGTCCTCTT

TGTCCCAGCC

3 CCAGGTCTG

GAGGCATAG

ACACGACCTD

GTGCCCAGGI

GTCCCCAGCc

GGCTCCTCG(

ATCCCCAGGC

TCACTCCCGC

GTGGTCTCGA

GGGCCACATT

GGAGATGGCC

CCGTTGTTTG

TCTGTCCAGG

CCTCAGGAGC

TGTTCTCCAG

AGGCTCTGGT

TGAGCTGGCA

TTTCGGGAGA

GCCAGGCTCC

GACCGTGGAG

TCCCAGGCAT

CCCAGGGTTG

TAAAAACAAC

TGTTGGGGGT

ATTTGCATTT

CACAGCCGGG

GATTGAAAAG

CTGGGGAGAG TCTTGGGACC *e.

CGGGACAGTG

TTGCTAAACA

CTGTGGCCAC

GGGTIGGGAGA

GCTCCTGCGC

TCCTCCTGCC

TGATGCTGTA

GCCTGGTGGT

TGTCCGGGAG

GCCCTTGGCA

CCTGGGGTTTq

AGATTCCGAA

TCTCCTTGGG

TTGGGTGGGT

CCTTCCTTAG

AGAATGGGTT

TCCCTGACTG

TGGCAACAGc

GCTGAGGGCT

TCCTG7CTTCC.

AGAAGGGCGC

CAGCAGTGGA i

GGAGGAGGGG

TGCCAGGCCC

AGGTGGCCTT

CGTCATGCGG

CACAGATGAG

ATGTGCATAG

GGCGGAGGGG

AGTCTGATGC

TGCGTGCTGG

TCTGGCATTT

GGGAGCCGTG

CTCCTGGACc

CGGACGCGTG'

kCCCACAGAA 7CTC743TCTG

AGCACCTGA

'GGTGGCTGC

;CCCCCGCCC

7ACCCTGGGA 3840 3900 3960 4.020 4080 4140 4200 4260 4320 4380 4440 4500 4560 4620 4680 4740 4800 4860 4920 4980 5040 5100 5160 5220 5280 5340 5400 5460 5520 CAACAGGGCA CAGGGTGACC TCATGTGGGC AGGTGGGTC TGTTCTGTAC ACACCTGG 5640

CCGCCGCT

GGAAGGATI

AGCCATTT=

GGAAGAGGC

AAGGGTCC7

GGTGCCTCI

TTCCAGGTG

GCCGAGAGG

CTCGAAGCT'

AGAGCCTGC(

TTTTTTTTT'.

CGATCTCGG(

TCCCGAGTAC

TAGAGACAGC

CGCCCGCCTC

GACCCATGT'r CGCAATAcTG

TGTGTTCACA

AATTAGTTGA

TTGTCTCCAG

GTTCAAGCGA

CACCACCGTG

GG GAGAGTTC

GAAGGCCC'

rG CTGTCTAC( 3G TCAAGCqrGC ~A GAGCGTTGC 'C CACTTGTGG

AGGACAGCC

T GGTGGCTTT r CGTGGGGAG,

-CTGCCCTCCC

r TTTTTTGAGI

-TCATGGCAAC

CTGGGATTAC

GTTTCTCCAT

GGCCTCCCAA

TTGAACCAAA

CAGACCCACC

TTTTTGGTTT

TGTCTTTTTT

GCCGCAGTGC

TTCTCCTlGCC

CCCAGCTAAT

TO GAAGGTGGGG

TGAGGGGACC

TG GCTGGCCCCC CAGGCcACC X TGCAAACTCC

TCCTCGG.JGA

GAGAGOTGAAG

GACACAGATC

'T GTCTGGGTGT

CACCAGTAGC

CTCCCTGGCTG

CTGAAGCTCA

G GGGCTTCTGA GGCCACAGCC T GGAAAAGATG

GCGTACTGCA

A. CGTGGGCGA

GCCGTGGCTG

2TGCCCCGACC CTTCTCCCTC C SCAGAGTTCAC

TCTTGTTGCC

CTCCGCCTCC TGGGTTCAAG

C

AGGCGTGCAC CACCATGCCT

G

ATTGGTCAGG CTGGTCTTGA

A

AGTGCTGGGA TTACAGGCAT

G.

TTCCAGCCAC CCTTTTATCT

G(

TAACACAACA GACAGTTCCT

TC

AATAGTT'rGA ATTAAGAGCC

AX

TTTTTCTTTT TTTTTTTTTT

TT

AGTGGCATGA TCTCAGCTCA

CC

TCAGCCTCCC GAGTACCTGG

TA

TTTTGTATTT TTAGTAGAGA CG CATGGCA2 TCTGTGC2

GACGGCTG

ACAGCTGC

CTTCCTGG

GCAGGGAC,

TGCCTTGG(

k.AACGTGCJ kCTCACAGI

~TGACCCAM

LAGGCTGGA

'GCTTTTTC

GCTAATTT

CTCCTGAC(

AGCCACCA(

2 AAGCATT]

ATGCCACC

ATAAGGTC

'TGAGACGG

GCAACCTC

GCTGGGTT

GGGTTTTA

GGCCTCCC

k.AATATAT IrCAGTGG 3CCTCAGC

L'ATTTTTA

'AGGTGAT

~CCAGACA

LAGAATGA

'AGCTAGC

AC TAGGGCCTTA GT GGGGCAGCCC GG TTTTCCCCAG TG GCAGGTGTTC

GOGGCTCACGCA

1G CTGTGTCCAG ~T TAATGATGCT PG0 CTCTGCGTGG C CCCCCACc.Dc

'TGTTTTTTTT

OTGCAATGGCA

C TGCCTCAG~C

TGTATTTTTAG

C TCAGATGATC

GCCCAGCCCT

[TGGAGGGCAT

GAAGGCCTGG

CACACACTGC

AGTCTTGCTC

CGACTCCCTG

TACAGGCATG

CTGTGTTGGC

AAAGTGCTGG

ACTTTTTTTT

CGCGATCTCA

CTCTCCAGTA

GGAGAGACOG

CCGCCTGCCT

AAAATATATG

AGAATTCTAC

TGATGTCTmJ' 5700 5760 5820 5880 5940 6000 6060 6120 6180 6240 6300 6360 6*420 6480 6540 6600 6660 6720 6780 6840 6900 6960 7020 7080 7140 72'0 7210 7320 7380 7440 7500 CAGGATGGTC TCGATCTCCT

GACCTCGTGA

GATTACAGGC GTGAGCCACC

GCACCCGGCC

TTTTTTTGAG ACGGAGTTTC

GCTCTTGTTG

CCTCACGGCA ACCTCCGCCTr

CCCGGGTTCA

GCTOGGATTA CAGGCATGTG

CCACCATGCC

GGTTTCTCCA CGTTGGTCAG

GCTGGTCTCA

TGGCCTCCCA AAGTTGGG

ATTACAGGTG

TGTGTCTTTA AGGCTGGTCA

AGCAAAGCAG

CTGGCTGTGA TCAATTCGT'r GTG7AACACCA TCTGCCCAcc

AATGTCTTTT

CCCAGGCTGG

AGTGATTCC

TGGCTAATTT

AACTCCTGAC

TGAGCCAACG

TAGGACTGGA

CTGTGCTTGG

TC4

AG~

CT

TG

CGC

AcC

TGTTTTGTTT

GATCTCGGCT

CTGAGTAGCT

TAGTAGAGAT

ATCTGCTTGC

TATTTATTTA

GGAGTGCAGC

TCCTGCCTCA

TTGTATTTTT

CCTCGTGATC

CTGTCTTTTA

ATTTGTTGAAC

CTCCATGGTG T CG'IrGGAGCC

G

GATGTCATCA

G

CCCTGGCTGG G

GCACATCGAGG

GCCTTGCCCT T AGCAGGCGCA G 4 GAGCGACCCC T GGCTGGCCAG G( AGGACTAGGG A' AGGGCTCCGT T

GAGATGGATGA

CCAGGTTTCA A TCGGGGGCAG

G

AGAGCCCTGG

CA

CCTCACCCGG GG

TGCCTGCGTGAG

GGACAAAAAT GT TGTTTGAGAC GGAGTCTGG CACTGCAGCC TCCATCTCC4 GGGATTAGAG GCGCGCGCC GGGGTTTCAC CATGTTGGTC CTCGGCCTCC

CAAAGTGCTC

TTTATTTATT TTTATTATTT AGTGCCATCT

CAGCTCACTG

GCCTCCTGAG

TAGCCTGGAC

1GTAGAGACG GGGTTTCACC 2TCCCGCCTC AGCCTCCCAA ATGTCCGAT GATGTCTAGG ;AAACTGGCT CCTGCAGCCT ~CACCTCCGT GGTGCTGTGA CTCTGTCACCC AGOCTGGAGG ACAATGGTG3T CGGGTTCAAGC GATTCTCCTG

CCTCAGCCTC

SCCACGCCCGG CTAATTTTTA

AAAATATTTT

AGGCTGGTCT TGAACTCTTG

GCCTTAGGTG

GGATTACAGG TGTGAGTGAT

GTATTTTATT

GAGATGGAGT CTCACTCTGT

TGCCCAGGCT

CAAGCTCCGC CTCCTGGGTT

CACGCCATTC

TGGTGCCCGC CACCATGCCC

AGCTAATTTT

GTGTTAGCCA GGATGGTCTG

GATCTCCTGA

AGTGCTGGGA TTACAGGCTT

GAGCCACCGC

AGCTTCCCTT CCTCTCTTTT

TCCTTGTGCA

GGATTTCTCG CTGTGTCTG

GGGGTGCCAC

GTGTGTGCTT TGTGTTTCT GTAAATTGGT

ACATCCCA'

CTCAGGGCC

GGTCACCTC

GACTTGGTP

TCCCACCTG

A.CCCCGGGG

%.GGCCTGAT

CACGGAGG

7TGTCACCA

LTCACTGGA

'GGGAGGG

,GCTCCCAC

GTAGGGCC

GCGAGCG

TCCCTGAG

AAACGGTA

GGACAAGA

r' TGTCCCAGA(

CCCTGCTCT)

GGTCTGCTGC

LGGTGCTTGG'I

CATCCCTGAA

CCCCTGCCTG

GCCTTAGAGc

GGCCCTGGCT

AGGCCTCCAT

GCCCGCGTTC

GGCTGGCCTG

AGGGAGCTGC

TCTGTCAGGA

GAGGCAGTGG

CCGGGTCTTA

GTTTCTTTAT

AGTCACACGC

3GTTGTCCTG k AAGGCCACr'

TGTCTCGCAK

TCACTGATG'

TGACAGGAGI

GGATTGGCO']

GCAACTGCCP.

CCCATTTCTC

GAGCCCTCAG

AACCAACACG

GAAGGACCCC

CCAGAGAGAG

GAGCCTAGGA

TGAGGACCTG

CGTG7GCTCCC

TAGACGCGGA

TCACTCCTGT

G CTGGCACTGG r' CTGGTGCTGG k. ATGCTG4GGG'r P AAAATATAGG

GTGTGGGAGA

CGGGGAAGAC

GAGACACAGC

GTCCCTGGAT

CAGAAGGAGG

CAGATGATTC

CAGTGCAGGT

TCCCCAAGGG

GAGGCCTGTG

CATCCTGCAT

GCACTCGGGCC

TGCAAACTCGC

ACGCGATTGC c

CCTAGGTGTA

TTGCCACTCA

CCAGGACTGG

AGCACCCGGG

GTGTAGGGAC

AGGCATTCTG

TTCCTTGGGG

CCTGAGAGCG

GCCACCCTCG

TCCAAGGACA

GACATTGAAG

GCAAGGTGAC

rCTTCTAGGA 3TCCAGCTGG

TTCAGAACG

~CAAACTN'GT

7560 7620 7680 7740 7800 7860 7920 7980 8040 8100 8160 8220 8280 8340 8400 8460 8520 8580 8640 8700 8760 8820 8880 8940 9000 9060 9120 9180 9240 9300 GGGGGAAGGG ATGGGGAGGC TTTGGTTGTG TCTGCAGCAG TTGGGAATGT GGGGCACCCG 9360

AGCTCCCAC

TCGGCTTGC.

TTAAACATG<(

GGTGGATCG(

CTCTAAAAjAJ

TCAGGAGACI

ATCACACCAC

AAAAAAAAAA

GCCAACAGCG

CCACTGTCCA

TGGCTTGAGG

ATTAGTGGTG

GTCTATGAGG

CTAGGAAACG

r GCAGAGGCGA CTGTGGAGA kTCCAGATCAT ACAGGGAACA ACAAGGGcGTC ACTCACGCC~ TTGAGCCCAG GAGTTTGACJ TAAAkAGAACA TTGGCCGGGC GAGGTGGGAC ATCACTTGAG TGCACTCCAG GCTGGGTCAC AAAAATCACA GGATCTGAAC TGTGAGAAGA TGGTCGGCCT GCCGGGCGCG

GTGCCTCACG

CCAGGAGTTT GAGGCCAGCC GCGCCTGTAG TCCCAGCTAG TTGAGACTGC AGTTAGCTGT CAGAGAGCACC TGCAGGTCAT CCATGCAGTA CTATGATTCA ACAACAGACA

GGGACCCCGT

r GGAATCCCAG CAGTTTGG3cA

GGCCAGGGTG

CCAGCCTGG CAACAGGGTG

AGACCCCGGT

GTGGTGGTAT GCATCTGTGG

TCCCAGCTAT

CCGAGGAGGT CAAGGCTGCA

GTGAGCTGTG

AGAGCAAGAC CCTGTCTCAA AAAAAAAAA AGAGATTTCT CCAAAGAAGA

CGCACAGAG

CATTAGTCAT GAGGGAAJACG TAAATCAAAA CCTGTAATCC CAGCACTTTA

GGAGAGCAGA

TGGGCAACAT AGCGAGACCA

ATAAATAGAT

TTGGGAGGCT GAGGGGGGAG

GATTCCCTGA

GATGGTGCCA CTGCACTCCA

GCCTGGGCGA

AAAACAGGGT GGGCGCGGTG

GTTCACGCCT

GTCTTTAAAA

AAAAAAAAAA

GTAATCTCAG CACTTTGGGA GGCCAAGGTG GGGGGATCAC

AAGGTCAGGA

9 .9 9 9 9 AGCCTGACtA

TCGTGGGCGC

GGGAGGCGGA

GCGAGACTCT

GCTACTTTGG-r

GGCAAGATTG

AAAAGGTCTA

AGCCCTCTGT

CTGGTCTCAT

ATCAGCATGC

GCCCTGGTTT

TTGCACTCCC

GCCCCTCCCAC

CCCACCTCTCC

TCTCCCTCCC

ACATGGTGAA

CTGTAATCCC

GGTTGCAGTG

GTCTCAAAAA

GGGCTGAGGC

CACCATTGCA

GGAAGAGTCC

GTTCTTGTCT

rTTAcACAcc

TCTGGGGCAG

b.TAGACAGAC

AGGGGCTG

:CTCTCCCTC

:CTCCCTGCC2

"GCCAGCCCC

ACCCCGTTCT

AGCTAATTAG

AGCCAATATC

AAAAAAATGC

AGGAGAATCG

CTCCAGCCTG

GCACCCTCTC

CTCCATACCT

AGGAAATTGA

ACCCCTGCAG

AGAGGTGGCA

k.GGGGCCCTG 2CTGCCAGCC kGCCCCTCCC

P'CCCACCTCT

ACTAAAAATA

GAGGCTGAGG

ACACCACTGC

TGAGCGTG4GT

CTTGAACCTG

GGAGACAGAG

CCCGCGGTGG

CATCACGGCA

GGCTCTTTGA

CCGCACAGGG

GTGGCGCTTC

CGCCCAGGTG

CTCCCACCT C k.CCTCTCCCT

CAAAAATTAG

CAGGAGAATC

ACTCTAGCCT

GGCGCATGcc

GGAGGCAGAG

TGAAACTCTG

CCACGCCGGG

CCGCAGGGTT

GAAGCCGTGG

TGCCTGGGGc 2GAGTCGGAC

AGCTGCTTG

TCCCTCCCTC

~CCTGCCAGCC

GTTTGTGACC

CGAGGTGTGG

ACTTGAAccc

GGTCAACAGA

TGTAGTCTCA

GTCGCAGTGA

TCTCAAAAAG

CTCCGCGCTG

GCAGCCACTC

TGATGATTTC

CCACACTAGT

rGCGATGTGC 3GTGCTGCCA

;CCAGCCCCT

CCTCCCACC

::ACCTCTCCC

I

942 0 9480 9540 9600 9660 9720 9780 9840 9900 9960 10020 10080 10.1.40 10200 10260 10320 10380 10440 10500 10560 10620 10680 10740 10800 10860 10920 10980 11040 11100 L1160 L1220 0 CCTCCCTGC CAGCCCCTCC TCCCTGCCAG CCCCTCCCAC CTCTCCCTCC CTCCAGCCCC TCCCACCTCT CCCTCCCTGC

CAGCCCCTCC

CTCCCACCTC

CCTCTCCCTC

CTTCTCTCTA

TTGCGCCCTG

GGTCCAGTCT

CCTGCAGGGC

TGTTAAAGTA

CACCTCTCCC

TCCCTCCCTG

CCTGCCAGCC

GTTTCCTGTT

GAGTCAGACC

CTCAGCCTCA

AGTGTAGCAG

GCTCTGTCGG

TCCCTGCCAG CCCCTCCCAC CCAGCCCCTC CCACCTCTCC CCTCCCACCT CTCCCTCCCT CAGTTTCAGG AAGGAGGCTG TGGGTTCACG TCCCAGCGCC GTTTCCTCAC

CTGTAAAGTG

TCACCTGGCT CAGCCACTGG TTCCCTCAGG GGTTCCGGGG

CTCTCCCTCC

CTCCCTGCCA

GGCTCATCCC

GGAACCCAGA

TCCACCTCTG

G43CTCCATGA

CAGCCCCAAC

GCCCATTCCC

CTGCCAGCCC

GCCCCTCCCA

TGCTGTGTCC

TGTAGGGAAT

GTGTGACCTT

TTAGATGCAC

AATCATACCT

CTGTCCTCCA

11280 11340 11400 11460 11520 11580 11640 11700

TGCACTGTG,

ACACTGTGC(

TGGACTCCT)

TGTGGGGGC']

TTGGTGCCTI

GAGCCGCGAC

GCCTGAGTTC

GTGGTGGCGG

TTGTGCCAAG

CAGGGCATCT

TGGCCCATGA

CAAATGTGGG

TGCCACTGCC

TGCCTGGGAT

ClrGGAGCTCT CCGC7VCTGT

GCACGTCTGC

GAAAATGCAG

TTGCCTAGGG

AGGCGGGCTG

ATTCCTGACC

GAAAGGGCTT

k. GACCTGCCC'

TGTGCTTAG,

k .TGGACCCCT(

"CACAAGACC(

"TTGACGCGTJ

TACCGTCCTC

CGCTCAGTGC

TGTGCGCTGI

CCTGAGCCTC

CTATGAGGGC

GTGGGTGATG

TCCCGCATCT

CTCGCTCCCC

CTGCTTT~CCA

GCAGTGGCCA

CTGGGCCTGG

GGGCACAGCA

CTCACGCCCT

GCCAGGGTGC

GGTCCTTTTC

TTAGCAGCGC

TGTGCCCAGG

T GCCACAGAGC k CCAGACACTG

AGCACCCAGC

GGCCCACTCC

[CTGGTGTGTG

ACTCCTTTTG

CCGCCCTGAT

CGCTGGTGGG

GACGTCCCCC

CTCCTGCTGG

CGCTGGCCAC

GCAAGCCCCT

CACCTTGGGG

GCAAGGAATA

CGGCAGCCCA

C

CCTGCACTCT

GCGGGGGCGCC

TTCCCAGAAC 1 CCAGGCACTG G

TCCCTGCAGCT

CATGATCTGAA

AGAGTGTAAC

GACGACGGGA

CTCGGTGCCT

TGCTTGTGCC

TGAGACGTGC

TTCTTITGAC

GTGCGGACCC

CACCGAGAGT

TTCCCGGCTT

1GCCGTCTCT

CATCTGGTGA

CCTGGGTCC

PGCCTCTCCCC

rACTTTGGAGC

;CCCGCCAAGC

;CTGCCTGCG C 'ACAGTCTCC C

£CCTCGCTCTT

TGGCAGGAGA

'CCCGAGGCC C

GACAGGCTGG

AGCCTGAGGG

GCCAGTGCAG

TCAGCGCAGG

TACATCTGGG

GGGGCTGGGA

GTAAGCTGGC

CGCTG4CATTC

CTTTGGGAGC

rCTGT'rGGCT

GTGGATCTCC

AGTGGCCGG

'CTAGGGTAT

~CTGCTCGTG

;GAGACACAC

'ACCCTGGAA ~TCCAGCTGG C

TGCAGAGTG

CATGGCTTG.G

AGGGCTACA TI AGCCCTGGC C

CTTCTGTGAG

CCTTCTGGTT

TGAGAGCCAG

CCTGGGCGGG

GCCGCGTGGCc

TGTTTGCCCA

AGTGTTGGCA

GAGTGGCACT

TTGCTGTTAG

TTTGGGGAGG

CTTCTGAGGC

rCTGCCATCC

GCACCGCTGC

3GGGTGGTTC

GGGAGACCC

kTGTTCTTTT

.GAAAACATC

:TGAGGCCGG

LGCGCAGCTG

~CAGCTGTCC

CTGGGGCTG

CAGCCTGGC

GCCACCTCA

GAGGCAGGA

11760 11820 11880 11940 12000 12060 12120 12180 12240 12300 12360 12420 12480 12540 12600 12660 12720 12780 12840 12900 12960 13020 .4 a CAGAGGCGGA AGCCAGCTCT ATGAGGCCAG CGCTGGGCAA GCCCATGCCC AGGGAACGTC ACAGCTGTGG GAGTACAGGG 13080 GCTCCGGGTT CTGAGCCCGT

CCACTGTGCA

CATCATTGGC TlGTGCCCACA

GCCGAGTIGGG

GTGCTGCTGC CCTCTCCAGG

GCACTGCTGT

TGCTTGCCCC CCCCCCCACC ATCCTCTTCC CCCTGCTGGC TGCCCGGGGA GGTGTTTGGG TGAGCCTCAG TGTGCCCATC AGGAGCdTAA TGAAGGGTGG GAGTGGAGAG GGATGCAAGG CGTGCAGGGG CACCAGGAGC

CGGCCCTCAT

CCCCAGCGGC AGGTAGCATA CGTATGAAGC CGTCTCCAGA CGGCCCTTTT

TGAGCTGGCTC

CGCAGACTCC CCTTTCTCAT CTCCCTCGTT

C

TGCCTGCCTG TGGGTCCCGG GAGGACCTGA CTGGGGACAG TTCAGCCGTG GGAGGGATCT G TCCCCAGCTA GTCTCACACC CCGTGTCTGG G

TCGTGGCC(

TGATGGGAJ

GCCCGCACZ

TACCTTGC~j

GGATGGTGT

GGTCAGTGC

GGGTCACAAi rCTCCCCTr% 3CTCTCCTT(

TGTTT'ITC(

AGCCTCCG.P

;GCTGCCCA7

TAAGGACAG

ACCCAGAGA

GAGGCTGCC

CATIGGAAGT

rTCAAATGA rGGAAGCCG ;TCATGGCT

CCCTGTCC

T GGCCTCAGGA

TGGCTCGTAC

T CCGGCTGCCC

CGCTGGATCT

3 CCGGGCGCJAG ATGGCCAGTT P' TCCTCCATTG

ACACACTOGA

7GGGGGAGGAG GAGGGCCCCT GCACCTGCCC

ACACAGGCTG

GCCTGGCTCC

ATGTCAGCTG

AACTGGAAGG

GTGGCCCCGA

CTACACCCCA

CAGGTGGCT

ATCTGTGTAG

GCAAGGACAT

GGCCGGAGTC TCCATCCCTG GTCACCCCCG

GCATCTCATC

AATGCCGCTG

AGCCTGGGGC

CCCTCGTGCA GGGCTCTGTT

S

GCTTGGGGCC

CAGGGTTGTG

ATCTGCCCAG

CCGTTAATTT

AAGGAGCACA

GGGCCGCAGT

GCCCATTTCC

GGCGGAGGGG.

CCTGGGTCTG

GGCGGCCCCT

GGGGTGCCGG

TTCT'rrGGGG

GCCTGGGGCAC

TTCCCTCTGC

TCAGTCCCAC

TI

AGAAGGCCCA

TGGCAGCCTC

GCCGGCCTCC

CCCGGGGCTG

AAACAGGATC

GCGCAGAGGG

GGGGGTGGCA

TCACCCTGGG

AACCAGCTCC

GCGTCCTGTC

2CGAGCCGGT 3CCTGGCGCAC 3CTCCGTCCGC

TCAGCTCTG

GTGGATTGG G 'GTTGCATTC C

CCCCAAGACT

GTCCTGTATC

CTG4GCCCTCC

CACTGTTTTT

ATTTCCGGCC

AAACAGATGA

CTG3CCGCCTG

CCTGCTCTCG

I'CCAGGAGAG

2rGCCCCTGC

XCCCCCAGCC

ACCCGCTGC

CCCCCAGAC

LGTGTGAGAC

IAGGGCCCCG

CCGACCCCGC

TCCCGGCCC

A

TC

GGAGGGACGG GCCTGGGGGT

GACGGGGCCT

CGAGGGAGGA

CAGTTTCCAG

rGACCACACG

CCCACTCAGC

['CTGAGGCAG

3GAGCTGCCC

~CTCCCCCG

.'GCCAGCCTC

GGCAGGGGGC

GCGGTTACAT

TGAGGCGGCC

TGTCTGGAAT

ATCTGGTCTG

GTCTGGTTTG

CACACCCAGG

CCCAGGAGCG

ACCCCCACcC

GGTAGGCGGA

GCACCGTCCC

CCTCACTCTC

CGGCTGGCCC

TCTCCAGCGC

CTCGTGGGGC

GCCAGCAGcc

AAACTGCAGC

CTTAAATAGA

AGCGAGGAAG

CCACACTGCA

CCTCTTGCTG

ATGGGGCCTC

P.AGCTCCGCA

A.GCGCGGGCG

GTGCAGATGT

SGGAGTGGGC

rCTGGGGCCA

;AAGTTCTCC

CTGTGGGGC

I

I

I

1 13140 13200 13260 13320 13380 13440 13500 13560 13620 13680 13740 13800 13860 13920 13980 14040 14100 14160 14220 14280 14340 14400 14460 14520 14580 14640 L47b o .4760 .4820 .4880 .4940 CCAACTGTGG GCAGAGCCCA GGGGGAGGGC AGGAGAGCCA GCGCCTGGCT

GGGAACACCC

CTGAGGGGCC GAGGCTCCAG GGCGAGGGGG CCCGACCTGG

GGTTCACACG

GGGCAGACCC GCTGCAGCAT GAGACACGTG TCAGCTACCT

CGGGCCGGCA

GCTGCCCACA GCCCTGGGAC GTGGCCCCAC CTGTGACGGG

TGTGGAGGGG

GCCTGGCCAC ACCCTCTGCT GTTGCTGCTC CTGCTCCAGG A ITGGCAAGG GGGGTGAAGA CCCGTACTGT GOCCACACAC CTGGGACTTC

CTTCTCCACC

CCAGCAGCCG CTAAGGAGCC CGCTGGGTCC CACGCTAGGA

TGGTCCTAAC

TTCCAGA'rCG GACGCTCGGC.GCTGGGGACC CCTTGTGTCC

CGGGGCTGGG

GCCCCCATGG GGGTGTACTC CTCCCGACAA GCTTGGCTTC

AGCTTCCCTG

CTGGCCCTCG GGCACCCATC AGGCTGTCCC TGTGCACCTG

GCTCCCACCC

TAGCAGGAAC TGGGTGAGG AGTGCGTGGG GCAGCAAGGG

CCTGGGACCCC

TGCACTCTGC TCTGTGCTCT TGCCTGGGCT TAGGGCCGCT CGGTGGTCCT

G

GCCTGGGCCC TGCTGTGTCC CCCATCCTTG CAGGGAACCA GAACGTG7GGG

G

AGACAGCGGC GATGATGTCA CCTGGCGGGT GCAGAGGAAG

CCCGAGGGGCG

GGCTGGCGCG AGGCTGCCTG GCTAGGCCTT GGCGTTCCCC CAGAACGGCG

A

CAGATGGAGA CGTGAAAAAG TACGGGAGCA AGCGAGGTGA

GGACTCCACGG

9

TGCTGTTCC(

CCAGGGGGC)

TGCACCTGGC

GCCGAGCGGC

GGAGAAGGAC

GCAGGGCTGC

GGGATGGGCG

CTGGCTTGTC

GCCAAACATC

CCCCATGCCT

TGTCCCTTCC

AGGGCTCCTG

CGCCGCAGCC

TCCCCCTCGG

AGAATGGCCT

-TGTCCCTGA)

k. CCTGAGTCC9J

-TCCTGTCTGC

GTCCCCAAGz

CCAGCCTGGA

CTGCTGGCGT

GGGAGCCGGG

AGCTCCCAGC

TTrCAGGCTTT

GGGGGCAGGT

AGGGGGCCTG

CGCCTCGGGT

GCTGGAAAGT

GCATGGTGCT

CTTGCTGGTC

IGCCCACACC'.

ACCCAGGGCJ

GCCCCAGCTo *CCT'rGCTGCz

*GCCTGGCACC

GGAAGAAGTG

GGGCTCTGGG

AGCAGCCACT

TCCTTCTTTC

GCGAGAGCCT

CCTGTGTTCA

CCCGGTGCCr

CCCTCCTCAG

TGGGCAGTGG

TCCCAGCCAC

r GAGTCCTGCC k. GACGCTTCCP

CATTCCACTC

TrTCTGGGCC

CAGGGAGTGC

TCCATGGCAC

GTCCTCGGCT

CTTGATGGAT

CTTTCTCCCG

GTGCCCCTCC

CCGTGGCCTC

CATTTCTCCC

GTCTAACTGC

GTGTGAGTCC

CACCCTGTCC

CAGGGCAGAT

LCACCCTGGGG

CCCTGGGCCC

TTGGGCTGGG

ATGGCCAGAA

CCCCAGGCCT

GACCTGCCCC

TI'TCCAGAAA

TGGCCTGGGT

CTGGGGCAGT

TGCAGCACCTC

TAAAGCATTGC

AGTTCCTCACC

AGCTGCCTCA C CACCCCACGG

C

G4

G]

cc

GG

CIA

PT

CCCGGGTGGC

GGCTGGCCCT

CAGCCTCCAG

GTGCTGGAA

CAGTGGTGCC

TCCTCCCGCC

GCACCGTCCT

GGAGCACATC

PTCCAGCTCA

'AGAGGACCC

;CTGCCAGAT

CAGGGCArC2

GGGTGGGGG

TGGCAAAAG

GGACCCCTG

~TTCCACAC

~TGGGGGAC

;GGAGCTCG

."GGGGCCG

:GGTGAcAG

TTCACAGT

CCCCTGCC

GAGGGT

GAGCTGCT

CACAGCTG-

CGCCCCTT

rCTGCTGC 2ACAGTGT

-=TTCTCGI

15000 15060 15120 15180 15240 15300 15360 15420 15480 15540 15600 15660 15720 15780 15840 15900 15960 16020 16080 16140 16200 16260 16320 16380 16440 16500 16560 L6620 6680 .6740 .6800 GTGGATGCCT AGCAGCGCGG CTGTGGGCCC ACCCATCCTT ATGGGCAGTG

GGGAGCACCT

1 CAGCCCGTGT CCCTACCTTG GTGTAGAGGA GGGGACGGCA GAGAAGCAGG

GTTCAGTTAG

GGGGGAAGTG GTGGCCCTGC CGGAGGGGCC GTTCCCTGTG TGCCTGGCCC

CCAGATCCTC

TCCCCTCCCG GAGCCCAGGG CACAGGCATA GGCTCTCTGA GTGTCCCACA

GCCCCTGGGG

GAAGGGAA'CT GCACCCCCAA CCGTGCCCTC CATCCGCAGA TGGAACGAGA

AGCTCCGGGA

GCCAGTGCCC AGCGTCTCAT CTGTCTGGGC ACCCAGCCCA GGTGAGGGCC

TGGCTCCACC

GTCCGTGGCT GGTGCTGCTT CCTGGCACGG AGAAGGCCTC GGCTGCTCTG

TCCCCTCAGC

TGGGGTGGCC TCTGGTCCCC TTCTTTGTTG GTTCCCTTCT CAAGCTCTTG

CCCTGGCCCC

GGGCCCCACC GGGCAGCCTG TGTGTGCGTC TCTCCTGCGC CGGGTAGGCT

CCTGTGGGAG

CGGAGCTCCG GTGGGAGGAG CAGGGCTGGA GGCTGGCAGG GGCTGOGCGG

GTGTTCAGGG

ATGGAGGCCG CCCCGGCTTG GGGCTGGCTG CCGGGTGGTC ATTGCTGGGA

AGAGCAAGTC

TAGGCGGAGG CACCTGCTGG GTCACTCGTG GGGAGGGTGA CACCTGGGGA

AGTAGAGCC

CGTGGCAGGA GGTGAGGCCT CGGGGTCCTG GGGAGCAGGG GGGTGGTTG

CAGACCTIGCG

GAGCCATAGT CCTGTGCCAG GAGCACTACT GGGAGTGCGT GGGACCAGGA

GGGGTGCCCA

GGGTGGGCGG CAGAGTGACC CCCGAGGTGC TTGAGGCCGA GGGGAGcqG AGTTCTCG3T TTGCCCCAGC TCTCTGTCTA CTCACCTCCG CATCACCAGC TCCAGGACCT

GGTTTGTAAC

TCGGGCAGCT CTGAAAAGAG AGACATGCTG CCGCCCTGTG GTTTCTGTTG

CTTTTTCTTC

16860 16920 16980 17040 17100 17160 17220 17280 17340 17400 17460 17520 17580 17640 17700 17760 17820 17880 17940 18000 18060 18120 18180 L8240 L8300 .8360 .8420 8480 8540 8600 8660

ACTGACTACT

GCCTGGTTTT

CTCCATCCTT

GGTGCTGGAG

TGATTCTCCT

GACATGGGAT

TCTTTTTTTG

TTTTTTTTTA

TGCAGGGGTG

GCCTAAGCCT

GTTTTTCCTA

TTTTTGGAGT

TTTTTATTTT

CGATCTCAGC

CCTGAGTAGC

*J S

S

ACTAATTCTG

CTCCTGACCT

AGCCATTGCA

TTTTCTTC

CAGTGGCGTG

CTCAGCCTCC

ATTTTTAGTA

ATGATCCACC

GGCCATCTTT

TAGTTTTGGT AGAGACAGGG

CAGGTGATGC

CCCGGCTCTT

TTTTTT TT

ATCTTGGCTC

TGAGTGGCTG

GAGACAGGGT

CACCTTGGCc

CTTTCCTTGC

GCCCGCCTCA

TCCCCTTCTC

CTTTTGAGAT

ACTGCAACCT

GCACTACAGG

TTCACCCTGT

TCCCAAAGTT

1 .TICCTT.L

CGGCTGTGAC

TTTCTCTTTC

TTGAGATGGA

TCACTGCAJAC

TGGAATTACA

TGTCTCCGTG

GCCTCCCAAA~

CTTTTCTTCT

GGAGTCTcGC

TCGCCTCCCG

CTCCCGCCGC

TGGCCAGc3AT(

CTGGCATTAC

CAATTGTGCT

TTTCCTCCCT

GCTTCACTCT

CTCTGCCTCG

GGTGCTTGCC

TTGGTCGGTC

GTGCTGGGAT

CTICTCTCCTC

TCTGTCACCA

3GTTCACGTG

ATGCCCGGC

;GTCTCGATC

GGAGTGAGC(

TCTTCTAATT

CCCTCTCACC

TGCAGGATGG

CGGGTTCAAG

ACCACGCCCG

TGGTCTTGAA

TACAGGCAGG

CCTTTCTTTC

GGCTGGATTG

ATTCTCCTGC

TATkIT'T''GC

IVTTGATCTC

:ACCGTGCCC

J

a

I

1 1 1 .555 TTTTCTTTCG AGACCGGTC GCCCAGGCTG GACTGCAz~GTG GCACAATCAT AGCTCACTGC AGCCTCGACT

TCCCTGGCTC

AAGCCATCCT TCCTCCTCAG CCCCCCGAG.

CTGGCTGATT CTTTTTTTCC

TTGTAGAGA

CAAACTCCTG GCCTTCCCAA

AGCACTGGG

CTTTTCTTCT TTTTAACTGcG

AATAGTTGA,

TATTTTW3C CTTTAGTATG

TCGTGTAAG'

TTTCTAATTT TA TrTATATT TTGCGTAGA) TGGTCTTTGA TGTTTTATTT

ATTAATTATC

TCGCCGTTTC ACCCAGGCTG

GAGTACAGTC

TCTCTGGGCT CAAGTGATTT

TTCTCTCCTC

ATGCCGCCAT GCCTGGCTAA

TGTGTATTTT

AGGGTGGTTT CAAAATCCTG

GGCCCAGGCG

GTTACCGGCG TGTGCCCAGT

GCCTGGCCGT

CTCGAGGTGG CGCCTGCTCC

CCTGTGCTCC

CACAGTCATA CCTGGTGrG

GTCCCACAGT

ATGGGGGCCC CTCGAGTCTG

TGTGGGGGCT

GGGGGACTGT GGACAGGGGA

TGGGGGGCCT

T AGCTGGAACT

ACAGTTAC,

,T GGGGTCTTGC

TATGCTGT(

T TTACAGGCAT

AAGCCACCI

C GTTTTCTTTA

TTAGCTGTG

r TGCTAGTGCT

TTTCTGAGA

k. GTTGTGTATT

TTAGATGGA

TATGTATTTA

TTTATTTT'P

ATGCGATCTC

AGCTCCCTG'

TACCTCCCGA

GTACTTGGG)

*TTGTAGATAC

GGGGTCTCAC

ATCCTTCCGT

CTCAGCTCCC

CTTGGAGGTC

TTGTTTCTCTI

CTGGTAGCCT

GGTAGTGAGC

GGGACCACCC

TGTTGGGTTC

GTGGACAGG

TTGGGAGACC

TGGCCCTGCG TGGGATGGGT ~C ACTACCATC C ATCCTGGTCT *C ACCCAGTTTC

GTCAGGAGGG

,T TGTAGTTTGT

GTTAGGTCGC

GAGGTAGAGTC

r AGCCTTGACC SCCCCAGGCt3C

TGTGTTGCC

ACGGTGCTGT

GGGTTTATGC

CTGCTI'CTCA

AGAACAGGAG

ITGGCTCTGT

TGGGGGTCCG

CTGAGATGGG

AGTGTTCATT

AAGGGTGGGA

CTCTGGCCTA

CCACAACCTG*

GCTGTGAGTG

CCGCCTCTTG

CCAGGGATAT

TTAATTTAAG

CCCCAATATC

rcClrGGGGGC 2 3AGGCGGTGC 2 7TTCCCACCA. 2 'CGTTTGAGT 2 18720 18780 18840 18900 18960 19020 19080 19140 19200 19260 19320 19380 19440 19500 19560 19620 19680 19740 19800 19860 19920 19980 20040 20100 20160 0220 0280 0340 0400 TGCCCTTCCT GGCCCTGGGT GGACAGGTCC ATGTGGCACT CGGCATAGGG

S.

S

C

S

C

TGCAGAGGGc

TGGGTCTTCC

GGCCATAGCT

CTAGGGGCTC

CTCCGGGCGC

TCCCCCAGTC

CTGCTCAGCT

AAGCAACAAC

TGAAATGTAA

CCTTCTGCCC

AG'DTCACTGC

TGTCAGGGTG

GACCTGGTCC

*TGAGGCCCCC

*ATCAGAAAGT

TGGGGATGCT

TGGCCCTGAC

TGGACGTTGG

GTGCCAGCAT

GTGGGGGCTT

AAGATTTCTA

GTTGTGGTrC

TCCCAGTTGG

CTGCTTGGAG

GCTCCAGGGC

CCAACACCTG

CCCCTCCTGA

GGCAATGT

CCACGGCCAC

GCTCCTGGCG

GCGGGGCTCA

CCATCAGCTT

CGTTAGAAGA

TTTGGGTGGG

TCCGTGTCCC

CCCCCCAGTG

CTGGTTGCCA

CCCCTGCCCT

CCTCTGGGAG

GGGATGGGCC

TCACTCCTCA

AACCTCTCGG

CTCCGGGTGG

TGCCGAATCc

AGGAATATTT

GTCCTGGCTG

CTTCCAGGCT

CCGGCTTGGT

GTGGGGGGCT

GCAGAAACCT

TGGGGAGCTC

CAGGGAAGGCc

GAGACGTCTC

CGCTGGCAGA

GCTGGCGGCA

CCCGTCTCTT

GCTAATTTAT

GACCCCAGGC

TGAGACCAGA

TGGGGCAGGG

GGCATAGACC(

AGGCCTCTCC TGGCTTGGr'r

TCCCCAGAG

GTGACTGTGG CCTGGCGTGG CTGCCGCGAT GGGCGGAGGA GCAGCAGGTG CGGTGtTGC 20520 AGCCCGAGC AGCCACGTGT GCTGGGCCTG

GCTCCCTGGC

TCCCCTTGCT GGACAGTGGC TGTGGTGAGT

GCCGGTGGGT

CAGCCAGT GGACCTGGGC CCTGCAGACA

CTGGGCAGG

GGGGGCCTCC GGGCCAAG AACAGCATGG

GAGCCTGTGA

GGCGTGGGGT GGAGCCAGGA GGAGCAGJAC

CCGGGGTCCA

AGGAGTATGT CGCCTGCCTC CCTGACAACA GCTCAGG4CAC CAGCTGCCCA CGAAGGCCTG CTTCAGCCAG

AGGCCTGCAG

GCCAGGGCCT CGCAGCCCTC TCGGAGCAGG

GCTGGTGCCT(

CCAGTGCCTC CTTTGCCTGC CTGTCCCTCT GCTCCGGCCC

C

CCTGTAGGGG CCCCACCCTC CTCCAGCACG TCTTCCCTGC

C

TGGGGCCCCA CGGACCTCTG GCCTCTGGCC AGCTAGCAGC

C

TCCCTGTCAC TGCCACACGC 7GGACTTCG GAGACGGCTC

C

GGCCGGCTGC CTCGCATCGC TATGTGCTGC CT'GGGCGCTA

T

CCCTGGGGGC CGGCTCAGCC CTGCTGGGGA CAGACGTGCA

Q(

CCCTGGAGCT CGTGTGCCCG TCCTCGGTGC AGAGTGACGA

G~

AGAACCGCGG TGGTTCAGGC CTGGAGGCCG CCTACAGCAT

CC

CGGCCCGAGG TGAGTGTCTG CTGCCCACTC CCCTTCCTCC

CC

CAGAGCCTGG TACCCCCGTC TTGGGCCCAC ACTGACCGTT

GA

TCTCCAGCGG TGCACCCGCT CTGCCCCTCG GACACGGAGA

TC

TGGCCAGCCT

CTGCTTGGCA

GGGGCCAGCT

CTGTCCTTCC

CTCAGGAAJGG

CCTCTCTGGG

GTGCGGCGGG

CGGATGTGGG

GTGGCTGCCT CTTCTAGG2YG CGTGGCAGCA

GTGTCCTTTT

CGCCTTCTGC

TTCTCCACCG

'TGTGGGGCG

GCCCAGCCCT

CCGCCACCT

CCTGCCCCCA

TCCCCAGGG GCCAcccTGG 'TTCCACATC

GCTGCCCCGC

GCCGAGGTG GATGCcCG CACGTGACG GCCGTGCTG 3TGGAAGCG

GCACCTGCCG

k.GCCTCGAC

CTCAGCATCC

TGGCCCTG GGCGAGGAGC *AGGGCCAT

CCAGATGGG

CACCCTCG TTCCCACCGG TTCCCTGG CAACGGGCAC 20580 20640 20700 20760 20820 20880 20940 21000 21060 21120 21180 21240 21300 21360 21420 21480 21540 21600 21660 21720 21780 21840 21900 U1960 ~2020 208*0 214-0 2200 2260 2320 2380 a a

TGCTACCGCC

TGGGCCGGGG

CGGGTCACCA

CACTGGGGCA

CCCTGGTGAG

GGTGGACATG

LTGCAL15GGG

GGCTGGTGGG

AGTGATGGGG

CCCTGCCATC

*TGGTGGTGGA

CCGCCCTGGc

GGTGCCTGCC

GAGACTGCGG

CAGGTGGCGC

AGCTGGGGGC

ATCCCTGCCG

CCCTGGTCTC

CTCCCAGCGG

CCACACCCGC

GAAGGCGGCC

AATGGTGGAC

CCCACCCCCC

CTGGGGAGTC

CGGCCGGTGG

AGCCTCCGGA

GTACCCACAG

CGGGCTCTGA

GCTGCTGTGA

CCCCAGGAGC

TGGCTGCAGG

AGTCCCGCCG

GAGGGGCCAT

TCAGGAGGAA

GGCCGTTCCTr

CACTCCTGG

GCCCCGTGGG

GCCTCAGTTT

GGGTGGGAGG.

CTAGACGTGT4 GGCGAGGcCT

CGCAGGAGCA

TGCAGCGCTT

AGGTTGGGAG

GGAGGTGGGA

GTCAGCTCTG

CACGCCATAC

TGGGTGCTGC

CCCCATCTGG

ATGGAGGAGT

GGATCGGCTT

GTGTCAGGcc

CCTGGTCTCC

ATCTCTGAAG

GCTGGGccGG

CAGATGCAGA

GGGAGGTGGc

TGTGAGCCTG

A.AAGGGGGAC

3CCCTGAGCC

:TCGACTGTG

2 2 2 2 2 2 CAGGGGGTYG AGGTGGGCCC

AGCGCCGCAG

AACTGGCTGC CCGGGGAGCC ACACCCAGCC ACAGCCGAGC ACTGCGTCCG

GCTCGGGCCC

ACCGGGTGGT GTAACACCGA CCTGTGCTCA CCCGGAGGTG TGCGGGGGGC CAGGCAGGGG CCGAGCGCCC GCGGTGGAGC CTGGGCTGAG GGCTCGGTCC CCAGTCTGTT CGTCCTGGTG CACTCGCCAC CCCAGGCCCA GTGCAGGATG GGGACCTGCA GGGACCCCTG ACGCCTCTGG AGCCCGTGGA GGTAGTCGGC CCCCCACGTT GGCCTTGCCT GCCCTGCCCA CTGTGGGTCT TTGTGCCCAG TGAAGATGGT TGGGAAAATC GCGCCGCACA

GCTACGTCT

CCTGAGACGC TGGCTGTGG' GAGGAGGGGC 'rGGTGGGGG( TCCTGGGCCC TGGCCCGGCG CCGAGAACCT

CCTCGTGGGA

CACAGCAGGA

CGGCCTCTCA

CTACAACCG CCCTCCTGCC CGCCAAAAAA

CTTGGGGGCC

CAGAGTGCAG AGAGGAAAGC ATTACCTCCA GGCCTTTTCT CTIGAGCGTGT GTGAGTTATT

TCCTGCCCC(

TGTGGGGGT(

GGAGTCTGG(

GGTCATGGTI

TGGGACCCAC

CACAGCAGG7

GGCCTCTCTG

GGTGGACAGA

GGGTGGGGCC

CTGGGCTGGG

GGTGCAGGCA

TCCCCTCCTC

CAGGACCCAG

CTGCIrGCCG

GCCAGGGCTA

GGGGCCCCCC

TCAGGCCACC

TGCAGGCCCC

CTCTCCCAGT

CTCTCCCAGC

-CATGGACAG'

-TGATGGCTC(

CTTCAGGCTC

TTCCCGGGCC

GAGCTCCGGC

GGGACTCTGG

AGCTTTCACG

GCAGGGGTTC

TGCCTGvGGGG AGTGvCTGCCC GTTG3GGCATC

ACAGGGACCC

CTGGCCCCCG

CTGGACGCCT

CCCGGGGCCC

GCGCAGTACT

TTCCI)GTCTG

TCCCACGTCC

GGGAGAAGCT

ACAGClr.CTC TTCCACCGGA GTCTTCCTCT 3 CTCTCCTTCC

GGATGGGGTC

TGCGTCTGAG

GGCCCGCCCA

GTGGTGGGTG

TCTGCTGGTC

CAGAGACACC

CCGGCCTGGG

AGGTGGGGAG.

TCTGACGGTG

CGGAGAACGG

CGTGCATGCC

CCTGCCACCC

CCTATGCGCT

CGGTGTCG

CTGCCCAGGG

TTGCCACCTC CTCGCCTGGG C CTTCCTGTCT G

CTCCCCTCTT

TGTG\GAGCTG

CCGTGAAGCC

GCTGCGGCTG

GTGGGTGGTG

CTGTGGCCAC

AGCTCATTCC

TCAGTCGGCT

ACCTGTCCTC

GCCTGTGGGC

CAGCGAGCCT

k.GGGGGACGC

XCAGGCCTGCC

k.TGGAGAGAG

:CCTGACCTG

N'cGGTCTG .'GACCTCCGA

C

CCTTGGCAC

;CCAGGTCTTG

CCTGAAAGGC

CGAGCGACAG

CCTGGGAAGT

AGGCGGCCCC

TTCCTCACCA

CAGGTGTACC

GGCGCCGCAG

CAGAGTGGTT

AGGTGTCCTG

GGCCGGAGAC

ACAGCAAGGC

k.AATCAGGGC

,AGAGCAGGTC

['GGTGCCCTG

~CCAATGGCT G .ITCCTCTTCT C ;GTCTGTTCC C r3CACCAGACA CTCTGCAGT G AGCTGTGCC T GCCTGTGTC C G CGAGCTGCAG P TAGGGGCCTG

GTTTTCGGGC

CCTCACTGTG

GCGCCCAGTG

GCCCCGCACG

TGCCCCTGGA

TTAATGTTGC

GTTTACTCAC

AGGTCAGGGG

GAGCCAGGCC

TCGGGTAGGG

CTGCCCACCA

CGGCCGAATT

GGCTCCTCAG

GACTCGGGGT

CCCAGTCTTA

GGGGTGGATT

GGACGCAGCA

7AGGATTGCT

=CAACACCC

~CCCOGACAA

,AGCCAACAT

;CACGTCAGG

~CGTPrCCCGC

TGCATCTCC

.CACCCAGCC

CCCTCGGCC

CCTCTTCCT

22440 22500 22560 22620 22680 22740 22800 22860 22920 22980 23040 23100 23160 23220 23280 23340 23400 23460 23520 23580 23640 23700 23760 23820 23880 23940 24000 24060 24120 24180 24240

S

5*5* S S GTGTCCCCCG GTCTGCAACT GTCCTGCCTG TCCTTGTCAC GAGCACGTG GGGAGGCTCC TTGAGGTGTG

GCTGACGAA

GTCCACGGGC

CATGACCGT

CTCCACGGCC

AGGATGTCC

GGCCCTGGCG CCCTCCTGC2 TACCTdTCCG

CCAACGCCTC

TGGGCCTGCC

CTGGGCTTGA

GTGGGCAATG

GCTGGGCTGC

GGCTCAGCCT

CCTGGGGGCA

GTGCCCGGCT

CTCAGTGAGG

CTCAGCCTGC

GAGGCCCGTG

CCCAGGCAGG'

AGGGCAGCAG

CGGGCTACCT(

ACTCATTCCA C

CTGCCTGTGC

GGCCCAACCC

GCGTGTCCAG

GGGTCATCTA

TGGTGCTCCA

GTGTCAGCGC

GCCCCTGGGA

GGGAGCACGT

GGGTGACGGC

TACTGCAGGG

TGCCTGCAGA

:CCAGTTACT

;GTGGGCTT

TGTCTCATT

jAGTCTCTCA kGTCTGAACC

;GGGACAGGG(

;CCATCAGAA)

CTCCCCTCAC

1'GAGAAGAC

GGGAAACTGA

CGGACAGTG A

:CTCTCCTC

kCAGGCTAAG GCGGGGAGCCC TGCGTGTCCA CCCTCATCCG

TCGTGCGGGG

AGGACGTGAT GCAGCCCTGC CTCCCTCTCC

ACAGGTCACC

r CATGCTCCCT GGTGACCTCG TTGGCTTGCA

GCACGACGCT

k CTGCTCGCCG GCTCCCGGCC ACCCTGGTCC

CCGGGCCCCG

GTCATGGCTG CCCCACTTGC CAGCCCAGCT

GGAGGGACT

CCTGCGGCTG CTTGCAGCCA CGGAACAGCT

CACCGTGCTG

TGGACTGCGG CTGCCTGGGC GCTATGAGGT

CCGGGCAGAG

GCACAACCTC TCCTGCAGCT TTGACGTGGT

CTCCCCAGTG

CCCTGCCCCC CGCGACGGCC GCCTCTACGT

GCCCACCAAC

GGTGGACTCT GGTGCCAACG CCACGGCCAC

GGCTCGCTGG

CCGCTTTGAG AATGTCTGCC CTGCCCTGGT

GGCCACCTTC

GACCAACGAT ACCCTGTTCT CAGTGGTAGC

ACTGCCGTG

GGTGGACGTG GTGGTGAA ACAGCGCCAG

CCGGGCCAAC

GGAGGAGCCC ATCTGTGGCC TCCGCGCCAC

GCCCAGCCCC

S.

S

S

S

GAGCCCCCGT

TTTGAGGTGG

TGGGTACATG

CTTGGGAGGG

AGTGTAGGTG

CCGGGAGGGT

CTTAC4GAT

GGCTGGAGAG

CCCGGGCACC

TCCAGGAGGC

CCCGCAGAGG

2

C

C

I

L.

C

C

k.GTCCTAGTG

'AGGGTGCTC

;GGGACGTCG

AATTCCTGG

CACAAAATG

GCCCTCTGC

CTGATGGGA

rGTCTCCAT rGGCGTGAC rGCTCCGAG

AGAGAGAG

GCACAGAG

;TGTCCCAG

,TGCCCCGC(

rGCAGAGTCC

GTGAGTA'TGG

ACACAGGGCG

GCCCCGGGCA

AAAGTCACGG

AATTTAAAAC

TGTG3TTCTCG

AACTGCGGGC

CTTGCGGGTA

CTGTGCAGCC

CTCTCTGGGT

GTGGACTCTT

D.GGTTGAGGC2 MCGGGCyrTG TGGGACTCT c

CCGAGGCTCC

TGAGGCCTGG

GGTCCTGCTG

CTCTGACAGT

TCTGCTCCCT

CCTGGCTAA

TGCCCGCGGT

CCTGCCTCTT

TGTCCTGGGT

3AGGAGCTGGC

['GTAGCTGGT)

kTTAGTAGTAC

;CTCCCATGGC

:CAGCCCGACG

ACCACCAGCC

CTTCCCAGTG

GCTGGCTCCT

GGCTCCGCTA

GACCTCACAC

GCGAGTGGCT

GCCACCATGC

CACCAGGGGC

rCTGTAAGcc

;GCAAGAGCG

4CTAGGTTITG

'TACATGGCT

ATGCAGAGC

;GGAGGTGTG

'ACCATTCCC

2 24300 24360 24420 24480 24540 24600 24660 24720 24780 24840 24900 24960 25020 25080 25140 25200 25260 25320 25380 25440 25500 25560 25620 25680 257.40 258.00 25860 25920 25980 26040 26100 =TCACAGAG CCCAGGCTGA rACAGCCCCG TGGTGGAGGC CGGCTCGAC

ATGGTCTTCC

CAACGACAAG CAGTCCCTGA CCTTCCAGAA~ CGTGGTCTTC AATGTCATITr ATCAGAGCGyC GGCGG'rC'

CAGGGCW

GACGCTGC

CCTGCCAC

AACGTCAO

GTCTCCACj

CTGGTGGAC

GGGCACCAC

GCTTTTCTC

AGGCTGCAC

GGGGCGTGA

CCCACCCCT

ATGGGGAGC,

ACCCCTCGGI

GTGAGGGAT(

GCTCCCCAGJ

CTGATGGCTI

AAGCTGGGCC

GCCCCGAGTG

TACACCTGTG

AGGTGCAGCC

CAGGTGGGGG

CCGTGCTGGC

CCTCCCTGCC

TCACCTTCTA

GGGACGGCTC

GGGGCACCTA

CGGATGTGCG

AGCAGGGCGC

CCTTCGACAT

ACCTGCGGGC

TC AAGCTCTCA .GG GCGGGCTCC.

CA TGGCTGTGG CT GGGCTCACT( Z7G TGAACTACAl IG TGCCGGCCGI 'T CGGCCGTGGA ,G CTCTTGTCCC ;A GCCTCGGTTT G GGAGCCGGGA C TGCAGAGTGG G TCCCGGTTCA P, GGCCCTCCAC r GGCCCAGGTG 3AGGGGGTGAG

SCAAGCTGCCC

AGGCCCTACT

CCTGAACTGC

CAGCTGCACT

CTCCGTCCCG

GTTCACCCCG

TCC!GCGGCT

ATCTAATGCC

CTCC!GTGGCT

C

CCCGCACCCG C

-CCCTGTCCTG

CCACGTGCGC

C

CGTCTTTGAGG

CCCCGTGGTG G GCGGGACGGC

A

ACAGAACTrGCA GTAGGTGGGCG GGGGTGGGGA GCGGAGGGGA TGGGCCGcG A CCTTCACCTC TGCCTTCTGC TCTGCTTCAT

GCTGCCCGAG

STGAGTGGAGG GAGGGACGCC AATCAGGGCC

AGGCCTCTCA

SACGCCTGTCC CTGCAGCTGA CGGCCTCCAA CCACGTGAGCy CGTAACCGTG GAGCGGATGA ACAGGATGCA

GGGTCTCCAG

GCTGTCCCCC AATGCCACGC TAGCACTOAC

GGCGGGCGTG

GGTCGCCTTC CTGTGAGTGA CTCGGGGCC

GGTTTGGGGT

AGCCCCAGCC TCAGCCGAGG GACCCCCACA

TCACGGGGTT

CCCTGTCTGT TGGGAGGTAAJ CTGCGTGCAC

AGGAGCCCTG

GAGGCCTCAG CACAGCCGGG TGGGCCCTCA

ATGGAGGCCC

AGCCTCGGCT GGGTCCCAAG CACCCCCTGC

CCCGCCACCG

CTCACTGCGT CCCACCGCCC CGGCAGG rGj ACCTTTGGGG CAGTTCCAGC CTCCGTACAA CGAGTCCTTC

CCGGTTCCAG

CTGGTGGAGC ACAATGTCAT GCACACCTAC

GCTGCCCC!AG

a a a GGGGCCAC'pD

CCCTTCCTC(

GGGGTGAGGC

GCCCCCCGCc

TGGAGGCGG'I

CACGTGGCT1 3GCTCCTCAC 3CCCCACTCG

E'TCGAGAACC

;TGGGTGTGA

:TGCCCTCGC

,CCCAGAGCC

TGGAGGTCA

AGCTCCGCG

T CAGCGCC!G CC!GTGCTlGT

CAGTGACCG

3CCTTTCAGG( :CCAACAGCcC

AGGGGCCAGC-

CTCCCCGGGC

GCGTCCTCGC

'GGGAGCCTGG

GCGGGGGGCT

GGCCTGTCCC

GGACGCAGCA

GTGACGGCGT

CTGGGGTGT

AGCCGGCTGC

ACAACACGGT

.GACTCAGCGT

CGGTGCAGAC

CGGGCCCGGA

TGGGTGCGGC

-TCTGAGCACG

*TCACTGTGAC

CGTGGGGGGA

CTGGCTCTTG

CAGGCAGCCC

GACCCTTAAG

TCTGCCGAGC

CACAGGTGAG

GGTGCCTGTG

CC'IGGTGGCC

TCTTTACACG

CAACCACACC

GAGCGGTGCG

GGACATGAGC

GGTCCCCCCA

CTCACCTGGG

GTGGACAGGG

CTGCTCTGCT

TCAGTGCTGC

GCTGGGCCGC

GGGTGGGGAG

TACCTCCTGA

AGCGTGCGCG

GGCCGGCCCG

TGGGACTTCG

PATGCCTCGA

3CGGCCCAGG 2 26160 26220 26280 26340 26400 26460 26520 26580 26640 26700 26760 26820 26880 26940 27000 27060 27120 27180 27240 27300 27360 27420 27480 27540 27600 27660 27720 27780 ~7840 ~7900 ~7960 GGGCGACAAC ATCACGTGGA GGCAACAGTG GAGCATGTGT CAGCCCCGCC GGCCACCTGG CCCGGAGCCT

GCACGTGCTG

GCATCCCCAC

GCAGCCTGAC

ACCTCTTCGA

CTGGACCTTC

CGGTGACACA

CAACTTCACG

GCGTGAACAG

GGCGCATTAC

CCCTGCAGCC

AGAGAGGCAG

CCTGGCCCCC GTTCCCCTAC CCCGTGCCAG

GGGCCCTGAG

CAGTCACCGC

GTCCAACAAC

AGCCCGTGCT GGTCACCAGC CGTACCTGr'r

CTCTGCTGTGC

ACGGTGGGTG GCTCGAGGT

C

CCGTTAGGTG GCCGGCTGGA

A

GAAGCGOCGC GTGCGGGGGC rD GAGCGTGAGC TTCAGCACGT

C(

CTGTGACCGC TGCACGCCCA

T(

GGGCACCTTC AATATCATCG

TC

CTTCGTCTAT GTCCTGCAGC

T

CCCCACCAAC CACACGGTAC

AC

CAGCTGGACT GCCTGGAGGG

AC

GCTCACCGTC TCGAGGCCGG

CA

AGCGCCTGGG

CCGACTGCAC!C

GTCTTCGT

GCGCGGCT

GGGGATGG4

CGGAGCGG(

TTCACCAGC

TTTGTGCAG

CGCTACAcc 3TGACGTTC kTCTCTGC'I

LTCAAGGTC,

;GCCGTGGG(

CGGAGGTCI

TGAGGTGAC

CGTCGTCAA

GCTGGAGGc :7CCTGGGGG

'ACGGCTGA

ATAGAGGG

;CTGCAGGC

'AGGGGCCC

CCTACCAT

TGGACTTC

GTCCTTG

'CACACCC

MCACCGTG

~CGGAGGC

;CACCAAT

'CACCATG

ICAGCTGGC

CC TGGAGGTGCT GCGCGTTGAA

CCCGCCGCCT

CA CGGCCTACGT CACCGGGAJAC

CCGGCCCACT

DT CCTCCAACAC GACCGTGCG

GGGTGCCCGA

A CGTTCCCCCT GGCGCTGGTG

CTGTCCAGCC

A TCTGCGTGGA GCCAGAG4GTG

GGCAACGTCA

;C TCGGGGACGA GGCCTGGCTG

GTGGCATGTG

T GGGACTTTGG CACCGAGA

GCCGCCCCCA

A TCTACCGAGA CCCAGGCTCC

TATCTTGTGA

GCCAATGACTC AGCCCTGGTG

GAGGTGCAG

~ATGGCTCCCTj TGGGCTGGAG

CTGCAGCAGC

GCCCCGCCAG CTACCTGTG

GATCTGGGGG

CCCACGCTTA CAACAGCACA

GGTGACTTCA

CCGCAGCGAG GCCTGGCTCA

ATCTGACGGT

TGCA.AGCCCC ACGGTGGTGC CCCTGAATG(2 CGGCAGTGAT GTGCGCTATT

CCWGGGTGCT

TCCTACCATC TCTTACACCT

TCCGCTCCGT

GAACGAGGTG GGCTCCGCCC

AGGACAGCAT

GCTGCAGGTG GTGGGCGGTG

GCCGCTACTT

CGTGGTTAGG GATGGCACCA

ACGTCTCCTA

OGCCCTGGCC GGCAGCGGCA

AAGGCTTCTC

GTGCAGCTGC GGGCCACCAA

CATGCTGGGC

GTGGAGCCTG TGGGGTGGCT

GATGGTGGCC

28020 2808o 28140 2&2 00 28260 28320 28380 28440 28500 28560 28620 28680 28740 28'800 28860 28920 28980 29040 29100 29160 29220 29280 29340 29400 ~9460 .952 0 .9580 9640 9700 9760 9820

S.

S S

S

S

5.5.

GCCTCCCCGA

GGCAGTGGTG

CCATTTACCA

AACCCGCTGG

CTCAGCATCA

TTTTGGGGGC

AGCAGCAAGC

CGGCTCAATG

ACCCAGCTGC

TCGTATACAC

CCCATAGCTT

GCTCAGCCAA

GGGCCAGCGA

AGCTGGCCAC

GTGGCCCTCA

CCTCCAACGC

CG

7Dc

CGC

G

GC

TGI

AGT

AGCGTCACCC

GAGGAGGGGC

GGCCTGCACT

GAAGTGGATG

k.GCTTCGTGG 3TGAGCTGGT 3TCTTCCCGG

'TCTCAGCCA

TCAGTGCCGA

TGAGCTGGGA

TGGTCACCAT

TGCAGGTGCC

CGGCCGGGTC

GCTGGGCTGT

ATGCTGGCAC

GCTGGCTGGT

GACCTCCGAG

GACGGCAGGG

TGTGAGTGGC

CTCTGTGCCC

GCCCGGCGGC

CTTCTCCAC

2 2 2 2 2 GAGCCCATCG TGGGCCTGGT GCTGTGGGCC AGCAGCAJAGG TGGTGGCGCC CGGGCAGCcTG

GTCCATTT

GGGGCCAAi

GACCACGTX

ATCGTGGTC

GCCACGGGC

GCCTGGTAC

GACGTCACC

GCCCTGGGC

GCCCTGCAG

CCCAGCCCC

ACAGATGA04

AACGCCTMC

GCCTGCCGG(

CAGCGCAAC9

TACCGCTGGC

GCCCTGCCCC

GTGGGGCACT

ATCCAGGCCA

TACCGCGTGT

AACCTGGAGG

CAGGTCAGTG

AGAGAACACC

CAGCATGGGG

TGGGGCTCTC

GCGCTGAACT

GCTGGCGrGG

ACCAACCAGA

CCTGGTCATC

CT0TaITCTGA

ACCTGCCACA

AGATCCTGCT GGCTGCCGGC CCGAGGTGCT CCCCGGGCCC TGAGCGTGCG GGGCAAAAAC TGGAGGCCGT GACTGGGCTG CTGAGAGGAA CTTCACAGCC TCTCGCTGCA GAAGGTCCAG ACACGCCCGT GGCCGCGGGG TCAGCTGTCA CCTTCCGCCT

GCAGGTCGGC

CGTTTCTCCC ACAGCTTCCC

CCGCGTCGGA

CACGTGAGCT GGGQCCCAGGC

GCAGGTGCGC

CAGGTGCCCA ACTGCTGCGA

GCCTGGCATC

CGCGTGCAGC GCGGCTCTCG

GGTCGCCTAC

GGCGACTCGC TG0TCATCCT

GTCGGGCCGC

CTGTTGGAGA TCCAGGTGCG CGCCTTCAAC A GTGAGAACC A GCGGCCCCTI

GGCGTGTGG(

7CCAGGGCCGJ

ACCTGGTGAC

3AGCCGGAGG']

ACTTGGAGGC

AGGTGTATCC

GCGTGGACGT

ACTGCTTTGT

ATGTGACGGT

GGTCAGACAC

ACGGCGACCA

CGTGGCAGGG

CAGCTTrGCCA

AGGGGGTCTC

AGGCCACGTC

TTGGGCCCCG

AGTACACCTT

CGGTGGGTGC

TACTGTTTTC

TGCAAATTCT

GTTCCACGTA

G CACGCTGGTG 3 CTTCACCAAC

SCTACCACTGG

~GCACTCCTAC

CTTCTTCGTG

GGACGTGGTC

CCACGTTGAC

CACCGCCAGC

GAGCCGGCCT

GTTTGTCGTG

GGCCCCCGAG

ACGGGACCTG

GACGCCGCTC

CCGTCCTCCA

CCAGGGCTGGC

CCGCGCTGTC GCCCCTTGTr c

CGGGAGCAGCA

CAGCCTGACC G

CGCCCGCCCCT

CGTGTTTTAGT

ATGTAACACG A CAGTCTTCAA~ G

CTGGAGGTTC

CGCTCGGCGC

GACITTTGGGG

CTGAGGCCTG

GCGCAGGCCA

CTGCCCCTGC

CTGCGCGACT

TGCCAGCGGC

CGGCTGGTGC

TCATTTGGGG

CGCCTGGTGC

3TGCTGGATGC kGTTTCCACTC ['GCCCCTCAC C 'CCGTCCTCA

G

'CCTGGGCCG

TCGGCCTGCA

,CGGTCACCAT

TGTGGAAGG

C

CGGCCACTrr G GCTGGTGGA G4 CAGCCTGCT 1 CCACATATG Ca

AGGACGCCGT

AGTTTGAGGC

ATGGGTCGCC

GGGACTACCG

CGGTGACCGT

AGGTGCTGAT

GCGTCACCTA

CGGGGCGCCC

TGCCGCGGCT

k.CACGCCACT

XATCATTGAC

;GAGCGAGTCC

X3GCCTGTGT CGTCCACAC C :TGCCTGGTG0 GCTCTGCTrT GAGGGAGGC TCCACGGGA G CGGCCGCAA 0 CCTTGGACA 0G 3CCGCACGC T AGCTTrGCT'

CCAGTATGTG

CGCCACCAGC

AGGGCAGGAC

CGTGCAGGTG

CCAGGTGCTG

GCGGCGATCA

CCAGACTGAG

AGCGCGTGTG

3GCGCTGCCT 3ACACAGAGC

;GGTGGCTCA

TrACGACCCC

GCTTCGACA

'CATGAGCCC

GCCCCGTCC

AAAACTGGA

GGCGGGTGT

CGGCTGGCG

3;AGGAGGCC 2CCAGCCTC 2TCCCCTCT rCCTTCCAA 29880 29940 30000 30D60 30120 30180 30240 30300 30360 30420 30480 30540 30600 30660 30720 30780 30840 30900 30960 31020 31080 31140 31200 31260 31320 31380 31440 31500 31560 31620 31680 S. S S 9S

*SSSSS

S

5555 5.55

*S

S S

S

S

S

.555

S.

5.55

S.

S

S. S

SS

S.

TCTAGTGGC AAAAGCTACA CAGTCCCCTA GCAATACCAA CAGTGAGGA GAGCCCCTTC CCACCCCAGA GGTAGCCACT

GTCCCCA

CTCTCTG

GTCAGGC(

CAGCTGG(

GTTCCATC

GTCAGGCC

TCCCCCCA

TACACCAG

TGGAAGGT

GCCCCTGG<

CAGGCCAA2

TGGCCGGG~

AGTGAGCCG

CAAGCGAGG

GGGGACGGG

ACCCCTTCID

ATGAGACCA(

TGCGGGACc(

AGGGCTGCGC

TCTTCCCACT

AGTGCAGGCC

TCCCGTGATG

CGCTGGTGTA

TCTACAAGGG

TCGAGGTGGG

ACAGGTGAGC

TGCTCGTAGG

AGTCTGGC TG

CCAGCACGTC

CTUGGAGGGG

TGGAGCTTTG

0CC CATGTCCCTG

TTGCTGC

GAC CGGCCAGGAG

GCTTCGT

300 GCCTGCTGGT

GCCCCAG.

MT GATTOGGT

CTTCCCA

~CC AGCTCAGCCT

CCTGACC(

~TA CGTGGCAGCT

GCGGTCC]

.G GGCCCTCAGT

GAGCATTG

ACGCACACTCC

AGTGTCCT

S0 CAAACCGGAT

GAGTATCC

~AACCTGGAGT

TTGGGAGC

~T AGACCTGTGT

TGGAGGTA,

~CCCATTGTGT

CCTTGGAG

C AGCTCCTACG

TGTACTTGC

GGTGAGTGTTG

AGCGGGGTG

GCCTGCAGGCA

GAAGTGGGG

CCTGCAGCGG

TGGGCTGCA

-CACATCCACG

GGCACTGCA,

CGAGGGATAC

ACCTTCACG(

CTCCATCCGC CTGTCCCCc GGGCGCTGTGjy CACGcCCjc TGCGTOGGGOG GAGCAGCGGX CCGTGGGGAC

CGTCCCTCAG

CGCCCTGCTG CTGCGGCGCT1 CAGCCTCTCC

AGCTACGGAG

CCTGGCCGTG

GTGGTGCAGG

CAGGCCGTGG

GAGGGCGCCC

TCTTTGGCCA

TCACCCTCCC

CACGGGCTCA

CCGCTAGTGT

ATCGAGTACT CGTTGGCCCp ACGTCACATC

TGCTGCATGC

CAGAGGGCTC ATCCCGGG3CC ;TG TGGTGGGCCG GTTCTCACCC

TCACGCTCCC

GAC CCTGAGCCCG TGOTGGCTGC

TCCTGCTGCT

AT GGGCGTCT03T TCCCCAGTCC

CTGCTTTCCT

3AG GGGTCGTCTG AGGGGAGGGT

GTGGGAGCAG

AG GCCCTGGCTA AGGGCTGCAG

GAGTCTGTGA

'CA CACCCACACA TACGTCTCTT

CTCACACGCA

;CC TGCCTCCTGC TAG0GTCCAG

CTGGGTCCAG

CT GCCCTGTGTA TGCCCTTCCG

CCGTCCAAGT

TG GGAGGGAGTG AGCTCACCGG

CAGTGGCCAG

AG CATCCTCCAT GGGTCCCCCA

GTCCTTCCAG

~C CCCACTC~CC CGCCAGGTGC

TGATCCGGAG

VG0 TGTGTCCTGC AAGGCACAGG

CCGTGTACGA

AGGGCCGCTGC CTCAATTGCA

GCAGCGGCTC

*T GGGCGGGCTG GGGATGGTC

CCATGGCCGA

C TGACAGGGCA GAGGGTTGCG

CCCCCTCACC

C GTACGTCA CAACAAGACG

CTGGTGCTGG

GGCATGCGACT GGTGCTGCGG

CGGGGCGTGC

CTCACGGTGCT GGGCCGCTCT

GGCGAGGAGG

'ACCGCCCG~C GCTOGGGC

TCTTGCCGCC

~CCACCAAGGT GCACTTCGA

TGCACGGGTG

ATCCCCCGAC TCTGTGACGT

CACGGAGCCC

GCTGGCATGA CGCGGAGGAT GCTGGCGCCC 3 GTCGCCAGGGc CCACTGCGAG GAGTTCTGTG 3 CCGTG CTGCC CCCGr'rTC AGGCCACACT 3 ACCAGCTGGG AGCCGCGrG GTCGCCCTCA 3 CCGAGACTGC~ CACCTGCTCA, CCACCCCCTrC 3 AGAGCCCAAC GGCAGCGCAA CGGGGCTCAC 3 GCTCCCAGGG CTGCTGCGGC AGGCCGATCC 3 GGTCACCGTG CTGAACGA'30 TGAGTGCAGC 3: GTGCTTGGGA CCAAGACCTG TACCCCTGCC 3: CCAGAATA ATCCCAGTGA CCCTGAAGCA 3: 31740 31800 31860 31.920 31980 32040 32100 32160 32220 32280 32340 32400 32460 3252'0 32580 32640 32700 32760 32820 32880 32940 ~3000 ~3060 3120 318'0 3240.

3 30.0: 3360 3420 3480 ~540

GCACCCCG.

CCACAATG4 ACAG3CTCA(

CGGGAGTCC

TGCCCCCTG

CGGCAGCAC

CACACTGTG

CCCCACCTG

AGACGGGCA(

TCCTCGGTC~

GCCTCTCGGC

GCTGCTCT13T

CCCCTCCTCC

CCCCCCAGCC

CTTCCCCTCC

CGTCCCCCAG

CCCCTCcTCC

CCCTCCCCTC

AC CTTCCGCTCC CAGCAGCCAC

ACCCACCGGG

CA GCCCCCGCCC AGGAGGGCCC

ATGTGCTTAC

'T GTTGTGGTC AGTGCCCGCA

TCACACAGCG

,T GGGCATCTGC TGGCCTCCTG3

CCGGCCTCCT

,C CTGCCCCAGT ACGAGCGGGC

CCTGGACGG

C GAGCCCAGAT ACGCAAGAAC

ATCACGGAGA

G ATGACATCCA GCAGATCGCT

GCTGCGCTG

C TCACCCTGCC CCGCATGCCT

GCCACGGCAC

G CTTGGCCGAG GAGCTGAGCC TCCAGcCTG

C

V' CTGACCTGCT TCAGTAGCCT CAGCCGTTCT

G

GGACCCAGGG TGTAAAGAGG GGCCCAGATG'1 GCCCTCCACT CTCCCCTCCC CTCCCCTCCC

C

CCTCCCCTAG CCCTTCCCCT CCTCCCCTCC C CTTCCCC'rCC TCCCCTCCCC TAGCCCTTCC

C(

TCCCCTCCCC TAGAccTTCC CCTCACCTCC

I

CCCCTCCCTC CCCTAGCCCC TCCCCTCCCC

CJ

CCC TCCCTCT TCCTCCCCCT CCCCTCCTCC

CC

CTGTCCCCCC TCCTCCCCTC CTCCCTCCrc

CC

CCCTCTCCGG

CGTCTGCTTT

CCTGTTTTGC

CCATGAAGA

TCTAGCACGT

AACTGCACCC

GCGCTGCTGA

CAGCTTGCTG

GCGCAGAGcc

CAAGCACGAG

CTCTGGTGTC

CCTGAGGGTC

CCCAG'rGCAT

GGTAGGATGG

PGGGTTCAGC

CCCCCAGGGC

CTCCTTCCT

GCCATGGCGT

;TCCTGTGTG

AACGCAGGGT

GGGGAGGGA

CTAAGAAGAT

CTTCCCTCC

CCTAGCCCCT

CTAGCCCTT

TCCCTTCTTC

CTCCTCCCC

TCCCCTACCC

CCGCTGAG

CCCCTCCACT

L'TCTCCCC

TCCTCCCC!CT

CTTCCTCC CCTCTCCTCC 33600 33660 33720 33.780 33840 3390o 33960 34020 34080 34140 3420o 34260 34320 34380 34440 34500 34560 34620 34680 34740 34800 ~4860 14920 4980 5040 5100 5160 5220 5280 5340 5400 CCCCCTCCTC CCTCCTCCCT CCTCCCCCTC CTCCTCC'rCC CCTCCTCCCT

CCTCCCCTCC

TCCCCTCCCC TCCTCCCCCT CCCCCCTCCC

TTCCTCCCCC

CTCTCCTCCT

CCCATCCCTC

4 S

S.

S.

9905 45.55.

S

S

5.

S S 0@S S

S

a 555.

55.5 .5.5

S

0O 0 S S 55 CTTCCATT'rC

TTTCTTCTCC

T'rCTCCTCTC CCCCTCcTCC

CCCCTCCTTC

CCGGCTCCTC

TCCTCCCCTC

CTCCTCCTAT

TCC!CTCCTCC

TCCCTCCCTT

TTTTCATCCTr CCTCCqrT'

CTCCTCCCAT

TCCTCCCCTC

CTCATCCCCC

CTCCCATCCC

CCCTGCCCTC

TCTCTCCTCC

TCCcTTCTTc

CCTCCCATTC

TACCCCTCCTr

CTCATCCCCC

TCcTCTCCTT

TCCTCCCCGI

CTCTCCTCcr

CTCCC!CTTCT

CCTCCTTTCC

CCCCTCCTcc

CTCCTCCCT

TCCTCTCCTT

CCcTCCTcCT

*TCCCCCCTCC

TCCCATTCTC

CACCTCCCCT

CCCCT'rCTc TCCTcTTTTC

CCCCTCCCAT

CCTCCCACCC

CCCTCCTAAC

CCTCCTCCCC

TCCCCTCCCC

TCTCCGCTCC

TCTTCTCCCC

CCTCTTCTCC

TCCCCCT CCT

CCCTCTCCTC

CCCCCTCCTC

CTCTCCTCCC

CATGCCCCCT

3 3 3 3 3 3' 3' TCCCCCTCCT CTCCTCCCCT CCTTCCTCCT

CCTCTCCTCC

CCTCCCCTCC TCCCATCCCC CTCCTCCCCT CCTCCCTCCT~

CCCATCCCAT

TCCTCCCCTT CTCTCCCCTC CTCTCCTCCC CTCCTCTCCT CTCCTCCTCT

CCTCCCCTCC

TCCCATCCCC

TCTCCTCCCC

TTCCTCCCCT

CTCCTCCTCT

TCCCCTTTTC

CTCTCTTTCT

CTTCCCTCCT

TTCCCCTTCC

TCTCTCCCCT

CCCCTCCTCT

IJ

CCCTCCCCTC

TI

TCCCCTCCCC

TI

TCTTCCTTCC

T

CTCCTCCCCT T1 TTCCCTCCCC

T

CTTTCCTCTT

C(

TCCCTCCCCT T9] TCCCCCTTCT

CT

CCCTTCTCTC

CC

CCCCTCCCCT

CT

CTCTCCCCTC

CC

CTCCTCTCCC CCi TGAAGAGGTG

CC'

GGTCATGC.AG

AG(

CTCTCCAGCT

C

TGTGCA.AGGA

GT

CAGGGAGC'rC

GT

GCTCATCCTrG

A

CATCCTCAACAC

CCCTTTCTC

TGC

TCCCCCTCCC

CTC

CCTCCTC

TCATCCC(

CCCCCTCC

CCCCTCCC

CCTTTTCI

TTCCTCCC

CCTTTCCT

rTTCCCCT

PCTTTTCC(

~CCCCTCC(

'TCTCCTCC

CCTCTTCC

CTCTTCCC

CTCTTCCC

CCTCTTCCQ

,CCTCCCC'

'CTCCCCCJ

'CCCCTCCC

CCTTCTCT

CCCCCTTC

CTCTCCTC

CTTTTCTC

PTGTGTGG

~CACAGAA

kGGGCTGG

;GGGCCAG

,TGCCGCT

GCAGAGA

ACAGGTG

CCA TCCCCCCTCC CCT CCTCTCTCCT 'TT CCCCCTCCTC CC TTCTCTT'jT VCT TCCTCTCCTC TT TCCTTCTCCC CC CCTCCTCCTT CT CCTTTCTCCT T CTTCCCCTCC ~C TCCTCTTCCC

C

C CTCCTCTCCC

C

C TCCCCTTCCC

C

C TCCCCTCCTC

T

C TCCCCTTTTC

T'

C TCCCCTCTTC

C

r CCTCCTCCCT

C(

PTCTCTCCCCT

CC

CTCTCCCCCT

TC

CTCCCCTTCT

CI

TCTCCCCTCC

CC

TCCCCCTTCC

CT

CACTCCCCTC TCi TCGGTGGGCT

GC

AATGCTTAGTGA

GGGTGGGAGCCC

GAGCGGGGCT

G

CGTGCCTGJA, GC1 CCACCGCGGG

CAC

CCGCGGCCCG

TGC

TCTCCTC

CCCCTCOi

CCCCTCC'

CCCTCCT(

CCCTTCTC

CTGTTCTC

TTCTCTGT

rCCTTTCCl

CTCCTCT

TCTCCTC(

TCTTCCCC

TCCCCTCC

TCCCTCCC

TCCCTCTC

CCTCTCCTI

XCTTTCC(

~CCTCTCC(

~TCTCCCC]

*CCCCCTTC

TCTCCCCT

CTCCTCTC

CTCTCTCC

kTCACGTG 3GAGGCTG 3GTGAGGA iCACTGCT LGACGCT3

CGTGACG

CCCATGC

7CC ACTCCTCTCC 'CC TCCTCTCCTT TC TCCCCATCCC

CCCCTTCCTCC

CTCCTGTCCT

.T CCCTTCCCTT 'f CTCTTCCTTT 'C TCCCCTTCTC C CCCTCCCCTC

C

T CTTCCCCTCC

C

r CCCCTCCTCT

T

V CTTCCCTCCC

C

-TCTTCCCCTC C4 *TTGTCTTCCC

IN

CTCTTCCCTC cC CTCTTCCCCT

CC

CCCTTCWCTC

CC

CTCCTCTCCC CC TCTCCCCTCC CC GTCCTCTCCT

CT

CCCCTTCTCT

CC

TCCCCACT(

CCCTCCTCC

CCTTCCCC

TCCCCTCTT

CCCTCCCTT

CTCCCCTrw

CCCCTCCAC'

rTCCTTTTCC TCTTCCCCq

CTCCTCTT'I

CCCTCCCCT

TTCCCCTCC

CCTTCTCTT

CCCTCCTC

CTCTTCCT

CCTCCGCT

~CTCCCCTC

'TTCTCTCC

CCTTCTCT

CCACCCTT

IC 35460 'T 35520 'T 35580 'C 35640 T 3570o r 35760 S35820~ 35880 35940 36000 36060 3612.0 361.80 362:4.0 36300 36360 36420 36480 36540 36600 36660 36720 36780 36840 36900 36960 37020.- 37080 37140 37200 37260 es

SO

SS

0O

S@*S

S

0

S

0050 @500

SS

S. S

S

0 OOOS*e 0 0055 0

CCTCCTCCTC

GTCCCCAGGT

TGGGGGTCCA

CCCGTGTAA

GGCTCCACAC

CACAAGCTG

CCCACCGCCA

CACCCGCCCG

CGCTCTCATG

GGAGGCCCTG

GTCAAGTGGG

GAGGAGGGCG

AGGGGCCCAG

AGGCCATGAT

TCGGAGACAG

CCCCGTGCGG

CCCATCTTCG

CATTCTCCTC

CTCCCTC

CTCCCCCCAA~

CCCCCAJA TTCCCATCCT CCGCGTCGCC

TTTGCCCCAT

CATCCCCCTC CCCCAXATCC .00. a 60

CCCCTCCC

CCCCCCCG'

CCTTCCCCI,

TCTTTTCT(

GTCCTCATc

TCCTTCTGC

CCTCCGGCTr

ACCTCACGC

CAGCCCTCA

CTGACCTCT

ACGCTGGCV3A TGCTATGGc( GCCCTGGCCj CCCTTTGGC9

ACACAGGCCC

AAGGTGCCCA

AACTCCGTTG

AACCCTGCGG

GGGTGGGGCA

TTCCATGGGT

AGAGAGGAGC

TTTCAGGCCC

TGAGCTTCCC

AACCTGAGCC

GCTCGGCTAG

CCTTCTTCAT

CATGGGTCAG

GACCGGGTAT

CTACCCCTTC

GCCACTTCCG

ACTTCAGCGA

TTCCCTATTA CCATCCCTTT -CTCCCCGTCC TTTTGTCCAT -CCTTATCCCC CTTCCCCTCC ACCCTTTTCC TTCCTTTTTC CCATCACCTT CCCCCTCCCC TGCACCTCGC TCTCTGCCCC CCCCTTTTrG CCTGCCCCCA TGTCTGCAGG AGACCTCATC AGCTGGCAGC CGAGTCACCA CCCTCATGCG CATCCTCATG GCGAGGAGAT CGTGGCCCAG TCTCCATCTC

TCTCCCCTTT

TCCCCTCATC

TTCCTCATCC

CTTTCCCCCT GCTCCTCTTC CTCCCTCTCC

CCATCATCCC

CCTCCACCAC

TCTCTCTCCA

CTCAGGTTCC

CCCTTTCTCC

CCCTCCCTCT

ACCTCCCTGT

CACCTGGCCA

GCTCGGACGT

rCTCGGATGG

TGGCGTCCCA

::GCTCCCGCG TGCTCAACGA 3GCAAGCGCT

CGGACCCGCGC

TCTCCATTTC

CCCTCATCCC

TTCTCCCTTC

CCTCATCTTC

GCTTCCCCCT

CAGCCCCCAC

CTCTGCACPG

GCGGGCACCA

GGCCTACAAC

3GAGCCCCTG 7 AGCCTGCTG 3GCGCCCCAG k ACCTCAGTGJ

ATATCAGCA)

GCGCCCAGA]

ACAACTCGGP

TGGTCCAGCC

CCGGGCTGCA

CACGCGGCCC

GTCTCTGGG

TGGGGGCCAC

GTGGCAGAGG

GGCAGGCGTG

CTACCTGGCA

CAGGAGGATC

TTCCCCGGGG

CATTGCCTGG

GGGCTCTGAG

CCTGCCCAGG

CTGGTCGGCG

GGAGGACATG

3 GCCTGGCTG k. CGTGGTGCA(

CTACACCGT(

CCCCATCGAC

CTGGGCTGCC

CCAGGCCTCC

TCTGCAGCTC

CCTGGCCTTG

AAATTTGCTT

GGAGAAGCAG

GTGGGCTCAG

TGACCTGCGC

GTCTACCTAC

CGCCCAGAGT

TGAGCTCTGC

GTTACTIGGCC

ACTGCGACAT

AGCAGAGACC

CTGCAGGTGT

GTGTGGCGGA

LALTTCTCCA TCCCCGAGGC TTTiCAGCGGG 3CTCATCTC TGGTGGACTC

CAATCCCTTT

TCCACCA.AGG TGGCCTCGAT

GGCATTCCAG

CGGCTGGCCT CAGAGCGCGC

CATCACCGTG

CGGGGCCACC GCAGCTCCGC

CAACTCCGCC

GTCGGTGCTG TGGTCACCCT

GGACAGCAGC

AACTATACGC TGCTGGACGG

TGCGTGCAGC

TTCTTGGGGG GAAGGCGTTT CTCGTAGGGC TCTGTTTCAP GGGCTGC'rGG GGGCCTGGCC GTGccAGCTC TGGTGCAGAG GCTCCTA'rGC GAGGGCCATCY GTGGGTGTCC

CCCGGGTGGT

GTTCTGCCCC AGGCCACTAC CTGTCTGAGG ACTCGGAGCC CCGGCCCAAT

GAGCACAACT

CACTCCAGGG TGCTGACCAC

CGGCCCTACA

GGGCCAGCCT GGCAGGGCAG

GGCAGGGCAT

CCATGGGG~c GGCAGGcAGC GAGGGGAcTG CCAACCTGGC GGAGCCTGGG

CTCACGTCCG

CAGCGGGGAG TTACCATCTG

AACCTCTCCA

CCGTGGGCCT GTACACGTCC CTGTGCCAGT CAGAGGGGCT GCTGCCCCG GAGGAGACCT 37320 37380 37440 37500 37560 37620 37680 37740 37800 37860 37920 37980 38040 38100 38160 38220 38280 38340 38400 38460 38520 38580 38640 38700 38760 38820 38880 38940 3-9000 39060 39120 CGCCCCGCCA

GGCCGTCTGC

TGCCCCCAAG

CCATGTCCGC

CTGCAGAGTC GAGGAGGGCC CGTGACCTCC TGGccCGGC ATCGTCATGC

TGACATGTGC

CACAAGCTGG ACCAGTTGGA GGCCGCTTCA AGTACGAGAT CGCAGCGGGG TGGCAGGGCC AGTGAGTCTC

GTCGCAGGCG

GTGTGTTCAT

CCTGGGAATG

CCTAGCTGGA AGTAGGTGCC TGGCCCCACA AGTGACGTGA

G

TCCTGACTGC ATAGCTCGTC

TI

TTCAGTACCT CCATTTTCCT

T

GTTTTTCTTT TTTTAGAGAC

G

GATCTTGGCT CACAGCAACT Ti CCTGAGTAC TGGGAGTACA

Q<

GCCAGGCGAA CTCCTGACCT

C~

GACAGGTIGTG AGCCACCACA

CC

CTCACCCG(

TTTGTGTTJ

TGGGTGGGC

GGCTGTGTC

TGTGTGCCT

TGCCAGCCG

CCTCGTCAA

rCCCCTGCT( rCAGAACAAc

.CCTCGTGAC

~GTCAGTCAG

;CATCGCTAC

CTCAGACGG

TCATTGGAA

GAGTCTCAC

CCAGCTCCC

3TGCACACC kGGTGATCC

TGGCTGTG

C ACCTCACCGC CTTCGGCGCC

AGCCTCTTCG

CTGTGAGTGA CCCTG3TGCTC

CTGGGAGCCT

*T CGGCTCTATC CTGAGAAGGC

ACAGCTTGCA

TCACAGGGC CGACAGCGGA

TGTWACTAC

G GTGACCTACA TGGTCATGGC

CGCCATCCTG

G GGCCGCGCCA TCCCTTTCTG

TGGGCAGCGG

G ACAGGCTGGIG GCCGGGGCTC

AGGTGAGG

TCACTGGCTG TGCTGGTTGC

ACCCTCTGG

;GCAGTTTTTG CAGTGCTGTG

TGAAGGGCTC

CACTCACTGT CCCTGAGGAC

TAGGACAGCT

GGTGGGCAGC CCACGTTCTG

CACAGTAGCG

CACTGTGGGA GACTGTGCAT

CCACCCGCGA

AGGCGCCAGC ACCCTCCCCG

TGGCTGTP'TC

TTGCCCTTCT GGCATTCCCT TTTTGTT'rTC TCTGTTGCCC AGGCTGGAGT

GCAATGGCAT

GGGTTTAAGC CATTCCCCTT

AAGCGATTCT

ACCACACCCA GTTAATTTTT

CACCATGTCA

GCCTGCCTCG GCCTGCCAGA

GTGCTGGGAT

TTCCCATTTT TTATCTCTGT

GCTGCTTTCC

39180 39240 39300 39360 39420 39480 39540 39600 39660 39720 39780 39840 399 00 39960 40020 40080 401 40200 40260 40320 40380 40440 10500 10560 10620 0680 0 7A 0 0800 0860 0920 0980 TCTTCATTGC CCAGTTCrrT CTTTTGATTA CCTACTTrrTA AAAACTGTCG

GCCGGGCGCG

GTGGCTCACA

GAGATCGAGA

TTAGCCCGGC

AATGGCGTGA

GCCTGGGTGA

GGTCTGTCAC

AGGGACGGGT

CAGTGCGGGT

AAGTTACAGT

AAATTGCAGT

TGTGGCTCCT

CCTGTAATCC

CCATCCTGGC

GTAGTGGcAG

ACCCGGGAGG

CACAGCAAGA

TGGGAGAGGA

GTGTGGTGCG

CACTGGTTGT

TCTTTCCATG

AACCGCAGCT

TGAGTGCGCA

GAGCACTTTG

TAACGGTGAA

GCGCCTGTAG

CGGAGCTTC

CTCCATCTCA

GGTGACACAG

GGTCACCGGT

GGTGTGGACT

TAACTTAATC

CCTTGTGTAT

CAGGCCAAAG

GGAGGCCAGC

ACCCTGTCTC

TCCCAGCTCC

AGTGAGCTA

AAAAAAAAAG

CTTCACGCTT

TGTGGCATGA

GAGGCGTGTG

ATGTCCTTA

GGCAGAGCCG

CTGAGATGAC

CAGGCAAATC

TAATAAAAJAG

TTGGGAGACT

GATTGCGCCA

AAAAAAAATA

TGCAGTCTGT

CTGAGGCGTG

CAGCCATGTT

GGTCCTGCTG

TGCAAAGCCG

TTGCCTGGGA

ACGGGGTCAG

TACAAAAAAA

GAGGCAGGAG

CTGCACTCcA

CTGTCACCTG

GCATGAACTG

GACAGGTGTG

TGCATGTCAC

TTAATTGGAC

GGACTGCq

TGCCACACT

4 4 4 4 4 4 4

GTTGGGCI

GTGGGCA'j

AGAGICCT'I

AGCGTGTc

CTGCCCCT

CAGGGCTC

GCAGCGCCI

TGGTGGAG

AGGTTGGGC

GGCGACGCI

TTTGACAAC

ATCCAGAGG

TGGTACGGG

CTTCCTGCCI

AGCACGGGGi

GTGTCCAGC(

CGGAGCAAG(

GCACCATGCC

AGGCTGCTCC

GAGAGAAGAC

ACGGACGACT

CGCTTCCGAA

AGTTAGTCCC

CCCAACACTT

GGCAACATAG

CGCCTGTAAT

CGAGACCAGC

TGGGCATGGT

CATGAACCCA

G(C AGACCGAG( CA TGCTGTAT( C ACCGCAACI 'A AGATCCGAC .T GCCCCCGCA LG CCCTGCCTG T CTTCCTGGT, A GGAGGTGCTD A. GGGTGGTCC' 3, CCCTTTTGCC -ACATCTGGC'.j

CCACCTGCTG-

CTGTTGGCGA

*AGCCCTTCCT

ATGTGTCCAG

TGGTTGTCTA

TGGGCTGGGG

TAGGGCCGCC

GGAAGGGTCA

TCAGAAGCCA

GCACAGCAGC

'C TCCCACCCCTj CCCTCTTGCC

TCCCAGGTAC

G3 GGTGGACAGC CGGAGCGGCC

ACCGGCACCT

CCTGGACATC TTCCGGATCG

CCACCCCGCA

GTGGCACGAC AACAAAGGTT

TGTGCGGACC

r TGGGGCGCCC TGCGAGCCTG

ACCTCCCTCC

3 TTCCTGCAGC ACGTCATCGT CAGGGAcCTG AATGACTGGC TTTCGGTGGA GACGGAGGCC GCCGCGAGTA AGGCCTCGTT

CCATGGTCCC

GCCCCGTGGC CTCCTGCAGT

GCGGCCCTCC

CTTCCGGCGc cTGcTGGTGG CTGAGCTGCA

C

CTCCATATG GACCGGCCGC CTCGTAGCCG CGTTCTC!CTC ATCTGCCTCT

TCCTGGGCGCC

CTCTGCCTAC AGGTGGGTGC

CGTAGGGGTCG

GCCCCTCAC CTCACCTGTG TGGCCTCCTC

T

GCTGAGCCCG CTGAGCGTCG ACACAGTCGC

ID

TCCCGTCTAc CTGGCCATCC TTTTTCTCT

CC

CTGGGGACCC GGGAGTACTG GGAATGGAGC

C~

CACGGCCCAC

GGACGGCGAC

CAGCCTGGGT

CTGCCAAGCT

TGCGCCTCTG

CAGAcGGcAC

AACGGGGGCC

kICTCCGTGGG TGCCTTcTA

;CGTGGCTTC

TTCACTcGC

'AACGCCGTG

GGGCAGCCT

CCTCCACAC

~TTGGCCTG

CGGATGTcc Ir'GGCTCG ;TCCAcCAA

LGGGAGAAA

CAGACGCC

G3CTGTGCA

AGAGGCTG

CCTGTAAT

CCAGCCTG

3TGGCTCA 2AGGAGTT 4 k.ACTTAGC 4 ;AGAATGG 4 ~CATCCTG 4 41040 41100 41160 41220 41280 41340 41400 41460 41520 41580 41640 41700 41760 41820 41880 41940 42000 42060 42120 42180 42240 42300 42360 42420 ~2480 L2540 L2600 2660 2720 2780 2840

ACTTTCCAGT

ACACACTTGA

GAATGGTGAA

ACGCCAGATA

GCTGCAGccA

GCAGCCTTAG

AGAACGAGGG

ACTCAGAAGA

GAGGGAAAGG

CTAGACTGAC

CACTTT(3CTA ATGCACTCCA GAAGAAAATC TCAGTACATC

TATAGGAGT

TTAGAAACGT

CAGGTGGCCG

CAAGACCCCA

CCCAGCACTT

CTGGCCAACA

GGCGGGCGCC

GGAGGCGGAG

CCCAGTGGCC

AGGTGGGCGG

TCTATATAAA

TGGGAGGCCG

CAATGAAACC

TGTAGTCCCA

CTTGCAGTGA

TCTCCAAAAA

TAGAATITTT

GGGCCGGGTG

ATCTGAGTCC

ACATTAJAJA,

AGGCGGGCAG

CCGACTCTAC

GCTACTCGAG

GCCGAGATTG

AAAAAAAAAA

CTAAGCAGTT

TGGTGGCTCA

AGGAGTTGA

GGGCCAGGCG

ATCACTTGAG

TACAAATACA

AGGCTGAGGC

CGCCACTGCA

CC

AG

CG

GA,

G

GCi GGCAACGGAG

CAAGACTCCA

CAGGCTCAGA GCCTTCACGA AAATCCCACA

AAGAAAAGCT

AAGGAAGAAT TAACACCAAT 4 4 CCTTCACAGA

CTCTTTCC

GGGAGGCCGC ACCCCTTAi ACCCCAGCAG

CACACAGA

CGTGGCAGGA ACCAGAGGC AT'GGCCGGGT

GTGGTGGC]

GATCACTTGA

GGTCAGGAG

ACTAAAAATA

CAAAAAATT

GGAGGCTGAG

CCAGGACAJA

TGCGCCATTG

CACTCCAGC

ATTTAAAACT CTGTTCCTT, GCGAGGGGCT GCCATcACG( CTGTCAGATG

GCACCGGGC

TGAGCAGGTC

TGAGCTGCCC

CCGAGCCCCA CACCTGcCGG GTGCTGGACA

GCTCCTTCCT

GGGGTCCTGG GCTGGGcTGG TGCACCTCTC AGCAGGCCTT AA GAATACAG

GGAATGCACAC

3A AGGCGCATP M ACATGTGGC *C ACACCTGTA *T TCCAAGACC.

'A GCTGGGCAD T CGCCTGAAC(

TGGGTGACAC

PGCTGCACCAG

3ACGGTGCAC.

rCTGTCCTGTC

CCCGCTGACC

GCAGCAGGTG

CACGTTCTCA

GG4GTCCTGCC

TGTTGGACAG

AAACCTCGAG

GTCCTTGCTG

AAGCCCAGGG

GGTACCTTGC

CTCAGTTGGC

GCACGGGGCC

CCCTACTCGC

CTGAAGCTCA

TGATCCAGCAC

I'GGAAACGGA

C

AGAGGAGGGG

C

3GGGTGCCAGG 3GAAAGAGCC A GGTGGGAACG CTTCCCATTC

ATACGGAAAC

~G TGGGGTCCTC AAGAGGTTAC ATG4CAAACTA LGCCGCGACCA GGAGGGGTG CTCCCGAGTc T GCTCGTATTT AAGTTAATTA

AAATGGAACG

ATCCCAGCACT TTGGGAGCG

GAGGCGGGCA

A GCCTGGCCAA CACAGTGAAAJ

CCCCGTCTCT

3GTGGCAG C CCTGTAJATCC

CAGCTACTCA

3CGGGAGGTGG AGGTTGCAGT

GAGCTGAGAT

CGAGACTCCA TCTAAAAAAG

AAAATATGAJA

TCTGCTGTCA AGTGTTCAGT

GGCACACGTC

TGTCCCATAT ATCCAGCATT1 CTAGGAcAT'r TGCTGAGGAG GTGGCTTCTC

ATCCCTGTCC

ACTGCCCTCG TCCTGCAGGT

GGCTGGGAGC

CTGGACATCG ACAGCTGCCT

GGACTCGTCC

GGCCTCCACG CTGAGGTGAG

GACTCTACTG

GCCTTGGCGC AGCTTGGACT

CAAGACACTG

ATGAAGAGTG ACTTGT'rTCT

GGATGATTCT

42900 42960 43020 43080 43140 43200 43260 43320 43380 43440 43500 43*560 43'620 43680 43740 43800 43860 43920 43980 44040 44100 44160 44220 44280 14340 14400 44"60 4520 4580 4640 4700 *00*

AAGAGGTGG(

CGGGGGTGTC

CCGGGAGCAC

GTGTGTGTGA

GGCCCTCCGG

GTAGCAATCT

ACGGCTTCTC

TGGGG7GAGA

TGTACCTCTA

CCCTACCCAA

TCGGGGGAGG

CGCCTGGc3GT

TCTGAACCTC

TTCCCTAGAG

CGGGCTGCGT

GTTTGCTCGG

CACATCCCCT

CGAGGGAACG

GCGGCAGCTG

CCTGGCCAGC

GGAGGGGGCT

GATGAAGACC

GACACCCACA

GGGGAThCC

AGGGTGGGGT

TGTTGTCTGT(

cc

GG

TG

TG

;CG

CA

CTGGTGC;z

TGTCTGW-

TCCGTGCG

ACCCGCGC

GACCTGCT

3CGGGCCA

CCAAATC

-=GCAGC

CCTTGCC

)GCTCAGC

GGACTCA

'AGGGCTG

TGGGATC

LGGTCACTGTC

GCTCCATGTC

TGACTGGAcc

CACCTGCAGT

CAGTGACCCG

TGGGCTGGGC

CTTCTCAGCA

TGGGCCCACC

GAGGGGGTcA

AGCCTGTGAG

GGCCAGGCAG

TGGCTGCACC

TCTGGGGTGC

GTCACACCAC

GGGGTGGGCT

CTGGTGTGCT

TCCATTGTGG-

CCAGAGGAGG

TCAGGTGAGC

CTATGCCTCC

GCAGCCCAGC

TGTCCGGCTC

CCGTGGTTCC

ACTTCACTTC

4 4 4 4 CCTCTAGGA GGGAGCAGGC TCATGGGGCT 'rrGTAGGAGC AGAAAGGCTC

CTGTGTGAGG(

CTGGCCGGGG

CCACGTTTTT

TAAATACCCC ATTTTTGGCC GGCCGAGGTG GCCAGATGAC AAACCCCGTC TCTACTAAAA

TCCCAGTTAC

AGTGAGCCGA

AAAAACAAAA

TAGAGGTTAC

CGCACCCACG

AGGTGTGCTG

CAGTGGCATG

TGCACAGCGG

CAGAATTACC

GCTGCTTTTG

GTTAAGCAACC

CTTCCTGATT'

TGGTTG3GTTT

AGCCCCAGGTA

TTTCTGACGGC

TTCCTCAACC C TTGGGTTTGT C GCTCCTTTCC c.

CCGGCGCCTc T CTCTGCCAGC G GAATAGTIGA

GC

TGCCCAGACT

C

CAAGCAGTTA

T

CCGGCTAATT

T

TGGTCTTGAA ci CAGGCGTGAG

C

AGACAGGGTC

T

TCGGGAGACT

GATCGCGCCA

AAATTCCTCA

CTTGTATGTA

GCGTGTTCCC

AGGTCCACAC

CAGTGCAGGT

CTGCGGTGTC

rAATGACGCA ATCCACATC

'AAGAACTAA

.ACAAAAGGCA

'AAAAATACAC

,TCTCCGGCC C AGCTCAGAC T TTCCCCGTC C( CTCCACCCC T A.AC CAGAG C 3CCCr.CA T kGCAGCCTGC TC

CTGGGTI'A

;AGTGCACT

CG

TGCCTCAG CC "ITGTGT CT CCTGACCT CC

ACCACGCCTG

ACTGTCTC CA

ATCTTGGTCT

GCCGCGGTC

CTGACGTCAG

ATACAAA

GACGTAGGAG

CTCCACTCCA

ATTTCTTGGT

GTCACCCACA

ACGCGTGTGA

GCCCTG4CCG

GCGGTCCCC

PCGGTTTGGG

ETTCTCAGAAC

'AGTTTCATT

T

LGAGGTATGA

A

.CATAACCAT C

AGTATCGGGA

AAAGCTCTC T(x CCGCATCCA C) CTTGCTCGG

AC

TGCGTCCT

TC

kCGGCCTTC CC 'CCCTGCCA CT CCTGAGTC AG

TTTTATTTTT

~ATGATCT CO4 TCCCAAGT AG(

GTTTTAGTAC

TGATCCAC ccI

?LCCAAGTTGA

1CTCCTGA C CACAGCAGTG

AGAAATTATG

GCTCACACGT

GTAATCCCAG

CAGTTCGAGA

CCACCCTGGC

TTAGCCGCGC

ATGCTGGCAG

AATCGATTCA

ACCTGGTACC

GCCTGGGCAA

CAAGAGCGAJA

TGTTTTCTAA

CTTATCAACA

rACTCACCCA

CATGGCAGCC

CCCGGGCTC TGCCATGCCC E'TGCACTGCA

GCTGCCTCCAC

GCCCACAG

GCCACACCAC

'AACTACCCC CTGTGACATT 'ACATCCCTC GCACTAAGTC

G

GTGTTAT TCCTTrTGAGT

C

CTGCCCCTG GACTCAAACAA

GCCGGTTT

CACTTTGGCA

CAACATGC(

GCGCCTCTAC

TGAAGGTTG'I

ACTCCGTCTC

AATGGTCATA

3GCGGCGGAG

['CCTATGCTC

;GATTCACTG

LGGGCCTCCA

IGCACAGCAA

TGCGTGACT

CTTCTCATT

~AAGGAAAA

~TAAATTGC

k.TGCTGACC

~CTCCCGGC

TCCCGCG

S

ALCATGAGG(

kiATCCAGC(

,AAATCCAC

~CAGAGCGC

ACTGCTTC

CTCACTC

'TGCGCCTC

CCATGCCT

CCCTGAG

P.TTI'ATTT

CTCACTC

TAAGATT

k.GAGGAGG kTCTCAGC

;GCTACGT

.ICAAGTGA

CATCTTTATG

GTAGTCACTA

ATTCAGTCCT

GTGCCC'CA

GGCCTGACCA

AGCCTCCAGC

AK

Cl

CC

C

r44760 ~'44820 '44880 44940 45000 45060 45120 4518o 45240 45300 45360 45420 45480 45540 45600 45660 45720 45780 45840 45900 45960 46020 46080 46140 46200 46260 46320 46380 46440 46500 46560 AGCCTGCACC CTCCcQ'CCTG CCCTATTrCGC CATTCTCCGT TCATTTGTCT

TGCTATAAAG

TTTTGACATG CAGTCTCTGT.

CAAAGTCTCC

CTCCCACGTT

ACAGCCCCC

CCOCCACAG

TTTCACCATC

TTACCCAGCC

CTCCCAAAAT

GCTCACATTA

CATTTTTTAA

TTTTTTGTAA

TCCTCCTCCC TCAGCCTCCT

GAAGTGCT

GAGAGACA

GGTGATG

TCTCGCAG'

TAGCAGCTC

GGTCACTGC

GGGATTTGP,

GCATGGGAC

CCAATCATA

TGTAAGGGC

GGGACGCAG4

GCACCACTC(

GACCCAAGA(

CCTGGAGG4CC

GAAGACAGAC

GAACTGGGA~z

GGATGCCCC'I

ACTGGTGGAG

GCTCAGCCTG

CCCCCCGGGC

CCTCGGCTGG

ACGGGGGACC

ACTGGTGGCC

GACGCCTGTG

GGCCAAGGAA

TGCGGCCTGT

GACACTCCTG

CTITTGCCCGG

CCCAGCTCCA

CTGTGTGTICT

GGTAGAGTCT

GG GATTACAG GC AAAACAGG 3C TGACGAGG rT GGTCTCGT(

GGGACCGG(

'C TCCTGGAGI ~A AGGCATTC.P 'A GACACACTG G TTTGCAGGG A GCTGGTCAG 3CGGACGCCTI

-CACTCTCGT'

3GCTCAAGALAj

-GGGATGAATJ

ACGCTGGCGC

CAGCCCCAGC

AGCCCCTCCC

GGTCTGCGGA

CTCCTGGTGG

GTGAGTGTTG

GAGCCACTGA

CCTCTGAAGC

AAGCGGCTGC

AGCGCACGTG

GAAGCCCGCA

GCCCCTGCCA

TCCCCCT'rTC

TCTCCCTCCT

ATGCCCACTC

GCCCCCAGGT

TGGGGCGCCC

TTGAGACACT GCGCCCAGCC

AAGAGTGTC'

GCATTCAGTG CAGTGTGACC

CTGGGTCAG(

GCAGGTACGG GAGAGCGTCC

TGAGAGCCCC

TCCCCCTCAA CGTGTCTTCG CTGCCTCTG7 ATATCAGCAT GGTGGCCCGA

TGCAGTGGCA

ACAAGCAGAT CTCTGGCCTC

AGGGAGCCCT

ATGTTT CCTT GTCCAGAAGT

TAATTTTAGG

CGTCTCTAGA TTGTAGAGAT GCTTGTTGGA 9 a T TGAAGGGGG G CTGTGGGCG.

S ACTTCGGT@i r TGGGGTAGG< k CTGCCCGCC( r' CACAGCCTAc

TGCAGAGGC'I

CAGCGAGGCE

TGTGAGCTGC

AGCGCCTGCT

CTGTGGCTGT

CGTGGCTCCT

AGGTGAGGGG

CACCCCCTCC

ACCCGGATGA

TGCCCCGCGT

AGGTCAAGAG

CCTCCGTCTC

CTCACCTCAG

ACCCCACGCC

CTGCCTGGCC

GGGGTTCCGG

CCTGCCAGCT

G CTCATTGCIz A TGGGTTTAI

:CTGGAGTGC-

3 TCTTCCGGC AGO 1'AACA

CATGTCCCT

GGGGGAGCDI

GTCCAGGAC

C~TCTCACAG(

GCCGGCCTM

GGCTGTCTC~z

GTCCAGCAGC

GCTGCCAGGCG

CCAGGTCTTG

AGATGACACC

ACGGCCACCC

GCTACATGGC

TTGTCTCCCA

AAGGCCCTTA

CCCCACTTGC

CTGAAGGCCC

GCAGGGTGTG

CACCTTCCTG

&C CCTGAGAGAc 'C AGCAGCAAG4C ;C TCTTGGTTrc T TTTTGTCGGG T GGGCTTGGCT C AGGTCCAGCA

GGGCCACCCA

N GGTGTGCTTG 3TCTGTCTCTG 3TGTGCCTCCC

GGGTGGGTGG

*GCCAGCTTCC

*GTAGGCTACA

C

CTGGAAGCCC

CTGGTAGAGA

CACGGCTTTG

C

ATGCTGCGGGT

CCTCCCACCCA

GGGGTTCAAT

G

TGCCCCAGTC

C'

CTAAGCACCA

C

TGC

T

rGCCATT Al CAGCCACACC

T

r TTTATCCTCC

SCCGTTCTTTC

GGACTCGGCG

ACCTCTTCTC

CAGCCTCGGT

ACACACTGTT

CCATAAACCT

TGGTTGOAGAC

TGTGCACTGC

GGGCGGGAGA

CTGGCTCCCA

GGGACCCTGT

GCAACTGCCT

CTCCTGGGGA

GCCCAGGCCT

CGTAGCCCCG

CTTCCCCAGG

TGGCCCACGG

3TGCGAGCTT

EGGCCTCATT

;GCCTCCATC

.GTACTTCTC

~CCCGGCTOT

ACTCTTCCT

GAGCCTGGG

TGCACGCAG

CTCTGCAGC

CTGCCAGGG

TGCAGTGGC

CCCTGGCCA

3CCGCAGCC 46620 4668o 46740 46800 46860 46920 46980 47040 47100 47160 47220 47280 47340 47400 47460 47520 47580 47640 47700 47760 47820 47880 47940 48000 48060 48i120 481.80 48240 48300 48360 18420 ATGGCTCCAG CCGTTGCCAA GGGCCCCCCC GTCCACCAGA GGCCAGCTAT GGGGATGCCT GCAGGAGCTG CACAGCCGGG GTCTGTCTTC TGGGCTTTAG CATGTGTAGA TACCTTTGTG CAGAGGGGAG GGACACAGGT CTGTCTGCCC CAGAACATCC CAGGGCAGTG GGAGCCATGT GGGCAGTAGG GGCTGGAGCG' GGATGGCCCA CGTGCTGCTG CCCCACGGCT GCGGCAGGTG C AGCCCTGCTG

TCACTGTGGG

GCCTCCTGGT

GTACATGCTT

CATGCCATGG GCACGCCTAC CCTTCCTGGC

CATCACGCGG

TTTTGCCTTT AGTCCAGCCA GCTGCTAGAA CTGGAGGTAG CCGTGTCTTG

CAGTGCACAG

CCAGGATAAG GCTGAGAAGC TCCCTGGGTC TCTGGTGGCC PGTGACTGAT GCTGTGGCAG CCTACGTCC ACGGGAACCA C ~GGCTGCAGG AAGGTGAGCT ,GAGAGcAGC CTTTAGCGGA

G

CCTCTTAAC ACCGCCGTTT c

CTGGGGCCAG

TTTCTGCTGG

CGTCTGCAAA

TACGGGCATC

GACCCTAGGG

GTGCTGCTGG

GACGGGCCCA

CCAGGTCTAG

GCTCACTCGA

'TCTGAGGAG

TCCAGCCCA

;GCAGGGCGT G ~CTCTGGCAT C CTTCTCTGT

A

TTAAATCGTT

CCCTAGCTGT

CCTCTTGTTG

GTGACCTTTG

c TGGTAACGTT GTCTAATTGA TGGCTGCTGG GAGGGTTCCC TGGGGTGGCG

GCTGACCACI

TGACCCTGCI

GCGCCATCAA

CGGTGCACTG

GACATGTGGA

CATCAGTAGG

TGACAGACAA

CCGTGGCCAG

GGCGGGCATG

TCTGGCCAT

~AGCTGGGGC

;CCCCAAGAC

AGCCCTGCT

.TATGAGAGA

CGAACCAGA

CCTGGCCCC

G3GGTCCACA PiGAGTCCTC

CAGAGCGAG

CGGCCTCCT

kccccTCTC

GTGCAGGA

;CACACT

;TCACCAGC

GCCCCTCA

7ACTGACCC

CCGGCCGT

GCCCTGGC

CTG3CCTCT

CGTCCCGC

4848o 48540 48600 48660 48720 48780 48840 48900 48960 49020 49080 49140 49200 49260 49320 49380 49440 49500 49560 49620 49680 49740 49800 49860 49920 49980 50040 50100 50160 50220 GCTCAGGCGA GCTGGCCAGC AGGAAACACT CCTGTTGGGT

GGCCTGGGGC

CGTGCTCGGC

TCTGTGTGTT

CGCAGGAGGC

ACAATGGCTC GGGGACGTGG

S

S

SSSS

GGCCCCGGGC

GACCAGCCTG

CGGCAGGGCA

GCTGGGCCTG

GCTGGACAAC

CAGGAGCCCA

GCCACGCCTG

GCACCCTCTG

GGGGCTGCAC

CGCCCTCAGC

GCTCACCTCG

GTCTACGCCA

GCTCCGGGGT

TGGTCCTGGG

AGCCTGGAGG

AGGTGGGAGC

CCCTCACTCC

CACTGCGCGG

CGCAGGAGCC

GCCGCCGTCA

GTCCGCCCCT

GTACGCCCGT

TCAGCACTCT

TTCAGCACCA

GCCTATTCAG

AGGACAAGGG

GCCGGAAGGG

GCTCCTGTGC

AGAGCCGCGA

TCCCTCCCCT

TCCGGCCCCC

rCCCCGCAGC 3CGCTGTGTT

:GCTGCGCCT

I'TGCGCTGCG

ACCCAGACCC

GCGATTAcGA

CGCCGGATCT

AGTAGTTCTC

CTGGGGTGCG

CGTGTATGAC

CCGGCTGCGC

GCCCTCTCCG

GCTGGCCTAG

TCCCGCCCTG

(fCTGGAGCTC

CGAGTTCCCG

CCGCCTCAGC

TTTGATGAGG

TCCCGGCCCC

CGTTGGCTGG

GCTGGGGTGA

CAGGAGTGCC

GCACCCACGC

AGCGGGGGCT

TTCCTGCAGC

GGGTGGCCGC

GCGGCTTCCA

CCACCCGCTC

A.CGCGCTACA

3CGGCCGGCC( 3CGGGCCTCT CCCCGGCCAG ACCCCGCGCC

TCCCACCGGC

CCCCTCGCGG GGCCCCGCCC GGCAGCGTCT CACCCCTCGC AGCGCCCCGC CCCCTCGCAG 50280

CGTCCCGCCC

CCCGGCAGCG

GACCGCGCCC

CCCGTACTTG

GGCTGCTGGT

CTGACCGCCA

AGGTGGCGCA

TGGTCAAGGT

GCAGACAGAT

TCTTTGGCAAC

TGGTGCTCGG

AGGGCGTCTT

GCTCGTGTCTT

CCCTGGGACT

G

GTGTGTGGGG C

CCTCGCAGGG

TCCCGCCCCC

CCCACAGGTG

GCACAGGGAA

GGCGCTGACG

GTGGACCCGT

GCTGAGCTCC

GAGGGCTGGG

PTCTCGTCCG

;ACATTATGCC

;GTAGCCTAC

G

,GCTCAGCTC

CCTGTGTGG A GGCTCTCTA C TCTGGGCAC T A.CCACGCCT T4 T'GGAGTTGT T( STACGGCCC A( rGACTGAGC C( GCTGCCCT C2 TGGCTCCG AlI CCTGGGCC G GGCCCTGC TC GCAGCAGC TG 1'GGCCCAT cc I'GTGGACC TO4 CAGCAGCA

T

I'CAGTATT AC~ r'CCCCAGA GAC

CCCCGCCC

TCGCAGGG

TGCCTGCT

GGGCGCTG

GCGGCCACI

TTCGTGCG

GCAGCCCG~

CCGGTGGGC

'AGGCTGCC

GAGCTCTG

CCCAGCTG

,GCTCAGCT

.CTCCCTC'D

CCTGTGTCC

GCGGCTGT(

GCGTGGAGI

CCTGCGCAC

;TGGGGGGG

CTGTGCCG

'CGCTCCTC

'CCTCGCA

CTGGGGAC

CCCAGTT

ACAGCCT

CCGGGCCT

CCACTGG

IAGTCCTC

[W"ITTGCC

CG GCAGCGT( ~CC CCGCCCCC GC TGTTCGCC GC GCGTGCTG G0 CACTGGTA 2G GCCGCCCG VG GCCTGGCG~ *G CGGGGCTG( C AGCAGCTAC C CAGAGCTCC G CCATCCTGG

GTACGCCCTC

3GAGCGTGGC

TGCCGAGTC

SGGGCGCCCT,

SGCTGTACCG<

GCTGCGCC'rc

AGAGGGACAC

CCCCCAGTTC

CAGGGGCTCC

CCCCTCCACC

AAGGTGTGAG

TGACCGACTrC

GCAAGGCC!GC

GCGGCCAGCA

CCCCAGCAGG

CTTCCTGGCG

GCTrGTCAAGG 7CC GCCCCCT( 3GC AGCGTCCC .GT GCACTTCC CG GCTCGGAC CG CCTCGCC CG CCGCTTCA G~C CTCOCTGC 3G CGCACACC *G CTTCGTGC(

GGGGTCAC

~T AGGTGACTG 'A CTGGTGTCG C CAGGCCCTG C TGGCACCTG 1CGOCTGGGo.A

SCCGGCCTG

-TGGATGGGCC

-GCCCTGG4GCj

*CGCCACAAAG

AAGGTATCCC

TCCTCCAGCC

CCTGAGCCCT

AACCAGGCCA

AGGAGCAGCC

CTGCCCAGCC

ACACCCCT4pC

GGGGTGGGCC

CCGAGGGCCA

CCGCTGGCGC

CTACGAGATG

CAAGGAGGTG

TGCAGCCGGA

AGGGATGGAG

CCCACCCAGC

GCTGAGCGTG

AGCCGTGTTC

CTACCAGCTG

CGGATCTTCC

GGCCAGTCGG

CAAGGTCCAc

AGTGGACACCC

CTGCACGTAGC

TTTAAAGAGGC

CGT AGGGCCCCGC 'TC CCGCCCTCCT ~CC GTGGCCGAGG ;CC TGGGCGCGGT AG CTGGGTGCCG CT AGCTTCGACC TC TTCCTGCTTT 2C AGGGCTGCAA C CAGTGGTCCG :C TTGGGCCTXG C GCOGCCGGGG C CTTCCCCGCA T TGGTGCTGTrc T CACCCCTGCT 3CTGTTATTC'p

SAGCCCCAGA

TCAGCAAGGT

CTGCCCAGGG

TCCGCTT'rGA

CGGATGTGCC

AGCTGGATGG

CCCGCCTCCA

CAGAGGACGT

GGGCGCCCGC

GCCTTGCCCG

GGGCCAAGAA

GTGGAGTCGG

GGCAGAATGG

GCTTCAGCAC

50340 50400 50460 50520 50580 50640 50700 50760 50820 50880 50940 51000 51060 51120 51180 51240 51300 51360 51420 51480 51540 51600 51660 51720 51780 51840 51900 51960 52020 2 080 i2140 ~CAGGCAG GGGCATCTGT 2TGTGTGGCC AACCAGGACC CAGGGTCCCC

TCCCCAGCTC

GACACAOCAG TATTOGACGG TTTCTAGCCT COGTC ATATCCCATC CTGAATGC AATTATTC CCGAGGAIC CAGGTACAGC GGGCTGTGCC CGGCCCCACC CCCTGGGCAG ATGTCCCCCA TGCTGGCTTC AGGGAGGGTT AGCCTGCACC GCCGCCACCC TGCCCCTAAG TCCAGTTCCT ACCGTACTCC CTGCACCGTC TCACTGTGTG TCTCGTGTCA TGGTGTTAAA ATGTGTATAT TTTTGTATGT CACTATTTTC ACTAGGGCTG GCCCAGAGCT GGCCTCCCCC AACACCTGCT GCGCTTGGT.A GGTGTGGTGG

CTGCTAAGGC

TTATTACCTC

GTAATTTATA

AGGGGCCTGC

CGTTATGGCA.

GCCCGGCTG(

GCCAGGCAC'

AAGAGAGCAC

TCAGAGGACC

GAGGAAGGT(.

CCCAGGCAGC

GGCATGGCCG

AATAAAAGAG

TTATTTATTT

CTCACACAAA

CATAGCCAGG

GCACCAGAGG

GGCTTGGGCA

CTTGGGCAGC

GCTTGATGTG

GCTATGATGC

TGGCACCTGG

CAGGGCCATC

GGTG3TCC!ACA

TGCTTGGAT(

P CTCATCACC(

CGCCCAGGCC

-CCAGGGTGG1

ACTGTGTGTC

*CTCAAGGCCC

CTTCTAGAGC

CTGTCTGACT

CACTGACAGG

CTCGGTGAAG

TGTGGGCTCG

TAGGCTGGGG

GTAAGTCTGG

CAGCACACCC

GCGGAGCGGG

ACCTGTGAGG

GCCTGTCCCA

T13GCGGGCCA

AGGCCCTCCA

3CGAGCTTGG<

CAGAGGCCT'

TGCTGGCATC

TAGAGGAAAI

TGTGTGTGTC

TCGGAGCTGG

CTCGACACCC

GCAATCTGTG

CAATACCGTC

TCCTCCACCG

GCTGGAGTCT

TTGGAGTAGG

GAGGCGTGGC

CGCCTGAGGG

CAATCCACTT

CCATCTGGGG

CCAGCTCACG

CGAAGGGCAG

TGTCTGGGGA

-CTTGGGCCGG

r GTCATCCTCC

AGGTCTGGGC

GACTCCTCCT

CGCGCGCGCA

CTGTGCCTGC

CCCCAACCCC

CCTCTATGTC

CAAGGCCAGT

AGGAGATGAG

GTGCAGGGGC

CGGCTTCCTCC

AACCGCTCTG C AGCCCCATAT T1

GGAGGGGTAG

ACGTAGGCAG

CCTGGACCCA C

TGCTGGGGGC

CTTGCCCCAG

AAGTAGCAGG

GGGGGCTGGC

CGCGCGAGTG

TTCTGTGTAC

CGCACCAAGC

TGTGCACTGG;

GCAGGAGGGA

"CGCTTCCGC

V'TTGCTATGGC

;CAGATCTGA CCACACACC C ~CCCTACCCG C

,TATCGGTGG

GGGTGAGCTC

CCCCACTCAC

ACAGCTGTCT

GCCAGGTAGC

ACTAGGCATG

TCCCAGGGTG

TGCTGTATGG

CACTTCTGTG3 1GACAAAGTC

GGTCAGGACT

3GGCCCCGGC

[GGCCCACCT

ACGGAGGGT

GGCAGAGGC

GCCCCACAG

TGGCGGAGC

K3TTGGAGCG

ACTATCAGG

ATTTGCGTG

5220o 52260 52320 52380 52440 52500 52560 52620 52680 52740 52800 52860 52920 52980 53040 53100 53160 53220 53280 53340 53400 53460 53520 53577 GTTGCGGTCA GACACGATCT TGGCCACGCT GACTTGGTGG TCACGCCAGG.CCCAGGG INFORMATION FOR SEQ ID NO:2: SEQUENCE CHARACTERISTICS: LENGTH: 53526 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2: TGTAk-ACTTT TTGAGACAGC ATCTCACCCT

GTTCCCCAGG

CATGGCTCAC TGCAGCGTCA ACCTCCTGGG

TCTACTTGAT

TGTAATAAJAC CCTCCTGCAJA TGTCTTTGTT

TTTCAJATC

TTCGTGGGTT GATGTTCTAT TTTGTTTTTG

TGTGTGTGTG

TTGAGACACA GTCTTGCTCT TGTTGCCCAG

GCTGGAGTGC

CTGCAACTTC CACCTCTTGG GTTCAAGAGA

TTCTCCTGCC

GATTACAGGC GCCGCCACCA CACCCCGCTA

ATTTTGTATT

TCCATATG TCAGGCTGGT CTCAAACTCC

CGACCTCA

CCCAAAATGC TGGGATTACA GGCGTGAGTC

ACCGCACCTGC

AACACAACAG TTCATAATAT ATTCTACATA GACCATACCT

G

CTCTTTTCCC ATTTAACACC TTTTGCCTTA OGTTTATTTT

T

ACTTACTTTG TTTGCAGT'rT CCTGTCTTTT TTTTTTTTTT

T

CTCACTCTGT CACCCAGcGCT GGAGTGAAGT GGCGGGATCT

C

CTCCTGGGTT CATGCGATTC TCCTGCCTCA

GC'ITCCCGAA~T

TGCCACCATG CCCAGCCAAT TTTTGTATTT TTAGTAGACA

CC

CAGGATGGCT CAATCTCTTG ACCTCGTGAT CCACCTGCCT

C(

ATTACAGGCA TGAGCCACG TGCCTGGCCT TITTTTTCT

TI

CTGTCACCCA GGCTGGAGTG CAGTGGGGTA ACCTCAGGTC

AC

GGTTCCAGTG ATTCTCCTGYC~ CTCAGCCTCC CGAGTAGCTG

O

CATGCCTGGC TAATTTTTGT ATTTTTAGTA GAGACGGOT

TT

CTGGAGTGCA

GTGGTGTGAT

CTGTAAACTT CGAGGGAAGG TTTGTATTTC

ACAGTTTAGC

TGTGTGTTTT

GTGTTTTTTT

AATGGTGTGA

TCTTGGCTCA

TCAGCCTTCC

GAGTAGCTAG

rTTAGTAGAG

ATGGGGTTTC

rGATCCGCCC

ACCTCAGCCT

;CCAATGTTC

TATTTTTGAG

;TTATGTGTA GATAAACAGA CTGGTATCA

ATACTGGCAC

TTTTTTTTT

GAGACAGAGT

GGCTCACTG

CAACCTCTAC

P.GCTGAGAC

CACAACTGTG

3GGGTTTCA

CCATACTGSC

MGCCTCCCA

AAGTGCTGGG

~TTGAGATG GAGTCTrCACT ~TGCGACCT

CCGCCTCCCG

~ATTACAGG CACCCACCAC 120 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 15-60 1620 1680 1740 1800

S

GGTCTCGAAC

ACAGGTGTA

CCCCCTTTTA

AAGAAACATT

TTGCTCTT

TCACTCTTGT

CTCCTGGGT

TGGcACCACC

TCTTGGCCTC

GCCACTGTGC

GGCTAACAAT

TCCCTCACGT

TCACCACATG

TGCCCAGGCT

CAAGCGATTC

CCCAGCTAAT

ATGTGACCCG

CTGGCCTGGC

TATTCACTGT

CTTCTTCCCT

GATTTTGTTT

GGAGTGCCAT

TCCTGTCZTCA

TTTGTATTT

CCTGCCTTGG

TTTCTTGTTT

TAATAAAAC

GAACCAAACA

TTTTGTTTCT

GGCACAATCT

GCCTCCTGAG

TGCCACGT

CCTCCCAAAG

CTTTTCTCCT

CCTCAGGTCT

AGATCTCTGG

TTG WrTTTTG

CAGCTCACTG

TAGCTGGGAT

TGGCCAGGTT

TGCTGGGATT

CTTCTAGTTT

GTATTTTATC

CACATTTTAT

AGATGGAGTC

CAACCTCCAC

TTAGTAGAGA CG TTCA CCATGTTGGT CAGGCTGGTC

TCGAACTCCT

GATTACAGGC

ATGAGCCACC

GACCTTGTGA

TCTGCCCACC

ACGCCCGGCC

CCCATGGTTT

TTGGCCTCCC

AAAGTGCTGG

TTCAAATAGT TTAGAATTTC ATTTCCAGGT AACTAATTTG CTTCTTTAAA CTAAACAAT'r GCATTTTATT CCACAACCGC

CATATGTCTT

CTTCAAAcAAJ TTCTATTTAA GAAATCCTTT TCATTGAGAC TTGGTTAATC

TGTTTTGC'I

AATCTTAAC

TACCATCCA

GCTCTGTTG

CTACTGCCT

TTTTTGTAT'

TGATCTTGT(

CACTCCCAG(

ACTCTTTTGC

CTGGGCTCAC

CAGTTTG7GC'I

GGTCTCCAAC

ACCGGAGTGA

CTCATTTAAT

AATAAATAAG

TCTTTCAATA

CCCTCTGTCT

GTCGG7GAGGC

AACCGCGGAA

CTGGCCCACA

ACGCACTTTA

CTGCAGTGCG

GCGTGGGGCG

AGCCTCCGGA

CCTGCACCCG

AGGAGCCGCG

GAGCGGCCTG

CCATCCAGCC

'C ATTTGGCAC ;T CTGTCATT' .C CTGCTGTcYI C CCAGGCTGG C AGGCTCCCT r TTTAGTAGA 3ATCTGCCCG

CAGTTCTT=

-CCAGGCGGG

-ACGCTCCTC(

AATTTTGGC'

*TCCTGGACTC

GCCACTGTGC

AAAGGGAATA

GCAATAAATG

AGCTCTCACC

CTCTCTCAGC

TGCGGGTACT

GAAGGATCAG

CCACAGGAGA

GCCTGCAGCG

ACGGCGGTGC

GAGCTTCCGG

TGCCAGTCCC

CCCCGCCCCC

GCGGGGCCCG

GCCCCGAGCC

CGCGCCCGCC

AGTTTCTTGT

ACTGCAATTA

ACCTGGTAAA

GTGCAGTGGC

GTAGCTGGGA

ATGAGGTTTC

CTCGGCCTCC

TTTCTTTrTrT

GGCTGTTTCT

AAAGCTGGGT

TTTCTTTTTT

ACAACCTCTG

TTATAGGTGC

ACCATGTTGG

CAAAGTGCTG

CCATTTTTTT

GTGCAGTGGC ACAATCACGG #ease C.0

GGCCTCAGCC

P' AATTT'ITGTP.

AAGGGATCCA

CCTGCTGGCA

ATTGTAGCAC

AATGGATGGG

ATCAACCTCC

CAGGAAACCT

GACTCGGGCC

GGTGGAGCCT

AGGGCGGAGC

GGGCGGAGCG

TTCCAGACGC

AGGCCCCGCC

TCATCGCTGG

CCTCGCCCCG

CACTGCAGCG

CCGAGCGGGC

ATGCCGTCCG

TCTCGjAGTAC

GAAACGGGGT

CCTTCCTCc

AATTTCTTAA

ACTTTTTCTA

GAATGAAGGA

CATTGCCTGT

GGGGTAGGGA

GCGCACGGAG

GTGGCTGCTG

AGATGGCACC

TGAAAAATAG

TCCGCCCCAC

CTGCTGCCGA

CCCGGTCGCG

TCCGCCCCGCC

CCAGCGTCCG I GTCGCTCAGC I

CGGGCCCCGCC

TC-CCTCCACT

TTGGAATACA

TTTTTTTGAG

CCTCCCAGGT

CTGCCACCAT

CTAGGCTGGT

GGATTACAGG

rTTTTTCGAG

CTCAGCGCAG

:!TGGGACTAC

TCGCCAT

CTCTCAAAG *CTGTCTGTG C

,AGCTGTGAA

GTGGGTTTC C CTCTCTCTT C GCTTGGAGC C rCGCGGGAGA AGGAGGAGG A L'GCCCACCG C, rCGTGCTCC 'ID rCGCATGCG CC CTGTGGAG C 'GTGGCGAA C 'CGCGCGGG GI ;CGGGCGGC CC ;CAGGTCGC C.

GGAGTCCTTG

ATCGCAGCCT

ACGGAGTCTT

TCAAGCGATT

GCCCAGCTGA

CTCGAACTTC

CATGAGCCAC

ACAGGATCTT

CCACTGCCTA

bjAGCGTGAGC

['GGCCAGGCT

rTCTGGGATT

CTCAGTGAC

'ATTCAATGG

TCCCTCTTG

CCCCTCTCT

AGCGGGTGC

AGGATCCAC

ACCCGCCGC

TTCCCGCCC

GGCCGACT

CCCGGGAAC

3GAGGGTGA: 3GGGCGGAG3 kGGAGGAGG

;AGCTCCCG

~CGCAGCC

1860 1920 1980 2-0 2100 2160 2220 2280 2340 2400 2460 2520 2580 2640 2700 2760 2820 2880 2940 3000 3060 3120 3180 3240 3300 3360 3420 3480 3540 3600 .TGAGCTGCG GCCTCCGCGC GCGCGCGGCC CTGGGGACGG CGGGGCCATG CGCGCGCTGC CCTAACGATG CCGCCCGCCG 3660

CGCCCGCCCG

GCCCCGGGCG

CCGCCTGCCG

TCCCCGCGGA

GGACGGGCGG

CGCTCCCAGG

GAGCCGCGGT

CACCCGGGGG

GGACAAACAG

GAGAGGTGGG(

GATTTGATGG

GAAGAAGGGG

TGTGAGGGGT

CTCAGGCGCT C CCGTGGGGGG

T

TTATGGAGAC G GAATCCTGAC 'DN

CCTGGCGCTG

CGGCTGCGGG

CGTCAACTGC

CGCCACAGCG

GCGTGGGCGG

GGCGAGGCTC

TGGCACGGCC

CTCTGCAGAC

TCGCTAATTG

3ATGGCTGTA( kTGTGCAAGA I ;GTGAACGGT C ,GGGGCAGGG TGCTATTGG G TAAAGCCTT G CTGCCCAGA G ~TGACCATC Ci

GCCCTGGGCC

CCCTGCGAGC

TCGGGCCGCG

CTGTGAGTAG

GTTCCCTGGC.

CGGCGCGGCA

CCGGGGAGCC

GCCAGCGGGG

3AGAGGAATT 3GGGGCGGCA

~TTGGGCTGA

;TGAGCAAAG)

VGGAGGTGG

G

TTCCAAGGC TCATGTTCG C CCAGGTCTG T GAC.GCATAG G

TGGGCCTGTG

CCCCCTGCCT

GGCTGCGGAC

CGGGCCCAGC

CCGGGAcGGG

CGGCGGGCCC

GAAAAACCCC

GCGGGGCGCG

GGGATGCGGc 3GGAAGAGTTC

['GCTTAGGAA

CCGTGAGGC1

;CTCGCGGGTG

'ATCCTGAGA

A

TTTCGGGAGA

GCCAGGC'rC C' GACCGTGGA G2

GCTCGGGGCG

CTGCGGCCCA

GCTCGGTCCC

GGCACCCGGG

AAGCAGGACG

TGCTAAATAAJ

GGGTCTGGAG

"AGGCCGCGC

-TGGGGCTGC

~CAGGAGGTG 9]

;GGGCGATGAC

IGGAGGCTGG c

GGCTGGGGTC

CAGGGGTGAG

TAAAAACAA C PGTTGGGGG T NTTTGCATT

T

CTGGCGGGGG

GCGCCCGGCG

GCGCTGCGCA

AGAGGCCGCG

CGGGCCAGGA

GGAACCCCTG

ACAGACGTCC

rCAGCTGGGA 3GGGTACCCG

'CTGGAAAAG

;GTGGGTCCA

CACGGGACG

ATGAAGGGC

GGGGGATTG

AiGGTGGCCT

CGTCATGCG

ACAGATGA

3720 3780 3840 390o 3960 4020 4080 4140 4200 4260 4320 43.80 4440 4500 4560 4620 4680 4740 4800 4860 4920 4980 5040 5100 5160 5220' 5280' 5340 5400 5460 5520

GGAAACAGGT

GCAGGTTT

GACTAAGATA

CCTTGTATTT

GATCCCTGGG

TGGTTTTGTA

GTGTCCTTGG

CAATGGAGCC

GTGTCTGG.CG

ATTGCATCAG

GCCAGGCCGG

TTGGAGAGGT

GGAACTATGA

AGCAGACAGT

CCCAGGCTCC

GGACGTGGCA

ACGTTTCTGG

GGCTTTGCTG

CGTGCCCCTC.

GCTGTCTCTG

ACCTACCCCA

ICACTGGGGA

GACACGACCT

GGTGCCCAGG

TGTCCCCAGC

AGGCTCCTCG

CATCCCCAGG

GTCACTCCCG

GGTGGTCTCG

GGGGCCACAT

TGGAGATGGC

CCCGTTGTTT

CTCTGTCCAG4 CCCTCAdGAG4

GTGTTCTCCA

ACCCAGGGTT

GCTGGGGAGA

CCGGGACAGT

CTTGCTAAAC

CCTGTGGCCA

AGGGTGGGAG

TGCTCCTGCG

CTCCTCCTGC

GTGATGCTGT

GCCCTGGTGG

CTGTCCGGGA

GGCCCTTGGC

GGATTGAAAA

GTCTTGGGAC

GTCTCCTTGG

ATTGGGTGGG

CCCTTCCTTA

AAGAATGGGT

CTCCCTGACT

CTGGCAACAG

AGCTGAGGGC

TTCCTGCTrC

GAGAAGGGCG

AICAGCAGTG

GGGCGGAGGG

CAGTCTGATG

GTGCGTGCTG

TTCTGGCATT

GGGGAGCCGT

TCTCCTGGAC

GCGGACGCGT

CACCCACAGA

TCCTCTGTCT

CCAGCACCTG

CTGGTGGCTG

GTCCCAGGCA TCACAGCCGC GATGTGCATA ATGGTGTCCA TGAGAGCAGC CTGAGCGGAG AGCAAGGCCC 0 CCTGCCTrGT GTTGTCCTCT TAGGCTCTGG TCCTGGGGTTr TGGAGGAGGG

GGACCCTGGG

AGTTGGTGGC CTGTCCCAGC GCAACAGGGC ACAGGGTGAC GCCGCCGCTG GGAGAGTTCT AGGAAGGATG TGAAGGCCCT

CTGAGCTGGC

CTCATGTGGG

GGAAGGTGG4G

GGCTGGCCCC

AAGATTCCGA

CAGGTGGGTG

GTGAGGGGAC

CCAGGCCACC

CTCCTCGGGG

GGACACAGAT

ATGCCAGGCC

CTGTTCTGTA

CCA.TGGCAAA

CTCTGTGCTG

AGACGGCTGG

CACAGCTGCT

CCCCAAGTGT

CACACCTGGG

CTAGGGCCTT

TGGGGCAGCC

GTTTTCCCCA

GGCAGGTGTT

CAGCCATTTT GCTGTCTACC CTGCAAACTC

GGGAAGAGG

CAAGGGTCC"

AGGTGCCTC'

GTTCCAGGTC

TGCCGAGAGC

GCTCGAAGCI3

CAGAGCCTGC

T'TTTTTTTT

ACGATCTCGG

CTCCCGAGTA

GTAGAGACAG

CCGCCCGCCT

TGACCCATGT

TCGCAATACT

GTGTGTTCAC

CAATTAGTTG

CTTGTCTCCA

GGTTCAAGCG

GCACCACCGT

CCAGGATGGT

GGATTACAGG

TTTTTTTA

ACCTCACGGC

AGCTGGGATT

GGGTTTCTCC

TTGGCCTCCC

3GTCAAGCTG k AGAGCGTTG P' CCACTTGTGi 3GAGGACAGC

'TGGTGGCTT!

TCGlr7GGGA(

CCTGCCCTCC

TTTTrTTTGAC

CTCATGGCAP

GCTGGGWATTP.

GGTTTCTCCA

CGGCCTCCCA

TTTGAACCAA

GCAGACCCAC

ATTTrTGGTT

ATGTCTTTTT

GG4CCGCAGTG

ATTCTCCTGC

GCCCAGCTAA

CTCGATCTCC

CGTGAGCCAC

GACGGAGTTT

AACCTCCGCC

ACAGGCATGT

ACGTTG3GTCA

AAAGTGTTGG

G GAGAGGTGA C TGTCTGGGTI 3 CTCCCTGGC :D GGGGCTTCT( r TGGAAAAGA' 3ACGTGGGCAC

CTGCCCCGAC

ACAGAGTTCA

CCTCCGCCTC

CAGGCGTGCA

TATTGGTCAG

AAGTGCTGGG

ATTCCAG4CCA

CTAACACAAC

TAATAGTTI2G

TTTTTTCTTT

CAGTGCA'rG

CTCAGCCTCC

TTTTTGTATT

TG3ACCTCGTG

CGCACCCGGC

CGCTCTTGTT

TCCCGGGTTC

GCCACCATGC

GGCTGGTCTC

GA ITACAGGT

A

TCACCAGTAG CCTTCCTGGG

GGGCTCACGC

r GCTGAAGCTC AGCAGGGACA GCTGTGTCCA SAGGCCACAGC CTGCCTTGGG TTAATGATGC V GGCGTACTGC AAAACGTGCT GCTCTGCGTG AGCCGTGGCT GACTCACAGA CCCCCCACCC CCTTCTCCCT CCTGACCCAT GTGTTTTTTT CTCTTGTTGC CAAGGCTGGA GTGCAATGGC CTGGGTTCAA GCGCTTTTTC CTGCCTCA.GC CCACCATGCC TGGCTAATTT TGTATTTTTA GCTGGTCTTG AACTCCTGAC CTCAGATGAT ATTACAGOCA TGAGCCACCA CGCCCAGCCC CCCTTTTATC TGCAAGCATT TTGGAGGGCA AGACAGTTCC TTCATGCCAC CGAAGGCCTG AATTAAGAGC CAAATAAGGT CCACACACTG TTTTTTTTTT TTTTGAGACG GAGTCTTGCT ATCTCAGCTC ACCGCAACCT CCGACTCCCT CGAGTACCTG GTAGCTGGGT TTACAGGCAT TTTAGTAGAG ACGGGGTTTT ACTGTGTTGG ATCTGCCCAC CTCGGCCTCC CAAAGTGCTG CAATGTI'CTT 'TAAAAATATA' TACTTTTT GCCCAGGCTG GAGTGCAGTG GCGCGATCTC AAGTGATTCT CCTGCCTCAG CCJTCTCCAGT CTGGCTAATT TTGTATTrTTT AGGAGAGACG AAACTCCTGA CCTCAGGTGA TCCGCCTGCC GTGAGCCAAC GCGCCCAGAC AAAAATATAT 5580 5640 5700 57 5820 5880 5940 6000 6060 6120 6180 6240 6300 6360 6420 6480 6540 6600 6660 6720 6780 6840 6900 6960 7020 7080 7140 7200 7260 7320 7380

GTGTGTCTTT

CCTGGCTGTG

TTGTTTTGTT

TGATCTCGGC

CCTGAGTAGC

TTAGTAGAGA

GATCTGCTTG

TTATTTATTT

TGGAGTGCAG

CTCCTGCCTC

TTTGTATTTTJ

ACCTCGTGAT C

CCTGTCTTTT

AATTTGTTGA

A~

CCTCCATGGT G TCGTTGGAGC C AGATGTCATC A ACCCTGGCTG G GGCACATCGA

G

GGCCTTGCCCT'

CAGCAGGCGC

AC

GGAGCGACCC CJ GGGCTGGCCA

C

GAGGACTAGGG2 GAGGGCTCCG

T

AGAGA~TVGAT

G

GCCAGGTTTC A CTCGGGGGCA G AAGAGCCCTIG GC GCCTCACCCG G

AAGGCTGGTC

ATCAATTCGT

TTGTTTGAGA

TCACTGCAGC

TGYGGATTAGA

TGfGGGTTTCA

CCTCGGCCTC

A ITTATTTAT

CAGTGCCATC

k.GCCTCCTGAC

['AGTAGAGACC

CTCCCGCCT C LAATGTCCGA

~GAAACTGGCT

TCACCTCCGT

GACATCCCA GCTCAGGGC C 13GGTCACCT C 3GACTTGGT A MTCCCACCT GC ACCCCGGG C E'AGGCCTGA TNC CCACGGAG C LTTGTCACC A 'ATCACTGG AG ,TGGGGAGG C AGCTCCCA C

GGTAGGCC

AGCCGAGC C GTCCCTGA GC( AAG4CAAAG

TGTGAACA,

CGGAGTCTC

CTCCATCT(

GGCGCGCCC

CCATGTTGC

CCAAAGTGC

TTTTATTAT

r'CAGCTCAC

TAGCCTG

GGTTTCAi

AGCCTCCC

rGATGTCTA(

CCTGCAGC(

GGTGCTGTC

TGTCCCAG~z

CCCTGCTC'I

3GTCTGCTG 3GTGCTTGG

'ATCCCTGA

CCCTGCCT

CCTTAGAG

KGCCCTGGC

GGCCTCCA

CCCGCGTT

GCTGGCCT

GGGAGCTG

CTGTCAG

ikGGCAGTG

~CGTCTT

GTAGGACTGG AGAAAGAATG

AAGAATTCTA

ACTGTGCTTG GACCACCTAG

CTGATGTCTT

CTCTGTCACC CAGGCTGGAG

GACAATGGTG

CGGGTTCAAG CGATTCTCCT

GCCTCAGCCT

ACCACGCCCG GCTAATTTTT

AAAAATATTT

CAGGCTGGTC TTGAACTCTT

GGCCTTAGGT

GGGATTACAG GTGTGAGTGA

TGTATTTTAT

TGAGATGGAG TCTCACTCTG

TTGCCCAGGC

GCAAGCTCCG CCTCCTGGGT

TCACGCCATT

CTGCTGCCCG CCACCATGCC CAGCTAATTT C CTGTTAGC k. AAGTGCTGG 3 GACCTTCCCI

TGGATTTCT(

AGTGTGTGC'.

LGGTTGTCCTC

AAAGGCCAC9

CTGTCTCGCP.

TTCACTGATG

ATGACAGGAG

GGGATTGGCG

CGCAACTGCC

TCCCATTTCT

TGAGCCCTCA

CAACCAACAC

GGAAGGACCC

CCCAGAGAGA

AGAGCCTAGG

GTGAGGACCT

C AGGATGGTCT G ATTACAGGCT r TCCTCTCTTT

CTGTGTCTT

P' TTGTGTTTCT

GCTGGCACTG

TCTGGTGCTG

AATGCTGG

TAAAATATAG

AGTGTGGGAG

TCGGGGAAGA

ACAGACACAC

GGTCCCTGGA

GCAGAAGGAGC

GCAGATGATTC

CCAGTGCAG

GTCCCCAAG

AGAGGCCTGTG

GCATCCTGCAT

GGATCTCCTG

TGAGCCACCG

TTCCTTGTGC

GGGGCTGCCA

TGTAAATTCG

GCCTAGGTGT

GTTGCCACTC

TCCAGGACTG

GAGCACCCGG

AG.TGTAGGGA

MAGGCATTCT

=TCCTTGGG

E'CTGAGAGC

;GCCACCCTC

.MCCAAGGAC

'GACATTGAA

GCAAGGTGA

,tCTTCTAGG

GCTCCAGCTG

7440 7500 7560 7.62 0 7680 7740 7800 7860 7920 7980 8040 8 100 8160 8220 8280 8340 8400 8460 8520 8580 8640 8700 8760, 8820 8880 8940 9000-6 9060 9120 9180 9240

S

S

ACCTGGCTCC CGCACTCCG GTCCCTGCGT GAGAAACGCT AGTTTCTTTA TTAGACGCGG ATGCAACTC

GCCAAACTTG

TGGACAAAAA TGTGGACAAG AAGTCACACG CTCACTCCTG TACGCGATTG CCGGCAGGGG TGGGGGAAGG GATGGGGAG CTTTGGTTGT GTCTGCAGCA GTTGGGAATG

TGGGGCACCC

GAGCTCCCA

ATCGGCTTGi

TTTAAACATX

GGGTGGATC(

TCTCTAAAA?

TTCAGGAGAC

GATCACACCA

AAAAAAAAAA

GGCCAACAGC

ACCACTGTCC

ATGGCTTGAG

TATTAGTGGT

AGTCTATGAG

ACTAGGAAAC

C TGCAGAGGCG

CATCCAGATCA

3 GACAAGGGGT 3CTTGAGCCCA

ATAAAAGAAC

TGAGGTGGGA

CTGCACTCCA

AAAAAATCAC

GTGTGAGAAG

AGCCGGGCGC

GCCAGGAGTT GGCGCCTGTA

G

GTTGAGACTG C

GGTCTTTAAAA

ACTGTGGAGA

TACAGGGAAC

CACTCACGCC

GGAGTTTGAC

ATTGGCCGGG

CATCACTTGA

GGCTGGGTCA

AGGATCTGAA

DTGGTCGGCC

)GTGCCTCAC

"GAGGCCAGC

TCCCAGCTA

AGTTAGCTG

.AAAAAAAAA

'GGCCAAGGT

ACCCCG'ITC

AGCTAATTAG

AGCCAATAT

C

A.AAAAAATG

C

A.GGAGAATC G

"TCCAGCCTG

3CACCCTCT C( 7TCCATACC T kGGAAATTG A kCCCCTGCA G( kGAGGTGGC A GGGGCCCT G CTGCCAGC CC

CAGAGAGCAC

ACTATGATTC

TGGAATCCCA

ACCAGCCTGG

CGTGGTGGTA

GCCGAGGAGG

CAGAGCAAGA

CAGAGATTTC'

TCATTAGTCA

GCCTGTAATc

CT'GCAGGTCA

AACAACAGAC

GCAGTTTGGG

GCAACAGGGT

TGCATCTGTG

TCAAGGCTGC

CCCTGTCTCA

TCCAAAGAAG

TGAGGGAAAC

XCAGCACTTT

JrGGGCAACA TAGCGAGACC TGTAATCTCA GCACTTTGG

CAGCCTGACC

GTCGTGGGCG

CGGGAGGCGG

AGCGAGACTC

AGCTACTTTG

AGGCAAGATT

GAAAAGGTCT

GAGCCCTCTG

CCTGGTCTCA

CATCAGCATG

TGCCCTGGTT

CTrGCACTcC

AGCCCCTCCC

*AACATGGTGA

CCTGTAATCC

AGGTTGCAGT

TGTCTCAAAIA

GGGGCTGAGG

GCACCATTGC

AGGAAGAGTC

TGTTtrGTC

ITTTACACAC

CTCTG.GGGCA I

TATAGACAGA

CCGAGGGGCT

ACCTCTCCCT

3TTGGGAGGC GATGGTGcc

LAAAACAGGG

rGGGGATCA

'ACTAAAAAT

GAGGCTGAG

ACACCACTG

TGAGCGTGG

~TTGAACCT

3GAGACAGA :7CCGCGGTG4

:ATCACGGC

;GCTCTG

:CGCACAGG

;TGGCGCTTC

.VCCCAGGTC

~CTCCCACC

TGAGGGGGGA

ACTGCACTCC

TGGGCGCGGT

CAAGGTCAGG

ACAAAAATTA

GCAGGAGAAT

CACTCTAGCC

TGGCGCATGC

GGGAGGCAGA

GTGAAACTCT

GCCACGCCGG

k~CCGCAGGGT k.GAAGCCGTG-

'TGCCTGGGGC

:CGAGTCGGGC

CAGCTGCTT C .'CTCCTCCC

I

TCCATGCAGT

AGGGACCCCG

AGIGCCAGGGT

GAGACCCCG

GTCCCAGCTA

AGTGAGCTGT

AAAAAAAAAA

b.CGCACAGAT

,TAAATCAA

kGGAGAGCAG kATAAATAGA 3GATTCCCTG

.GCCTGGGCG.

;GTTCACGCC

GTTTGTGAC

CGAGGTGTG

A.CTTGAACC

GGTCAACAG

T'GTAGTCTC

-TCGCAGTG

PCTCAAAAA

.'TCGCGCT

3CAGCCACT

PGATGATTT

'CACACTAG

GCGATGTG

;GTGCTGCC

9300 9360 9420 9480 9540 9600 9660 9720 9780 9840 9900 9960 10020 10080 10140 10200 10260 10320 10380 10440 10500 10560 10620 10680 10740 10800 10860 10920 10980 11040 TCCCACCTCT CCCTCCCTGC CAGCCCCTCC CACCTCTCCC TCCCTGCCAG

CCCCTCCCAC

11100 CTCTCCCTCC CTGCCAGccc CTCCCTGCCA

GCCCCTCCCA

CCAGCCCCTC CCACCTCTCC CCTCCCACCT

CTCCCTCCCT

ACCTCTCCCT CCCTGCCAGc CCTTCTCTCT

AGTTTCCTGT

TTTGCGCCCT GGAGTCAGAC TGGTCCAGTC TCTCAGCCTC CCCTGCAGGG CAGTGTAGCA TTGTTAAAGT AGCTCTGTCG ATGCACTGTG AGACCTGCCC GACACTGTGC

CTGTGCTTAG

GTGGACTCCT

ATGGACCCCTC

CTGTGGGGGC TCACAAGACC C CTCCCACCTC

TCCCTCCCG

CCTCTCCCTC CCTCCAGCCC CTCCCTGCCA

GCCCCTCCCA

GCCAGCCCCT

CCCACCTCTC

CCCTCCCACC TCTCCCTCCC TCAGTTTCAG

GAAGGAGGCT

CTGGGTTCAC

GTCCCAGCGC

PGTTTCCTCA

CCTGTAAAGT

3TGACCTGGC

TCAGCCACTG

3TTCCCTCAG

GGGTTCCGGGC

'GCCACAGAG CAGAGTGTAA

C

LCCAGACACT GGACGACGGG 'AGCACCCAG CCTCGGTGCC

T

GGCCCACTC CTGCTTGTGC C CCAGCCCCTC

CCACCTCTCC

CTCCCACCTC

TCCCTCCCTG

CCTCTCCCTC

CCTGCCAGCC

CCTCCCTGCC

AGCCCCTCCC

TGGCTCATCC

CTGCTGTGTC

GGGAACCCAG ATGTAGGGAJA CTCCACCTCT

GGTGTGACCT

GGGCTCCATG

ATTAGATGCA

'CAGCCCCAA CAATCATACC ;GCCCATTCC

CCTGTCCTCC

AGCCTGAGG GTGAGAGCCA .GCCAGTGCA GCCTGGGCGG TCAGCGCAG GGCCGCGTGG TACATCTGG GTGTTTGCCC

ATTGGTGCCT

AGAGCCGCGA

TGCCTGAGTT

GGTGGTGGCG

GTTGTGCCAA

CCAGGGCATC

CTGGCCCATG

CCAAATGTGG

CTGCCACTGC

CTGCCTGGGA

TCTGG-AGCTC

CCCGC-TGCTG

GGCACGTCTG

GGAAAATGCA

CTTGCCTAGGC

TTTGACGCGT

GTACCGTCCT

CCGCTCAGTG

GTGTGCGCTG

GCCTGAGCCT

TCTATGAGGG

AGTGGGTGAT

GTCCCGCATC

CCTCGCTCCC

rTTGCTTTCC

TGCAGTGGCC

PC'TGGGCCTG

MGGGCACAGC

;CTCACGCC.C I ;GCCAGGGTG C

TCTGGTGTGT

CACTCCTTTT

CCCGCCCTGA

TCGCTGGTGG

CGACGTCCCC

CCTCCTGCTG

GCGCTGGCCA

TGCAAGCCCC

CCACCTTGGG

PGCAAGGAAT.

kCGGCAGCCC 3CCTGCACTC kGCGGGGGCG

~TTCCCAGAAC

CCAGGCACTC

GTGAGACGTG

GTTCTTTTGA

TGTGCGGACc

GCACCGAGAG

CTTCCCGGCT

GAGCCGTCTC

CGGGGCTGGG

CGTAAGCTGG

CCGCTGCATT

TCTTTGGGAG

TTCTGTTGGC

TGTGGATCTC

CCATCTGGTG ACAGTGGCCG

TCCCTGGGTC

GTGCCTCTCc

ATACTTTGGA

PGCCCGCCAA

PGCTGCCTGc

CACAGTCTC

:ACCTCGCTrC

;GTGGCAGGA

'TCCCGAGGC

CCCTAGGGTA

CCCTGCTCGT

GGGAGACACA

GCACCCTGGA

GCTCCAGCTG

CCTGCAGAGT

TTCATGGCTT

GAAGGGCTAC

CCAGCCCTGG

AAGTGTTG4GC

CGAGTGGCAC

CTTGCTGTTA

CTTTGGGGAG

TCTTCTGAGG

CTCTGCCATC

GGCACCGCTG

TGGGGTGGTT

GGGGGAGACC

CAITTTCTTT

A~TGAAAACAT

GCTGAGGCCG

GAGCGCAGCT

3GCAGCTGTC

MTCTGGGGCT

XCCAGCCTGG

3 11160 11220 11280 11340 11400 11460 11520 11580 11640 11700 11760 119S2.0 118 SO 11940 12000 12060 12120 12180 12240 12300 12360 12420 12480 12540 12600'' 126 1272*CF L2 780 L2840 L2900 .2960 GAGGCGGGCT GGGTCCTTTT CTCCCTGCAG CATTCCTGAC CTAGCAGCG CCATGATNCTG AAGACAGGCT GGCTTCTGTGx AGGCCAccTC AGAAAGGGCT TTGTGCCCAG GCAGAGGCGG AAGCCAGCTC TTCCTTCTGG TTGAGGCAGG 13020

AATGAGGCC

GGCTCCGGC-

CCATCAT'rG

TGTGCTGCT

TTGCTTGCC

ACCCTGCTG

TTGAGCCTC,

GTGAAGGGT(

GCGTGCAGGC

ACCCCAGCGC

TCGTCTCCAC

TCGCAGACTC

GTGCCTGCCT

CCTGGGGACA

CTCCCCAGCT

TGCTTGGGGC

CCAGGGTTGT

CATCTGCCCA

CCCGTTAATT

AAAGGAGCAC

GGGGCCGCAG

AGCCCATTTC

GGGCGGAGGG

CCCTGGGTCT

AGGCGGCCCC

GGGGGTGCCG

TTTCTGG

CGCCTGGGGC

ATTCCCTCTG

,A GCGCTGGGC ;T TCTGAGCCC G CTGTGCCCA G CCCTCTCCA C CCCCCCCCA 2CTGCCCCGGG k. GTGTGCCCA! 3GGAGTGGAG

GCACCAGGA(

CAGGTAGCAJ

ACGGCCCMT

CCCTTTCTCA

GTGGGTCCCG-

GTTCAGCCGT

AGTCTCACAC

CTGGCAGCCT

GGCCGGCCTC

GCCCGGGGCT

TAAACAGGAT

AGCGCAGAGG

TG7GGGGTGGC

CTCACCCTGG

GAACCAGCTC

GGCGTCCTGT

TCCGAGCCGG

GGCCTGGCGC

GGCTCCGTCC

ACTCAGCTCT

CTGTGGATTG

.A AGCCCATGCC 'G TCCACTGTGC ,C AGCCGAGTGG G GGCACTGCTG C CATCCTCTTC G AGGTGTTTGG r CAGGAGCGTA Ek GGGATGCAAG 3CCGGCCCTCA r' ACGTATGAAG

TTGAGCTGGC

TCTCCCTCGT I

GGAGGACCTG

GGGAGGGATC

CCCGTGTCTGC

CGTCCTGTAT C CC'rGGCCCTC C GCACTGTTT T CATTTCCGGC C

GAAACAGATGA

ACTGCCGCCT G GCCTGCTCTC G CTCCAGGAGA G CCTGCCCCTG C( TCCCCCCAGC C( ACACCCGCTG C~ GGCCCCCAGA C( GAGTGTGAGA Cl GGAGGGCCCC G

CAGGGAACGT

ATCGTGG4CCC

GTGATGGGAT

TGCCCGCACA

CTACCTTGGC

GGGATGGTGT

AGGTCAGTGC

GGGGTCACAA

TTCTCCCC TT

CGCTCTCCTT

I'GTGTTTTTCC

rcAGCCTCCG '.GGCTGCCCA

=GAAGGACA

GACCCAGAGA

AGAGGCTGC C

CCATGGAAGT

TTTCAAATGA

CTGGAAGCC Gi GGTCATGGC T TCCCCTGTC C' 3GAGGGACG G "ACGGGGCC T

'*GAGGGAGG.A

AGTTTCCAG)

rGACCACAC G'] CCACTCAG C CTGAGGCA G ;GAGCTGCC CC CACAGCTGTG GGAGTACAGG TGGC-CTCAGG ATGGCTCGTA TCCGGCTGCC CCGCTGGATC GCCGGGCGCA GATGGCCAGT TTCCTCCATT GACACACTGG TGGGGGAGGA GGAGGGCCCC

AGCACCTGC

CGCCTGGCT

GAACTGGAA

2CTACACCC

ATCTGTGTM

GGCCGGAGr.

GTCACCCCC

'AATGCCGCI

.CCCTCGTGC

ACCCCCACC

GGTAGGCGG

GCACCGTCC

CCTCACTCT

2GGCTGGCC rCTCCAGCG 77CCTGGGGG 3GCAGGGGG

;CGGTTACA

['AGGCGGC

WqrCGGA

LTCTGGTCT

'TCTGGTTT

'ACACCCAG

C CACACAGGCT C CATGTCAGCT 3 GGTGGCCCCG

ACAGGTGGGC

k. GGCAAGGACA r~ CTCCATCCCT

GGCATCTCAT

GAGCCTGGGG

AGGGCTCTGT

CCTCGTGGGG

AGCCAGCAGC

CAAACTGCAG

CCTTAALATAG

CAGCGAGGAA

CCCAQACTGC

TCCTCTTGCT

CATGGGGCCT

TAAGCTCCGC

CAGCGCGGGC

TGTGCAGATG

GGGGAGTGGG

GTCTGGGGCC

GGAAGTTCTrC 1308o 13140 13200 13260 13320 13380 13440 13500 13560 13620 13680 13740 13800 13860 13920 13980 14040 14100 14160 14220 14280 14340 .14400 14460 14520 14580 14640 14700 14760 14820 9 S

S

9.5.

9 CTCAGTCCCA CTGTTGCATT CCCCGACCCC GGCTCCCCCG GCCCAGGAGC GCCTGTGGGG

CAGAAGGCC

GCCAACTGT

CCTGAGGGG

CGGGCAGAC

TGCTGCCCA

GGCCTGGCC~

AGGGGTGAAC

CCCAGCAGCC

CTTCCAGATC

TGCCCCCATG

CCTGGCCCTC

ATAGCAGGAA

CTGCACTCTG

TGCCTGGGCC

CAGACAGCGG

.C AGCCCCAAGA CTTCCCGGC 'G GGCAGAGCCC AGGGGGAGG C CGAGGCTCCA GGGCGAGG@ C CGCTGCAGCA

TGAGACACG'

-AGCCCTGGGA CGTGGCCCCj 'CACCCTCTGC TGTTGCTGC'I ACCCGTACTG

TGGCCACACA

*GCTAAGGAGc CCGCTGGGTC *GGACGCTCGG CGCTGGGGAC GGGGTGTACT CCTCCCGACA GGGCACCCAT

CAGGCTGTCC

CTGGGGTGAG GAGTGCGTGG CTCTGTGCTC TTGCCTGGGC CTGCTGTGTC CCCCATCCTT CGATGATGTC ACCTGGCGGG C CTGCCAQGCC CAGGCTTCAC

CCACCCTCGC

G CAGGAGAGCc AGCGCCTGGC

TGGGAACACC

SGCCCGACCTG GGG TTCACAC GCCCGGGTGG r GTCAGCTA~C TCGGGCCGGC

AGGCTGGCCC

SCCTGTGACGG GTGTGGAGGG

GCAGCCTCCA

CCTGCTCCAG GATTGGCAAG

GGTGCTGGGA

CCTGGGACTT CCTTCTCCAC

CCAGTGGGC

CCACGCTAG2 ATGGTCCTp.A

CTCCTCCCC

CCCTTGTGTC CCGGGGCTGG

GGCACCGTCC

AGCTTGGCTT CAGCTTCCCT

GGGAGCACAT

CTGTGCACCT GGCTCCCACC

CTTCCAGCTC

GGCAGCAAGG GCCTGGGACC CCAGAGGACC TTAGGGCCGC TCGGTGGTCC

TGCTGCCAGA

GCAGGGAJACC AGAACGTGcGj

GGCAGGGCAT

TGCAGAGGAA GCCCGAGG(Y3

CGGGGTGGGG

14880 14940 15000 15060 15120 15180 15240 15300 15360 15420 15480 15540Q..

15600 15 660 15720 GGGCTG7GCGC GAGGCTGCCT GGCTAGGCCT TGGCGTTCCC CCAGAACGyc GATGGCAAAA

GCAGATGGAG

GTGCTGTTCC

ACGTGAAAAA

CTGTCCCTGA

CCCAGGGGGC ACCTGAGTCC a

CTGCACCTGG

GGCCGAGCGG

GGGAGAAGGA

GGCAGGGCTG

TGGGATGGGC

CCTGG. TTGT

GGCCAAACAT

TCCCCATGCC

GTGTCCCTTC

TAGGGCTCCT

CCGCCGCAGC

TTCCCCCTCG

CTCCTGTCTG

GGTCCCCAAG

GCCAGCCTGG

CCTGCTGGCG

GGGGAGCCGG

CAGCTCCCAG

CTTCAGGCTT

TGGGGGCAGG

CAGGGGGCCT

GCGCCTCGGG

CGCTGGAAAG'

GGCATGGT(GC

GTACGGGAGC

AGCCCACACC

TACCCAGGGC

GGCCCCAGCT

ACCTTGCTGC

AGCCTGGCAC

TGGAAGAAGT

GGGGCTCTGG.

CAGCAGCCAC

rTCCTTCTTT rGCGAGAGCC 3CCTITGTTC

PCCCGGTGCC

PCCCTCCTCA

.TGGGCAGTG

AAGCGAGGTG

TGAGTCCTGyC

AGACGCTTCC

TCATTCCACT

ATTTCTGGGC

GCAGGGAGTG

GTCCATGGCA

GGTCCTCGGC

TCTTGATGGA

CCTTTCTCCC

TGTGCCCCTC

ACCGTGGCCT

PCATTTCTcC 3GTCTAACTGC 3GTGTGAGTCC

AGGACTCCAC

CCAGGGCAGA

ACACCCTGGG

GCCCTGGGCC

CTTGG3GCTGG

CATGGCCAGA

CCCCCAGGCC

TGACCTGCCC

rTTTCCAGAA.

GTGGCCTGGG

CCTGGGGCAG

TGCAGCACC

'TAAAGCATT

AGTTCCTCA

'AGCTGCCTC

GGGGACCCCT

TGCTTCCACA

GGCTGGGGGA

CTGGGAGCTc

GGTGAGGGCC

ACCGGTGACA

TGG3TTCACAG

C.CACCCCTGC

AATGAGGTGT

TGGGAGCTGC

rTTCACAGCT

TCTCGCCCCT

3GTTCTGCCT

GGCACAGTG

kCCCTGTCTC 15840 15900 15960 16020 16080 16140 16200 16260 16320 16380 16440 16500 16560 16620 16680 GAGAATGGCC TCTTGCTGGT TGTGGATGCC TAGCAGCGCG TCAGCCCGTG TCCCTACCTT CTCCCAGCCA

CCACCCTGTC

GCTGTGGGCC CACCCATCCT GGTGTAGAGG AGGGGACGGC

CCACCCCACG

TATGGGCAGT

AGAGAAGCAG

GTGCCTGGCC

AGTGTCCCAC

ATGGAACGAG

GGGGGGAAG

CTCCCCTCC

GGAAGGGAA

AGCCAGTGCi

CGTCCGTGG(

CTGGGGTGG(

CGGGCCCCAC

GCGGAGCTC(

GATGGAGGCC

CTAGGCGGAC

CCGTGGCAGG

GGAGCCATAG

AGGGTGGGCG

TTTGCCCCAG

CTCGGGCAGC

CACTGACTAC

TGCCTGGTTT

CCTCCATCCT

GGGTGCTGGA

GTGATTCTCC

GACTAATTCT

ACTCCTGACC

GAGCCATTGC

CTTTTCTTT

GCAGTGGCGT

CCTCAGCCTC

CATTTTTAGT

CATGATCCAC

GGTGGCCCTG

GGAGCCCAGG

TGCACCCCCA

CCGGAGGGGC

GCACAGGCAT

ACCGTGCCCT

CGTTCCCTGT

AGGCTCTCTG

CCATCCGCAG

CAGCGTCTCA TCTGTCTGGG CACCCAGCCC AGGTGAGGGC

-TGGTGCTGC

-CTCTGGTCC,

CGGGCAGCC'

-GGTGGGAGG

*GCCCCGGCT'.

GCACCTGCTC

AGGTGAGGCC

TCCTGTGCC2!

GCAGAGTGAC

CTCTCTGTC'I

TCTGAAAAGA

TGACATGGGA

TTCTTTTTTT

TTTTTTTTTT

GTGCAGGGGT

TGCCTAAGCC

GTAGTTTTGG

TC-AGGTGATG

ACCCGGCTCT

CTTTTT~TT

GATCTL'GGCT

CTGAGTGGCT

AGAGACAGGG

CCACCTTGGC

T TCCTGGCAC( C CTTCTTTGT'.

r GTGTGTGCG' k. GCAGGGCTIGC P GGGGCTGGCI

;GGTCACTCGU

TCGGGGTCCT

GGAGCACTAC

CCCCGAGGTG

ACTCACCTCC

GAGACATGCT

TGTTTTTCCT

GTTTTTGGAG

ATTTTTATTT

GCGATCTCAG

TCCTGAGTAG

TAGAGACAGG

CGCCCGCCTC

TTCCCCTTCT

TCTTTTGAGA

CACTGCAACC

GGCACTACAG

TTTCACCCTG

CTCCCAAAGT

GAGAAGGCCT CGGCTGCTCT P GGTTCCCTTC

PCTCTCCTGCG

,AGGCTGGCAG

'GCCGGGTGGT

GGGGAGGGTG

GGGGAGCAGG

TGGGAGTGCG

CTTGAGGCCG

GCATCACCAG

GCCGCCCTGT

ACGGCTGTGA

TTTTCTCTTT-

TTTGAGATGG

CTCACTGCAA

CTGGAATTAC2

GTGTCTCCGT(

AGCCTCCCAA)

CCT'rTTCTTC TGGAGTCTCG C

TTCGCCTCCC

GCTCCCGCCG C TTGGCCAGGA TCTGGCATTA C

TCAAGCTCTT

CCGGGTAGGC

GGGCTGGGCG

CATTGCTGGG

ACACCTG3GGG

GGGGTGGTGT

TGGGACCAGG

AGGGGAGGTG

CTCCAGGACC

GGTTTCTGTT

CCAATTGTGC

CTTTCCTCCCJ

k.GCTTCACTC 9J ZCTCTGCCTC C kGGTGCTTGC C ;TTGGTCGGT C LGTGCGGGA

'I

'CTCTCTCCT C ~TCTGTCACC A IGGTTCACGT G 'CATGCCCGG C GGTCTCGAT C AGGAGTGAG

C

GCGGGGATGG 16740 GGGGAGCACC 16800 GGTTCAGTTA 16860 CCCAGATCCT 16920 AGCCCCTGGG 16980 AAGCTCCGGG 17040 CTGGCTCCAC 17100 GTCCCCTCAG 17160 GCCCTGGCCC 17220 rCCTGTGGGA 17280 GGTGTTCAGG 17340 AAGAGCAAGT 17400 PiAGTAGAGGC 17460 3CAGACCTGC 17520 kGGGGTGCCC 17580 3AGTTCTCGG 17640 VGTTTGTAA 17700 C1'TTTCTT 17760 TrCTTCTAAT 17820 CCCTCTCAC 17880 TGCAGGATG 17940 CGGTA 18000 ACCACGCCC 18060 TGGTCTTGA 18120 rACAGGOAG 18180 ::CTTT'CTTr 18240 3GCTGGATT 18300 L'TCTCCTG 18360 PAATTTTTG 18420 VCTTGATCT 18480 'ACCGTGCC 18540

S

S

CGGCCATCTI

CGCCCAGGCX

CAAGCGATCC

CCTGGjCTGAT

TCAAACTCCT

CCTTTTCTTC

GTATTTTTGG

TTTTCTAATT

CTGGTCTTTG

CTCGCCGTTT

CTCTCTGGGC

CATGCCGCCA

TCTTTCCTTG CTTTCTCTTT

GTTTTCTTT(

GGACTGCAGT GGCACAATCA

TAGCTCACTC

TTCCTCCTCA GCCCCCCGAG TAGCTGGAJAC TCTTTTTTTC CTTGTAGAGA TGGGGTCTTG, GGCCTTCCCA AAGCACTGGG TTTACAGGCA TTTTTAACTG GAATAGTTGA CGTTTTCTTT CCTTITAGTAT GTCGTGTAAG TTGCTAGTGC TTAITTATAT TTTGCGTAGA AGTTGTGTAT ATGTTTTATT TATTAATTAT

GTATGTATTT

CACCCAGGCT GGAGTACAGT GATGCGATCT TCAAGTGATT TTTCTCTCCT CTACCTCCCG TGCCTGGCTA ATGTGTATTT TTTGTAGATA GAGACCGGGT CTTGCTCTGT CAGCCTCGAC TTCCCTGGCT TACAGTTACA

CACTACCATG

CTATGCTGTC CATCCTGGTC TAAGCCACCA CACCCAGTTT ATTAGCTGTG

TGTCAGGAGG

TTTTCTGAGA TTGTAGTTTG TTTAGATGGA

GTTAGGTCGG

ATTTATTTpT

GAGGTAGAGT

CAGCTCCCTG TAGCCTTGAC AGTACTTGGG ACCCCAGGCG CGGGGTCTCA CTGTGTTGCC 18600 18660 18720 18780 18840 18900 18960 19020 19080 19140 19200

C-AGGGTGGT'.

TGTTACCGGC

CCTCGAGGTC

ACACAGTCAM

GATGGGGGCC

TGGGGGACTG

GTGCCCTTCC

GTGCAGAGGG

TTGGGTCTTC

AGGCCATAGC

ACTAGGGGCT

GCTCCGGGCG

GTCCCdCAGT GC743CiCAGC

TAAGCAACAA

GTGAAATGTA

CCCTTCTGCC

CAGTTCACTG3 r TCAAAATCC'

-GTGTGCCCAC

GCGCCTGCTC

ACCTGGTTG7

CCTCGAGTCT

TGGACAGGG

TGGCCCTGGG

CTGAGGCCCC

CATCAGAAAG

TTGGGGATGC

CTGGCCCTrGA

CTGGACGTTG

CGTGCCAGCA

TGTGGGGGCT

CAAGATTTCT

AGTTGTGGTT

CTCCCAGTTG

CCTGCTTGGA

rGGGCCCAGGC

TGCCTGGCCG

CCCTGTGCTC

GGTCCCACAG

GTGTGGGGGc ATGyGGGGGCC.

TGGACAGGTC

CAGGCCTCTC

TCCCCTCCTG

TGGCAATGTG

CCCACGGCCA

GGCTCCTGGC

TGCGGGGCTC

TCCATCAGCT

ACGTITAGAAG

CTTTGGGTGGC

GTCCGTGTCC C GCCCCCCAGT G

GATCCTTCCG

TCTTGGAGGT

CCTGGTAGCC

TGGGACCACC

TGTGGACAGG

TTGGCCCTGC

CATGTGGCAC

CTGGCTTGGT

ACCTCTGGGA

TGGGATGGGC

CTCACTCCTC2 3AACCTCTCG C k.CTCCGGGTGC r~TGCCGAATc C AGGAATATT

;GTCCTGGCT

:CTTCCAGGCT

;CCGGCrTGGT

TCTCAGCTCC

CTTGTTTCTC

TGGTAGTGAG

CTGTTGGGTT

GTTGGGAGAC

GTGGGATGGG

TCGGCATAGG

rTCCCCAGAT 3TGGGGAGCT

CAGGGAAGG

kGAGACGTCT

~CGCTGGCAG

;GCTGGCGGC

.CCCGTCTCT G3CTATTTA GACCCCAGG

C

TGAGACCAG

TGGGGCAGG

CACGGTGCTG

TGGGT N'ATG

CCTGCTTCTC

CAGAACAGGA

CTTGGCTCTG

TTGGGGGTCC

GCTGAGATGG

GAGTGTTCAT

CAAGGGTGGG

CCTCTGGCCT

XCCACAACCT

!LGCTGTGAGT

kCCGCCTCT

"'CCAGGGATA

TTAATTTAA

CCCCAATAT

,TCCTGGGGG

19.320 19380 19440 19 500 19560 19620 19680 19740 19800 19860 19920 19980 20040 20100 20160 20220 20280 20340 20400 CTGTCAGGGT GGCTCCAGGO CCTGGTTGCC AGTGGGGGGC TOCCATAGAC

CCTTCCCACC

AGACCTGGT

TGTGACTGTI

CAGCCCGAGC

ATCCCCTTG(

CCAGCCAGGI

GGGGGGCCTC

GGGCGTGGGG

GAGGAGTATG

TCAGCTGCCC

GGCCAGGGCC

TCCAGTGCCT

ACCTGTAGGG

GTGGGGCCCC

C CCCAACAC 3GCCTGGCG 3CAGCCACG

-TGGACAGT

GGGACCTGC

CGGGCCAAC

TGGAGCCAG

TCGCCTGCC

ACGAAGGCC

TCGCAGCCC'

CC'rTTGCC'B

GCCCCACCC'

ACGGACCTC]

CT

TG

TG

T

T

GCCCCTGCCC TGCAGAAACC GCTGCCGCGA TGGG3CGGAGG TGCTGGGCCT GGCTCCCTGG CTGTGGTGAG TGCCGGTGGG CCCTGCAGAC ACTGGGCAG GAACAGCATG GGAGCCTGTG AGGAGCAGAA CCCGGGGTCC CCCTGACAAC AGCTCAGGCA GCTTCAGcCA

GAGGCCTGCA

TGAGTGGGAP.

AGCAGCAGGT

CTGGCCAGCC

TIGGGGCCAGC

GCTCAGGAJAG

AGTGCGGCGG

AGTGGCTGCC

CCGTGGCAGC

3CGCCTTCTG

CCCGTTTGAC

GCGGGTGGTG

TCTGCTTGGC

TCTGTCCTTC

GCCTCTCTGG

GCGGATGTGG

TCTTCTAGGT

AGTGTCCTTT

CTTCTCCACC

CTCCCTGTCA

CTGCCACAC(

GGGCCGGCTG

CCTCGCATCC

GCCCTGGGGG

CCGGCTCAGC

GCCCTGGAGC TCGTGTGCCC CAGAACCGCG GTGGTTCAGG CCGGCCCGAG GTGAGTGTCT GCAGAGCCTG

GTACCCCCGT

GTCTCCAGCG GTGCACCCGC CTGCTACCGC CTGGTGGTGG C'rGGGCCGGG GCCGCCCTGG CCGGGTCACC AGGTGCCTGC GCACTGGGGC AGAGACTGCG GCCCTPGGTGA GCAGGTGGCG AGGTGGACAT GAGCTGGGGG CCTGCACGGG GATCCCTGCC GGGCTGGTIGG GCCC1X3GTCT CAGTGATGGG GCTCCCAGCG T' CTCGGAGCAG 3CCTGTCCCTC P CCTCCAGCAC

GGCCTCTGGC

CTGGGACTTC

CTATGTGCTG

CCTGCTGGGG

GTCCTCGGTG

CCTGGAGGCC

GCTGCCCACT

CTTGGGCCCA

TCTGCCCCTC

AGAAGGCGGC

CAATGGTGGAC

CCCCACCCCCC

GCTGGGGAGTC

CCGGCCGGTG

CAGCCTCCGG

GGTACCCACAG

TGCTCCGGCc

GTCTTCCCTG

CAGCTAGCAG

GGAGACGGc'r

CCTGGGCGCT

ACAGACGTGC

CAGAGTGACG

GCCTACAGCA

CCCCTTCCTC

CACTGACCGT

3GACACGGAG

.'TGGCTGCAG

!AGTCCCGCCC

~GAGGGGCCA

"TCAGGAGGA

;GGCCGTTCC 1

,CACTCCTGG

GCCCCGTGG G

CCCCGCCACC

CCTCCCCAGG

CCTTCCACAT

CCGCCGAGGT

ATCACGTGAC

AGGTGGAAGC

AGAGCCTCGA

TCGTGGCCCT

CCCAGGGCCA

TGACACCCTC

kTCTTCCCTG 3CGCAGGAGC

.TGCAGCGCTJ

M'GGTTGGGAC

LGGAGGTGGG

WGCAGCTcr G r-ACGCCATA C :TGGGTGCTG C

CCCCATCTGG

TCCTGCCCCC

GGCCACCCTG

CGCTGCCCCG

GGATGCCGCT

GGCCGTGCTG

GGCACCTGCC

CCTCAGCATC

GGGCGAGGAG

rCCAGATGGG 3TTCCCACCG 3CAACGGGCA kGTGTCAGGC

='CTGGTCTC

!ATCTCTGAA

LGCTGGGCCG

CAGATGCAG

'GGGAGGTGG

TGTGAGCCT

AAAGGGGGA

GCCCTGAGC

GGCTGGTGCC TGTTGGGGC GGcccAGccc 20460 2052o 20580 20640 20700 20760 20820 20880 20940 21000 21060 21120 21180 21240 21300 21360 21420 21480 21540 21600 2.1660 21720 21780 21840 21900 21960 22020 22080 22140 22200 22260 CCGGGCTCTG AGCCTCAGpT GGCTGCTGTG AGGGTGGGAG

GATGGAGGAG

CCCCTGCCAT CCCACACCCG CCCCCAGGAG CCTAGACGTG TGGATCGGCT TCTCGACTGT

GCAGGGG

GAACTrG( CACCGGG3

GCCCGGA(

GCCGAGCG

CGGCTCGG

GCACTCGC

GGGGACCT

GAGCCCGT

AGGCCTTGC

CTTr3TGCCC

CATTACCTC

GTCCTGCCC

CTGTGGGGG

GGGAGTCTG

AGGTCATGG

TTGGGACCC)

GCACAGCAGC

TGGCCTCTCI

AGGTG4GACAG

TGGGTGGGGC

ACTGGGCTGG

TGGTGCAGGC

CTCCCCTCCT

ACAGGACCCA

TrGC'TCC

GGCCAGGGCT

CGGGGCCCCC

CTCAGGCCAC

CTGCAGGCCC

CCTCTCCCAG

GTG GAG4GTGGGCC CAGCGCCGCA GGGCGAGGCC TTCAGCCTGG

AGAGCTGCCA

CTG CCCGGGGAGC CACACCCAGC CACAGCCGAG CACTGCGTCC

GGCTCGGGCC

POG TGTAACACCG ACCTGTGCTC AGCGCCGCAC AGCTACGTCT GCGAGCTtJCA GT GTGCGGGGGG CCAGGCAGGG GCCTGAGACG CTGGCTGTGG

TTAGGGGCCT

CC CGCGGTGGAG CCTGGGCTGA GGAGGAGGGG CTGGTGGGGG

GGTTTTCG

TC CCCAGTCTGT TCGTCCTGGT GTCCTGGGCC CTGGCCCGGC

GCCTCACTGT

CA CCCCAGGCCC AGTGCAGGAT GCCGAGAACC TCCTCGTG

AGCGCCCAGT

GC AGGGACCCCT GACGCCTCTG GCACAGCAGG ACGGCCTCTC

AGCCCCGCAC

*G AGGTAGTCGG CCCCCCACGT TCTACAACCT GCCCTCCTGC

CTGCCCCTGG

C TGCCCTGCCC ACTGTGGGTC TCGCCAAA ACTTGGGGC CTTAATG3TTG 'A GTGAAGATGG TTGGGAAAAT CCAGAGTGCA GAGAGGAAAG CGTTTACT2A C AGGCCTTTTC TCTGAGCGTG TGTGAGTTAT TCCTGAAAGG

CAGGTCAGG

C CCATGGACAG TTTCCACCGG AGTCTTCCTC TCGAGCGACA GGAGCCAGG3C T CTGATGGCTC GCTCTCCTTC CCTCCCCTCT TCCTGGGAAG

TTCGGGTAG

*GCTTCAGGCT GGGAlrGGGGT CTGTGGAGCT GAGGCGGCCC

CCTGCCCACC

r ATTCCCGGGC CTGCGTCY3A GCCGTGAAGC CTTCCTCACC

ACGGCCGAAT

I GGAGCTCCG CGGCCCGCCC AGCTGCGGCT GCAGGTGTAC

CGGCTCCTCA

TGGGACTCTG GG PGGTGGGT GGTGGGTGGT GGGCGCCGCA

GGACTCGGG

GAGCTTTCAC GTCTGCTGGT CCTGTGGCCA CCAGAGTGGT TCCCAGTCTpqT AGCAGGGG'rT CCAGAGACAC CAGCTCATTCY CAGGTGTCCT

GGGGGTGGAT

CTGCCTGGGG GCCGGCCTGG GTCAGTCGGC TGGCCGGAGA

CGGACGCAC

GAGTGCTGCC CAGGTGGGGA GACCTGTCCT CACAGCAGG CCAGGArrC AGTTGGGCAT CTCTGACGGT GGCCTTV CAAATCAGGG CCCCAACACC 2 CACAGGGACC CCGGAGAACG GCAGCGAGCC TGAGAGCAGG TCCCCGGACA 2 GCTGGcCCcc GCGTGCATrC CAGGGGGACG CTGGTGCCCT GGAGCCAj~cA 2 GCTGGACGCC! TCCTGCCACC CCCAGGCCTG CGCCAATGGC TGCACGTCAG 2 ACCCGGGGCC CCCTATGCGC TATGGAGJAGA GTTCCTCTTC TCCGTTCCCG 2 CGCGCAGTAC TCGGTGTGTG GCCCTGACCTI GGGTCTGTTC CCTGCATCWT 2 CTTCCTGTCT GCTGCCCAGG GTCTGGGTCT GTGCACCAGA CACACCCAGC 2 CTCCCACGTC C'PIGCCACCT CTGACCTCCG ACCTCTGCAG.TGCCCTCGGC 2~ TGGGAGAAGc TCTCGCCTGG GCCCTTGGCA CGAGCTGTGC CTCCTCT'pCC 2~ 22320 22380 22440 22500 22560 22620 22680 22740 22800 22860 22920 2-2980 23040 23100 23160 23220 23280 23340 23400 23460 23520 ~3580 ~3640 3700 3-760 3820 3480 3940 4000 4060 4120

S.

S S

S

S

S

5.5.

5**S S S TCTCTCCCAG CACAGCTGCT CC ITCC TOTGTCCCCC GGTCTGCAjAC

TGTCCT

CTTGAGGTGT GGCTGACGAAJ

GCGGGG,

GGTCCACGGG CCATGACCGT

GAGGAC(

CCTCCACGGC CAGGATGTCC TcATGC'j TGGCCCTGCy~ GCCCTCCTGC

ACTGCTC

GTACCTCTCC GCCAACGCCT

CGTCATG

TTGGGCCTGC CCTGCCTGTG

CCCTGCO

GCTGGGCTTG AGGCCCAACC

CTGGACT(

GGTGGGCAAT GGCGTGTCCA GGCACAc GCTGGGCTGv CGGGTCATCT

ACCCTC

CGGCTCAGCC TTGGTGCTCC

AGGGAC

GCCTGGGGGC AGTGTCAGCG CCCGCTpT'j' CGTGCCCGGC TGCCCCITGG

AGACCAC(

GCTCAGTGAG GGGGAGCACG

TGGTGGACC

CCTCAGCCTG CeGGTACGG

CGGAGGAGC

CGAGGCCCGT GTACTGCAG

GAGTCCTAG;

CCCCAGGCAG GTGCCTGCAG

ACAGGGTGC

GAGGGCAGCA GCCCAGTTAC

TGGGGACGT,

TCGGGCTACC TGGTGGCTT

TAAATTCCT(

AACTCATTCC ACTGTCTCAT TTCACAAAAj CGAGCCCCCG TGAGTCTCTC

ACGCCCTCW.

TTTTGAGGTG GAGTCTGAAC CCCTGATGGy; CTGGGTACAT GGGGGACAGc3

GCTGTCTCCA

CCTTGGGAGG GGCCATCAGA

AATGGCGTGA

CAGTGTAGGT GCCTCCCCTC

ACTGCTCCGA

GCCGGGAGcyG TCTGAGAAGA

CTCAGAGAGA

GCTTTACAGA TGGGGAAACT

GAGOCACAGA

T'GGCTGGAGA GCCGGACAGT

GAGTGTCCCA

CCCCGGGCc CTCCTCPCCTP

CTGTGCCCCG

GTCCAGGAGG3 CGACAGGCTA

AGGGCAGAGT

TUTC TGCCAGGTCT TGGCCTGTGT CCTCTCCCCG 24180 GCCT GTCCTTGTCA CGAGCACTGT GGGGAGGCTC 24240 'GCC CTGCGTGTCC ACCCTCATCC GTCGTG3CGG3G 24300 3TGA TGCAGCCCTG CCTCCCTCTC CACACGTCAC 24360 'CCC TGGTGACCTC GTTGGCTTGC AGCACGACGC 24420 'GCC GGCTCCCGGC CACCCTGGTC CCCGGGCCCC 24480 GCT GCCCCACTTG CCAGCCCAGC TOGAGGGCAC 24540 3CT GCTTGCAGCC ACGGAACAGC TCACCGTGCT 24600 3CG GCTGCCTGGG, CGCTATGAGG TCCGGGCAGA 24660 .CT CTCCTGCAGC TTTGACGTG TCTCCCCAGT 24720 -CC CCGCGACGt3C CGCCTCTACG TGCCCACCA 24780 TC TGGTGCCAAC GCCACGGCCA CGGCTCGCG 24840 SA GAATGTCTGC CCTGCCCTGG TGGCCACCTT 24900 -A TACCCTGTTC2 TCAGTGGTAG CACTGCCGG 24960 3T GGTGGTGA AACAGCGCCA GCCGGGCCAA 25020 'C CATCTGTGGC CTCCGCGCCA CGCCCAGCCC 25080 T GGTGAGTATG GCCGAGGCTC CACCACCAC 25140 T CACACAGGOC GTGAGGCCTG GCTTCCCAGT 25200 SGGCCCCGGGC AGGTCCTGCT GGCTGGCTCC 25260 3 GAAAGTCACG GCTCTGACAG TGGCTCCGCT 25320 P' GAATTTAAA CTCTGCTCCC TGACCTCACA 25380 CTGTGTTCTCv GCC!TGGCTAA AGCGAGTGGC 25440 AAACTGCGGG CTGCCCGCGG TGCCACCAG 25500 TCTTGCGGGT ACCTGCCT2T TCACCAGGGG 25560 CCTGTGCAC CTGTCCTGGG TTCTGTAAGC 25620 GCTCTC'rGGG.TGAGGAGCTGv GGGCAAGAGC 25680 GGTGGACTCYp TTGTAGCTGG TACTAGGTwrT 25740 GAGGTTGAGG CATTAGTAGT ACTACATGGC 25800 GCCCGGGCTTj GGCTCCCATG GCATGCAGAG 25860 CGTGGGACpC~ TCC.AGCCCGA CGGGAGGTGT 25920 CCTCCACAGA GCCCAGGC1YG ACACCATTCC 25980

S

S S

S.

@0

S

0

S.

0 1)

S

S

S

O '55 .4 e.g.

S

0 CCCCGCAGAG GTACAGCC( TCAACGACAA

GCAGTCCC]

CGGCGGTCTT

CAAGCTCTC

GCAGGGCGGG

GGCGGGCTC

GGACGCTGCC ATGGCTGTG ACCTGCCACC

TGGGCTCAC

CAACGTCACC GTGAACTAC, GGTCTCCACA GTGCCGGCC( GCTGGTGGAC

TCGGCCGTGC

TGGGCACCAG GCTCTTGTCC TGCI'rTTCTG AGCCTCGGT1 GAGGCTGCAC GGGAGCCGGG CGGGGCGTGA cTGcAGAGTG GCCCACCCCT

GTCCCGGTTC

GATGGGGAGC

AGGCCCTCCA

GACCCCTCGG TGGCCCAGGT GGTGAGGGAT GAGGGGGTGA AGCTCCCCAG TCAAGCTGCC C GTGGTGGAGG CCGCCTCGGA CATGGTCTTC

CGGTGGACCA

[G ACCTTCCAGA ACGTGGTCTT CAATGTCATT

TATCAGAGCG

'A GTAGGTGGGC GGGGGTGGG AGGGGAGGGG

ATGGGGCGGG

ACCTTCACC2'j CTGCCTTCTG CTCTGCTTCA

TGCTGCCCGA

GGTGAGTGGAG GGAGGGACGC CAATCAGGGC

CAGGCCTCTC

T GACGCCTGTpC CCTGCAGCTG ACGGCCTCCA

ACCACGTGAG

ACGTAACCGT GGAGCGGATG AACAGGATGC

AGGGTCTGCA

3 TGCTGTCCCC CAATGCCACG CTAGCACTGA

CGGCGGGCGT

;AGGTGGCCTT CCTGTGAGG ACTCGGGGGC

CGGTTTGGGG

CAGCCCCAGC CTCAGCCGAG GGACCCCCAC

ATCACGGGGT

TCCCTGTCTPG TTGGGAGGdTA ACTGGGTGCA

CAGGAGCCCT

AGAGGCCTCA GCACAGCCGG GTGGGCCCTG

AATGGAGGCC

GAGCCTCGGC TGGGTCCCAA GCACCCCCTG

CCCCGCCACC

ACTCACTGCG TCCCACCGCC CCGGCAGGTG

GACCTTTGGG

CCAGTTCCAG CCTCCGTACA ACGAGTCCTT

CCCGGTTCCA

GCTGGTGGAG CACAATGTCA TGCACACCTA

CGCTGCCCCA

GGGGGCCACT GCCTTTCAG CTCTGAGCAC

GGGTCCCCCC

CCCCTTCCTC CCCAACAGCC CTCACTGTGA

CCTCACCGG

26040 26100 26160 26.220 26280 26340 26400 26460 26520 26580 26640 2'6700 26760 26820 26880 26940 27000 27060 27120 27180 27240 27300 27360 ~7420 17480 .7540 7600 7660 7720 7780 7840

GCTGATGGCT

GAAGCTGGGC

TGCCCCGAGT

GCTACACCTG

GCAGGTGCAG

AGCAGGTGGG

GACCGTGCTG

CGCCTCCCTG

CGTCACCTTC

CGGGGACGGC

GAGGGGCACC

GGCGGAT

GGAGCAGGGC

TAGGCCCTAC

CCCTGAACTG

GCAGCTGCAC

TGCTCCGTCC

CCGTTCACCC

GGTGCCGCGG

GCATCTAATG

CCCTCCGTGG

TACCCGCACC

TCCCCTGTCC

TACCACGTGC

TGGGGTGAGG

CGCCCCCCGC

TTGGAGGCGG

CGCACGTGGC

CGGGCTCCTC

CTGCCCCACT

CCTTCGAGAA

CTGTGGGTGT

CGCTGCCCTC

TGACCCAGAG

GCCTGGAGGT

GAGGGGCCAG

CCTCCCCGGyG

TGCCGTCCTC

TTGGGAGCCT

AGGCGGGGGG

CGGGCCTGTC

CCTGACGCAG

GAGTGACGGC

GCCTGGGGGT

CCAGCCGGCT

CAACAACACG

CGGACTCAGCC

CGCGGTG4CAG

GCGTGGGGGG

CCTGGCTCTT

GCCAGGCAGC

GGGACCCTTA

CTTCTGCCGA

CCCACAGGTG

CAGGTGCCTG

GTCCTGGTGG

3TCTTTACA 3CCAACCACA

'TGAGCGGTG

,IWACATGA

iCGGGCGACA) AGTGGAcAGG GCTGCTCTroC

CCTCAGTGCT

AGGCTGGGCC

GCGGGTGGGG

AGTACCTCCT

TGAGCGTGCG

CCGGCCGGCC

CGTGGGACTT

2CTATGCCTC

'GGCGGCCCA

;CCTGGCCGT

CATCACGTG

2 2 2 2 2 2 2 CGCGTCT'rrG

AGGAGCTCCG

GCCCCCGTGG

TGGTCAGCGC

GACCTTCGA

GTACCTGCG

GGCCCGG3AG, CTGCATccc(

CTACCTCTTC

GACGGTGACj

CCGCGTGAAC

CACCCTGCAG

TGCCTGGCCC

CACCCGTGCC

GACAGTCACC

GGAGCCCGTG

GCCGTACCTGx

GGACGGTGGG

CACCGTTAGG

C ATGGGGGAC G GCACAGAAC

CCTGCACGTG

-ACGCAGCCT(

-GACTGGACC

CACAACTTCI

*AGGGCGCATT7

CCAGAGAGGC

CCGTTCCCCT

AGGGGCCCTG

GCGTCCAACA

CTGGTCACCA

TTCTCTGCTG

TGGCTCGAGG

GTGGCCGGCT

G GCACCGTGCT GTCGGGCCCG GAGGCAACAG

TGGAGCATGT

T GCACAGTGAC CGTGGGTGCG GCCAGCCCCG

CCGGCCACCT

*TGGTCTTCGT CCTGGAGGTG CTGCGCGTTG

AACCCGCCGC

SACGCGCGGCT CACGGCCTAC GTCACCGGGA

ACCCGGCCCA

TCGGGGATGG CTCCTCCAAC ACGACCGTGC GGGGGTG4CCC CGCGGAGCGG CACGTTCCCC CTGGCGCTGG

TGCTGTCCAG

ACTTCACCAG CATCTGCGTG GAGCCAGAGG

TGGGCAACGT

AGTTTGTGCA G4CTCGGGGAC GAGGcCTGGC

TGGTGGCATG

ACCGCTACAC CTGGGACT'rT GGCACCGAGO

AAGCCGCCCC

AGGTGACGTT CATCTACCGA GACCCAGGCT

CCTATCTTGT

ACATCTCTC TGCCAATGAC TCAGCCCTGG

TGGAGGTGCA

GCATCAAGGT CAATGGCTCC CTTGGGCTGG

AGCTGCAGCA

TGGGCCGTGG GCGCCCCGCC AGCTACCTGT

GGGATCTGGG

GTCCGGAGGT CACCCACGCT TACAACAGCA

CAGGTGACTT

GGAATGAGGT GAGCCGCAGC GAGGCCTGGC

TCAATGT.GAC

GGTGAAGCGG CGCGTGCGGG GGCTCGTCGT CAATGCAAGC

CGCACGGTGG

TGGGAGCGTG.AGCTTCAGCA CGTCGCTGGA

GGCCGGCAG']

0 0 S*0.

0 GCTCTGTGAC CGCTGCACGC CGTGGGCACC

TTCAATATCA

CATCTTCGTC TATGTCCTGC CTTCCCCACC AACCACACGG CTACAGCTGG ACTGCCTGGA CTCGCTCACC GTGCTCGAGG GGGCAGCGCC TGGCCGACT GGCCGCCTCC

CCGAACCCAG

TGGTGGCAGT

GGTGTCGTAT

CGAGCCATTT

ACCACCCATA

AGGGAACCCG

CTGGGCTCAG

TGGCCTCAGC ATCAGGGCCA GCCCTTTTGG

GGGCAGCTGG

CCATCCCTGC

TCGTCACGGC

AGCTCATAGA

TACAGCTIGCA

GGGACAGGGG

CCGGCACCTA

GCACCATGGA

CTGCCGTCZA

ACACTTGGTC

GCTTCCCCAC

CCAACGCCAC

GCGAGCCCGG

CCACGGGCAC

GGGTCCTACC

TGAGAACGAG

GGGGCTGCAG

GGCCGTGGTT

CCCGGCCCTG

CCATGTGCAG

CTTCGTGGAG

CACAAGCGTc

CTTGGAGGAG

ACCCGGCCTpG

CGTGGAAGTG

AGGCAGCTTC

CAATGTGAGC

GATGTGCGCT

'ATCTCTTACA

GTGGGCTCCG

GTGGTGGGCG

AGGGATGG3CA

GCCGGCAGCG

CTGCGGGCCA

CCTGTGCGGT

ACCCTCAGTG-

.GGGCTGAGCT 4

CACTTGGTCA

GATG-TGCAGG

GTGGCGGCCG

TGGTGCTGG

TGCCCCTGAJA

ATTCCTGGT

CCTTCCGCTC

CCCAGGACAG

GTGGCCGCTA

CCAACGTCTC

GCAAAGGCTT

CCAACATGCT

GGCTGATGGT

CCGAGCTGGC:

GGGAGACCTC

CCATGACGGC

L'GCCTGTGAG

3GTCCTCTGT 2 27900 27960 28020 28080 28140 28200 28260 28320 28380 28440 28500 28560 28620 28680 2'8740 28800 28860 28920 28980 29040 29100 29160 29220 29280 29340 29400 29460 29520 ?9580 ~9640 ~9700 CGGCAGCAGC AAGCGIYGGCC CTCATGTCAC CATGGTCTTC CCGGATGCTG GCACCTrTCTC

CATCCGGC

GGAGGAGC,

GCTGGTCC,

CGGCGGGG(

CGGAGACC)

GCGCATCG1

CATCGCCAC

CTACGCCTG

CCGCGACGT

CAACGCCCT

TGTGGCCCT4

CAGCCCCAG

GGACACAGA

GGTGAACGCC

GCTGGCCTGC

ATCACAGCGC

TGAGTACCC

TGTGGCCC!TG

GCCTGT3GGG

GAGCATCCAG

CTCATACCGC

CCCCAACCTG

GACACAGGTC

GCICCAGAGAA

GTCCCAGCAT

TGGATGGGGC

GTGTGCGCTG

GGCGGCTGGC

GGCCACCAAC

CCTCCCTGGT

CTCTCTGTTT

TC AATGCCTC CC ATCGTGGG TTTCAGATi 'C AACCCCGA( C GTGGTGAGC 'G GTGCTGGAC G GGCACTGAC G TACTTCTCG C ACCTACACG G GGCAGTGAG 3CAGAGCGGCI

-CCCCGGCGD

r GAGCCCAGG(

-TCCAACCTGC

*CGGGAGCCG(

*AACTACTTIGC

TGGGAGGTGI

CCCGGCGTGG

CACTACTGCT

GCC!AATGTGA

GTGTGGTCAG

GAGGACGGCG

AGTGCGTGGC

CACCCAGCTT

GGGGAGGGGG

TCTCAGGCCA

AACTTTGGGC

GTGGAGTACA

CAGACGGTGG

CATCTACTGT

CTGATGCAAA

CA ACGCAGTC CC TGGTGCTG CC TGCTGGCTI 3G .TGCTCCCC( IG TGCGGGGC) ;G CCGTGAGT( ;A GGAACTTC.P 'C TGCAGAAGG C CCGTGGCCG A ACCGCAC!GC C C(CTGCTTCA, 3 TGGCCTACCJ 3 CCGAGCACT(

-TGAGCTTCT'

AGGTGGACG]

AGGCCCACG'I

ATCGCACCGC

ACGTGAGCCG

TTGTGTTTGT

CGGTGGCCCC

ACACACGGGA

ACCAGACGCC

AGGGCCGTCC

GCCACCAGGGC

TCTCCCGCGC

CGTCGCCCCT

CCCGCGGGAG

CCTTCAGCCT

GTGCCGCClCG

TTTCCGTGTT

TTCTATGTAA

CTGGGTCTCA

GCCACGTAC.'

GGCCAGCAGC

AAGGTGGTGG

CGGCTCAGCT

GTCACCTTCC

GCCCCGTTTC

TCCCACAGCT

AAACCACGTG AGCTGGGCCC GCTGCAGGTG

CCCAACTGCT

AGCCCGCGTG

CAGCG(CGGCT

CCAGGGCGAC TCGCTGGTCA C GGGGCTGTT T GGTGCTGGA C CAACCGCTCI k CTGGGACTr

-CTACCTGAG(

[P CGTGGCGCAc 7GGTCCTGCCC

TGACCTGCGC

CAGCTGCCAG

GC(CTCGGCTG

CGTGTCATTT

CGAGCGCCTG

C(CTGGTGCTG

GCTCAGTTTC

TCCATGCCCC

CTGGCCCGTC

TGTCTCCTGG

TGTTCTCGGC

CAGCACGGTC

GACCGTGTGG

CCCCTCGGCC

TTAGTGCTGG

CACGACAGCC

G GAGATCCAGG G GTTCAGGAC!G 3G(CGCAGTTTG r GGGGATGGGT 3C(CTGGGGACT 3G(CCACGGTGA

CTGCAGGTGC'

GACTGCGTCA.

CGGCCGGGGC

GTGCTGCCGCC

GGGGACACGCC

GTGCCCATCA

TI

GATGGGAGCG

CACTG7GGCCT

G

TCACCCGT(CCA

-CTCAGTGCCT

G

GCCGGGCTCT

G

CTGCAGAGGG

A

ACCATTCCAC

G

AAGGCCGGCC

G

AC 'TGCCTTG

G

TGGAGGCCGC

A(

TGCTTCAG(CT T

ACCTCACGGC

CGCCCGGGCA

G(CCTGCAGGT

T(CCCCCGCGT

AGGCGCAGGT

GCGAGCCTGG

CTCGGGTCGC

TCCTGTCGGG

TGCGCGCCTT

CCGTCCAGTA

AGGCCGCCAC

CGCCAGGGCA

AC(CGCGTGCA.

CCGTCCAGGT

TGATGCGGCG

CCTACCAGAC

3CCCAGCGCG

GCTGGCGCT

ACTGACACA

'TGAGGGTGG

.GTCCTACGA

TGTGGCTTC

CACCCATGA

GTGGGCCCC

CTTTAAAAC

3GCTGGCGG 3GAGCGGCT 2AAGGAGGA k.CAGCCCAG

MCTCTC(CC

M'CTTCCTT

29760 29820 29880 29940 30000 30060 30120 3018o 30240 30300 30360 30420 30480 305 30600 30660 30720 30780 30840 30900 30960 31020 31080 31140 31200 31260 31j,20 31380 31440 31500 31560 a*.

CCAAACCTGC

CACAGTTCCA

TACACAGTCC CCTAGCAATA CACTGTCCCC

AGCCCATGTC

TCCCCTCTCT

GGACCGGCCA

TGCTGTCAGG CGGGGCCTGC

CGTACAGTCT

CCAACAGTGA

CCTGTTGCTG

GGAGGCTTG4G

TGGTGCCCCA

TCAAGCCACA TATGCTCTAG

TGGCAAAAGC

GGAAGAGCCC CTTCCCACCC

CAGAGGTAGC

GATGTGGTGG GCCGGTTCTC

ACCCTCACGC

TGACCCTGAG CCCGTGGTGG

CTGCTCCTGC

GAGTGGGCGT CTGTTCCCCA

GTCCCTGCTT

TCCTCAGCTG GCCTGATTGG GGGTCTTCC

GCAGGTTCC

GTGAGTCAC

CGCATCCCC

CCAGTACAC

AAGTTGGAA,

CCAGGCCCC'

CCAGCAGGC(

GGAGTGGCC(

ACGAAGTGAc

GCTCCAAGCC

CCGAGGGGAC

CACCACCCCI

CTGGATGAGA

GTGCTGCGGG

GAGGAGGGCT

CGCCTCTTCC

GGTGAGTGCA

GCCCTCCCGT

GCCCCGCTGG

TGTGTCTACA

CACTTCGAGG

CTCAACAGGT

CCTCTGCTCG

TCACAGTCTG

ATCCCCAGCA

'A TCCCAGCTC r3 CCTACGTGC C CAGGGGCCC C AGAACGCAC G GTGGCAAAC r GGGAAACCTI

-AAATAGACC'

3GGTGCCCAT J

CCGCAGCTC(

AGGGGTGAGIl *GGGGCCTGC4A

TCTGCCTGCA

CCACCACATC

ACGGCGAGGG

GCGCCTCCAT

CACTGGGCGC

GGCCTGCGTG

GATGCCGTGG

TGTACGCCCT

AGGGCAGCCT

TGGGCCTGGC

GAGCCAGGCC

TAGGTCTTTG

GCTGCACGGG

CGTCATCGAG

:A GCCTCCTG.Z ;C AGCTGCGGT T CAGTGAGCA A CTCCAGTGT C GGATGAGTA' 3 GAGTTTGGG, r GTGTTGGAG( P' GTGTCCTTGC

TACGTGTACJ

GTTGAGCGGC

GGCAGAAGTG-

GCGGTGGGCTI

CACGGGCAGT

ATACACCTTC

CCGCCTGTCC

TGTGCACGCC

GGGGGAGCAG

GGACCGTCCC

GCTGCTGzCGG

CTCCAGCTAC

CGTGGTGGTG

GTGGGAGGGC

GCCATCACCC

CTCACCGCTA

TACTCGTTGG

C AGAGGGGT( LC CCAGGCCCJ 'C CTCACACCC

TGCCTGCCI

CTCTGCCCT

T CCTGGGAGG k~ GCAGCATCC 3 TAACCCCAC 3 AGTGTGTGT(

TGGAGGGCC(

GTGTGGGCGC

GGGCTGACAC

GCACGTACGI

GCAGGCATGC

ACGCTCACGG

CCCAACCGCC

CTCACCACCA

CGGGATCCCC

TCAGGCTGGC

CGCTGTCGCC

GGAGCCGTGC

CAGGACCAGC

GCCCCCGAGA

TCCCAGAGCC

GTGTGCTCC

CCCTGGTCAC

C

'A

G

T

r

TCTGAGGGGA

GCTAAGGGCT

CACATACGTC

CTIGCTAGGGT

TGTATGCCCT

AGTGAGCTCA

CCATGGGTCC

CCCACGCCAG

GGGTGTGGGA

GCAGGAGTCT

TCTTCTCACA

CCAGCTGGGT

TCCGCCGTCC

CCGGCAGTGG

CCCAGTCCTT

GTGCTGATCC

*5

C

SCTGCAAGGCA

CAGGCCGTGT

3CTGCCTCAAT

TGCAGCAGCG

GCTGGGGATG GGTCCCATGG GGCAGAGGGT

TGCGCCCCCT

TCAGCAACAA

GACGCTGGTG

GACTGGTGCT GCGGCGGGGC TGCTGGGCCG

CTCTGGCGAG

CGCCGCTGGG

GGGCTCTTGC

AGGTGCACTT CGAATGCACG CGACTCTGTG ACGTCACGGA ATGACGCGGA,

GGATG.CTGGC

AGGGCCACTG

CGAGGAGTTC-

TGCCCCCGGG TTrTCAGGCCA TGGGAGCCGC

TGTGGTCGCC

CTGCCACCTG

CTCACCACCC

CAACGGCAGC

GCAACGGGGC

AGGGCTrGCTrG

CGGCAGGCCG

CGTGCTGAAC GAGGTGAGTG 31620 31680 31740 31800 31860 31920 31980 32040 32100 32160 32220 32280 32340 32400 32460 32520 32580 32640 32700 32760 32820 32880 32940 33000 33060 33120 33180 33240 33300 33360 33420 CAGCCTGGGA GGGGACGTCA TGCCTGGAGC

TTTGCAGAGG

AGCAGCACCC CGACCTTCCG CTTTCCACAA TGCAGCCCCC AGAAACAGCT CAGTGTTGTG ACCCCGGGAG TCGTgrGGCAT GCTGTGCCCC CTGCCTGCCC ACGAGCGGCA

GCACCG.'GCC

GGGTCCACAC TGTGGATGAC2 GATGGCCCCA CCTGCTCACC( AGGGCAGACG GGCAGCTTGG C GGCGTTCCTC GGTCTCTGAC C AGGGTGCCTC TCGGGGGACCC AAGATGCTGC TCTGTGCCCT

C

CCCCTCCCCT CCTCCCCTCC C

CATCTGCTC

GCTCATCCC

CTCCCAGCA

GCCCAGGAG

GGTCAGTGCi CTG4CTGGCC' CAGTACGAGc

CAGATACGCI

%TCCAGCAGPA

~TGCCCCGCA

~CGAGGAGCT

TGCTTCAGT

'AGGGTGTAA'

CACTCTCCC

CTAGCCCTT

CTCCTCCCC

CCCTAGAC

;C ATGCGTGC'r 'G GGCCCCAGA G CCAcACCCA G GCCCATGTGi 2CGCATCACA( P' CCTGCCGGCc -GG~cccTGGi

AGAACATCAC

TCGCTGCTGC

TGCCTGCCAG

GAGCCTccAG

AGCCTCAGCC

AGAGGGGCCC

CTCCCCTCCC

CCCCTCCTCC

TCCCCTAGCC

CTTCCCCTCA

T GGGACCAAGA G ATAAATCCCA C CGGGCCCTCT

TTACCCTGTT

AGCGTCTAGC

TCCTGCGCTG

CGTGGCGGCA

GGAGACTCTG

GCTGGCCCAG

GGCACTGGGT I1 CCTGGGCTCC TI GTTCTGTCCT

G

AGATGTGGGGA

CTCCCCCTTC C CCTCCCCTAG C( CTTCCCCTCC T( CCTCCTCCCG C

CCTGTACCC,

GTGACCCTpI

CCGGCGTCT(

TTGCCCATGI

ACGTAACTGC

CTGACAGC~pr

GAGCCCAAGC

3TGTCCCTGA

M'CATGGTAG

'CAGCCcccc

TCCTGCCAT

TGTGAACGC

GGGACTAAG

CTCCCCTAG

CCTTTCCCT

CCCTCCCC

Va oe*

TCTTCCCCC(

TACCCCTTCC

CCACTCGTCC

CCCCTCCCC I

CCTCCCCCTC

CTCCTCCCCC

CCTCCTCCCC

TCCCCCTCTC

TCCCCCTTCC

GCTCCTT

TCCCCTTCTC

TCTCCCCCCT

CTCCTCCCCT

TCCTCCCGGC

TCCTCTCCTC

CAGCCCTTC4

-CCTCCTCCC(

-CCCAGCCCCJ

CCTCCCCCTC

*CCCTCCTGTC

TCCTCCCTCC

TCCCCTCCTC

CTCCTCCCAT

ATTTCTCCCT

TCTCCTCCCT

CTCTCTTTTC

CCTCCCCTCC

CCTTCCTCCT

TCCTCTCCTC

CCCTCCTCAT

c4 CCCTCCCCTA GCCCCTCCCC TCCCCCTTCC

TCCCCTCCTC

CCTCTTCCTC

CCCCCTCCTC

TCCCTCCTCC

CCCCTCCCCC

CCCTCCTCCC

CCTCCCCCTG

CCCTTTCTCT

ATCCTTCCCT

TTCCTCCTCC

CCCATTACCC

CCCTCCTCAT

CCCCCTCCTC

CCCCTCCCCI

CCCTCCTCCC

CCCTCCTCCT

CTCCCTTCCT

ATCCCTC'CT

CCCTCCTCTC

CCTCCCTCCC

TCTTCCCTCC

CATTCCCCCT

CTCCTCTCCT

CCCCCTCCTC

TCCTTCCCTC

'CCTCCCCCTT

*TCCTCCCCTC

CCTCCCCTCC

CCCCCTCCCC

CCCGTTCCCA

CTCCTCACCT

CTTCTCCCCT

TTTCCTCCTC

CCTCCCCCCT

CCCCTCCTCC

TCCTTCCCTC

CTCCTATCCC

CCTCCCCTCT

CTCCCCCCTC

TCCCTCCTCC

CCTCCCCTCC

TTCTCTCCCC

CCCCTTCTCC

TCTCCTCTTC

TrlTTCCCTCT

CCCATTCCCC

CACCCCCCTC

CTAACCCCCC

c 33480 .k 33540 3 33600 33660 33720 33780 33840 33900 33966 3 4020 34080 34 0 3-4200 34*260 34320 34380 34440 34500 34560 34620 34680 34740 34800 34860 34920 34-980 35040 35100 35160 35220 35280 CTCCCCTCCT CCTATTCCCC CTCCTCTCCT CCCCTCCTTC CTCCTCCTCr

CCTCCCATGC

CCCCTCCTCC CCTCCTCCCA TCCCCCTCCT CCCCTCCTCC CTCCTCCCAT TCCTCTCCTC CCCTTCTCTC CCCTCCTCTC CTCCCCWCCT CTCCTCTCCT

CCCATCCCCC

CCTCTCCTCC

35340 35400

CCTCCTCCC

ACTCCTCTC

CTCCTTTCC

CCCTTCTCC

TCTTCTCCC

CCTTTCTCT

CTTTTCTTC

CCACTTTCC4

TTTCCTCTC'.

CCCCTCCCC'.

TCTTTCCCTc

CCCCTTCCCC

CCTCCTCTTC

CTCTTCTCCI

TCCTCTTCCC

TTCCTCTTTC

CCGCTTCCCT

CCCTCTCCCC

TCTCCCCCTT

TCTCTCCCCT

CCCTTCTCTC

CCCCTCTCCT

TCATGTGAAG

CCCTGGGTCA

GTGGGCTCTC

GGGCGTGTGC

CCCAGCAGGG

ATGATGCTCA

GACAGCATCC

'A TCCCCCCTC 'C TCCCCTCAI 'T CCCCTCCCC T CCTCTCCCC C TTTTCCCTT C TTTCTTTCC C CTCCTCCTT 2CTTCCTTTC( r CCCCTTCTIT.

CCTCTTCCCC

-CCCTCTTCTC

-TCCCCTCCTC

*CTTCCTCTC7

CCCCTTCTCT

TCCCCTCCTC

CTCTTCCCCT

CCCCTTTCTC

CTTCTCTCCC

CTCTCCCCCT

CCCCTCTCCC

CCCTCCCCTC

CTCCCCCCTT

AGGTGCCTTG

TGCAGAGCCA

CAGCTGCAGG

AAGGAGTGGG

AGCTCGTATG

TCCTGCAGGC

TCAACATCAC

'C TCCCATCCCC 'C CCCCTCCTCT 'C TCCTTCCCCC T CCCCCTTCTC T TCTCTTCCTC T CCCTTTCCTT r CCTCCCCTCC

-CCTCTCCTTT

P TCCCTCTTCC

TCCCCTCCTC

CTCCCCTCCT

TTCCCTCCCC

TCCCCTCCCC TCCCCTCCCC TTCCCTCCCC CCCCTCCTCC T CCCCTTCTCT C CTCCCCTCTC C TCTCTCTCCC C CCTTCTCTCC C' TCCTCTCCCC C TTCTCCACTC C( TGTGTCGGT G CAGAAAATGC T GCTGGGGGTG G GCCAGGAGCG G

CCGCTCGTGCC'

CCTCCTCTCC

CTCCTCCCCT

TCCTCCCCCT

TTTTTCCCTC

TCCTCCCCTT

CTCCCCTGTT

TCCTTTTCTC

CTCCTTCCTT

CCTCCCCTCC

rTCCCCTCTC

TCCCCTCTTC

PTCCCCTCCC C =CTCTTCCC TI 'rTTCTTCCC T 'CTCCCCTC T CCCTCCCCT T CCCTCCCCT C CCCTTCTCT C' TTCTCTCCC C( CTCCCCTCT C( rTCCCTCTC C' CCTCTCCTC T GCCTGCATC AC ['AGTGAGGA GG 'AGCCAGGT G~ ;GCTGGACA C )GAAGCAGA CC

TCCCCACTCC

CCCCCTCCTC

CCTTCTCCCC

CTCCTCCCTT

CTCCCCTCCT

CTCCTCCCTT

TGTTTCTCTT

rCCTCTCcCCC

TCTTCCCCTC

TCTCCTCCCC

TCCTTCCCTC

ATCCCCCTTC

CCTCCTCCCC

GTCCTCCCTC

CCCTTCTCCC

CCTTTCCCCT

TTCTCTTCCT

CCCTCCTCTT

7TCCTCTTCC CCTCCCCTCC

~CCCTCCCC]

~TCCTCTTCC

'CCCCTCTTC

CTCCTTGTC

CCTCCTCTT

TCCCCTCTT

TCCCCCCTT

CCCTCTCCT

CTTCTCTCC

CCTGTCCT

rCTCCCCCT

TCCCCTCC

GTGGTCCC

;CTGTGGG

LGGACCCGT

GCTGSGCTC

CTGCACAA

'ACGCCCAC

,TGCCACCC

CCTCTTCCCT

CTCCCCTTCC

CCCTCCCCTT

TTCCCTGCCC

CCCTCCCCTC

CCCCTCCCCT

CTCTCCCCTC

CTCCCCCTTC

CCTCCCCCCT

CTCCTCTCCA

TCTCTCCCCT

TCCTCCGCTC

CAGGTGGAGG*

GTCCAGTCAA.

GTAGAGAGGA

CACACAGGGG

GCTGGAGGCC

CGCCATCGGA

GCCCGCCCCG

35460 35520 35580 35640 35700 35760 35820 35880 35940 36000 36060 36120 36180 36240 36300 36360 36420 36480 36540 36600 36660 36720 36780 36840 36900 36960 37020 37080 37140

*S

S S 5 5*SS AGAGACCACC

GCGGGCACCG

AGGTGCCGCG GCCCGTGCCC

TO

TGCGGCCCTT TCCTCTGCCT CCCTCCTCCC

CCCAACCGCG

CTTCGTCCCC CTCCCCTCCC CCCAATTCCC

ATCCTCATCC

TCCTCCCCCT CCCCCTTCCC TATTACCATC

CCTTTTCTCC

ATTTCCCCCC CCGTCCTCCC CGTCCTTTPG

TCCATTCCCC

ATCCCCCTTC CCCTCCCTTA TCCCCCTTCC

CCTCCCTTTC

CCTTCTCTTT TCTCTACCCT TTTCCTTCCT

TTTTCCTCCC

TCTTCGTCCT CATCCCCATC ACCTTCCCCC

TCCCCCCTCC

CCCCTTCCTT CTGCCTGCAC CTCGCTCTCT

GCCCCCTCAG

CCCACCCTCC GGCTCCCCCT TTTTGCCTGC CCCCACCCTC

C

CACTGACCTC ACGCATGTCT GCAGGAGACC

TCATCCACCT

CACCACAGCC CTCAGAGCTG GGAGCCGAGT

CACCATCTCGG

ACAACCTGAC CTCTGCCCTC ATGCGCATCC TCATGCGCTC

C

CCCTGACGCT GGCGGG3CGAG GAGATCGTGG CCCAGGGCAA~

G(

TGCTGTGCTA TGGCGGCGCC CCAGGGCCG GCTGCCACTT

C~

GCGGGGCCCT GGCCAACCTC AGTGACGTrvG TGCAGCTCAT C9] CCTTTCCCTT~ TGGCTATATC AGCAACTACA CCGTCTCCAC

C~

TCCAGACACA GGCCGGCGCC CAGATCCCCA TCGAGCGGCT

CC

CCGTGAAGGT GCCCAACAAC TCGGACTGGG CTGCCCGGGG~

C

CCGCCAACTC CGTTGTGTC CAGCCCCAGG CCTCCGTCGG

TG

GCAGCAACCC TGCGGCCcGG CTGCATCTGC AGCTCAACTA

TA(

GCAGCGGGTG GGGCACACGC GGCCCCCTGG

CCTTGTCTTGG

AGGGCTTCCA TGGGTGTCTC TGGGAATr TGCTTTCTGT

TTC

TGGCCAGAGA GGAGCTGGGG GCCACGGAGA AGCAGGTGCC

AGC

TATGCTTTCA GGCCCGTGGC AGAGGGTGGG CTCAGGAGG

CC

GTGGTTGAGC TTCCCGGCAG GCGTGTGACC TGCGCGT'rCCC TGAGGAACCT GAGCCCTACC TGGCAGTCTA CCTACACTCG

GAG

CAACTGCTCG GCTAGCAGGA GGATCCGCCC

AGAGTCACTCCA

CTACACCTT TTCATTTCCC CGGGGTGAGC TCTGCGGGCC

AGC

GGCATCAG GTCAGCATTG CCTGGGTTAC TGGCCCCA

GG.

GACTGGACCG GGTATGGGCT CTGAGACTrGC GACATCCAAC

CTG

GTCCGCTACC CCTTCCCTGC CCAGGAGCAG AGACCCAGCG

GGG~

TCGCCTTTGC

CCCATCCCAT

CCCTCCCCCA

ATTCCCATTC

ATCTCTCTCC

CCTTTTCTCC

TCATCTTCCT

CATCCCCCTC

CCCCTGCTCC

TCTTCTTCTC

TCTCCCCATC

ATCCCCCTCA

NCCACTCTCT

CTCCAGCTTC

;TTCCCCCTT

TCTCCCAGCC

CTCTACCTC

CCTGTCTCTG

GCCAGCTCG

GACGTGCGGS

ATGGTGGCG

TCCCAGGCCT

CGCGTGCTC

AACGAGGAGC

CGCTCGGAC

CCGCGGAGCC

E'CCATCCCC

GAGGCTTTCA

[TTCTGGTG

GACTCCAATC

LAGGTGGCC

TCGATGGCAT

CCTCAGAG

CGCGCCATCA

ACCGCAGC

TCCGCCAACT

CTGTGGTC

ACCCTGGACA

GCTGCTG

GACGGTGCGT

3GGGAAGG CGTTTCTCGT 3 ATGGGCT GCTGGGGGCC 3 TCTGGTG CAGAGGCTCC 3 ,TCGTGGG TTCCCCCGG 3 CCAGGCC ACTACCTGTC 3 CCCCGGC CCAATGAGCA 3 GGTGCTG ACCACCGGCC 3: CTGGCAG GGCAGGGCAG 31 'kCGGCAG GCAGCGAGGG 3 3CGGAGC CTGGGCTCAC 3f kGTTACC ATCTGAACCT 39S 37200 37260 37320 37380 37440 37500 37560 37620 37680 37740 37800 378.60 37-920 379 38040 38100 38160 38220 38280 38340 ~8400 8460 8520 8580 8640 8760 8820 3880 ~940 '000

CTCCAGCC

CCAGTACT

GACCTCGC

CTTCGTGC,

AGCCTCTG

TTGCACGT(

ACTACATCC

TCCTGCAC.P

AGCGGGGCC

AGGGGCGCA

CTGGGAGTG

GGCTCGTGnl

CAGCTCCTA(

TAGCGTGGC(

CGCGATCCT'(

GTTTCTTCAC

TTTTCGTTT7I GGCATGATC7

ATTCTCCTGA

TGTCAGCCAG

GGGATGACAG

TTTCCTCTTC

GCGCGGTGGC

GTCAGGAGAT

AAAAATTAGC

AGGAGAATGG

CTCCAGCCTG

ACCTGGGTCT

AACTGAGGGA

GTGTGCAGTG

GTCACAAGTT

AC

'GI

GT

TTCCGCTGGT CGGCGCTGCA GGTGTCCGTG GGCCTGTACA CGTCCCTGTrG AGCGAGGAGG ACATGGTGTG GCGGACAGAG GGGCTGCTGC

CCCTGGAGGA

CGCCAGGCCG TCTGCCTCAC CCGCCACCTC ACCGCCTTCG

GCGCCAGCCT

CCAAGCCATG TCCGCTTTGT GTTTCCTGTG AGTGACCCTG

TGCTCCTGGG

GAGTCGAGGA GGGCCTGGGT GGGCTCGGCT CTATCCTGAG

AAGGCACAGC

CCTCCTGGGC CCGGCGGCTG TGTCCTCACA GGAGCCGACA

GCGGATGTAA

CATGCTGACA TGTGCTGTGT GCCTGGTGAC CTACATGGTC

ATGGCCGCCA

GCTGGACCAG TTGGATGCCA GCCGGGGCCG CGCCATCCCT

TTCTGTGGGC

TTCAAGTAC GAGATCCTCG TCAAGACAG CTGGGGCCGG

GGCTCAGGTG

GGGGTGGCA GGGCCTCCCC TGCTCTCACT GGCTGTGCTG

GTTGCACCCT

;TCTCGTCGC AGGCGTCAGA ACAAGGCAGT TTTTGCAGTG

CTGTGTGAAG

'TCATCCTGG GAATGACCTC GTGAGCACTC ACTGTCCCTpc

AGGACTAGA

TGGAAGTAG GTGCCAGTCA GTCAGGGTGG GCAGCCCACG

TTCTGCACAG

CACAAGTGA CGTGAGCATC GCTACCACG TGGGAGACTG

TGCATCCACC

CTGCATAGC TCGTCTCTCA GACGGAGGCG CCAGCACCCT

CCCCGTGGCT

ACCTCCATT TTCCTTTCAT TGGAATTGCC CTTCTGGCAT TCCCTTT'rTG 39060 39120 39180 39240 39300 39360 39420 39480 39540 39600 39660 39720 39780 39840 39900 39960 40020 40080 40140 40200 40260 40320 40380 40440 10500 10560 L0620 0680 0740 0800 0860

TCTTTTTTTI

TG-GCTCACACG

GTAGCTGGGA

GCGAACTCCT

GTGTGAGCCA

ATTGCCCAGT

TCACACCTGT

CGAGACCATC

CCGGCGTAGT

CGTGAACCCG

GGTGACACAG

GTCACTGGGA

CGGGTGTGTG

CGGGTCACTG

ACAGTTCTTT

GAGACGGAGT

ICAACTTCCAG

GTACAGGTGC

GACCTCAGGT

CCACACCTGG

TCTTTCTTTT

AATCCGAGCA

CTGGCTAACG

GGCAGGCGCC

GGAGGCGGAG

CAAGACTCCA

GAGGAGGTGA(

GTGCGGGTCAC

CTCACTCTGTr

CTCCCGGGTT

ACACCACCAC

GATCCGCCTG

CTGTGTTCCC

GATTACCTAC

CTTTGGGAGG

GTGAAACCCT

T(GTAGTCCCA

'TTGCAGTGA

rCTCAAAAAA

'ACAGCTTCA

:CGGTTGTGG

TGCCCAGGCT

TAAGCCATTC

ACCCAGTTAA

CCTCGGCCTG

ATTTTTTATC

TTTTAAAAAC

TGTCGGCCGG

CCAGGCAGGC

AAATCACGGG

GTCTrCTAATA AAAAGTACAA GCTCCTTGGG

AGACTGAGGC

GCTGAGATTG

CGCCACTGCA

AAAAGAAzAAA AAATACTlGTC CGCTTTIGCAG

TCTGTGCAG

CATGACTGAG GCGTGGACAG GGAGTGCAAjT

CCCTTAAGCG

TTTTTCACCA

CCAGAGTGCT

4 4 4 4 4 GTTGTGGTGT GGACTGA~c

GTGTGCAGC

CCATGTAACT TAATCATTC

CTTGAGGTCC

ATGTTTGCAT

TGCTGTTAAT

TGGACAAATT GCAGTAACCG

CAGCTCCTT(

GCCTGTGTGG CTCCTTGAGT

GCGCACAGG(

CACGTGTTGG GCAGCAGACC

GAGCCTCCCI

CCC-ACGTGGG CATCATGCTG

TATGGGGTGC

GCGACAGAGC CTTCCACCGC

AACAGCCTGG

TGGGTAGCGT GTGGAAGATC CGAGTG7,GGC AAGCTCTGCC CCTCTGCCCC

CGCATTGGGG

CTCTGCAGGG CTCAGCCCTG

CCTGGTTCCT

GGCACGCAGC GCCTTCTTCC

TGGTCAATGA

GGGCCTGGTG GAGAAGGAGG

TGCTGGCCGC

GTGGGAGGTT GGGCAGGGTG

GTCCTGCCCC

TTCTAGGCGA CGCAGCCCTT

TTGCGCTTCC

GCTTCTTTGA CAAGCACATC

TGGCTCTCCA

3TGTATGGCAG AGCCGTGCAA

AGCCGGGACT

CAAAGCTGAG ATGACTTGCC

TGGGATGCCA

CCCCTCCCTC TTGCCTCCCA

GGTACCACG

ACAGCCGGAG CGGCCACCGG

CACCTGGACG

ACATCTTCCG GATCGCCACC

CCGCACAGCC

ACGACAACAA AGGTTTGTGC

GGACCCTGCC

CGCCCTGCGA GCCTGACCTC

CCTCCTGCGC

GCAGCACGTC ATCGTCAGGG

ACCTGCAGAC

CTGGCTTTCG GTGGAGACGG

AGGCCAACGG

GAGTAAGGCC TCGTTCCAG

GTCCCACTCC

GTGGCCTCCT GCAGTGCGGC

CCTCCCTGCC

GGCGCCTGCT GGTGGCTGAG

CTGCAGCGG

TATGGGACCG GCCGCCTCGT

AGCCGTTTCA

CTCGCATCCA

CCGTGTGGTA

AGCCTCTTCC

CACACAGCAC

GCCTGGTGTC

TGTCCCGGAG

CCTCGGCACC

ACCAAAGGCT

AGAAAGAGAG

ACGCCACGGA

GTGCACGCTT

GGC'PGAGTTA

GTAATCc~cAA~

GCCTGGGCAA

GC'rCACGCCTC GAGTTCGAGA c

TTAGCTGGGC

GAGGGCCACC

CGGGGCTGT9

TGCCCAGCCC

GGGGCATGTG

CAGCGTGGTT

CAAGGTGGGC

ATGCCTAGGG

GCTCGGGAAG

AAGACTCAGA

CGACTGCACA

:CGAAAGCA

'TCCCTTAGA

:ACTTCAGGT

ATAGCAAGA

;TAATCCCAG

~CAGCCTGGC

LTGGTGGCGG

TGCTGCGTTC

GGCGACTCTG

TCCTCATCTG

CCTACAGGTG

CCTCTTCCTG

GGTGCCGTAG

TTCCTGCCCC TCAGCCTCAC CTGTGTGGcC TCCAGGCTGA G4CCCGCTGAG

CGTCGACACA

GTCTATCCCG TCTACCTGGC

CATCCTT'TTT

TGGGGCTGGG GACCCGGGAG

TACTGGGAAT

CCGCCACTTT CCAGTGCTGC

AGCCAGAGGG

GGTCAACACA CTTGAGCAGC

CTTAGCTAGA

AGCCAGAATG GTG2AAAGAAC

GAGGGCACTT

GCAGCACGCC AGATAACTCA

GAAGAAGCAA

CTCCAGAAGA AAATCTCAGT

ACATCTATAG

AACGTCCCAG TGGCCGGGCC

GGGTGTGGTG

GGCCGAGGTG GGCGGATC'rG

AGTCCAGGAG

CCCCATCTAT ATAWAA'r'r

AAAAAGGGCC

CACTTGGGA GGCCGAGGCG

GGCAGATCAC

CAACACAATG AAACCCCGC

TCTACTACAA

GCGCCTGTAG TCCCAGCTAC

TCGAGAGGCT

GGCGCCAACG

GGGTCGGGG3C

TCCTCTCCTC

GTCGCTGTTG

CTCTTCCGGA

GGAGCCTGGG

AAAGGCGTCC

CTGACCAGGG

TGCTAAGCAG

GCACGCGGCT

GAAGTGAAGA

;CTCACGCCT

rTTGAGACCA kGGCGCGGTG

TGAGGTCAG

kTACAAAAAC 4 4 40920 40980 41040 41100 41160 41220 41280 41340 41400 414 41520 411580 41640 41700 41760 41820 41880 41940 42000 42060 42120 42180 42240 42300 42360 12 42 0 12480 12540 ~2600 2660 2720 AATGGCATGA ACCCAGGAGG CGGAGCTTGC AGTGAGCCGA GATTGCGCCA

CTGCACT~CA

TCCTGGGCAA

CGGAGCAAGA

AAGCTCAGGC TCAGAGCCTr' CCAATCCTTC

ACAGACTCTT

GAAACGGGAG GCCGCACCCC AACTAACCCC AGCAGCACAC GAGTCCGTGG CAGGAACCAG GAACGATGGC CGGGTGTGGT GGGCAGATCA CTTGAGGTCA TCTCTACTAA AAATACAAAA ACTCAGGAGG CTGAGCCAGG GAGATTGCGC CATTGCACTCC ATGAAATTTA AAACTCTGTT C ACGTCGCGAG GGGCTGCCAT C ACATTCTGTC AGATGGCACC TGTCCTGAGC AGGTCTGAGCT GGAGCCCGAG CCCCACACCT G CGTCCGTGCT GGACAGCTCC TACTG3GGGGT CCTGGGCTGG G CACTGTGCAC CTCTCAGCAG GC ATTCTAAGAG GTGGGTTCCC T GGTGCCGGGG GTGTGCGGGC TC ACCACCCGGG AGCAGGTTTGM

C]

GGGCTGTGTG TGTGACACAT CC GTGCTGGCCC! TCC!GGCGAGG G TGTGGGTAGC AATCTGCGGC AG GGAGGACGGC TTCTCCCTGG CC TGAGCTG3GGG TGAGAGGAGG

G

CCTCCTGTAC CTCTAGATGA AG.

CCAGCCCCTA CCCAAGACAC

CC

GGCTCTCGGG GGAGGGGGGA T74 GTTCCCGCCT GGGGTAGGGT GG( CTCCATCTCC AAAAAAAAAA AAAAAAAATC

CCACAAAGAA

CACGATAGAA TTTTTCTAAG CAGTTAAGGA

AGAATTAACA

TCCAAGAATA CAGCAGGTGG GAACGCTTCC

CATTCATACG

TTAGGAATGC ACACGTG3GGG TCCTCAA3AG

GTTACATGCA

AGAGAAGGCG CATAAGCCGC GACCAGGAGG

GGTTGCTCCC

AGGCCACAG TGGCTGCTCG TATTTAAGTT

AATTAAAT

GGCTCACACC TGTAATCCCA GCACTTTGGyG

AGGCGGAGGC

GGAGTTCCAA GACCAGCC']G GCCAACACAG

TGAAACCCCG

FLATTAGCTGG GCATGGTGGC AGGCACCTGT

AATCCCAGCT

%CAATCGCCT GAACGCGGGA GGTGGAGGTT

GCAGTGAGCT

-AGCCTGGGT GACAGCGAGA CTCCATCTAA

AAAAGAAAAT

~CTTAGCTGC ACCAGTCTGC TGTCAAGTGT

TCAGTGGCAC

ACGGACGGT GCAGATGTCC CATATATCCA GCATTCTAGG G3GCTCTGTC CTGTCTGCTG AGGAGGTGGC

TTCTCATCCC

a.

a.

a a a a

GCCGCCCGC

CCGGGCAGC

TCCTCACG'I

CTGGGGGTC

CTTTGTTG

kGAGAAACC

;CGTGTCCT

"CGGAAGCC

:CCTGGTAC

ACGCTCAG

CTGGCACG

AGCCCCTA

GCTCTGAA

ACCTGATC

1CATGGAA

~CCAGAGG

~GTGGGGT

AG4GTGCTGG2

TCTCAGGCC']

CTGCCGCCTI

GACAGATGAA

TCGAGCCCTG

TGCTGGGTGT

CAGGGTGTCC

CTTGCTGACC

TTGGCCGGAC

GGGCCAGGCG

CTCGCCTGCC

GCTCACCCTT

CAGCAGGTCC

ACGGACCTGCc

AGGGGCCGG

GCCAGGG4CAG

CATCGACAG(

CCACGCTGAC

GGCGCAGCTI

GAGTGACTTG

GTGCAGGTCA

CTGTGGCTCC

GTGCGTGACT

CGCGCCACCT

CTG4CTCAGTG

GGCCATGGGC

AAATCCTTCT

GCAGCTGGGC

TTIGCCGAGGG

TCAGCAGCCT

ACTCAGGCCA

GGCTGTGGCT

TGCCTGGACT

GTGAGGACTC

GGACTCAAGA

TTTCTGGATG

CTGTGTCTGG

ATGTGGTCAC

GGACGGGGGT

GCAGTCTGGT

ACCCGTCCAT

TGGGCCCAGA

CAGCATCAGG

CCACCCTATG

GGTCAGCAGC

GTGAGTGTCC

GGCAGCCGTG

GCACCACTTC

TGACCACTGC CCTCGTCCTG

CAGGTGGCTG

42780 42840 42900 42.960 43020 43080 43140 43200 43260 43320 43380 43440 43500 43560 43620 43680 43740 43800 43860 43920 43980 44040 44100 44160 44220 44280 44340 44400 44460 14520 14580

ACTTCTCTK

CCTTCCCTC

TGAGGCTGG

GTTTTTAAA

TGGGAGGCC

TGGCGAAACI

TGTAGTCCC

4

GTTGTAGTG~

GTCTCAAAAZ

TCATATAGAG

CGGAGCGCAC

TGCTCAGGTG

CAGTGCAGTG

CTGCATGCAC

AGCAACAGAA

TGACTGCTGC

TCATTGTTAA

GAAAACTTC

ATTGCTGGTT

TGACCAGCCC

GGGGATTTCT

,A ACCTCTGTTG TCTGTGGAAA GAGCCTCAqyG

GGATCCCCAG

T AGGGAGGGAG CAGGCTCATG GGGCTTTGTA GGAGCAGAAA C CGGGGCCACG TTTTTATCTT GGTCTCAGAG

CAGTGAGAAA

.T ACCCCATTTT TGGCCGGGCG CGGTGGCTCA

CACGTGTAAT

G AGGTGGCAG ATGACCTGAG GTCAGCAGTT

CGAGACCAGC

C CCGTCTCTAC TAAAAATACA AAAAATTAGC

CGGGCATGCT

k. GTTACTCGGG AGACTGAGGT AGGAGAATCG

ATTGAACCTG

k. GCCGAGATCG CGCCACTGCA CTCCAGCCTG

GGCAACAAGA

CAAAAAAJATT CCTCAATTTC TTGGTTG3TTT

TGTAACTTAT

GTTACCTTGT ATGTAGTCAC GCACATAGTC

ACGCACATGGC

*CCACGGCGTG TTCCCACGCG TGTGACCCCG GGCTCTGCCA

I

TGCTGAGGTC CACACGGCCC TGCCGTTGCA CTGCAGCTGC

C

GCATGCAGTG CAGGTGCGGT GCCCCGGAGC CACAGGCCAC

A

AGGGGCTGCG GTGTCTGGGT TTGGGTAACT

ACGCCCTGTGA

TTACCTAATG ACGCATTTCT CAGAACACAT

CCCTGGCACTA

TTTTGCATCC ACATCTAGTT TGATTTGTGT

GTTATTCCTT

GCAACCAAGA ACTAAAGAGG TATGAACTY2 CCCTGGACTC

A

TGATTTACAA AAGGCAGATA ACCATCACAT GAGGGCATCT

T'

GGCCCCAGAA

GGCTCCTGTG

TTATGGGCGG

CCCAGCACTT

CTGG3CCAACA

GGCAGGCGCC

GTAGGTGAG

GCGAAACTCC

AAPCAAATGG

AGCcGGCcG

'GCCCTCCTA

TGCAGGATT

CCACAGGGC

CATTTGCAC

AGTGGTGCG

77AGTGCTTC t.ACAAAAAG

PATGAATAA

44640 44700 44760 44820 44880 44940 45000 45060 45120 45180 45240 45300 453'60 45420 45480 45540 45600

GGTTTTAAAA

CAGGTATCTC

GACGGCAGCT

ATACAGAGTA

CGGCCCAAAG

CAGACTCCGC

CCGGCTTCCT CAACCCTTGG CCGTCCCTTG

GAGGCTTGGG

CCGTGGCTCC

TCCTGGCGGC

TCCGTCTCTG

TAAAGGAATA

TCTGTTGCCC

ACGTTCAAGC

CACAGCCGGC

TTTGTCCTGG

TTTCCCAACG

GCCTCTGCCC

CCAGCGAGAG

GTTGAGGCTG

AGACTGGAGT

AGTTATCTGC

TAATTTTTTG

ACCCCTCTGC

CAGAGCAcGG

TGGCATTCCC

CCTGCTCCCT

GGTTATTTTT

GCAGTCGCAT

CTCAGCCTCC

TGTG3GT

TGGGGAAATC

CTCTGTGAAA

ATCCACACAG

CTCGGACAGT

GTCCTTCCTC

CCTTCCCTGC

TCCACTCCA

GAGTCAGACC

TATTTTTATT

GATCTCGGCT

2AAGTAGCTA

I'TAGTAGAGA

CAGGGGTAG~i

TCCAGATTCA

AGCGCGTGGC

GCTTCGGGCr

ACTGCAGCCT

GCCTGAGCCT

TGCCTCCCTA

CTGAGTCATT

TATTTTTTTG

CACTGCAAAG

AGATTACAGG

GGAGGTTTCA

-CACTACATGC

GTGCTTCCGC

CCTCACCCTC

GACCAGGTCG

CCAGCGCGTC

GCACCCTCCG

TTGGCCATTC

TGTGTTGCTA

AGATGGAGTC

TCTGCCTCCC

CGCCCGCCGC

45720 45780 45840 45900 45960 46020 46080 461.40 46200 46260 46320 46380 46440 CAGGCTGGTC TTGAACTCCT GACCTCGTGA TCCACCCATC TCAGCCTCCC AAAATGCTGA

I

GATTACAG

TGTAAAGAC

CTCcTGAJAc

CCTCCGAGA

CTTTCGGTG

CGGCGTCTC

TTCTCTAGC,

TCGGTGGTC~

CTGTTGGGA

AACCTGCATC

GAGACCCAAgI

ACTGCTGTAA

GGAGAGGGAC

TCCCAGCACC

CCTG3TGACCC

TGCCTCCTGG

GGGGAGAAGA

GCCTGAACT

CCCCGGGATG

CCAGGACTGG

CACGGGCTCA

AGCTTCCCCC

TCATTCCTCG

CCATCACGGG4

TTCTCACTGG

GCTGTGACGC

TTCCTGGCcA

CTGGGTGCGGC

CGCAGGACAC1 GCAGCCTTTG

C

CAGGGCCCAG C ,C GTGAGCCACC ACGCCTGACC

AAGTTGAGGC

A GGGTCTCACT GTCTCCAACT

CCTGAGCTCA

*T GCTGGGATTA CAGGCTTGAG

ACACTGCGCC

ACAGCAAAAC AGGAAGCATT

CAGTGCAGTG

ATGGGCTGACG AGGGCGCAGG

TACGGGAGAG

G CAGTTGGTCT CGTCCTCCCC

CTCAACGTGT

GCTCTGGGAC CGGGCATATC AGcATGGTGG CTGGCTCCTG GAGACACAG

CAGATCTCTG

LTTGAAAGGCA TTCATATGr'. TCCTTGTCCA

C

GGACAGACAC ACTGGCGTCT

CTAGATTGTA

CATAGTTTGC AGGGTTGAAG GGGGGCTCAT GGGCAGCTGG TCAGGCTGTG

GGCGATGGGTT

GCAGGCGGAC GCCTGACTTC GGTGCCTGGA

G

ACTCCCACTC TCGTTTGGGG TAGGGTCTTC

C

AAGAGGCTCA AGAAACTGCC CGCCCAGGTT

A

AGGCCGGGAT GAATTCACAG CCTACCATGT

C(

CAGAGACOCT GGCGCTGCAG AGGCTGGGG

A(

GGGAACAGCC CCAGGCAGCG AGGCTGTCCA

GC

TAGGTCATTT

TTTAATTTTT

AGTGATCCTC

CTGCCTCAGC

CAGCCAAGAG

TGTCTTTTAT

TGACCCTGGG

TCAGGCCGTT

CGTCCTGAGA

GCCCGGGACT

CTTCGCTGCC

TCTGTACCTC

CCCGATGCAG TGGCACAGCC 3CCTCAGGGA GCCCTACACA AAGTTAATT

TTAGGCCATA

;AGATGCTTG T'rGGATGGTT 'GCACCCTGA GAGAcTGTGC TATCAGCAG CAAGCGGGCG TGGCTCTTG GTTCCCT(C GGCTTT'ITG TCGGGGGGAc kCATGGGCT TGGCTGCAAC CTCAGGTC

CAGCACTCCT

~CTGGGGCC

ACCCAGCCCA

,ACAGGTGT GCTTGCGTAG 46500 46560 46620 4668o 46740 46800 46860 46920 46980 47040 47100 47160 47220 47280 47340 47400 47460 47520 47580 47640 47700 47760 17820 17880 ~7940 8000 8060 8120 8180 8240 8300 Ve 060*

CCCCTAGCCC

TGGAGGGTC'l GCCTGCTCC7

CGGGCGTGAG

GCTGGGAGCC

GGACCCCTCT

rGGCCAAGCG

'TGTGAGCGC

kGGAAGAAGC

.CTGTGCCCC

CCTGTCCCC

.CCGGTCTCC

*TCCAATGCC

CTCCCTGTGA

GCGGAAGCGC

GGTGGCTGTG

TGTTGCGTG

ACTGAAGGTG

GAAGCCACCC

GCTGcAcccG

ACGTGTGCCC

CCGCAAGGTC

TGCCACCTCC

CTTTCCTCAc

CTCCTACCCC

CACTCCTGCC

GCTGCCTCTC

CTGCTGccGG

GCTGTGGCTG

CTCCTGTCcA

AGGGGGCTGC

CCTCCCCAGG

GATGAAGATG

CGCGTACGGC

AAGAGGCTAC

GTCTCTTGTC

ACAGGTCTG]

CCTGGTGTGC

TCTCAGGcjTC

GCAGCGCCAG

CAGGGGTAGG

TCTTGCTGGA

ACACCCTGGT

CACCCCACG

ATGGCATGCT

TCCCACCTCC

CTCTGCTTCC

CTCCCTGGCC

GGTGGGTGCG

CTTCCTGGCC

CTACAGGCCT

AGCCCTG3TAC

AGAGAGCCCG-

CTTTGCACTC

GCGGGTGAGC

CACCCATGCA

TCAATGYCTCT

CAGTCCCTGC

CACCACTGCA

4 4 4 4 4 4 4 4 CTCAGAAGGC

CCTTAGGGGT

ACGCCCCCCA

CTTGCTGCCC

TGGCCCTGAA GGCCCCTAAG

GTGGCCTG

GGCCAGGT,

CAGCCATG

CCACAGGG(

CTGCTGGCC

ATCAAGCAC

CACTGGTC'I

GTGGACATG

GTAGGCAGA

GACAACTGT,

GCCAGCAGG

GCATGGGMC

GCCATGGAT(

GGGGCCCCCI

AAGACTTAA7

CTGCTCCCTP.

AGAGATGGTA

CCAGAGCTCA

GCCCCGGCCT

CCACACGTGC

TCCTCACAAT

GCGAGGGCCC

C'rCCTGACCA

CTCTCCGGCA

CAGGAGCTGG

AACTCGGCTGG

CCAGCCAGGA

CCTCAGCCAC

GACCCGCACC

GCCGTGGGGC

CTGGCCGCCC

3 TGTCTGCCCC

AGTCTTGGGC

TCCAGCCGTT

CCCCCGTCCA

GCTATGGGGA

AGCTGCACAG

TCTTCTGGGC

GTAGATACCT

GGGAGGGACA

TGCCCCAGAA

CAGTGGGAGC

GTAGGGGCTG

CAGGTGGGGT TCCGGGCAGG CGCCCCCTGC CAGCTCACCT GCCAAAGCCC TGCTGTCACT CCAGAGCCTC

CTGGTGTACA

TGCCTCATGC

CATGGGCACG

CCGGGCCTTC CTGGCCATCA TTTrAGTTTTG CCTTTAGTCC TTGTGGCTGC TAGAACTGGA CAGGTCCGTG

TCTTGCAGTG

CATCCCCAGG ATAAGGCTGA CATGTTCCCT GGGTCTCTGG GAGCGTGTGA CTGATGCTGT GTGTGTGCTG

CCATTACCCJ

TCCTGCAGCC ACACCTGCCG GTGGGCTGGG

GCCAGGCTGA

TG CTTTTTCT GCTGGTGACC CCTACCGTCT GCAAAGCGCC CGCGGTACGG GCATCCGGTG AGCCAGACCC

TAGOGGACAT

GGTAGGTGCT GCTGGCATCA CACAGGACGG GCCCATGACA GAAGCCCAGG TCTAGCCGG 1'GGCCGCTCA CTCGAGGCGG 3GCAGGTCTG AGGAGCTCTG GCCCACGTGC TGCTGCCCTA CGTCCACGGG AACCAGTCCA

GCCCAGAGCT

S S

S

5**e

CGGCTGCGGC

ITCGTTCCTCI

GCTGTGTGAC

ACGTTGTCTA

GGCGAGCTGG

GGGGCTCTGT

TCGGCCGCAG

GGCTCGGGGA

CGGGCGTCTA

GCCTGGCTCC

GGGCATGGTC

GCCTGAGCCT

ACAACAGGTG

GCCCACCCTC

GCCTGCACTG

CTCTGCGCAG

TGC-ACGCCGC

TCAGCGTCCG

AGGTGCGGCT

TGTTGAGAGA

CTTTGCCCTC

ATTGATGGCT

CCAGCAGGAA

GTGTTTCAGC

GAGGCTTCAG

CGTG3GGCCTA

CGCCAAGGAC

GGGGTGCCGG

ClrGGGGCTCC

GGAGGAGAGC

GGAGCTCCCT

ACTCCTCCGG(

CGCGGTCCCCC

GAGCCGCGCT C

CGTCACGCTGC

CCCCTTTGCG C

GCAGGAAGGT

GCAGCCTTTA

TTAACACCGC

GCTGGGAGGG

ACACTCCTGT

ACTCTACCCA

CACCAGCGAT

TTCAGCGCCG

AAGGGAGTAG

AAGGGCTGGG

TGTGCCGTGT

'GCGACCGGC

CCCTGCCCT

CCCCGCTGG

CAGCTCCCG

;TrTCCr )6 'GCCTCGAGT TGCGCCGCC

GAGCTGGCAG

GCGGAGCTCT

CGTTTCCT'rC

TTCCCTGGGG

TGGGTTTTGA

GACCCTCCCG

TACGACGTTG

GATCTGCTGG

TTCTCCAGGA

GTGCGGCACC

ATGACAGCGG

TGCGC2TrCCT =rCGGGGTG C 'CTAGG4CGGC CCTGCCACC C kGCTCACGCG

C

CCCGGCGGC C 'CAGCGCGGG C

GGCGTGCCCC

GGCATCAGCC

TCTGTATATG

TGGCGCCGAA

TGAGGCCCTG

GCCCCAGGGT

GCTGGGAGAG

GGTGAGCAGA

3TGCCGCGGC

ACGCCACCC

;GGCTACGTG

C-AGCTGCAC

~CCGCAGTCA

7TCCACAGCC

GCTCCTACT

TACAGCCCG

GGCCGCGCC

CTCTCGCTG

48360 48420 48480 48540 48600 48660 48720 48780 48840 48900 48960 49020 49080 49140 49200 49260 49320 49380 49440 49500 49560 49620 49680 49740 49800 49860 49§20 49980 50040 50100 50160

CCTCTGCT

CCCGCCCC

CGCAGCGT

CCCGCCCC

CTCCTGAC(

CGAGGCCCC

GCGGTGGC

TGCCGCTGA

CGACCAGGT

GCTTTTGGT

TGCAAGCAG

GTCCGTCTT

CCTGGTGGT(

CGGGGAGGG(

CCGCAGCTCC

CTGTGCCCTC

CTGCTGTGTG

ATTCTCCGCT

CAGGACTACG

AAGGTCAAGG

CAGGGTGCAG

TTTGAAGGGA

GTGCCCCCAC

GATGGGCTGA

CTCCAAGCCG

GACGTCTACC

CCCGCCGGAT

GCCCcGGCCA

AAGAACAAGG

GTCGGAGTGG

AATGGCTGCA

CA CCTCGGTP CT CGCGGGGC CC CGCCCCCT GG CAGCGTCC :G CGCCCCCC, T ACTTGGCA(

CTGGTGGC(

~C CGCCAGTGC G GCGCAGCTC C AAGGTGAGG

ACAGATTTCT

r GGCAAGACA GCTCGGGGTAi

-GTCTTAGCTD

TGTCTTCCqX

GGACTGGGC]

TG3GGGCTCTC

GGCGCTACCP

AGATGGTGGA

AGGTGGGTAC

CCGGACTGAC

TGGAGCCGCT

CCAGCGCTGG

GCGTGAGCCT

TGTTCGAGGC

AGCTGGAGCA

CTTCCCGTGG

GTCGGGGTGT

TCCACCCCAG

ACACCGCTCA

CGTAGGTTCC

.G CCCGTCCCCG 'C CGCCCGGCAG G CAGGGCCCCG G CCCCCTCGCA :AGGTG3TGCCT

GGGAAGGGCG

TGACGGCGGC

CCCGTTTCGT

LGCTCCGCAGCC

CTGGGCCGGT

GTCCGCAGGC TATGCCGAGCcT CCTACGCCCA G AGCTCAGCTC

A

TGTGGACTCC

C

CTCTACCCTG 7X GGCACTGCGG C' CGCCTTGCGT

G

GTTGTTCCTG CC

GCCAGACC

CGTCTCACC

CCCCGGCAG

GGGCCCCGC

GCTGCTGTT

CTGGCGCGT(

CACGGCACTc 3CGCGGCCGC

~CGTGGCCTG

;GGCGCGGGG

'GCCCAGCAG

CTGCCAGAG

CTGGCCATC

GCTGTACGC

rCTGGAGCG 3TCCTGCCG rGTGGGGCG

'AGAGCTGT

;CAGGCTGC

.C GCGCCTCCCA

CCGGCAGCGT

C CTCGCAGCG3C

CCCGCCCCCT

C GTCCCGCCCC

CTCGTAGGC

C CCGGCAGCGTj

CCCTCCCGCC

c GCCGTGCACT

TCGCCGTGC

3CTGCGGCTCG GAGCcTGGGyC GTACGCCTG CCCAGCTGGyG CCGCGCCGCT

TCACTAGCTT

GCGGCCTCGC

TGCTCTTCCT

CTGGGCGCAC ACCCCAGGC CTACGCTTCG

TGCGCCAGTG

CTCCTGGGGG TCACCTTGG CTGGTAGGTG ACTGcGcG~c CCTCACTGGT

GTCGCCTTCC

TGGCCCAGGC

CCTGTTGGTG

AGTCCTGGCA

CCTGTCACCC

CCCTACGGCT

GGGGGCTGTT

ACCGGCCGC

CTGGGAGCCC

GCCTCTGGAT GGGCCTCAGC 5022o 50280 50340 50400 50460 50520 50580 50640 50700 50760 50820 50880 50940 51000 51060 51120 51180 51240 51300 51360 51420 51480 51540 51600 51660 51720 51780 51840 51900 1960 2020 GGCCCAGTGG GGGGGAGAGG GACACGCCCT

GGGCTCTGCC

TGAGCCCCTG TGCCGCCCCC 0@ S @0 0*

S.

.006 0*SS*S

S

0005

OS

@9 5 900 0 0 5@590S

S

*560

S

SOSS

GCCCTCTCGC

CTCCGATGCC

GGGCCGGCTG

CCTGCTCACC

GCAGCTGCAC

CCCATCCCCG

GGACCTGGCC

CAGCACTTAG

GTATTACTTT

CCAGAGAGCA

TCCTCCAGG

TCGCACCCCT

GGGACAAGGT

CAGTTTGACC

AGCCTGCAAG

GGCCTGCGGC

ACTGGCCCCA

TCCTCCTPrCC

CTGCCGCTGT

GGCAGGGGCA

AGTTCCG4CCA

GCTCCAAGGT

CCACCTCCTC

GTGAGCCTGA

GACTCAACCA

GCCGCAGGAG

CAGCACTGCC

GCAGGACACC

TGGCGGGGGT

CAAAGTCCGC

ATCCCCGGAT

CAGCCAGCTG

GCCCTCCCGC

.GGCCACAGAG

CAGCCGGGCG

CAGCCGCCTT

CCTTCGGGCC

GGGCCGTGGA

5 CAAGGCCGAG

GGCCAGGCAG

TCTGTCTGTC TGTGGGCTTC OS S 0@ 0 AGCACTTTAA AGAGGCTGTG TGGCCAACCA GGAAGGACAC AGCAGTATTG

GACGGTTTCT

GTCCTCAGGT ACAGCGGGCT

GTGCCCGGCC

AAGGCTGCTG GCTTCAGGGA

GGGTTAGCCT

ACCTCTCCAG TTCCTACCGT

ACTCCCTGCA

TTATATGGTG TTAAAATGTG

TATATTTTTG

CCTGCGCCCA GAGCTGGCCT

CCCCCAACAC

TGGCAGCCCG GCTGCTGCTT

GGATGCGAGC

TGTCTGCCAG GCACTCTCAT

CACCCCAGAGC

GTAGCAAGAG AGCAGCGCCC AGGCCTGCTG

G

GCATGTCAGA GGACCCCAGG GTGGTTAGAG

G

GGGTGGAGGA AGGTGACTGT GTGTGTGTGT

G

TATGGCCCAG GCAGCCTCA2A GGCCCTCGGA

G

CTGTGGGCAT GGCCGCTTCT AGAGCCTCGA

C,

AAGTCAATAA AAGAGCTGTC TGACTGCAAT

C'

GGACTTTATT TATTTCACTG ACAGGCAATA

C(

CCGGCCTCAC ACAAACTCGG TGAAGTCCTC C1 CACCTCATAG CCAGGTGTGG GCTCGGCTGG

AG

AGGGTGCACC AGAGGTAGGC TGGGGTTGGA

GI

GAGGCGGCTT GGGCAGTAAG TCTGGGAGGC

GT

CACAGCTTGG GCAGCCAGCA CACCCCGCTG

A

*.:GAGCGCTTGA TGTGGCGGAG CGGGCAATCC

AC

AGCGGCTATG ATGCACCTGT

GAGGCCATCTGG

*CAGGTGGCAC CTGGGCCTGT CCCACCAGCT

CA(

CGTGCAGGGC CATCTGGCGG GCCACGAAGG

GC)

*CGCTGG

GGACCCAGGG TCCCCTCCCC

AGCTCCCTTG

AGCCTCTGAG ATGCTAATTT

ATTTCCCCGA.

CCACCCCCTG GGCAGATGTC

CCCCACTGCT

GCACCGCCGC CACCCTGCCC CTAAGTTATr' CCGTCTCACT GTGTGTCTCG

TGTCAGTAAT

TATGTCACTA TTTTCACTAG

GGCTGAGGGG

CTGCTGCGCT TGGTAGGTGT

GGTGGCGTTA

VTGGCCTTG GCCGGTGCTG

GGGGCACAGC

;CCTTGTCAT CCTCCCTTGC

CCCAGGCCAG

;CATCAGGTC TGGGAAGTA

GCAGGACTAG

;AAAAGACTC CTCCTGGGGG

CTGGCTCCCA.

TGTGCGCGC GCGCACGCGC

GAGTGTGCTG

CTGGCTGTG CCTGCTTCTG

TGTACCACTT

1CCCCCCCA ACCCCCGCAC

CAAGCAGACA

rGTGCC!TCT ATGTCTGTGC

ACTGGGGTA

-GTCCAAGG CCAGTGCAGG

AGGGAGGGCC

~CCGAGGAG ATGAGGCGCT

TCCGC!TGGCC

;TCTGTGCA GGGGCT2-rGC

TATGGGACGG

'AGGCGGCT TCCTCGCAGA

TCTGAAGGCA

GGCAACCG CTC TGCCCAC

ACACCCGCCC

GGAGCCCC ATATTCCCTA

CCCGCTGGCG

TTGGAGGG GTAGATATCG

GTGGGGTTGG

3GACGTAG GCAGG GTG AGCTCACTAT 2GCCTGGA CCCACCCCCA

CTCACATTTG

~TTGCG GTCAGACACG

ATCTTGGCCA

52080 52140 52200 52260 52320 52380 52440 52500 52560 52620 52680 52740 5 2-800 52:860 52920 52980 53040 53100 53160 53220 53280 53340 53400 53460 53520 3526 INFORMATION FOR SEQ ID NO:3: SEQUENCE

CHARACTERISTICS:

LENGTH: 894 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genoxnic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3: GGTGTGAGGG GTAGGGGCAG GGTGGGAGGT GGGCTCGCGG GTGGGCTGGG GTCATGAAGG GCCTCAGGCG CTCTGCTATT GGGTTCCAAG GCTATCCTGA GAACAGGGGT GAGGGGGGAT TGCCGTGGGG GGTTAA.AGCC TTGTCATGTT CGCTTTCGGG AGATAAAAAC AACAGGTGGC CTTTATGGAG ACGCTGCCCA GAGCCAGGTC TGTGCCAGGC TCCTGTTGGG GGTCGTCATG CGGAATCCTG ACTCTGACCA TCCGAGGCAT AGGGACCGTG GAGATTTGCA TTTCACAGAT GAGGAAACAG GTTTGGAGAG GTGACACGAC CTGTCCCAGG CATCACAGCC GGGATGTGCA.

TAGCAGGGGT TTGGAACTAT GAGGTGCCCA GGACCCAGGG TTGGATTGAA AAGGGCGGAG GGGACTAAGA TAAGCAGACA GTTGTCCCCA GC!GCTGGGGA GAGTCTTGGG ACCAGTCTGA TGCCTTGTAT TTCCCAGGCT CCAGGCTCCT CGC!CGGGACA GTGTCTCCTT GGGTGCGTGC TGGATCCCTG GGGGACGTGG CACATCCCCA GGCTTGCTAA ACATTGGGTG GGTTCTGGCA TTTGGTTTTG TAACGTTTCT GGGTCACTCC CGCCTGTGGC CACCCTTCCT TAGGGGAGCC GTGTGTCCTT GGGGCTTTGC TGGGTGGTCT CGAGGGTGGG AGAAGAATGG GTTCTCCTGG ACCAATGGAG CCCGTGCCCC TCGGGGCCAC ATTGCTCCTG CGCTCCCTGA CTGCGGACGC GTGTGTCTCG CGGCTGTCTC TGTGGAGATG GCCTCCTCCT GCCTGGCAAC AGCACCCACA GAATTGCATC AGACCTACCC CACCCGTTGT TTGTGATGCT GTAGCTGAGG GCTC INFORMATION FOR SEQ ID NO:4: SEQUENCE CHARACTERISTICS: LENGTH: 14060 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (ix) FEATURE: NAME/KEY: CDS LOCATION: 135. .13040 (xi) SEQUENCE DESCRIPTION: SEQ, ID NO:4: GCTCAGCAGC AGGTCGCGGC CGCAGCCCCA TCCAGCCCGC GCCCGCCATG CCGTCCGCGG GCCCCGCCTG AGCTGCGGCC TCCGCGCGCG-GGCGGGCCTG GGGACGGCGG GGCCATGCGC GCGCTGCCCT AACG ATG CCG CCC GCC C CCC GCC CGC CTG C CTG GCC Met Pro Pro Ala Ala Pro Ala Arg Leu Ala Leu Ala 1 5 120 .180 240 300 360 420 480 540 600 660 720 780 840 894 9* S 120 170 CTG GGC CTG CCC CTG TGG CTC CCC Leu Gay Leu Gly Leu Trp Leu Gly 20 CCG CTG GCG COG GGC CCC GCG CGC Ala Leu Ala Gly Gay Pro Gly Arg 218 266 GGC TGC Gly Cys GGG CCC TGC GAG CCC CCC TGC CTC TGC Gly Pro Cys Glu Pro Pro Cys Leu Cys 35

GC

Gly' CCA GCC CCC GC Pro Ala Pro Cly

GCC

Ala GCC TG CCC GTC Ala Cys Arg Val

AAC

Asn 50 TGC TCG CCC CC Cys Ser Gly Arg CTG COG ACG CTC Leu Arg Thr Leu CCC CC CTC CGC Pro Ala Leu Arg CCC C GACG CC Pro Ala Asp Ala CC CTA GAG Ala Leu Asp CTC TCC GAG ValgSeL His AAC CTG CTC Asn Leu Leu CTC GCA GAG Leu Ala Glu CC CTC GACGOTT Ala Leu Asp Val

CG

Gly CTC CTG C AAC CTC TCG CC Leu Leu Ala Asn Leu Ser Ala CTC OAT ATA AC Leu Asp Ile Ser AAC.AAG ATT TCT Asn Lys Ile Ser

ACC

Thr 105 TTA CAA CAA Leu Clu Clu 362 410 458 506 554 602 GGA ATA Gly Ile 110 TTT GCT AAT TTA Phe Ala Asn Leu

TTT

Phe 115 AAT TTA ACT OAA Asn Leu Ser Glu

ATA

Ile 120 AAC CTG ACT COO Asn Leu Ser Gly CCC TTT GAG TCT Pro Phe Glu Cys

GAG

Asp 130

CCC

Arg TGT GGC CTC CC Cys Gly Leu Ala CTG GTGCGAG

CCC

Val Val Gln Pro 150

TG

Trp 135 CTG CCC CCA TOG Leu Pro Arg Trp

CC

Ala GAG GAG GAG Glu Glu Gln GAG GTC Gln Val 145 GAG CCA CCC AG Glu Ala Ala Thr TCT CCT Cys Ala 155 a GCG CCT GCC Gly Pro Gly GAG ACT GCC Asp Ser Gly 175 TCA CCC ACC Ser Cly Thr 190

TC

Ser 160 CTG CCT CCC GAG Leu Ala Gly Gin

CCT

Pro 165 CTG CTT GC Leu Leu Cly ATC CCC TTG CTC le'Pro Leu Leu 170 TCT COT GAG GAG Cys Gly Glu Glu

TAT

Tyr 180 GTC CCC TCC CTG Val Ala Cys Leu GAG AAC AGC Asp Asn Ser GTG GGA GCA Val Ala Ala TCC TTT TCA OCT Ser Phe Ser Ala GCC TTC TG TTC Ala Phe Cys Phe 215 CAC GAA CCC CTG His Olu Cly Leu 650 698 746 794 842 890 CTT GAG Leu Gin 205 CCA GAG CC Pro Glu Ala TG AGC Cys Ser 210 GAG GAG Glu Gin ACC CCC GAG Thr Gly Gin

C

Gly 220 a CTC GCA 0CC CTC Leu Ala Ala Leu

TCG

Ser 225 GGC TCC Gly Trp, CTG TOT GGG Leu Cys Gly C CCC GAG Ala Ala Gin 235 GGC CCC CCC Cly Pro Pro 250 CCC TCG ACT Pro Ser Ser

CC

Ala.

240 TGG TTT CCC TG Ser Phe Ala Cys

CTC

Leu 245 TGC CTC TG TCC Ser Leu Cys Ser CCA CCT CCT Pro Pro Pro 255 GCC CCC ACC TGT Ala Pro Thr Cys

AGG

Arg 260 GGC CCC ACC CTC CTC CAG CAC GTC Cly Pro Thr Leu Leu Gin His Val 265 938 TTC CCT Phe Pro 270 GCC TCC CCA CCC Ala Ser Pro Gly ACC CTG GTG GG Thr Leu Val Gly

CCC

Pro 280 CAC GGA CCT CTG His Gly Pro Leu TCT GGC CAG CTA Ser Gly Gin Leu

GCA

Ala 290 CCC TTC CAC ATC Ala Phe His Ile GCT CC Ala Ala 295 CCG CTC CCT Pro Leu Pro

GTC

Val 300 ACT GCC ACA CGC Thr Ala Thr Arg

TG

Trp 305 GAC TTC GGA GAC Asp Phe Cly Asp

GC

Gly 310 TCC GCC GAG CTG Ser Ala Glu Val GAT CC Asp Ala 315 GCT GGG CCG Ala Gly Pro GTG ACG GCC Val Thr Ala 335 GCC TCG CAT CC Ala Ser His Arg

TAT

Tyr 325 GTG CTG CCT GGG Val Leu Pro Gly CGC TAT CAC Arg Tyr His 330 CTG CCC ACA Leu Gly Thr GTC CTG CCC CTC Val Leu Ala Leu CCC GCC Gly Ala 340 CCC TCA CC Gly Ser Ala

CTG

Leu 345 CAC GTG Asp Val 350 CAG CTG GAA CC Gin Val Glu Ala

OCA

Ala 355 CCT GCC CCC CTG Pro Ala Ala Leu

GAG

Glu 360 CTC CTC TGC CCC Leu Val Cys Pro TCG CTC CAG ACT Ser Val Gin Ser CAC GAG Asp Giu 370 AGC CTC GAC Ser Leu Asp

CTC

Leu 375 ACC ATC CAC AAC Ser Ile Gin Asn

CC

Arg 380 986 1034 1082 1130 1178 1226 1274 1322 1370 1418 1466 1514 1562 1610 GGT GGT TCA GCC Gly Cly Ser Gly

CTG

Leu 385 GAG CCC GCC TAC Ciu Ala Ala Tyr

AC

Ser 390 ATC GTG CCC CTG Ile Val Ala Leu CCC GAG Cly Ciu 395 o 9* GAG CCC CC Glu Pro Ala TTC CCT GCC Phe Pro Gly 415 CC CTG CAC CCC Ala Val His Pro

CTC

Leu 405 TGC CCC TCG CAC Cys Pro Ser Asp ACC GAG ATC Thr Giu Ile 410 AAG C CC Lys Ala Ala AAC CCC CAC TGC Asn Cly His Cys

TAC

420 CCC CTG GTG GTG Arg Leu Val Val

GAG

Glu 425 TGC CTG Trp Leu 430 CAG CCAG GAG Gin Ala Gin Glu TGT GAG GCC TCG Cys Gin Ala Trp

CC

Ala 440 CCC GCC CCC CTG Gly Ala Ala Leu

GCA

Ala 445 ATC GTG GAC ACT CCC CCC GTG GAG CC Met Val Asp Ser.Pro Ala Val Gin Arg

TTC

Phe 455 CTG GTC TCC Leu Val Ser ACC ACC TGC CTA Thr Arg Cys Leu CGG GTC Arg Val 460 CCC CTC Gly Val 475

GAC

Asp 465 GTG TCC ATC GC Vai Trp Ile Gly

TTC

Phe 470 TCG ACT GTG CAG Ser Thr Val Gin GAG GTG GC Ciu Val Gly CCA CC CCGCGAG CCC GAG Pro Ala Pro Gin Giy Clu 480 485 CCC TTC ACC CTG Ala Phe Ser Leu GAG AGC TGC Glu Ser Cys 490 CAG AAC TGG CTG Gin Asn Trp Leu 495 CCC GGG GAG CCA Pro Gly Glu Pro 500 CAC CCA GCC ACA GCC GAG CAC TGC His Pro Ala Thr Ala Glu His Cys 505 GTC CGG Val Arg 510 CCG CAC Pro His 525 CTC GGG CCC ACC Leu Gly Pro Thr

GGG

Gly 515 TGG TGT AAC ACC Trp Cys Asn Thr GAC CTG TGC TCA GCG Asp Leu Cys Ser Ala 520 AGC TAG GTC Ser Tyr Val

TG

Cys 530 GAG CTG GAG CCC Glu Leu Gin Pro

GGA

Gly 535 GOC GGA GTG GAG Gly Pro Val Gin

GAT

Asp GCC GAG AAG CTC Ala Glu Asn Leu

CTC

Leu 545 OTO GGA GCG CCC Val Gly Ala Pro

AGT

Ser 550 GOG GAC Gly Asp CTG AGG CCT Leu Thr Pro GTG GAG GTC Val Giu Val 575

CTG

Leu 560 GCA GAG CAG GAC Ala Gin Gin Asp

GGC

Gly 565 CTC TGA GCC Leu Ser Ala CTG GAG GGA CCC Leu Gin Gly Pro 555 CCG CAC GAG CCC Pro His Glu Pro 570 CGT GAA GCC TTC Arg Giu Ala Phe 585 CGG CCC GCC GAG Arg Pro Ala Gin ATG OTA TTC CG Met Val Phe Pro CTG CGT CTG AC Leu Arg Leu Ser GTC ACC AGG GCC OAA TTT Leu Thr Thr Ala Giu Phe 590

GG

Gly 595 ACC CAG GAG CTC Thr Gin Giu Leu

CGG

Arg 600 1658 1706 1754 1802 1850 1898 1-946 1994 2042 2090 2138 2186 2234 2282 CTG CGG Leu Arg 605 CTG GAG GTG Leu Gin Val

TAG

Tyr 610 COG CTC CTG AGC Arg Leu Leu Ser ACA GCA CG Thr Ala Gly 615 ACC CCG GAG Thr Pro Glu AAC GC AGC GAG Asn Cly Ser Glu GAG AGG AGG TCC Glu Ser Arg Ser CCG GAC Pro Asp 630 AAC AGG ACC Asn Arg Thr CAG CTG Gin Leu 0CC CCC GG Ala Pro Ala TG TTG CCG Cys Leu Pro 655 ATG CCA GGG Met Pro Gly GGA CC Gly Arg 645 TOG TGC CCT GGA Trp, Cys Pro Gly GCC AAC ATC Ala Asn Ile 650 CCC AAT GGC Ala Asn Oly CTG GAG GCC TCC Leu Asp Ala Ser

TGC

Cys 660 CAC CCC GAG CC His Pro Gin Ala

TG

Cys 665 TG ACG Cys Thr 670 TCA GO CCA GGG Ser Gly Pro Gly CCC GGG CCC CCC Pro Gly Ala Pro

TAT

Tyr 680 GOG CTA TGG AGA Ala Leu Trp Arg TTG CTC TTC TCG Phe Leu Phe Ser

GTT

Val 690 CCC GCG 000 CCC Pro Ala Gly Pro

CCC

Pro 695 GCG GAG TAC TCG Ala Gin Tyr Ser ACC CTC GAG GOC Thr Leu His Gly GAG GAT GTC Gin Asp Val 705 CTC ATG CTC Leu Met Leu 710 CCT GOT GAG CTC Pro Cly Asp Leu OTT GOC Val Gly 715 TTG CAG GAG Leu Gin His

GAG

Asp 720 GCT C CGCT GGG Ala Gly Pro Cly GCC GTC Ala.Leu 725' GTG CAC TG Leu His Cys TCG CCC GCT Ser Pro Ala 730 2330 CCC GGC CAC Pro Gly His 735 CCT GOT CCC CGG GCC CCG TAC CTC TCC GCC Pro Gly Pro Arg Ala Pro Tyr Leu Ser Ala 740 745 AAC 0CC TCG Asn Ala Ser TOO 0CC TGC Trp Ala Cys TCA TGG Ser Trp 750 CTG CCC CAC TTG OCA Leu Pro His Leu Pro 755 0CC CAG CTO GAG Ala Gin Leu Glu

GGC-ACT

Gly Thr 760

CCT

Pro 765 0CC TOT 0CC CTG Ala Cys Ala Leu

CG

Arg 770 CTG CTT OCA 0CC Leu Leu Ala Ala ACO GAA Thr Olu 775 CAG CTC ACC Gin Leu Thr CTO CTG GOC TTO Leu Leu Gly Leu

AGO

Arg 785 CCC AAC CCT OGA Pro Asn Pro Oly

CTO

Leu 790 COG CTG CCT Arg Leu Pro GAO GTC CG Olu Val Arg TOC AGC TTT Cys Ser Phe 815

OCA

Ala 800 GAG OTG GOC AAT Glu Val Gly Asn OTO TCC AGO CAC Val Ser Arg His 000 COC TAT Gly Arg Tyr 795 AAC CTC TCC Asn Leu Ser 810 OTC ATC TAC Val Ile Tyr GAC OTO GTC TCC Asp Val Val Ser

CCA

Pro 820 OTO OCT 000 CTG Val Ala Oly Leu

CG

Airg 825 CCT 0CC Pro Ala 830 CCC COC GAC Pro Arg Asp GOC COC Oly Arg 835 CTC TAC OTO CCC Leu Tyr Val Pro

ACC

Thr 840 AAC GOC TCA 0CC Asn Gly Ser Ala OTO CTC CAG OTO Val Leu Gin Val TCT GOT 0CC AAC Ser Oly Ala Asn 0CC Ala 855 ACO 0CC ACO OCT Thr Ala Thr Ala 2378 2426 2474 2522 2570 2618 2666 2714 2762 2810 2858 2906 2954 3002 3050 TOG CCT 000 C Trp Pro Gly Oly

AGT

Ser 865 GTC AGC 0CC COC Val Ser Ala Arg

TTT

Phe 870 GAG AAT GTC Olu Asn Val CTG OTG 0CC Leu Val' Ala CTG TTC TCA Leu Phe Ser 895 TTC OTO CCC GOC Phe Val Pro Gly CCC TOG GAG ACC Pro Trp Olu Thr TOC CCT 0CC Cys Pro Ala 875 AAC OAT ACC Asn Asp Thr 890 GAG CAC OTO 0Th His Val a. 'a a 4' OTG OTA OCA CTG Val Val Ala Leu TOG CTC AGT GAG Trp Leu Ser Olu

GG

Gly 905 GTO GAC Val Asp 910 OTG OTO OTG GAA Val Val Val Glu

AAC

Asn 915 AGC 0CC AGC COO Ser Ala Ser Arg AAC CTC AOC CTO Asn Leu Ser Leu

CG

Arg 925 OTO ACO GCG GAG Val Thr Ala Glu

GAO

Glu 930 CCC ATC TOT GGC Pro Ile Cys Gly

CTC

Leu 935 COC 0CC ACG CCC Arg Ala Thr Pro

AGC

Ser 940 CCC GAG 0CC COT Pro Olu Ala Arg

OTA

Val 945 CTG CAG GOA GTC Leu Oln Gly Val

CTA

Leu 950 OTO AGG TAC Val Arg Tyr AGC CCC OTO Ser Pro Val 955 AAC GAC AAG Asn Asp Lys 970 OTO GAG 0CC Val Giu Ala TCG GAC ATO GTC Ser Asp Met Val CGO TOO ACC ATC Arg Trp Thr Ile CAG TOO CTG Gin Ser Leu 975 ACC TTC CAG AAC Thi- Phe Gin Asn GTC TTC AAT Val Phe Asn GTC ATT Val Ile 985 TAT CAG AGO Tyr Gin Ser 3098 GCG GCG Ala Ala 990 GTC ACC Val Thr 1005 GTC TTC AAG Val Phe Lys GTG AAC TAO Vai Asn Tyr CTC TCA Leu Ser 995 AAC GTA Asn Vai 1010 CTG AOG GCC TOO Leu Thr Ala Ser ACC GTG GAG CGG Thr Val Giu Arg 1015 AAO- CAC GTG AGO AAO Asn His Val Ser Asn 1000 ATG AAC AGG ATG Met Asn Arg Met

CAG

Gin 1020 GGT CTG CAG GTO Gly Leu Gin Val TOO ACA Ser Thr 1025 GTG CCG GC Val Pro Ala GTG CTG TOO COO AAT Val Leu-Ser Pro Asn 1030 GCC ACG Ala Thr CTA GCA CTG Leu Ala Leu AOG GOG Thr Ala 1040 GGC GTG CTG Gly Val Leu GTG GAC Val Asp 1045 TOG GCC GTG Ser Ala Val GAG GTG GCC Giu Val Ala 1050 TTC CTG TGG ACC Phe Leu Ti-p Thr 1055 TTT GGG GAT Phe Gly Asp GGG GAG Gly Glu 1060 CAG GOC CTC Gin Ala Leu CAC CAG TTC CAG His Gin Phe Gin 1065 OCT CCG TAO Pro Pro Tyr 1070 AAC GAG TOO Asn Glu Ser TTC COG Phe Pro 1075 GTT CCA GAO Val Pro Asp 000 TOG Pro Ser GTG CTG GTG GAG CAC Val Leu Val Giu His 1085 AAT GTC ATG Asn Val Met 1090 CAC ACC TAO GOT GCC His Thi- Tyr Ala Ala 1095 GTG GCC CAG Val Ala Gin OCA GGT GAG Pro Gly Glu 1100 CTG ACG CAG Leu Thi- Gin 3146 3194 3242 3290 3338 3386 3434 3482 3530 3578 3626 36-74 TAC CTC CTG ACC GTG CTG GCA TOT AAT GOC TTC GAG AAC Tyr Leu Leu Thr Val Leu Ala Ser Asn Ala Phe Glu Asn 1105 1110 CAG GTG COT Gln Val Pro GTG AGC Val Ser 1120 GTG CGC GOC TCC CTO Val Arg Ala Ser Leu 1125 CCC TOO GTG Pro Ser Val GCT GTG GGT Ala Val Gly *3 p

Q

GTG AGT GAC GGC GTC Vai Ser Asp Gly Val 1135 CTG GTG GOC GGC CGG CCC Leu Val Ala Gly Arg Pro 1140 GTC ACC TTO TAC CCG Val Thi- Phe Tyr Pro 1145 AOG TGG GAC TTO GGG Thi- Trp Asp Phe Gly 1160 CAC CCG CTG His Pro Leu 1150 COO TCG OCT Pro Ser Pro GGG GGT Gly Gly 1155 GTT CTT TAO Val Leu Tyr GAO GGC Asp Gly 1165 TOO COT GTC Ser Pro Val OTG ACC Leu Thr 1170 CAG AGO CAG Gin Ser Gin CCG GCT Pro Ala 1175 TAT GCC TOG AGG GOC ACC TAO Tyr Ala Ser Arg Gly Thr Tyr 1185 GTG AGO GGT CG GCG GOC CAG Val Ser Gly Ala Ala Ala Gin 1200 CAC GTG OGO OTG GAG His Val Arg Leu Glu 1190 GOG GAT GTG CGC GTC Ala Asp Val Arg Val 1205 GCC AAO CAC ACC Ala Asn His Thr 1180 GTC AAC AAC ACG Val Asn Asn Thr 1195 TTT GAG GAG CTO Phe Glu Glu Leu 1210 3722 3770 CGC GGA CTC AGC GTG Arg Gly Leu Ser Val 1215 GTG GTG GTC AGC GCC Val Val Val Ser Ala 1230 TTC GAC ATG GGG GAC Phe Asp Met Gly Asp 1245 GAC ATG AGC CTG GCC Asp Met Ser Leu Ala 1220 GCG GTG CAG ACG GGC Ala Val Gin Thr Gly 1235 GTG GAG CAG GGC GCC CCC Val Ciu Gin Gly Ala Pro 1225 GAC AAC- ATC ACG TGG ACC Asp Asn Ile Thr Trp Thr 1240 GGC ACC Gly Thr 1250 GTG CTG TCG Val Leu Ser CCC CCG Gly Pro 1255 GAG GCA ACA Giu Ala Thr

GTC

Val 1260 3818 3866 3914 3962 4010 4058 GAG CAT GTG TAC Glu His Val Tyr CTG CGG. OCA Leu Arg Ala 1265 CAG AAC TGC ACA Cln Asn Cys Thr 1270 CTG ACC CTG Val Thr Val GCT CC Gly Ala 1275 GCC ACC CCC Ala Ser Pro GCC GGC Ala Gly 1280 CAC CTG CCC CGG AGC CTG His Leu Ala Arg Ser Leu 1285 CAC GTC CTG GTC TTC His Val Leu Val Phe 1290 GTC CTG GAG GTG Val Leu Clu Val 1295 CTG CGC GTT Leu Axg Val CAA CCC GCC Clu Pro Ala 1300 GCC TGC ATC CCC ACG CAC Ala Cys Ile Pro Thr Gin 1305 CCT GAC GCG Pro Asp Ala 1310 CCC CTC ACG Arg Leu Thr GCC TAC CTC Ala Tyr Val 1315 ACC GGG AAC CCG Thr Gly Asn Pro 1320 CCC CAC TAC Ala His Tyr CTC TTC Leu Phe 1325 CAC TGC ACC Asp Trp Thr TTC CCC CAT Phe Cly Asp 1330 CCC TCC TCC Gly Ser Ser 133 TTC ACG CCC Phe Thr Arg 1350

AAC

Asn 5 ACC ACC CTG CCC Thr -Thr Val Arg 1340 CCC TCC CCC Cly Cys Pro CTG CC CTG Leu Ala Leu ACG CTG ACA CAC AAC Thr Val Thr His Asn 1345 GTG CTG TCC Val Leu Ser 1360 AGC CCC GTG AAC AG Ser Arg Val Asn Arg 1365 AGC CCC ACC TTC CCC Ser Cly Thr Phe Pro 1355 CC CAT TAC TTC ACC Ala His Tyr Phe Thr 1370 ACC CTG CAG CCA GAG Thr Leu Gin Pro Glu 1385 9 eb 59** z AGC ATC TGC GTG Ser Ile Cys Val 1375 GAG CCA GAG Glu Pro Clu CTC CCC AAC Val Cly Asn.

1380 4106 4154 4202 4250 4298 4346 4394 4442 4490 ACC CAG TTT Arg Gin Phe 1390 GTG CAG CTC Val Gin Leu GCC CAC Gly Asp 1395 GAG CCC TGG Clu Ala Trp CTG CTG Leu Val 1400 GCA TCT CC Ala Cys Ala TCC CCC Trp Pro 1405 CCC TTC CCC TAC CCC TAC ACC TCC GAC TTT CCC ACC GAG CAA Pro Phe Pro Tyr Arg Tyr Thr Trp Asp Phe Cly Thr Clu Clu 1410 1415 1420 CCC CCC CCC ACC CCT CCC ACC GC Ala Ala Pro Thr Arg Ala Arg Cly 1425 CAC CCA CCC TCC TAT CTT GTG ACA Asp Pro Gly Ser Tyr Leu Val Thr 1440 CCT GAG CTG ACO TTC ATC TAC CGA Pro Glu Val Thr Phe le Tyr Arg 1430 1435 GTC ACC CCC TCC AAC AAC ATC TCT Val Thr Ala Ser Asn Asn Ile Ser 1445 -1450 GCT GCC AAT GAC TCA Ala Ala Asn Asp Ser 1455 GCC CTG GTG GAG GTG Ala Leu Val Glu Val 1460 CAG GAG CCC GTG CTG GTC Gin Glu Pro Val Leu Val 1465 ACC AGC ATC Thi- Ser Ilie 1470 AAG GTC AAT Lys Val Asn GOC TCC Gly Ser 1475 CTT GGG CTG GAG -CTG Leu Gly Leu Glu Leu 1480 CAG CAG CCG Gin Gin Pro TAC CTG Tyr Leu 1485 TTC TCT GCT Phe Ser Ala GTG GGC CGT Val Gly Arg 1490 GGG CGC CCC GCC Gly Arg Pro Ala 1495 AGC TAC CTG Ser Tyr Leu

TGG

Ti-p 1500 GAT CTG GGG GAC Asp Leu Gly Asp GGT GGG Gly Gly 1505 TGG CTC GAG Ti-p Leu Giu GGT CCG GAG Gly Pro Glu 1510 GTC ACC CAC GCT Val Thi- His Ala TAC AAC AGC ACA GGT GAC TTC ACC OTT AGG GTG GCC GGC TGG AAT GAG Tyr Asn Ser Thr Gly Asp Phe Thi- Val Arg Val Ala Gly Ti-p Asn Glu 1520 1525 1530 4538 4586 4634 4682 4730 4778 4826 4874 4922 GTG AGC CGC AGC Val Ser Arg Ser 1535 GAG GCC TGG Giu Ala Ti-p CTC AAT Leu Asn 1540 GTG ACG GTG AAG CGG CGC GTG Val Thr Val Lys Arg Arg Val 1545 CGG GGG CTC Arg Gly Leu 1550 GTC GTC AAT Val Val Asn GCA AGC Ala Ser 1555 CGC ACG GTG GTG Arg Thr Val Val 156i GAG GCC GGC AGT Giu Ala Gly Ser 1575 CCC CTG AAT GGG Pro Leu Asn Gly AGC GTG Ser Val 1565 AGC TTC AGC Ser Phe Ser ACG TCG CTG Thi- Ser Leu 1570 GAT GTG CC Asp Val Arg

TAT

1580 TCC TGG GTG CTC Ser Ti-p Val Leu TGT GAC Cys Asp 1585 CGC TGC ACG Arg Cys Thi- CCC ATC Pro Ile 1590 CCT GGG OCT CCT ACC Pro Gly Gly Pro Thi- 1595 ATC TCT TAC Ile Ser Tyr ACC TTC CC Thi- Phe Arg 1600 TCC GTG GGC ACC Ser Val Gly Thr 1605 TTC AAT ATC Phe Asn le ATC GTC ACG Ile Val Thr 1610 a. q a.

I

a GCT GAG AAC GAG GTG Ala Glu Asn Glu Val 1615 GGC TCC GCC CAG Oly Ser Ala Gin 1620 GAC AGC ATC Asp Ser Ile TTC GTC TAT GTC Phe Val Tyr Val 1625 CTG CAG CTC Leu Gin Leu 1630 ATA GAG GGG Ile Giu Gly CTG CAG Leu Gin 1635 OTG GTG GGC Val Val Gly GGT GGC Gly Gly 1640 CCC ACC Pro Thr 1645 AAC CAC ACG Asn His Thi- CGC TAC TTC Arg Ty-r Phe GAT G ACC Asp Gly Thr 1660 4970 5018 5066 5114 5162 5210 GTA CAG Val Gin 1650 CTG CAG GCC GTG GTT AGG Leu Gin Ala Val Val Arg 1655 AAC GTC TCC TAC Asn Val Ser Tyr AGC TG Ser T-p, 1665 ACT GCC TGG Th- Ala Ti-p AGG GAC Arg Asp 1670 AGG GGC CCG Arg Gly Pro GCC CTG Ala Leu 1675 GCC CCC AGC Ala Gly Ser GOC AAA GGC Cly Lys Cly 1680 TTC TCG CTC ACC GTG Phe Ser Leu Thr Val 1685 CTC GAG GCC GGC ACC Leu Giu Ala Gly Thi- 1690 p. TAC CAT GTG CAG CTG CGG GCC ACC AAC ATiG Tyr His Val Gin Leu Arg Ala Thr Asn Met 1695 1700 CTG GGC AGC GCC TGG GCC Leu Gly Ser Ala Trp, Ala 1705 GAC TGC ACC Asp Cys Thr 1710 GCC TCC CCG Ala Ser Pro 1725 ATG GAC TTC Met Asp Phe GTG GAG Val Giu 1715 CCT GTG GGG TGG CTG ATG GTG GCC Pro Val Gly Trp Leu Met Val Ala 1720 AAC CCA GCT GCC Asn Pro Ala Ala 1730 GTC AAC ACA Val Asn Thr AGC GTC ACC Ser Val Thr 1735 CTC AGT GCC Leu Ser Ala 1740 GAG CTG OCT GGT Glu Leu Ala Gly GGC AGT Gly Ser 1745 GGT GTC GTA Gly Val Val TAC ACT TGG Tyr Thr Trp 1750 TCC TTG GAG GAG Ser Leu Glu Glu 1755 5258 5306 5354 5402 5450 5498 5546 GGG CTG AGC Gly Leu Ser TOG GAG Trp Giu 1760 ACC TCC GAG Thr Ser Glu CCA TTT ACC Pro Phe Thr 1765 ACC CAT AGC TTC CCC Thr His Ser Phe Pro 1770 ACA CCC GGC CTG Thr Pro Gly Leu 1775 CAC TTG GTC His Leu Val ACC ATG ACG Thr Met Thr 1780 GCA GGG AAC CCG CTG GGC Ala Gly Asn Pro Leu Gly 1785 TCA GCC AAC Ser Ala Asn 1790 GCC ACC GTG Ala Thr Val GAA GTG GAT Glu Val Asp 1795 GTG CAG GTG CCT GTG AGT GGC Val Gin Val Pro Val Ser Gly 1800 CTC AGC Leu Ser 1805 ATC AGG GCC Ile Arg Ala AGC GAG Ser Glu 1810 CCC GGA GGC Pro Gly Gly AGC TTC Ser Phe 1815 GTG GCG GCC GGG Val Ala Ala Gly 1820 TCC TCT GTG Ser Ser Val TGG TGC TGG Trp Cys Trp CCC TTT TGG Pro Phe Trp 1825 GCT GTG CCC Ala Val Pro 1840 GGG CAG CTG Gly Gin Leu GCC ACG Ala Thr 1830 GGC ACC AAT GTG AGC Gly Thr Asn Val Ser 1835 GGC GGC AGC AGC Gly Gly Ser Ser 1845 ACC ATG GTC TTC Thr Met Val Phe 1855 CCG GAT GCT Pro Asp Ala GGC ACC TTC Gly Thr Phe 1860 AAG COT GGC Lys Arg Gly TCC ATC CGG Ser Ilie Arg 186~ TAC AAC CTC Tyr Asn Leu 1880 CCT CAT GTC Pro His Val 1850 CTC AAT GCC Leu Asn Ala ACO GCG GAG Thr Ala Glu 5594 5642 5690 5738 5786 5834 5882 TCC AAC GCA Ser Asn Ala 1870 GTC AGC TGG Val Ser Trp GTC TCA GCC ACG Val Ser Ala Thr 1875 p GAG CCC Giu Pro 1885 ATC GTG GGC Ile Val Gly CTG GTG Leu Val 1890 CTG TGG GCC Leu Trp, Ala AGC AGC Ser Ser 1895 AAG GTG GTG Lys Val Val

GCG

Ala 1900 CCC GGG CAG CTG GTC CAT TTT CAG Pro Gly Gin Leu Val His Phe Gin 1905 ATC CTG CTG GCT Ile Leu Leu Ala 1910 GCC GGC TCA GCT Ala Gly Ser Ala 1915 GTC ACC TTC Val Thr Phe CGC CTG CAG GTC Arg Leu Gin Val 1920 GGC GGG GCC AAC CCC GAG Gly Giy Ala Asn Pro Giu 1925 GTG CTC CCC Val Leu Pro 1930 5930 GGG CCC GGT TTC TCC CAC AGC TTC CCC CGC GTC GGA GAC GAG GTG GTG Gly Pro Arg Phe Ser His Ser Phe Pro Arg Val Gly Asp His Val Val 1935 .1940 1945 AGC GTG CGG Ser Val Arg 1950 GGC AAA AAC CAC GTG Gly Lys Asn His Val 1955 AGC TGG GCC GAG GCG GAG GTG CGC Ser Trp Ala Gin Ala Gin Val Arg 1960 ATC GTG Ile Val 1965 GTG CTG GAG Val Leu Giu GGC GTG Ala Val 1970 AGT GGG CTG Ser Gly Leu GAG GTG CCC Gin Val Pro 1975 GAG CCT GOC Giu Pro Gly GAG GGC GG Gin Arg-Gly ATC GCC ACG Ile Ala Thr 1985 GGG ACT GAG Gly Thr Glu AGG AAG TTG ACA Arg Asn Phe Thr 1990 AAC TGG TG Asn Gys Cys 1980 GGG CGG GTG Ala Arg Val 1995 GTG GAG AAG Leu Gln Lys 5978 6026 6074 6122 6170 6218 62:66 TGT GG Ser Arg 2000 GTG GGG TAG Val Ala Tyr GCC TG Ala Trp, 2005 TAG TTG TG Tyr Phe Ser GTG GAG GGG GAG Vai Gin Gly Asp 2015 TGG GTG GTG Ser Leu Val ATG CTG TG Ile Leu Ser 2020 GCG CG GAG GTG ACG TAG Cly Arg Asp Val Thr Tyr 2025 AGG GGG GTG Thr Pro Val 2030 GGG GGG GGG Ala Ala Gly CG TTG GAG Leu Leu Clu 2035 ATG GAG GTG G Ile Gin Val Arg 2040 GGG TTG AAG Ala Phe Asn GGG GTG Ala Leu 2045 GG AGT GAG Gly Ser Giu AAG GG AG Asn Arg Thr 2050 GTG OTG GTG GAG Leu Val Leu Glu 2055 GTT GAG GAG Val Gin Asp

CG

Ala 2060 6314 GTG GAG TAT GTG Val Gin Tyr Val GGG GTG Ala Leu 2065 GAG AGG GGG Gin Ser Oly GGG TGG Pro Gys 2070 TTG AGG AAG Phe Thr Asn G TG Arg Ser GGG GAG TTT Ala Gin Phe GAG GGG Giu Aia 2080 GGG AGG AGG Ala Thr Ser GGG AGG GGG Pro Ser Pro 2085

S.

S.

S

S.

5 4 p

*SSS

GAC TGG GAG TTT His Trp Asp Phe 2095 GGG GGT GTG GGG TAG Arg Arg Val Ala Tyr 2090 GAG AGA GAT GAG GGG Asp Thr Asp Clu Pro 2105 GO OAT GGG Gly Asp Oly TGG GGA GGG GAG Ser Pro Giy Gin 2100 AGO GGG GAG A-rg Ala Glu 2110 GAG TGG TAG His Ser Tyr GTG AGG GCT Leu Arg Pro 2115 COG GAG TAG CG Gly Asp Tyr-Arg 2120 OTG GAG OTO Val Gin Val 6362 6410 6458 6506 6554 6602 6650 AAC GCC Asn Ala 2125 TCC AAG GTG OTO AGC Ser Asn Leu Val Ser 2130 TTG TTC GTG Phe Phe Val GCG GAG Ala Gin 2135 GCG AG GTG Ala Thr Val

ACC

Thr OTG GAG GTG GTG GGG TG GG Val Gin Vai Leu Ala Gys Arg 2145 GTG GAG GTG CTO ATO GGG COA Leu Gin Val Leu Met Arg Arg 2160 GAG GGG GAG GTO GA GOTO GTC GTG CG Giu Pro Glu Val Asp Val Val Leu Pro 2150 2155 TCA GAG GG AAG TAG TTG GAG GG GAG Ser Gin Arg Asn Tyr Leu Glu Ala His 2165 2170 p GTT GAC CTG CGC GAC Val Asp Leu Arg Asp 2175 TGC GTC ACC TAC GAG Cys Val Thr Tyr Gin 2180 ACT GAG TAC GGC TGG GAG Thr Glu Tyr Arg Trp Giu 2185 GGG GG. GA GCG CGT GTG Gly Arg Pro Ala Arg Val 2200 GTG TAT GGC Val Tyr Arg 2190 AGC GGG AGG TGC! GAG GGG CG Thr Ala Ser Gys Gin Arg Pro 2195 GCC GTG Ala Leu 2205 CCC GGC GTG Pro Gly Val GAG GTG Asp Val 2210 AGG CCC GCT Ser Arg Pro CGG GTG Arg Leu 2215 GTG GTG CGG Val Leu Pro

GG

Arg 2220 GTG CG GTG GGT Leu Ala Leu Pro GTG GGG Val Gly 2225 GAG TAC TGC His Tyr Gys TTT GTG Phe Val 2230 TTT GTG GTG Phe Val Val TGA TTT Ser Phe 2235 6698 6746 6794 6842 6890 6938 6986 GGG GAG AG Gly Asp Thr GGA CTG ACA Pro Leu Thr 2240 GAG AGG ATG GAG GGC AAT CTG Gin Ser Ile Gin Ala Asn Val 2245 AGG GTG GCG Thr Val Ala 2250 CCC GAG GG CG Pro Giu Arg Leu 2255 TGA GAG AGA GG Ser Asp Thr Arg 2270 GTG GGG ATG Val Pro Ile ATT GAG OCT Ile Giu Oly 2260 GG TCA TAG CG GTG TG Gly Ser Tyr Arg Val1 Trp, 2265 GAG CTG GTG GTG Asp Leu Val Leu 2275 GAT COG AGG Asp Oly Ser GAG TGG TAG GAG CG Oiu Ser Tyr Asp Pro 2280 AAG GTG Asn Leu 2281; GAG GAG GGG Olu Asp Gly GAG GAG Asp Gin 2290 AGG GGG GTG Thr Pro Leu AGT TTG Ser Phe 2295 GAG TOG GGG His Trp Ala

TGT

Cys 2300 GTG GGT TGG AGA Val Ala Ser Thr GAG AGO Gin Arg 2305 GAG GGT GGG Oiu Ala Gly GGG TOT GCG Gly Gys Ala 2310 GTG AAG TTT 000 Leu Asp Phe Gly 2315 CG GG GGG Pro Arg Gly AG AOC Ser Ser 2320 AGG GTG AGC Thr Val Thr ATT GGA Ile Pro 2325 GGG GAG GG Arg Glu Arg CTG GCG, GCT Leu Ala Ala 2330

C.

o 0* a GOC GTG GAG TAG Oly Val Olu Tyr 2335 AGG TTC! AGC Thr Phe Ser C!TG AGG Leu Thr 2340 GTG TGG AAG Val Trp Lys GGG GGC CGG AAG Ala Gly Arg Lys 2345 7034 7082 7130 7178 7226 .7274 7322 GAG GAG OCG Giu Giu Ala 2350 ACG AAC GAG Thr Asn Gin AG CTG Thr Val 2355 CTG ATC COO Leu Ile Arg AGT GC Ser Gly 2360 COG GTO CG Arg Val Pro GTG TAG GAA Val Tyr Olu 2380 ATT OTG Ile Val 2365 TCC TTG GAG Ser Leu Giu TOT GTG Cys Vai 2370 TGG TGG AAO Ser Gys Lys GCA GAG GGG Ala Gin Ala 2375 OTG AGG GGC AGC Val Ser Arg Ser TGG TAG Ser Tyr 2385 GTG TAG TTO Val Tyr Leu GAG GGG CGG Olu Gly Arg 2390 TGG! CTC AAT TGG Cys Leu Asn Gys 239S AGG AGG GGG Ser Ser Oly TGG AAG GGA Ser Lys Arg 2400 COO GGG TGG GGT GGA COT ACG Gly Arg Trp Ala Ala Arg Thr 2405 TTC AGG AAG Phe Ser Asn 2410 7370 a. a AAG ACG CTG GTG CTG LYS Thr Leu Val Leu 2415 GAT GAG ACC ACC ACA TCC ACG GGC AGT GCA GGC Asp Giu Thr Thr Thr Ser Thr Gly Ser Ala Gly 2420 2425 ATG CGA CTG Met Arg Leu 2430 GTG CTG CGG CGG GOC GTG CTG CGG GAC GGC GAG GGA TAC Val Leu Arg Arg Gly Val Leu Arg Asp Gly Glu Gly Tyr 2435 2440 ACC TTC Thr Phe 2445 ACG CTC ACO Thr Leu Thr GTG CTG Val Leu 2450 GOC CGC TCT GGC GAG Gly Arg Ser Gly Giu 2455 GAG GAG GGC TGC Glu Giu Gly Cys, 2460 GCC TCC ATC CGC Ala Ser Ile Arg CTG TCC CCC Leu Ser Pro 2465 AAC CGC COG CCG Asn Arg Pro Pro 2470 CGC CTC TTC Arg Leu Phe CTG GGG GOC TCT TGC Leu Gly Gly Ser Cys 2475 ACC ACC AAG GTG CAC Thr Thr Lys Val His 2490 7418 7466 7514 7562 7610 7658 7706 CCA CTG Pro Leu 2480 GGC OCT GTG Gly Ala Val CAC GCC CTC His Ala Leu 2485 TTC GAA TGC ACG Phe Glu Cys Thr 2495 GGC TGG CAT Gly Trp His GAC GCG GAG Asp Ala Giu 2500 GAT GCT GGC GCC CCG CTG Asp Ala Giy Ala Pro Leu 2505 GTG TAC GC Val Tyr Ala 2510 CTG CTG CTG Leu Leu Leu CGG CGC TGT Arg Arg Cys 2515 CGC CAG GGC CAC TGC GAG GAG Arg Gin Gly His Cys Giu Giu 2520 TTC TGT Phe Cys 2525 GTC TAC AAG Val Tyr Lys GGC AGC Gly Ser 2530 CTC TCC AGC Leu Ser Ser TAC GGA Tyr Gly 2535 GCC GTG CTG Ala Val Leu

CCC

Pro 2540 CCG GGT TTC AGO Pro Gly Phe Arg CCA CAC Pro His 2545 TTC GAG GTG Phe Glu Val GGC CTG Gly Leu 2550 GCC GTG GTG Ala Val Val GTG CAG Val Gin GAC CAG CTG Asp Gln Leu GGA GCC Gly Ala 2560 GCT OTG GTC Ala Val Val GCC CTC Ala Leu 2565 AAC AGG TCT Asn Arg Ser TTO GCC ATC Leu Ala Ile ACC CTC CCA GAG Thr Leu Pro Giu 2575 CCC AAC GGC Pro Asn Gly AGC GCA ACG Ser Ala Thr 2580 GGO CTC ACA GTC TGG CTG Gly Leu Thr Val Trp Leu 2585 7754 7802 7850 7898 7946 7994 8042 8090 CAC GGG CTC His Gly Leu 2590 ACC GCT AGT Thr Ala Ser GTG CTC CCA GGG Val Leu Pro Gly 2595 CTO CTG CGG Leu Leu Arg 2600 CAG GCC GAT Gin Ala Asp CCC CAG Pro Gin 2605 CAC GTC ATC His Val Ile GAG TAC Giu Tyr 2610 TOG TTO; CCC CTG GTC Ser Leu Ala Leu Val 2615 GTG GCG GCA GAG CCC Val Ala Ala Giu Pro 2630 ACC GTO CTG Thr Val Leu

AAC

Asn 2620 GAG TAC GAG Oiu Tyr Giu CAG CAC CGA Gin His Arg CGG GCC CTG GAC Arg Ala Leu Asp 2625 GCC CAG ATA COO Ala Gin Ile Arg 2640 AAG CAC GAG CGG Lys His Oiu Arg 2635

AAO

Lys AAC ATC Asn Ile 2645 AOG GAG ACT Thr Giu Thr CTG GTG TCC Leu Val Ser 2650 I. CTG AGG GTC CAC Leu Arg Val His 2655 ACT GTG GAT GAC ATC Thr Val Asp Asp Ile 2660 CAG CAG ATC GCT OCT GCG CTG Gin Gin Ile Ala Ala Ala Leu 2665 GCC CAG TGC Ala Gin Cys 2670 ATG GGG CCC Met Giy Pro AGC AGO Ser Arg 2675 GAG CTC GTA TGC CGC Glu Leu Val Cys Arg 2680 TCG TGC CTG Ser Cys Leu AAG CAG Lys Gin 2685 ACG CTG CAC Thr Leu His AAG CTG Lys Leu 2690 GAG GCC ATG Giu Ala Met ATG CTC Met Leu 2695 ATC CTG CAG Ile Leu Gin

OCA

Ala 2700 GAG ACC ACC OCG Glu Thr Thr Ala GGC ACC Oly Thr 2705 OTG ACG CCC Val Thr Pro ACC 0CC Thr Ala 2710 ATC GGA GAC Ile Gly Asp AGC ATC Ser Ile 2715 CTC AAC ATC Leu Asn Ile GCA CCA CAG Ala Pro Gin 2735 ACA GGA Thr Gly 2720 GAC CTC ATC Asp Leu Ile

CAC

His 2725 CTG 0CC AGC Leu Ala Ser GAG TCA CCA Giu Ser Pro TCG GAC GTO CG Ser Asp Val Arg 2730 TCT COO ATO OTG Ser Arg Met Val 2745 CCC TCA GAO CTO Pro Ser 0Th Leu OGA 0CC Oly Ala 2740 OCO TCC( Ala Ser G 2750 COC TCC C Arg Ser A 2765 AG 0CC TAC AAC ln Ala Tyr Asn CTG ACC Leu Thr 2755 TCT 0CC CTC ATO CGC Ser Ala Leu Met Arg 2760 ATC CTC ATO Ile Leu Met GC OTO CTC ~rg Val Leu AAC GAG Asn Glu 2770 GAO CCC CTO Giu Pro Leu ACO CTG Thr Leu 2775 OCG 0CC GAO Ala Oly Giu

GAG

Oiu 2780 8138 8186 8234 8282 8330 8378 8426 8474 8522 8570 8618 8666 8714 8762 8810 ATC GTO 0CC CAG Ile Val Ala Gin 0CC AAG Oly Lys 2785 COC TCO GAC Arg Ser Asp CCO COO Pro Arg 2790 AOC CTG CTG Ser Leu Leu TOO TAT Cys Tyr 2795 GGC GGC 0CC Gly Oly Ala CCA 000 Pro Gly 2800 CCT 0CC TGC Pro Gly Cys CAC TTC His Phe 2805 TCC ATC CCC Ser Ile Pro GAG OCT TTC Giu Ala Phe 2810

S

AGC 000 0CC CTG Ser Oly Ala Leu 2815 0CC AAC CTC Ala Asn Leu AGT GAC Ser Asp 2820 OTO OTG CAG Val Val Gin CTC ATC TTT CTG Leu Ile Phe Leu 2825 OTO GAC TCC Val Asp Ser 2830 AAT CCC TTT Asn Pro Phe CCC TTT Pro Phe 2835 GGC TAT ATC Oly Tyr Ile AGC AAC Ser Asn 2840 TAC ACC OTC Tyr Thr Val TCC ACC Ser Thr 2845 AAG OTO 0CC Lys Val Ala TCG, ATO Ser Met 2850 OCA TTC CAG Ala Phe Gin ACA CAG Thr Gin 2855 GCC 0CC 0CC Ala Oly Ala

CAG

Gin 2860 ATC CCC ATC GAG Ile Pro Ile Giu CGG CTO 0CC Arg Leu Ala 2865 TCA GAG COC 0CC ATC Ser Glu Arg Ala Ile 2870 ACC OTG AAG OTO Thr Vai Lys Val 2875 CCC AAC AAC Pro Asn Asn TCG GAC TGG 0CT 0CC CGO 0CC CAC CGC AGC TCC 0CC AAC Ser Asp Trp Ala Ala Arg Oly His Arg Ser Ser Ala Asn 2880 2885 2890 TCC GCC AAC TCC GTT GTG GTC CAG CCC CAG GCC TCC GTC GGT GCT GTG Ser Ala Asn Ser Val Val Val Gin Pro Gin Ala Ser Val Gly Ala Val 2895 2900 2905 8858 8906 GTC ACC CTG GAC Val Thr Leu Asp 2910 A-AC TAT ACG CTG Asn Tyr Thr Leu 2925 AGC A.GC A-AC CCT GCG GCC Ser Ser Asn Pro Ala Ala 2915 CTG GAC GGC CAC TA.C CTG Leu Asp Gly His Tyr Leu 2930 GOG CTG CAT CTG CAG CTC Gly Leu His .Leu Gin Leu 2920 TCT GAG GAA Ser Giu Glu 2935 CCT GAG CCC Pro Oiu Pro 2940 TAC CTG GCA GTC TP.C CTA C-AC Tyr Leu Ala Val Tyr Leu His 2945 TGC TCG GCT AGC AGG AGO ATC Cys Ser Ala Ser Arg Arg Ile 2960 TCG GAG CCC CGG Ser Glu Pro Arg 2950 CGC CCA GAG TCA Arg Pro Glu Ser 2965 CCC AAT GAG C-AC AAC Pro Asn Glu His .'Asn 2955 CTC C-AG OCT GCT GAC Leu Gin Gly Ala Asp 2970 C-AC CGO CCC TAC ACC His Arg Pro Tyr Thr 2975 GGG AGT TAC CAT CTG Gly Ser Tyr His Leu 2990 TTC TTC ATT TCC Phe Phe Ile Ser 2980 AAC CTC TCC AGC Asn Leu Ser Ser 2995 CTG TAC ACG TCC Leu Tyr Thr Ser 3010 CCG GGG AGC AGA Pro Gly Ser Arg 298 C-AC TTC CGC TGG His Phe Arg Trp, 3000 GAC CC-A GCG Asp.Pro Ala TCG GCG CTG Ser Ala Leu 8954 9002 9050 9,098 9-146 9194 9242 C-AG GTG Gin Val 3005 TCC GTO GGC Ser Val Gly CTG TGC C-AG Leu Cys Gin TAC TTC AGC Tyr Phe Ser

GAG

Glu GAG 0-AC A~TG GTG Glu -Asp Met Val TGG CGG Trp Arg 3025 ACA GAG GO Thr Giu Oly CTG. CTG CCC Leu Leu Pro 3030 CTG GAG GAG ACC Leu Olu Glu Thr TCG CCC CGC Ser Pro Arg CA.G GCC Gin Ala 3040 OTC TGC CTC Val Cys Leu ACC CGC C-AC Thr Arg His 3045 CTC ACC 0CC TTC GOC Leu Thr Ala Phe Oly 0CC AGC CTC TTC GTG -Ala Ser'Leu Phe Val 3055 CCC CC-A AGC C-AT GTC Pro Pro Ser His Val 3060 CGC TTT OTO TTT CCT GAG Arg Phe Val Phe Pro Oiu 3065 CCG -AC-A GCG Pro Thr Ala 3070 CTG OTG ACC Leu VAl Thr 3085 OAT GTA AAC Asp Val Asn TAC ATC Tyr Ile 3075 OTC ATO CTG Val Met Leu AC-A TOT Thr Cys 3080 OCT GTO TGC Ala Val Cys 9290 9338 9386 9434 9482 9530 TAC ATG GTC P.TG Tyr Met Val Met 3090 0CC 0CC ATC Ala Ala Ile CTG C-AC Leu His 3095 AAG CTG 0-AC LYS Leu Asp

CAG

Gin 3100 TTG 0-AT 0CC AGC Leu Asp Ala Ser COO GOC Arg Gly 3105 COC 0CC ATC Arg Ala Ile CCT TTC TGT Pro Phe Cys 3110 COC TTC AAG Arg Phe Lys TAC GAG P.TC Tyr Giu Ile 3120 000 C-AG CGO GGC Gly Gin Arg Oly 3115 GOC COO GGC TCA Gly Arg Oly Ser 3130 CTC OTC AAG ACA GGC TGO Leu Val Lys Thr Gly Trp 3125 GGT ACC ACG 0CC CAC GTG GOC ATC ATG CTG TAT GG GT0 GAC AGC CG Oly Thr Thr Ala His Val Gly Ile Met Leu Tyr Gly Val Asp Ser Arg 3135 3140 3145 AGC GGC CAC COG CAC Ser Gly His Arg His 3150 CTG GAC GGC Leu Asp Gly 3155 GAC AGA 0CC TTC CAC CGC AAC AGC Asp Arg Ala Phe His Arg Asri Ser 3160 CTG GAC Leu Asp 3165 ATC TTC CGG Ile Phe Arg ATC GCC ACC Ile Ala Thr 3170 CCG CAC AGC CTG Pro His Ser Leu 3175 AAG ATC CGA GTG Lys Ile Arg Val TOG CAC GAC Trp His Asp 3185 AAC AAA GOG CTC AGC Asn Lys Gly Leu Ser 3190 GGT AGC GTG TG Gly Ser Val Trp 3180 CCT 0CC TOG TTC Pro Ala Trp Phe 3195 CGC AGC GCC TTC Arg Ser Ala Phe 9578 9626 9674 9722 9770 9818 9866 9914 CTG CAG CAC Leu Gin His GTC ATC GTC Val Ile VJal 3200 AGO GAC CTG CAG ACO OCA Arg Asp Leu Gin Thr Ala 3205 TTC CTG GTC AAT GAC Phe Leu Val Asn Asp 3215 TOG CTT TCG OTO GAG Trp Leu Ser Val Giu 3220 ACG GAG 0CC AAC 000 0c Thr Glu Ala Asn Gly Gly 3225 OTO OTO GAG Leu Val Giu 3230 AAG GAG GTO Lys Giu Val CTG CC Leu Ala 3235 GCG AGC GAC OCA 0CC Ala Ser Asp Ala Ala 3240 CTT TTG COC Leu Leu Arg TTC CG Phe Arg 3245 COC CTG CTG Arg Leu Leu GTG OCT Vai Ala 3250 GAG CTG CAG Giu Leu Gin CGT GOC Arg Oly 3255 TTC TTT GAC Phe Phe Asp

AAG

Lys 3260 CAC ATC TGG CTC His Ile Trp Leu TCC ATA Ser Ile 3265 TOG GAC COO Ti-p Asp Arg CCG CCT COT Pro Pro Arg 3270 AGC COT TTC ACT Ser Arg Phe Thr COC ATC CAG Arg Ile Gin AGO 0CC ACC Arg Ala Thr 3280 TOC TOC OTT CTC CTC Cys Cys Val Leu Leu 3285 ATC TGC CTC TTC CTG Ilie Cys Leu Phe Leu 3290 66 6

S

66 66 666* 6566..

6 6*66 6666 66 6 66* 6 GOC 0CC AAC 0CC Gly Ala Asn Ala 3295 GTO TOO TAC Val Trp Tyr 000 OCT Gly Ala 3300 GTT GOC OAC Val Gly Asp TCT 0CC TAC AOC Ser Ala Tyr Ser 3305 ACO 000 CAT Thr Gly His 3310 GTG TCC AGO Val Ser Arg CTG AGC Leu Ser 3315 CCG CTO AGC Pro Leu Ser OTC GAC Val Asp 3320 ACA GTC OCT Thr Val Ala 9962 10010 10058 10106 10154 10202 10250 OTT GGC Val Gly 3325 CTG GTG TCC Leu Vai Ser AOC OTO Ser Val 3330 OTT GTC TAT Val Val Tyr CCC CTC Pro Vai 3335 TAC CTG 0CC Tyr Leu Ala

ATC

le 3340 CTT TTT CTC TTC COG ATO TCC Leu Phe Leu Phe Arg Met Ser 3345 CCC ACA CCT 0CC 000 CAG CAG Pro Thr Pro Ala Oly Gin Gin 3360 COG AGC AAG GTO OCT Arg Ser Lys Val Ala 3350 OTO CTG GAC ATC GAC Vai Leu Asp Ile Asp 3365 COG AGC CCG AGC Gly Ser Pro Ser 3355 AGC TOC CTG GAC Ser Cys Leu Asp 3370 TCG TCC GTG CTG Ser Ser Val Leu 3375 GAC AGC TCC TTC CTC ACG TTC TCA GGC CTC CAC GCT Asp Ser Ser Phe Leu Thr Phe Ser Gly Leu His Ala 3380 3385 10298 GAG GCC TTT GTT Giu Ala Phe Val 3390 AAG AGT CTG GTG LYS Ser Leu Val 3405 GAC CTG CTC AGT Asp Leu Leu Ser GGA CAG ATG AAG Gly Gin Met Lys 3395 TGC TGG CCC TCC Cys Trp Pro Ser 3410 AGT GAC TTG TTT- CTG GAT GAT TCT Ser Asp Leu Phe Leu Asp Asp Ser 3400 GGC GAG GGA ACG CTC AGT TGG CCC Gly Glu Gly Thr Leu Ser Trp Pro 3415 3420 GAC CCG A~sp Pro 3425 TCC ATT GTG GGT AGC AAT CTG Ser Ie Val Gly Ser Asn Leu 3430 OCA CGG GGC CAG GCG GGC Ala Arg Gly Gin Ala Gly 3440 CAT GOG CTG GGC His Gly Leu Gly 3445 CCA GAG GAG Pro Glu Giu CGG CAG CTG Arg Gin Leu 3435 GAC GGC TTC Asp Gly Phe TCC CTG GCC AGC Ser Leu Ala Ser 3455 CCC TAC TCG Pro Tyr Ser CCT GCC Pro Ala 3460 AAA TCC TTC LYS Ser Phe TCA GCA TCA GAT Ser Ala Ser Asp GAA GAC CTG Giu Asp Leu 3470 ATC CAG CAG Ile Gin Gin GTC CTT Val Leu 3475 GCC GAG GGG Ala Glu Gly GTC AGC AGC CCA GCC Val Ser Ser Pro Ala CCT ACC Pro Thr 3485 CAA GAC ACC Gin Asp Thr CAC ATG GAA His Met Giu 3490 ACG GAC CTG CTC AGC Thr Asp Leu Leu Ser 3495 ACG CTG GCG CTG CAG Thr Leu Ala Leu Gin 3510 AGC ACT CCT GGG Ser Thr Pro Gly GAG AAG ACA GAG Glu Lys Thr Giu 3505 AGC CTG TCC Ser Leu Ser 3500 AGG CTG GGG Arg Leu Gly 3515 CCC CAG GCA Pro Gin Ala 10346 10394 10442 10490 10538 105 86 10634 10682 10730 10778 10826 10874 10922 10970 GAG CTG GGG Glu Leu Gly CCA CCC AGC Pro Pro Ser 3520 CCA GGC CTG AAC TGG Pro Gly Leu Asn Trp 3525 GAA CAG Glu Gin 3530 GCG AGG CTG TCC AGG Ala Arg Leu Ser Arg 3535 ACA GGA CTG GTG Thr Giy Leu Val 3540 GAG GGT CTG CGG AAG CGC CTG Glu Gly Leu Arg Lys Arg Leu 3545 CTG CCG GCC Leu Pro Ala 3550 TGG TGT GCC Trp Cys Ala TCC CTG Ser Leu 3555 GCC CAC GGG Ala His Gly CTC AGC Leu Ser CTG CTC CTG Leu Leu Leu GTG GCT Val Ala 3565 GTG GCT GTG Val Ala Val OCT GTC Ala Val 3570 TCA GGG TGG Ser Gly Trp, GTG GGT GCG AGC TTC Val Gly Ala Ser Phe

CCC

Pro CCG GGC GTG AGT GTT GCG TGG CTC Pro Gly Val Ser Val Ala Trp Leu 3585 GCC TCA TTC CTC GGC TGG GAG CCA Ala Ser Phe Leu Gly Trp Glu Pro 3600 CTG TCC AGC AGC GCC Leu Ser Ser Ser Ala 3590 CTG AAG GTC TTG CTG Leu Lys Val Leu Leu 3605 AGC TTC CTG Ser Phe Leu 3595 GAA GCC CTG Glu Ala Leu 3610 TAC TTC TCA CTG Tyr Phe Ser Leu 3615 GTG GCC AAG CGG CTG CAC CCG GAT GAA GAT GAC ACC Val Ala Lys Arg Leu His Pro Asp Glu Asp Asp Thr 3620 3625 11018 CTG GTA GAG AGC CCG GCT GTG ACC Leu Val Giu Ser Pro Ala Val Thi 3630 3635 GTA CGG CCA CCC CAC GGC TTT GCA Val. Arg Pro Pro His Gly Phe Ala 3645 3650 CGC AAG GTC AAG AGG CTA CAT GGC Arg Lys Val Lys Arg Leu His Gly 3665 ATG CTT TTT CTG CTG GTG ACC CTG Met Leu Phe Leu Leu Val Thr Leu 3680 CCT GTG AGC GCA Pro Val Ser Ala 3641 CTC TTC CTG GCC Leu Phe Leu Ala 3655 ATG CTG CGG AGC Met Leu Arg Ser 3670 CGT GTG CCC CGC Arg Val Pro Arg AAG GAA GAA Lys Giu Glu

GCC

Ala 3660 CTC CTG GTG TAC Leu Leu Val Tyr CTG GCC AGC TAT GGG GAT GCC TCA Leu Ala Ser Tyr Gly Asp Ala Ser 3685 3690 TGC CAT GGG CAC GCC TAC Cys His Gly His Ala Tyr 3695 CGT CTG CAA AGC GCC Arg Leu Gin Ser Ala 3700 ATC AAG CAG GAG CTG le Lys Gin Glu Leu 3705 GAG GAG CTC TGG CCA Glu Glu Leu Trp Pro 3720 CAC AGC CGG His Ser Arg 3710 GCC TTC CTG Ala Phe Leu GCC ATC Ala Ile 3715 ACG CGG TCT Thr Arg Ser TGG ATG Trp Met 3725 GCC CAC GTG Ala His Val CTG CTG CCC Leu Leu Pro 3730 TAC GTC CAC GGG AAC Tyr Val His Gly Asn 3735 CAG TCC AGC Gin Ser Ser S3740 11066 11114 11162 11210 11258 11306 11354 11402 11450 11498 11546 11594 11642 11690 CCA GAG CTG GGG Pro Glu Leu Gly CCC CCA CGG CTG Pro Pro Arg Leu 3745 CGG CAG GTG Arg Gln Val 3750 CGG CTG CAG Arg Leu Gin GAA GCA Glu Ala CTC TAC CCA Leu Tyr Pro GAC CCT Asp Pro 3760 CCC GGC CCC Pro Gly Pro AGG GTC Arg Val 3765 CAC ACG His Thr GGA GGC TTC AGC Gly Gly Phe Ser 3775 ACC AGC GAT Thr Ser Asp TAC GAC Tyr Asp 3780 GTT GGC TGG Val Gly Trp GCG CCG GAT Ala Pro Asp AAT GGC TCG Asn Gly Ser 3790 GGG ACG TGG Gly Thr Trp GCC TAT TCA Ala Tyr Ser 3795 TGG TCC Trp Ser 3805 TGC TCG GCC GCA Cys Ser Ala Ala 3770 GAG AGT CCT CAC Glu Ser ProHis 3785 CTG CTG GGG GCA Leu Leu Gly Ala GGC TAC GTG CAG Gly Tyr Val Gin 3820 CTG CGC TTC CTG Leu Arg Phe Leu 3835 GTG TTC CTG GAG Val Phe Leu Glu 3850 TGG GGC TC Trp Gly Ser TGT GCC GTG Cys Ala Val 3810 GAG CTG GGC CTG AGC CTG GAG GAG Glu Leu Gly Leu Ser Leu Glu Glu 3825 CAG CTG CAC AAC TOG CTG GAC AAC Gin Leu His Asn Trp Leu Asp Asn 3840 TAT GAC AGC GGO Tyr Asp Ser Gly 3815 AGC CGC GAC CGG Ser Arg Asp Arg 3830 AGO AGC CGC GCT Arg Ser Arg Ala 3845 CTC ACG CGC TAC Leu Thr Arg Tyr 3855 CGC CTC GAG TTC Arg Leu Giu Phe 3870 AGC CCG GCC GTG GGG CTG CAC GCC GCC GTC ACG CTG Ser Pro Ala Val Gly Leu Hius Ala Ala Val Thr Leu 3860 3865 CCG GCG CCC GGC Pro Ala Ala Oly 3875 CGC CCC CTG CC GCC CTC AGC GTC Arg Ala Leu Ala Ala Leu Ser Val 3880 CGC CCC Arg Pro 3885 TTT GCG CTC CCC CC Phe Ala Leu Arg Arg 3890 CTC AGC GCG Leu Ser Ala CCC CTC Gly Leu 3895 TCO CTO CCT Ser Leu Pro

CTG

Leu 3900 CTC ACC TCG CTG Leu Thr Ser Val TGC CTG Cys Leu 3905 CTC CTG TTC Leu Leu Phe GCC GTO Ala Val 3910 CAC TTC CC His Phe Ala OTO GCC Val Ala GAG GCC CGT ACT TOO CAC AGO GAA Glu Ala Arg Thr Trp His Arg Giu 3920 COG CCC TG Gly Arg Trp 3925 OCA GCC TGG GCG Gly Ala Trp Ala 3935 CGG TOG CTG CTG GTG GCG CTG Arg Trp Leu Leu Val Ala Leu 3940 CCC OTO CTO COG CTC Arg Val Leu Arg Leu 3930 ACC CC CCC ACO GCA Thr Ala Ala Thr Ala 3945 CCC CAC TOG ACC COT Arg Gin Trp Thr Arg CTG OTA CC Leu Val Arg 3950 CTC CCC CAC Leu Ala Gin CTO COT Leu Gly 3955 CCC OCT GAC Ala Ala Asp TTC ACT AC Phe Thr Ser 3975 TTC OTO Phe Val 3965 CCC OGC CC Arg Oly Arg CCC CCC CC Pro Arg Arg 3970

TTC

Phe GAC CAC OTO Asp Gin Val

C

Ala 11738 11786 11834 11882 11930 11978 1202 6 12074 12122 12170 12218 12266 12314 12362 12410 CAG CTO ACC TCC Gin Leu Ser Ser OCA CC Ala Ala 3985 COT GCC CTO Arg Cly Leu 0CC CC Ala Ala 3990 TCO CTG CTC Ser Leu Leu TTC CTG Phe Leu CTT TTC CTC Leu Leu Val AAC OCT CC Lys Ala Ala 4000 CAG CAG CTA CC Gin Gin Leu Arg 4005 TTC OTO CC Phe Val Arg CAG TOO TCC Cln Trp Ser p

S.

S.

S *n.

S *S S.

S

SOS.

55 5 5 @5S 55* GTC TTT OGC AAO Val Phe Cly Lys 4015 ACA TTA TOC Thr Leu Cys CCA OCT CTO Arg Ala Leu 4020 CCA GAO CTC CTO 000 CTC Pro Olu Leu Leu Oly Val 4025 ACC TTO OGC Thr Leu Oly 4030 CTO OTO OTO Leu Val Val CTC COO OTA CC Leu Cly Val Ala 4035 TAC GCC CAG Tyr Ala Gin CTC CTC Leu Leu 4045 OTO TCT TCC Val Ser Ser TOT OTO CAC Cys Val Asp 4050 CTG CCC ATC Leu Ala Ile GCC CAC CC Ala Gin Ala TCC CTC TOG AGC OTO Ser Leu Trp Ser Val 4055 CTC TTO OTO Leu Leu Val GAG TCC TG Oiu Ser Trp CTG TOC CCT 000 Leu Cys Pro Cly 4065 CAC CTO TCA CCC His Leu Ser Pro 4080 ACT COO CTC TCT ACC CTG TOT CCT CC Thr Oly Leu Ser Thr Leu Cys Pro Ala 4070 4075 CTO CTO TOT OTO COO CTC TOG OCA CTG Leu Leu Cys Val Gly Leu Trp Ala Leu 4085 4090 S.

S

136 CCC CTG TGC GGC Arg Leu Trp, Cly 4095 TAC GACGCCC TTG Tyr His Ala Leu 4110 GCC CTA CCC CTG GGG Ala Leu Arg Leu Gly 4100 CGT GGA GAG CTC TAC Arg Gly Giu Leu Tyr 4115 GGT GTT ATT CTC CGC TGG CGC Ala Val Ile Leu Arg Trp Arg 4105 CCC CCC GCC TGG GAG CCC CAG Arg Pro Ala Trp Clu Pro Gin 4120 GAG TAG GAG ATG Asp Tyr Ciu Met 4125 GTG GAG TTG TTC GTG Val Glu Leu Phe Leu 4130 CCC ACC CTC CC Arg Arg Leu Arg 4135 CTG TGC ATC Leu Trp Met 4140 GCC CTG AGG AAC GC AAG GAG TTG CC Gly Leu Ser Lys Val Lys Ciu Phe Arg 4145 GAG AAA Hius Lys 4150 GTC CCC TTT Val Arg Phe CAA CCC Giu Gly 4155 ATG GAG CCG GTG Met Clu Pro Leu 416( CAT GTC CCC GCA Asp Val Pro Pro 4175 TOG TCG AC GAG Ser Ser Ser Gin 4190 CCC TGT CCC TGG Pro Ser Arg Ser 0 TGG AGG Ser Arg 4165 CCC TCG AAG Gly Ser Lys GTA TGG CCC Val Ser Pro 4170 12458 12 506 12554 12602 12650 12698 12746 12794 12842 CCC AGG GGT Pro Ser Ala CCC TGG Gly Ser 4180 CAT CCC TG Asp Ala Ser GAG CCC TGG ACC His Pro Ser Thr 4185 GTG GAT CCC CTC Leu Asp Gly Leu 4195 AGG GTG AGC Ser Val Ser CTC CCC CCC GTG CCC Leu Gly Arg Leu Gly 4200 ACA AGG Thr Arg 4205 TCT GAG GCT Cys Glu Pro GAG CCC Glu Pro 4210 TGC CGG GTG Ser Arg Leu CAA CCC GTC Gin Ala Val 4215 TTC GAG CC Phe Glu Ala 4220 CTC CTG ACC GAG Leu Leu Thr Gin TTT GAG Phe Asp 4225 CGA CTG AAG Arg Leu Asn GAG CCC ACA Gin Ala Thr 4230 GAG GAG GTC TAG Giu Asp Val Tyr 4235 CAG GTG GAG Gin Leu Glu GAG GAG CG Gin Gin Leu 4240 GAG AC CTG CAA GC His Ser Leu Gin Gly 4245 CCT CCC CGA TGG CCC Arg Gly Pro Ser Pro 4260 S.

S.

0* 6@ @0SO

S

S

eSe.

0*@S

S.

p osi, S CC CCC CCC GCA TGT TCG Ala Pro Ala Gly Ser Ser 4255 CCCC AGG AG GC CGC Arg Arg Ser Ser Arg 4250 CGC CTG CCC CGA CA Gly. Leu Arg Pro Ala 4265 GTG GAG GTG CCC ACT Val Asp Leu Ala Thr 4280 CTC CCC AGC CCC CTT CCC CCC CC Leu Pro Ser Arg Leu Ala Arg Ala 4270 4275 CCC CCC AGG AGC ACA. CCC CTT CCC Cly Pro Ser Arg Thr Pro Leu Arg 4285 4290 ACT CCC GGT Ser Arg Gly CCC AAG AAG AAG GTG Ala Lys Asri Lys Val 4295 GAG CCC AGG His Pro Ser 12890 12938 12986 13034 13090 13150 13210 13270 AGO ACT TAGTGGTGCT TGGTGCGGC CCTGGGCCGT GGAGTGCAG

TGGAGCGC

Ser Thr TCGTATTAG TTTCGCCG TGCAAGGGG CAGGCCAGG CAGAATCGGT

GGAGGTACCT

TGCCAA

GTGTGCAA

CAGGCAGC CATTCTGT CTGTCTCCCGC TTGAGGAGTT

TAAAGAGGGT

GGAGCACGA CCCTCGGCTG CGCGCTCC TTCCCAAGGA

GAGAGCGTA

TTGGACGGTT TCTAGCCTCT GAGATGCTAA TTTATTTCCC CGAGTCCTCA

GGTACAGCGG-

GCTGTGCCCG GCCCCACCCC CTGGGCAGAT GTCCCCCACT GCTAAGGCTG

CTGGCTTCAG

GGAGGGTTAG CCTGCACCGC CGCCACCCTG CCCCTAAGTT ATTACCTCTC

CAGTTCCTAC

CGTACTCCCT GCACCGTCTC ACTGTGTGTC TCGTGTCAG3T AATTTATATG

GTGTTAAAAT

GTGTATATTT TTGTATGTCA CTATTTTCAC TAGGGCTGAG GGGCCTGCGC

CCAGAGCTGG

CCTCCCCCAJA CACCTGCTGC GCTTGGTAGG TGTGGTGGCG TTATGGCAGC

CCGGCTGCTG

CTTGGATGCG AGCTTGGCCT TGGGCCGGTG CTGGGGGCAC AGCTGTCTGC

CAGGCACTCT

CATCACCCCA GAGGCCTTGT CATCCTCCCT TGCCCCAGGC CAGGTAGCAA

GAGAGCAGCG

CCCAGGCCTG CTGGCATCAG GTCTGGGC. GTAGCAGGAC TAGGCATGTC

AGAGGACCCC

AGGGTGGTTA GAGGAAAAGA CTCCTCCTGG GGGCTGGCTC CCAGGGTGGA

GGAAGGTGAC

TGTGTGTGTG TGTGTGTGCG CGCGCGCACG CGCGAGTGTG CTGTATGGCC

CAGGCAGCCT

CAAGGCCCTC GGAGCTGGCT GTGCCTGCTT CTGTGTACCA CTTCTGTGGG

CATGGCCGCT

TCTAGAGCCT CGACACCCCC CCAACCCCCG CACCAAGCAG ACAAAGTCA

TAAAAGAGCT

GTCTGACTGC

13330 13390 13450 13510 13570 13630 13690 13750 13810 13870 13930 13990 14050 14060 INFORMATION FOR SEQ ID SEQUENCE

CHARACTERISTICS:

LENGTH: 4302 amino acids TYPE: amino acid TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: Met Pro Pro Ala Ala Pro Ala Arg Leu Ala Leu Ala Leu 1 5 10 Leu Trp Leu Gly Ala Leu Ala Gly Gly Pro Gly Arg Gly 20 25 Cys Glu Pro Pro Cys Leu Cys Gly Pro Ala Pro Gly Ala -,35 40 0O 0 S S 00 Oe 05.5

S

S

0

S

OSOe

S.

0 0 005 0

S

lOSS 55 0 @050

S

0055 Gly Leu Gly Cys Gly Pkh Val Asn Cys Ser Gly Arg Gly Leu Arg Thr Leu Gly Pro Ala Leu Arg 50 55 Ile Pro Ala Asp Ala Thr Ala Leu Asp Val Ser His Asn Leu Leu Arg 65 70 75 Ala Leu Asp Val Gly Leu Leu Ala Asn Leu Ser Ala Leu Ala Glu Leu 90 Asp Ile Ser Asn Asn Lys Ile Ser Thr Leu Glu Glu Gly Ile Phe Ala 100 105 110 Asn Leu Phe Asn Leu Ser Glu Ile Asn 115 120 Cys Asp Cys Gly Leu Ala Trp Leu Pro 130 135 Val Arg Val Val Gin Pro Giu Aia Ala 145 150 Leu Ala Gly Gin Pro Leu Leu Gly Ile 165 Gly Giu Giu Tyr Vai Ala Cys Leu Pro 180 185 Ala Ala Val Ser Phe Ser Ala Ala His 195 200 Ala Cys Ser Ala Phe Cys Phe Ser ThrC 210 215 Ser Glu Gin Gly Trp Cys Leu Cys Gly 1 225 230 Ser Phe Ala Cys Leu Ser Leu Cys Ser G 245 2 Pro Thr Cys Arg Gly Pro Thr Leu Leu G 260 265 Pro Gly Ala Thr Leu Val Gly Pro His G 275 280 Leu Ala Ala Phe His Ile Ala Ala Pro L4 290 295 Trp Asp Phe Gly Asp Gly Ser Ala Giu Vz 305 310 Ala Ser His Arg Tyr Val Leu Pro Gly Ar 325 33 Leu Ala Leu Gly Ala Gly Ser Ala Leu Le 340 345 Glu Ala Ala Pro Ala Ala Leu Giu Leu Va 355 360 Ser Asp Giu Ser Leu Asp Leu Ser Ile Gi1 370 375 Leu Giu Ala Ala Tyr Ser Ile Val Ala Lei 385 390 Ala Val His Pro Leu Cys Pro Ser Asp Th 405 41( Gly His Cys Tyr Arg Leu Val Val Giu Ly 420 425

L

A

T

1 31 ii .0

U

n

LI

r) ~eu Ser Gly Asn 125 rg Trp Ala Giu 140 hr Cys Ala Gly 155 ro Leu Leu Asp 70 ~P Asn Ser Ser .u Gly Leu Leu 205 y Gin Gly Leu 1 220 a Ala Gin Pro S 235 Y Pro Pro Pro P 0 i His Val Phe P 2 Pro Leu Ala S 285 Pro Val Thr A: 300 Asp Ala Ala G] 315 Tyr His Val T11 Gly Thr Asp Va 35 Cys Pro Ser Se 365 Asn Arg Gly G1: 380 Gly Giu Glu Pr4 395 Giu Ile Phe Pr Ala Ala Trp, Let 430 Pro Phe Glu Gin Pro Gly Ser Gly 175 Gly Thr 190 31n Pro Ila Ala ;er Ser 1 'ro Pro A 255 ro Ala S er Gly G la Thr A: -y Pro A: 3; ir Ala Va 335 1 Gin Va 0 r Val G1 y' Ser Gi o Ala Ar 40 3Gly AsI 415 i Gin Al Giu Gin Ser 160 Cys Val .Giu eu lia la.

er in rg La n y 0 Gin Giu Gin Cys Gin Ala Trp Ala Giy Ala Ala Leu Ala Met Val Asp 435 440 445 Ser Pro Ala Val Gin Arg Phe Leu Val Ser Arg Val Thr Arg Cys Leu 450 455 460 Asp Val Trp Ile Gly Phe Ser Thr Val Gin Gly Vai Giu Val Giy Pro 465 470 475 480 Ala Pro Gin Giy Giu Ala Phe Ser Leu Giu Ser Cys Gin Asn Trp Leu 485 490 495 Pro Gly Glu Pro 'His Pro Ala Thr Ala Glu His Cys Val Arg Leu Gly 500 505 510 Pro Thr Gly Trp Cys Asn Thr Asp Leu Cys Ser Ala Pro His Ser Tyr 515 520 525 Val Cys Giu Leu Gin Pro Gly Gly Pro Val Gin Asp Ala Giu Asn Leu 530 535 540 Leu Vai Gly Ala Pro Ser Giy Asp Leu Gin Gly Pro Leu Thr Pro Leu 545 550 555 560 Ala Gin Gin Asp Gly Leu Ser Ala Pro His Glu Pro Val Glu Val Met 565 570 575 Val Phe Pro Gly Leu Arg Leu Ser Arg Glu Ala Phe Leu Thr Thr Ala 580 585 590 Giu Phe Giy Thr Gin Giu Leu Arg Arg Pro Ala Gin Leu Arg Leu Gin 595 600 605 Val Tyr Arg Leu Leu Ser Thr Ala Gly Thr Pro Giu Asn Giy Ser Giu 610 615 620 Pro Giu Ser Arg Ser Pro Asp Asn Arg Thr Gin Leu Ala Pro Ala Cys 625 630 635 640 Met Pro Gly Gly Arg Trp Cys Pro Gly Ala Asn Ilie Cys Leu Pro Leu 645 650 655 Asp Ala Ser Cys His Pro Gin Ala Cys Ala Asn Gly Cys Thr Ser Gly 660 665 670 Pro Gly Leu Pro Gly Ala Pro Tyr Ala Leu Trp Arg Glu Phe Leu Phe *675 680 685 Ser Val Pro Ala Giy Pro Pro Ala Gin Tyr Ser Val Thr Leu His Gly :::690 695 700 Gin Asp Val Leu Met Leu Pro Gly Asp Leu Val Gly Leu Gin His Asp 705 710 715 720 Ala Gly Pro Gly Ala Leu Leu His Cys Ser Pro Ala Pro Gly His Pro C725 730 735 Gly Pro Arg Ala Pro Tyr Leu Ser Ala Asn Ala Ser Ser Tip Leu Pro 740 745 750 140 His Leu Pro Ala Gin Leu Glu Gly Thr Trp Ala Cys Pro Ala Cys Ala 755 760 765 Leu Arg Leu Leu Ala Ala Thr Giu Gin Leu Thr Val Leu Leu Gly Leu 770 775 780- Arg Pro Asn Pro Gly Leu Arg Leu Pro Gly Arg Tyr Glu Val Arg Ala 785 790 795 800 Glu Val Gly Asn Gly Val Ser Arg His Asn Leu Ser Cys Ser Phe Asp 805 810 815 Val Val Ser Pro Val Ala Gly Leu Arg Val Ile Tyr Pro Ala Pro Arg 820 825 830 Asp Gly Arg Leu Tyr Val Pro Thr Asn Gly Ser Ala Leu Val Leu Gin 835 840 845 Val Asp Ser Gly Ala Asn Ala Thr Ala Thr Ala Arg Trp Pro Gly Gly 850 855 860 Ser Val Ser Ala Arg Phe Glu Asn Val Cys Pro Ala Leu Val Ala Thr 865 870 875 880 Phe Val Pro Gly Cys Pro Trp Giu Thr Asn Asp Thr Leu Phe Ser Val 885 890 895 Val Ala Leu Pro Trp Leu Ser Giu Gly Giu His Val Val Asp Val Val 900 905 910 Val Giu Asn. Ser Ala Ser Arg Ala Asn Leu Ser Leu Arg Val Thr Ala 915 920 925 Giu Giu Pro Ile Cys Gly Leu Arg Ala Thr Pro Ser Pro Giu Ala Arg 930 935 940 Val Leu Gin Gly Val Leu Val Arg Tyr Ser Pro Val Val Giu Al'a Gly 945 950 955 960 Ser Asp Met Val Phe Arg Trp Thr Ile Asn Asp Lys Gin Ser Leu Thr 965 970 975 Phe Gin Asn Val Val Phe Asn Val Ile Tyr Gin Ser Ala Ala Val Phe 980 985 990 Lys Leu Ser Leu Thr Ala Ser Asn His Val Ser Asn Val Thr Val Asn 995 1000 1005 Tyr Asn Val Thr Val Glu Arg Met Asn Arg Met Gin Gly Leu Gin Val 1010 1015 1020 Ser Thr Val Pro Ala Val Leu Ser Pro Asn Ala Thr Leu Ala Leu Thr 1025 1030 1035 1040 Ala Gly Val Leu Val Asp Ser Ala Val Glu Val Ala Phe Leu Trp Thr 1045 1050 1055 Phe Gly Asp Gly Glu Gin Ala Leu His Gin Phe Gin Pro Pro Tyr Asn 1060 1065 1070

S.

*Q Glu Ser Phe Pro Val Pro Asp Pro Ser Val Ala Gin Val Leu Val Glu 1075 1080 1085 His Asn Val Met His Thr Tyr Ala Ala Pro Gly Glu TPyr Leu Leu Thr 1090 1095 1100 Val Leu Ala Ser Asn Ala Phe Glu Asn Leu Thr Gin Gin Val Pro Val 1105 1110 1115 1120 Ser Val Arg Ala Ser Leu Pro Ser Val Ala Val Gly Val Ser Asp Gly 1125 1130 1135 Val Leu Val Ala Gly Arg Pro Val Thr Phe Tyr Pro His Pro Leu Pro 1140 1145 1150 Ser Pro Gly Gly Val Leo Tyr Thr Trp Asp Phe Gly Asp Gly Ser Pro 1155 1160 1165 Val Leu Thr Gin Ser Gin Pro Ala Ala Asn His Thr Tyr Ala Ser Arg 1170 1175 1180 Gly Thr Tyr His Val Arg Leu Giu Val Asn Asn Thr Val Ser Gly Ala 1185 1190 1195 1200 Ala Ala Gin Ala Asp Val Arg Val Phe Glu Glu Leu Arg Gly Leu Ser 1205 1210 1215 Val Asp Met Ser Leu Ala Val Glu Gin Gly Ala Pro Val Val Val Ser 1220 1225 1230 Ala Ala Val Gin Thr Gly Asp Asn Ile Thr Trp Thr Phe Asp Met Gly 1235 1240 1245 Asp Gly Thr Val Leu Ser Gly Pro Glu Ala Thr Val Giu His Val Tyr 1250 1255 1260 Leo Arg Ala Gin Asn Cys Thr Val Thr Val Gly Ala Ala Ser Pro Ala 1265 1270 1275 1280 Gly His Leo Ala Arg Ser Leo His Val Leu Val Phe Val Leu Glu Val 1285 1290 1295 *Leo Arg Val Glu Pro Ala Ala Cys Ile Pro Thr Gin Pro Asp Ala Arg 1300 1305 1310 Leo Thr Ala Tyr Val Thr Gly Asn Pro Ala His Tyr Leo Phe Asp Trp, 1315 1320 1325 Thr Phe Gly Asp Gly Ser Ser Asn Thr Thr Val Arg Gly Cys Pro Thr :::1330 1335 1340 Val Thr His Asn Phe Thr Arg Ser Gly Thr Phe Pro Leo Ala Leu Val 1345 1350 1355 1360 Leu Ser Ser Arg Val Asn Arg Ala His Tyr Phe Thr Ser Ile Cys Val 1365 1370 1375 Glu Pro Glu Val Gly Asn Val Thr Leu Gin Pro Glu Arg Gin Phe Val *1380 1385 1390 142 Gin Leu Gly Asp Glu Ala Trp Leu Val Ala Cys Ala Trp Pro Pro Phe 1395 .1400 1405 Pro Tyr Arg Tyr Thr Trp Asp Phe Gly Thr Giu Glu Ala Ala Pro Thr 1410 1415 1420 Arg Ala Arg Gly Pro Giu Val Thr Phe Ile Tyr Arg Asp Pro Gly Ser 1425 1430 1435 1440 Tyr Leu Val Thr Val Thr Ala Ser Asn Asn le Ser Ala Ala Asn Asp 1445 1450 1455 Ser Ala Leu Val Giu Val Gin Glu Pro Val Leu Val Thr Ser Ile Lys 1460 1465 1470 Val Asn Gly Ser Leu Giy Leu Glu Leu Gin Gin Pro Tyr Leu Phe Ser 1475 1480 1485 Ala Val Gly Arg Gly Arg Pro Ala Ser Tyr Leu Trp Asp Leu Gly Asp 1490 1495 1500 Gly Gly Trp Leu Glu Gly Pro Glu Val Thr His Ala Tyr Asn Ser Thr 1505 1510 1515 1520 Gly Asp Phe Thr Val Arg Val Ala Gly Trp Asn Giu Val Ser Arg Ser 1525 1530 1535 Glu Ala Trp, Leu Asn Val Thr Val Lys A-rg Arg Val Arg Gly Leu Val 1540 1545 1550 Val Asn Ala Ser Arg Thr Val Val Pro Leu Asn Gly Ser Val Ser Phe 1555 1560 1565 Ser Thr Ser Leu Glu Ala Gly Ser Asp Val Arg Tyr Ser Trp, Val Leu 1570 1575 1580 Cys Asp Axg Cys Thr Pro Ile Pro Gly Gly Pro Thr Ile Ser Tyr Thr 1585 1590 1595 1600 Phe Arg Ser Vai Gly Thr Phe Asn Ile Ile Val Thr Ala Glu Asn Giu 1605 1610 1615 *Val Gly Ser Ala Gln Asp Ser Ile Phe Val Tyr Val Leu Gin Leu Ile **.1620 1625 1630 Giu Gly Leu Gln Val Val Gly Giy Gly Arg Tyr Phe Pro Thr Asn His 1635 1640 1645 *Thr Val Gin Leu Gin Ala Val Vai Arg Asp Gly Thr Asn Val Ser Tyr 1650 1655 1660 Ser Trp Thr Ala Trp Arg Asp Arg Gly Pro Ala Leu Ala Gly Ser Gly 1665 1670 1675 1680 Lys Gly Phe Ser Leu Thr Val Leu Glu Ala Gly Thr Tyr Hi Val Gin 1685 1690 1695 Leu Arg Ala Thr Asn Met Leu Gly Ser Ala Trp Ala Asp Cys Thr Met *1700 1705 1710 Asp Phe Val Giu Pro Val Gly Trp Leu Met Val Ala Ala Ser Pro Asn 171S 1720 1725 Pro Ala Ala Val Asn Thr Ser Val Thr Leu Ser Ala Glu Leu Ala Gly 1730 1735 174'0 Gly Ser Gly Val Val Tyr Thr Trp Ser Leu Glu Glu Gly Leu Ser Trp 1745 1750 1755 1760 Glu Thr Ser Glu Pro Phe Thr Thr His Ser Phe Pro Thr Pro Gly Leu 1765 1770 1775 His Leu Val Thr Met Thr Ala Gly Asn Pro Leu Giy Ser Ala Asn Ala 1780 1785 1790 Thr Val Glu Val Asp Val Gln Val Pro Val Ser Gly Leu Ser Ile Arg 1795 1800 1805 Ala Ser Glu Pro Gly Giy Ser Phe Val Ala Ala Gly Ser Ser Val Pro 1810 1815 1820 Phe Trp Gly Gin Leu Ala Thr Gly Thr Asn Val Ser Trp Cys Trp Ala 1825 1830 1835 1840 Val Pro Gly Gly Ser Ser Lys Arg Gly Pro His Val Thr Met Val Phe 1845 1850 1855 Pro Asp Ala Gly Thr Phe Ser Ile Arg Leu Asi Ala Ser Asn Ala Val 1860 1865 1870 Ser Trp Vai Ser Ala Thr Tyr Asn Leu Thr Ala Giu Giu Pro Ile Val 1875 1880 1885 Gly Leu Val Leu Trp Ala Ser Ser Lys Val Val Ala Pro Gly Gin Leu 1890 1895 1900 Val His Phe Gin Ile Leu Leu Ala Ala Gly Ser Ala Val Thr Phe Arg 1905 1910 1915 1920 Leu Gin Val Gly Gly Ala Asn Pro Glu Val Leu Pro Gly Pro Arg Phe 1925 1930 1935 Ser His Ser Phe Pro Arg Vai Gly Asp His Val Vai Ser Val Arg Gly 1940 1945 1950 Lys Asn His Val Ser Trp Ala Gin Ala Gin Val Arg Ile Val Val Leu 1955 1960 1965 *Glu Ala Val Ser Gly Leu Gin Val Pro Asn Cys Cys Glu Pro Gly Ile 1970 1975 1980 Ala Thr Gly Thr Giu Arg Asn Phe Thr Ala Arg Val Gin Arg Gly Ser 1985 1990 1-995 2000 a Arg Val Ala Tyr Ala Trp Tyr Phe Ser Leu Gin Lys Val Gin Gly Asp 2005 2010 2015 Ser Leu Val Ile Leu Ser Giy Arg Asp Val Thr Tyr Thr Pro Val Ala 2020 2025 2030 144 Ala Gly Leu Leu Glu Ile Gin Val Arg Ala Phe Asn Ala Leu Gly Ser 2035 2040 2045 Glu Asn Arg Thr Leu Val Leu Glu Val Gin Asp Ala Val Gin Tyr Val 2050 2055 206Oi Ala Leu Gin Ser Gly Pro Cys Phe Thr Asn Arg Ser Ala Gin Phe Giu 2065 2070 2075 2080 Ala Ala Thr Ser Pro Ser Pro Arg Arg Val Ala Tyr His Trp Asp Phe 2085 2090 2095 Gly Asp Gly Ser Pro Gly Gin Asp Thr Asp Giu Pro Arg Ala Giu His 2100 2105 2110 Ser Tyr Leu Arg Pro Gly Asp Tyr Arg Val Gin Val Asn Ala Ser Asn 2115 2120 2125 Leu Val Ser Phe Phe Val Ala Gin Ala Thr Val Thr Val Gin Val Leu 2130 2135 2140 Ala Cys Arg Glu Pro Giu Val Asp Val Val Leu Pro Leu Gin Val Leu 2145 2150 2155 2160 Met Arg Arg Ser Gin Arg Asn Tyr Leu Glu Ala His Val Asp Leu Arg 2165 2170 2175 Asp Cys Val Thr Tyr Gin Thr Glu Tyr Arg Trp Glu Val Tyr Arg Thr 2180 2185 2190 Ala Ser Cys Gin Arg Pro Gly Arg Pro Ala Arg Val Ala Leu Pro Gly 2195 2200 2205 Val Asp Val Ser Arg Pro Arg Leu Val Leu Pro Arg Leu Ala Leu Pro 2210 2215 2220 Val Gly His Tyr Cys Phe Val Phe Val Val Ser Phe Gly Asp Thr Pro 2225 2230 2235 2240 Leu Thr Gin Ser Ile Gin Ala Asn Val Thr Val Ala Pro Giu Arg .Leu *2245 2250 2255 Val Pro Ile Ile Glu Gly Gly Ser Tyr Arg Val Trp Ser Asp Thr Arg *2260 2265 2270 Asp Leu Val Leu Asp Gly Ser Giu Ser Tyr Asp Pro Asn Leu Glu Asp 2275 2280 2285 Gly Asp Gin Thr Pro Leu Ser Phe His Trp Ala Cys Val Ala Ser Thr 2290 2295 2300 Gin Arg Glu Ala Gly Gly Cys Ala Leu Asn Phe Gly Pro Arg Gly Ser 2305 2310 2315 2320 0 Ser Thr Val Thr Ile Pro Arg Glu Arg Leu Ala Ala Gly Val Giu Tyr 2325 2330 2335 Thr Phe Ser Leu Thr Val Trp Lys Ala Gly Arg Lys Giu Glu Ala Thr 2340 2345 2350 Asn Gin Thr Val Leu Ile Arg Ser Gly Arg Val Pro Ile Val Ser Leu 2355 2360 2365 Glu Cys Val Ser Cys Lys Ala Gin Ala Val Tyr Giu Val Ser Arg Ser 2370 2375 23-80 Ser Tyr Val Tyr Leu Glu Gly Arg Cys Leu Asn Cys Ser Ser Gly Ser 2385 2390 2395 2400 Lys Arg Gly Arg Trp Ala Ala Arg Thr Phe Ser Asn Lys Thr Leu Val 2405 2410 2415 Leu Asp Giu Thr Thr Thr Ser Thr Gly Ser Ala Gly Met Arg Leu Val 2420 2425 2430 Leu Arg Arg Gly Val Leu Arg Asp Gly Glu Gly Tyr Thr Phe Thr Leu 2435 2440 2445 Thr Val Leu Gly Arg Ser Gly Glu Glu Glu Gly Cys Ala Ser Ile Arg 2450 2455 -2460 Leu Ser Pro Asn Arg Pro Pro Leu Gly Gly Ser Cys Arg Leu Phe Pro 2465 2470 2475 2480 Leu Gly Ala Val His Ala Leu Thr Thr Lys Val His Phe Giu Cys Thr 2485 2490 2495 Gly Trp, His Asp Ala Giu Asp Ala Gly Ala Pro Leu Val Tyr Ala Leu 2500 2505 2510 Leu Leu Arg Arg Cys Arg Gin Gly His Cys Glu Giu Phe Cys Val Tyr 2515 2520 2525 Lys Gly Ser Leu Ser Ser Tyr Gly Ala Val Leu Pro Pro Gly Phe Arg 2530 2535 2540 Pro His Phe Giu Val Gly Leu Ala Val Val Val Gin Asp Gin Leu Gly 2545 2550 2555 2560 Ala Ala Val Val Ala Leu Asn Arg Ser Leu Ala Ile Thr Leu Pro Giu 2565 2570 2575 Pro Asn Gly Ser Ala Thr Gly Leu Thr Val Tx-p Leu His Gly Leu Thr 2580 2585 2590 a, Ala Ser Val Leu Pro Gly Leu Leu Arg Gin Ala Asp Pro Gin His Val 2595 2600 2605 S le Giu Tyr Ser Leu Ala Leu Val Thr Val Leu Asn Giu Tyr Glu Arg *2610 2615 2620 Ala Leu Asp Val Ala Ala Giu Pro Lys His Giu Arg Gin His Arg Ala 2625 2630 2635 2640 Gin Ile Arg Lys Asn Ile Thr 0Th Thr Leu Val Ser Leu Arg Val His 2645 2650 2655 Thr Val Asp Asp Ile Gin Gin Ile Ala Ala Ala Leu Ala Gin Cys Met 2660 2665 2670 a a. 146 Gly Pro Ser Arg Glu Leu Val Cys Arg Ser Cys Leu Lys Gin Thr Leu 2675 2680 2685 His Lys Leu Glu Ala Met Met Leu Ile Leu Gin Ala Giu Thr Thr Ala 2690 2695 2700- Gly Thr Val Thr Pro Thr Ala Ile Gly Asp Ser Ile Leu Asn Ile Thr 2705 2710 .2715 2720 Gly Asp Leu Ile His Leu Ala Ser Ser Asp Val Arg Ala Pro Gin Pro 2725 .2730 2735 Ser Glu Leu Gly Ala Glu Ser Pro Ser Arg Met Val Ala Ser Gin Ala 2740 2745 2750 Tyr Asn Leu Thr Ser Ala Leu Met Arg Ile Leu Met Arg Ser Arg Val 2755 2760 2765 Leu Asn Giu Giu Pro- Leu Thr Leu Ala Gly Glu Giu Ile Val Ala Gin 2770 2775 2780 Gly Lys Arg Ser Asp Pro Arg Ser Leu Leu Cys Tyr Gly Gly Ala Pro 2785 2790 2795 2800 Gly Pro Gly Cys His Phe Ser Ile Pro Glu Ala Phe Ser Gly Ala Leu 2805 2810 2815 Ala Asn Leu Ser Asp Val Val Gin Leu Ile Phe Leu Val Asp Ser Asn 2820 2825 2830 Pro Phe Pro Phe Gly Tyr Ile Ser Asn Tyr Thr Val Ser Thr Lys Val 2835 2840 2845 Ala Ser Met Ala Phe Gin Thr Gin Ala Gly Ala Gin Ile Pro Ile Glu 2850 2855 2860 Arg Leu Ala Ser Glu Arg Ala Ile Thr Val Lys Val Pro Asn Asn Ser 2865 2870 2875 2880 Asp Trp Ala Ala Arg Gly His Arg Ser Ser Ala Asn Ser Ala Asn Ser 2885 2890 2895 Val Val Val Gin Pro Gin Ala Ser Val Gly Ala Val Val Thr Leu Asp 2900 2905 2910 Ser Ser Asn Pro Ala Ala Gly Leu His Leu Gin Leu Asn Tyr Thr Leu *2915 2920 2925 Leu Asp Gly His Tyr Leu Ser Glu Glu Pro Glu Pro Tyr Leu Ala Val 2930 2935 2940 Tyr Leu His Ser Giu Pro Arg Pro Asn Glu His Asn Cys Ser Ala Ser 2945 2950 2955 2960 Arg Arg Ile Arg Pro Glu Ser Leu Gin Gly Ala Asp His Arg Pro Tyr 2965 2970 2975 Thr Phe Phe Ile Ser Pro Gly Ser Arg Asp Pro Ala Gly Ser Tyr His 2980 2985 2990 1I47 Leu Asn Leu Ser Ser His Phe Arg Trp, Ser Ala Leu Gin Val Ser Val 2995 3000 3005 3010 *e y Tr r Leu Cys Gin Tyr Phe Ser Glu Glu Asp met Val 3003015 302'0 Trp Arg Thr Giu Gly Leu Leu Pro Leu Giu Glu Thr Ser Pro Arg Gin 3025 3030 3035 3040 Ala Val Cys Leu Thr Arg His Leu Thr Ala Phe Gly Ala Ser Leu Phe 3045 3050 3055 Val Pro Pro Ser His Val Arg Phe Val Phe Pro Giu Pro Thr Ala Asp 3060 3065 3070 Val Asn Tyr Ile Val Met Leu Thr Cys Ala Val Cys Leu Val Thr Tyr 3075 3080 3085 Met Val Met Ala Ala Ile Leu His Lys Leu Asp Gin Leu*Asp Ala Ser 3090 3095 3100 Axg Gly Arg Ala Ile Pro Phe Cys Gly Gin Arg Gly Arg Phe Lys Tyr 3105 3110 3115 3120 Giu Ile Leu Val Lys Thr Gly Trp Gly Arg Gly Ser Gly Thr Thr Ala 3125 3130 3135 His Val Giy Ile Met Leu Tyr Gly Val Asp Ser Arg Ser Gly His Arg 3140 3145 3150 His Leu Asp Gly Asp Arg Ala Phe His Arg Asn Ser Leu Asp Ile Phe 3155 3160 3165 Arg Ile Ala Thr Pro His Ser Leu Gly Ser 'Val Trp Lys Ile Arg Val 3170 3175 3180 Trp His Asp Asn Lys Gly Leu Ser Pro Ala Trp, Phe Leu Gin His Val 3185 3190 3195 3200 Ile Val Arg Asp Leu Gin Thr Ala Arg Ser Ala Phe Phe Leu Vai Asn 3205 3210 31 Asp Trp Leu Ser Val Glu Thr Glu Ala Asn Gly Gly Leu Val Giu Lys 3220 3225 3230 *Giu Val Leu Ala Ala Ser Asp Ala Ala Leu Leu Arg Phe Arg Arg Leu 3235 3240 3245 Leu Val- Ala Glu Leu Gin Arg Gly Phe Phe Asp 'Lys His Ile Trp Leu 325*0 3255 3260 Ser Ile Trp Asp Arg Pro Pro Arg Ser Arg Phe Thr Arg Ile Gin Arg 3265 3270 3275 3280 0 Ala Thr Cys Cys Val Leu Leu Ile Cys Leu Phe Leu Gly Ala Asn Ala 3285 3290 3295 Val Trp Tyr Gly Ala Val Gly Asp Ser Ala Tyr Ser Thr Gly His Val 3300 3305 3310 0Q Ser Arg Leu Ser Pro Leu Ser Val Asp Thr Val Ala Val Gly Leu Val 3315 3320 3325 Ser Ser Val Val Val Tyr Pro Val Tyr Leu Ala Ile Leu Phe Leu Phe 3330 3335 3340 Arg Met Ser Arg Ser Lys Val Ala Gly Ser Pro Ser Pro Thr Pro Ala 3345 3350 3355 3360 Gly Gin Gin Val Leu Asp Ile Asp Ser Cys Leu Asp Ser Ser Val Leu 3365 3370 3375 Asp Ser Ser Phe Leu Thr Phe Ser Gly Leu His Ala Glu Ala Phe Val 3380 3385 3390 Gly. Gin Met Lys Ser Asp Leu Phe Leu Asp Asp Ser Lys Ser Leu Val .3395 3400 3405 Cys Trp Pro Ser Gly Glu Gly Thr Leu Ser Trp Pro Asp Leu Leu Ser 3410 3415 3420 Asp Pro Ser Ile Val Gly Ser Asn Leu Arg Gin Leu Ala Arg Gly Gin 3425 3430 3435 3440 Ala Giy His Giy Leu Giy Pro Glu Giu Asp Gly Phe Ser Leu Ala Ser 3445 3450 3455 Pro Tyr Ser Pro Ala Lys Ser Phe Ser Ala Ser Asp Giu Asp Leu Ile 3460 3465 3470 Gin Gin Val Leu Ala Glu Gly Val Ser Ser Pro Ala Pro Thr Gin Asp 3475 3480 3485 Thr His Met Giu Thr Asp Leu Leu Ser Ser Leu Ser Ser Thr Pro Gly 3490 3495 3500 Glu Lys Thr Glu Thr Leu Ala Leu Gin Arg Leu Gly Giu Leu Gly Pro 3505 3510 3515 3520 Pro Ser Pro Gly Leu Asn Trp Glu Gin Pro Gin Ala Ala Arg Leu Ser *3525 3530 3535 Arg Thr Gly Leu Val Giu Gly Leu Arg Lys Arg Leu Leu Pro Ala Trp *3540 3545 3550 *Cys Ala Ser Leu Ala His Gly Leu Ser Leu Leu Leu Val Ala Val Ala 3555 3560 3565 Val Ala Val Ser Gly Trp Val Gly Ala Ser Phe Pro Pro Gly Val Ser 3570 3575 3580 Val Ala Trp Leu Leu Ser Ser Ser Ala Ser Phe Leu Ala Ser Phe Leu 3585 3590 3595 3600 Gly Trp Glu Pro Leu Lys Val Leu Leu Giu Ala Leu Tyr Phe Ser Leu 3605 3610 3615 Val Ala Lys Arg Leu His Pro Asp Glu Asp Asp Thr Leu Val Glu Ser 3620 3625 3630 Pro Ala Val Thr Pro Val Ser Ala Arg Val Pro Arg Val Arg Pro Pro 3635 3640 3645 His Gly Phe Ala Leu Phe Leu Ala Lys Glu Glu Ala.Arg Lys Val Lys 3650 3655 3660 Arg Leu His Gly Met Leu Arg Ser Leu Leu Val TPyr Met Leu Phe Leu 3665 3670 3675 3680 Leu Val Thr Leu Leu Ala Ser Tyr Gly Asp Ala Ser Cys His Gly His 3685 3690 3695 Ala T yr Arg Leu Gin Ser Ala Ile Lys Gin Glu Leu His Ser Arg Ala 3700 3705 3710 Phe Leu Ala Ile Thr Arg Ser Giu Glu Leu Trp Pro Trp Met Ala His 3715 3720 3725 Val Leu Leu Pro Tyr Val His Gly Asn Gin Ser Ser Pro Giu Leu Gly 3730 3735 3740 Pro Pro.Arg Leu Arg Gin Val Arg Leu Gin Glu Aia Leu Tyr Pro Asp 3745 3750 3755 3760 Pro Pro Gly Pro Arg Val His Thr Cys Ser Ala Ala Gly Gly Phe Ser 3765 3770 3775 Thr Ser Asp Tyr Asp Val Gly Trp Glu Ser Pro His Asn Gly Ser Gly 3780 3785 3790 Thr Trp, Ala Tyr Ser Ala Pro Asp Leu Leu Gly Ala Trp, Ser Trp Gly 3795 3800 3805 Ser Cys Ala Val Tyr Asp Ser Gly Gly Tyr Val Gin Glu- Leu Gly Leu 3810 3815 3820 Ser Leu Giu Glu Ser Arg Asp Arg Leu Arg Phe Leu Gin Leu His Asn 3825 3830 3835 3840 Trp Leu Asp Asn Arg Ser Arg Ala Val Phe Leu Glu Leu Thr Arg Tyr 3845 3850 3855 Ser Pro Ala Val Giy Leu His Ala Ala Val Thr Leu A-rg Leu Giu Phe *3860 3865 3870 Pro Ala Ala Gly Arg Ala Leu Ala Ala Leu Ser Val Arg Pro Phe Ala 3875 3880 3885 Leu Arg..Arg Leu Ser Ala Gly Leu Ser Leu Pro Leu Leu Thr Ser Val 3890 3895 3900 Cys Leu Leu Leu Phe Ala Val His Phe Ala Val Ala Giu Ala Arg Thr 3905 3910 3915 3920 a Trp His Arg Glu Gly Arg Trp, Arg Val Leu Arg Leu Gly Ala Trp Ala 3925 3930 3935 Arg Trp Leu Leu Val Ala Leu Thr Ala Ala Thr Ala Leu Val Arg Leu *3940 3945 3950 Ala Gin Leu Gly Ala Ala Asp Arg Gin Trp Thr Arg Phe Val Arg Gly 3955 3960 3965 Arg Pro Arg Arg Phe Thr Ser Phe Asp Gin Val Ala Gin Leu Ser Ser 3970 3975 3986 Ala Ala Arg Gly Leu Ala Ala Ser Leu Leu Phe Leu Leu Leu Val Lys 3985 3990 3995 4000 Ala Ala Gin Gin Leu Arg Phe Val Arg Gin Trp.Ser Val Phe Gly Lys 4005 4010 4015 Thr Leu Cys Arg Ala Leu Pro Giu Leu Leu Gly Val Thr Leu Gly Leu 4020 4025 4030 Val Val Leu Gly Val Ala Tyr Ala Gin Leu Ala Ile Leu Leu Val Ser 4035 4040 4045 Ser Cys Val Asp Ser Leu Trp Ser Val Ala Gin Ala Leu Leu Val Leu 4050 4055 4060 Cys Pro Gly Thr Gly Leu Ser Thr Leu Cys Pro Ala Giu Ser Trp His 4065 4070 4075 4080 Leu Ser Pro Leu Leu Cys Val Gly Leu Trp Ala Leu Arg Leu Trp Gly 4085 4090 4095 Ala Leu Arg Leu Gly Ala Val Ile Leu Arg Trp Arg Tyr His Ala Leu 4100 4105 4110 Arg Gly Glu Leu Tyr Arg Pro Ala Trp Glu Pro Gin Asp Tyr Giu Met 4115 4120 4125 Val Giu Leu Phe Leu Arg Arg Leu Arg Leu Trp Met Gly Leu Ser Lys 4130 4135 4140 Val Lys Giu Phe Arg His Lys Val Arg Phe Giu Gly Met Glu Pro Leu 4145 4150 4155 4160 Pro Ser Arg Ser Ser Arg Gly Ser Lys Val Ser Pro Asp Val Pro Pro *4165 4170 4175 Pro Ser Ala Gly Ser Asp Ala Ser His Pro Ser Thr Ser Ser Ser Gin *4180 4185 4190 *Leu Asp Gly Leu Ser Val Ser Leu Gly Arg Leu Gly Thr Arg Cys Glu 4195 4200 4205 Pro.Glu Pro Ser Arg Leu Gin Ala Val Phe Glu Ala Leu Leu Thr Gin 4210 4215 4220 Phe Asp Arg Leu Asn Gin Ala Thr Glu Asp Val Tyr Gin Leu Giu Gin 4225 4230 4235 4240 Gin Leu His Ser Leu Gin Gly Arg Arg Ser Ser Arg Ala Pro Ala Gly 4245 4250 4255 Ser Ser Arg Gly Pro Ser Pro Gly Leu Arg Pro Ala Leu Pro Ser Arg **4260 4265 4270 Leu Ala Arg Ala Ser Arg Gly Val Asp.Leu Ala Thr Gly Pro Ser Arg 4275 4280 4285 Thr Pro Leu Arg Ala Lys Asn Lys Val His Pro Ser Ser Thr 4290 4295 4300 INFORMATION FOR SEQ ID NO:6: SEQUENCE CHARACTERISTICS: LENGTH: 19 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6: CACGACCTGT

CCCAGGCAT

19 INFORMATION FOR SEQ ID NO:7: SEQUENCE

CHARACTERISTICS:

LENGTH: 17 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:7: CTGGCGGGCG

AGGAGAT

17 INFORMATION FOR SEQ ID NO:8: SEQUENCE CHARACTERISTICS: LENGTH: 17 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:8: CTTTGACAAG

CACATCT

17 INFORMATION FOR SEQ ID NO:9: SEQUENCE CHARACTERISTICS: LENGTH: 17 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:9: CAACTGGCTG

GACAACA

17 INFORMATION FOR SEQ ID SEQUENCE

CHARACTERISTICS:

LENGTH: 18 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID AGGACCTGTC

CAGGCATC

18 INFORMATION FOR SEQ ID NO:11: SEQUENCE CHARACTERISTICS: LENGTH: 21 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:11: CTGCACTGAC CTCACGCATG

T

21 INFORMATION FOR SEQ ID NO:12: SEQUENCE CHARACTERISTICS: LENGTH: 21 base pairs TYPE: nucleic acid S* STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:12: ACGTTGGGCT CCTGGCGAAC

C

21 INFORMATION FOR SEQ ID NO:13: i) SEQUENCE CHARACTERISTICS: LENGTH: 25 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:13: AGGTCAACGT GGGCCTCCAA

GTAGT

INFORMATION FOR SEQ ID NO:14: SEQUENCE CHARACTERISTICS: LENGTH: 21 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:14: GCGCTTTGCA GACGGTAGGC

G

21 INFORMATION FOR SEQ ID SEQUENCE CHARACTERISTICS: LENGTH: 21 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID AGCGCAACTA CTTGGAGGCC

C

21 21 INFORMATION FOR SEQ ID NO:16: SEQUENCE

CHARACTERISTICS:

LENGTH: 21 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:16: GCCAAAGGGA AAGGGATTGG

A

21 INFORMATION FOR SEQ ID NO:17: 154 SEQUENCE CHARACTERISTICS: LENGTH: 17 amino acids TYPE: amino acid TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:17: Cys Ser Arg Thr Pro Leu Arg Ala Lys Asn Lys Val His Pro Ser Ser 1 5 10 Thr INFORMATION FOR SEQ ID NO:18: SEQUENCE CHARACTERISTICS: LENGTH: 160 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:18: GGAAACAGGT TTGGAGAGGT GACACGACCT GTCCCAGGCA TCACAGCCAG GACAGGACCT GTCCAGGCAT CACAGCCGGG ATGTGCATAG CAGGGGTTTG GAACTATGAG GTGCCCAGGA 120 CCCAGGGTTG GATTGAAAAG GGCGCAGGGG ACTAAGATAA 160 INFORMATION FOR SEQ ID NO:19: SEQUENCE CHARACTERISTICS: LENGTH: 131 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:19: GGAAACAGGT TTGGAGAGGT GACACGACCT GTCCCAGGCA TCACAGCCGG GATGTGCATA t: GCAGGGGTTT GGAACTATGA GGTGCCCAGG ACCCAGGGTT GGATTGAAAA GGGCGCAGGG 120 0.0000 GACTAAGATA A 131 131 INFORMATION FOR SEQ ID SEQUENCE CHARACTERISTICS: LENGTH: 60 base pairs TYPE: nucleic acid 155 STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (ix) FEATURE: NAME/KEY: CDS LOCATION: 1..60 (xi) SEQUENCE DESCRIPTION: SEQ ID CGC CCG CGC CGC TTC ACT AGC TTC GAC CAG GTG GCG CAC GTG AGC TCC 48 Arg Pro Arg Arg Phe Thr Ser Phe Asp Gin Val Ala His Val Ser Ser 1 5 10 GCA GCC CGT GGC Ala Ala Arg Gly INFORMATION FOR SEQ ID NO:21: SEQUENCE CHARACTERISTICS: LENGTH: 20 amino acids TYPE: amino acid TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:21: Arg Pro Arg Arg Phe Thr Ser Phe Asp Gin Val Ala His Val Ser Ser 1 5 10 Ala Ala Arg Gly INFORMATION FOR SEQ ID NO:22: S SEQUENCE CHARACTERISTICS: LENGTH: 60 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (ix) FEATURE: NAME/KEY: CDS LOCATION: 1..60 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:22: S CGC CCG CGC CGC TTC ACT AGC TTC GAC CAG GTG GCG CAG CTG AGC TCC 48 Arg Pro Arg Arg Phe Thr Ser Phe Asp Gin Val Ala Gln Leu Ser Ser 1 5 10 1..15 GCA GCC CGT GGC Ala Ala Arg Gly 20 o f 9* 1 r INFORMATION FOR SEQ ID NO:23: SEQUENCE CHARACTERISTICS: LENGTH: 20 amino acids TYPE: amino acid TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:23: Arg Pro Arg Arg Phe Thr Ser Phe Asp Gin Val Ala Gin Leu Ser Ser 1 5 10 Ala Ala Arg Gly INFORMATION FOR SEQ ID NO:24: SEQUENCE CHARACTERISTICS: LENGTH: 60 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (ix) FEATURE: NAME/KEY: CDS LOCATION: 1..60 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:24: GCT GCC CAG CAC GTA CGC TTC GTG CGC CAG TGG TCC GTC TTT GGC AAG Ala Ala Gin His Val Arg Phe Val Arg Gin Trp Ser Val Phe Gly Lys 1 5 10 ACA TTA TGC CGA Thr Leu Cys Arg INFORMATION FOR SEQ ID SEQUENCE CHARACTERISTICS: LENGTH: 20 amino acids TYPE: amino acid TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID Ala Ala Gin His Val Arg Phe Val Arg Gin Trp Ser Val Phe Gly Lys 1 5 10 Thr Leu Cys Arg 0G e o o INFORMATION FOR SEQ ID NO:26: SEQUENCE CHARACTERISTICS: LENGTH: 60 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (ix) FEATURE: NAME/KEY: CDS LOCATION: 1..60 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:26: GCT GCC CAG CAG CTA CGC TTC GTG CGC CAG TGG TCC GTC TTT GGC AAG 48 Ala Ala Gin Gin Leu Arg Phe Val Arg Gln Trp Ser Val Phe Gly Lys 1 5 10 ACA TTA TGC CGA Thr Leu Cys Arg INFORMATION FOR SEQ ID NO:27: SEQUENCE

CHARACTERISTICS:

LENGTH: 20 amino acids TYPE: amino acid TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:27: Ala Ala Gin Gin Leu Arg Phe Val Arg Gin Trp Ser Val Phe Gly Lys 1 5 10 Thr Leu Cys Arg S@oo INFORMATION FOR SEQ ID NO:28: SEQUENCE CHARACTERISTICS: LENGTH: 81 base pairs o. TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear S(ii) MOLECULE TYPE: cDNA 0 (ix) FEATURE: NAME/KEY: CDS LOCATION: 1..81

**S

*000 o

SR

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:28: GCC ACT GGC CCC Ala Thr Gly Pro AGC AGG ACA Ser Arg Thr GTC CTC CTT Val Leu Leu CCT TCG GGC CAA GAA CAA GGT CCA Pro Ser Gly Gin Glu Gin Gly Pro 10 CCT GGC GGG Pro Gly Gly CCC CAG CAG CAC TTA Pro Gin Gin His Leu INFORMATION FOR SEQ ID NO:29: SEQUENCE CHARACTERISTICS: LENGTH: 27 amino acids TYPE: amino acid TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:29: Leu Ala Thr Gly Pro Ser Arg Thr Pro Ser Gly Gin Glu Gin Gly Pro 1 5 10 Pro Gin Gin His Leu Val Leu Leu Pro Gly Gly INFORMATION FOR SEQ ID SEQUENCE CHARACTERISTICS: LENGTH: 81 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (ix) FEATURE: NAME/KEY: CDS LOCATION: 1..64 (xi) SEQUENCE DESCRIPTION: SEQ ID r r CTG GCC ACT Leu Ala Thr 1 CAC CCC AGC His Pro Ser GGC CCC AGC AGG ACA CCC CTT CGG GCC AAG AAC AAG GTC Gly Pro Ser Arg Thr Pro Leu Arg Ala Lys Asn Lys Val 5 10 AGC ACT T AGTCCTCCTT CCTGGCG Ser Thr INFORMATION FOR SEQ ID NO:31: SEQUENCE CHARACTERISTICS: LENGTH: 21 amino acids TYPE: amino acid TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:31: Leu Ala Thr Gly Pro Ser Arg Thr Pro Leu Arg Ala Lys Asn Lys Val 1 5 10 His Pro Ser Ser Thr INFORMATION FOR SEQ ID NO:32: SEQUENCE CHARACTERISTICS: LENGTH: 34 amino acids TYPE: amino acid TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:32: Ala Leu Thr His Gly His Ser Leu Leu Arg Asp Val Ser His Asn Leu 1 5 10 Leu Arg Ala Leu Asp Val Gly Leu Leu Ala Asn Leu Ser Ala Leu Ala 25 Glu Leu INFORMATION FOR SEQ ID NO:33: SEQUENCE CHARACTERISTICS: LENGTH: 34 amino acids TYPE: amino acid TOPOLOGY: linear (ii) MOLECULE TYPE: peptide ee (xi) SEQUENCE DESCRIPTION: SEQ ID NO:33: Leu His Gly Leu Lys Ala Leu Gly His Leu Asp Leu Ser Gly Asn Arg 1 5 10 Leu Arg Lys Leu Pro Pro Gly Leu Leu Ala Asn Phe Thr Leu Leu Arg 25 Thr Leu INFORMATION FOR SEQ ID NO:34: SEQUENCE CHARACTERISTICS: LENGTH: 34 amino acids c* TYPE: amino acid TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:34: Pro Ala Leu Pro Ala Arg Thr Arg His Leu Leu Leu Ala Asn Asn Ser 1 5 10 Leu Gin Ser Val Pro Pro Gly Ala Phe Asp His Leu Pro Gin Leu Gin 25 Thr Leu INFORMATION FOR SEQ ID SEQUENCE CHARACTERISTICS: LENGTH: 34 amino acids TYPE: amino acid TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID Gly Gin Thr Leu Pro Ala Leu Thr Val Leu Asp Val Ser Phe Asn Arg 1 5 10 Leu Thr Ser Leu Pro Leu Gly Ala Leu Arg Gly Leu Gly Glu Leu Gin 25 Glu Leu INFORMATION FOR SEQ ID NO:36: SEQUENCE CHARACTERISTICS: LENGTH: 34 amino acids TYPE: amino acid TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:36: Thr Ala Phe Pro Val Asp Thr Thr Glu Leu Val Leu Thr Gly Asn Asn 1 5 10 Leu Thr Ala Leu Pro Pro Gly Leu Leu Asp Ala Leu Pro Ala Leu Arg 25 Thr Ala INFORMATION FOR SEQ ID NO:37: SEQUENCE CHARACTERISTICS: LENGTH: 34 amino acids TYPE: amino acid TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:37: Leu Glu His Gin Val Asn Leu Leu Ser Leu Asp Leu Ser Asn Asn Ala 1 5 10 Leu Thr His Leu Pro Asp Ser Leu Phe Ala His Thr Thr Asn Leu Thr 25 Asp Leu INFORMATION FOR SEQ ID NO:38: SEQUENCE CHARACTERISTICS: LENGTH: 34 amino acids TYPE: amino acid TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:38: Ile Arg His Leu Arg Ser Leu Thr Arg Leu Asp Leu Ser Asn Asn Gin 1 5 10 Ile Thr Ile Leu Ser Asn Tyr Thr Phe Ala Asn Leu Thr Lys Leu Ser 25 Thr Leu INFORMATION FOR SEQ ID NO:39: SEQUENCE CHARACTERISTICS: LENGTH: 34 amino acids TYPE: amino acid TOPOLOGY: linear (ii) MOLECULE TYPE: peptide SEQUENCE DESCRIPTION: SEQ ID NO:39: *o Phe Gly Asn Met Pro His Leu Gln Trp Leu Asp Leu Ser Tyr Asn Trp 1 5 10 Ile His Glu Leu Asp Phe Asp Ala Phe Lys Asn Thr Lys Gln Leu Gin 20 25 Leu Val INFORMATION FOR SEQ ID SEQUENCE CHARACTERISTICS: LENGTH: 17 amino acids TYPE: amino acid TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID Leu Asp Leu Ser Asn Leu Thr Leu Pro Gly Leu Leu Ala Leu Leu Thr 1 5 10 Leu INFORMATION FOR SEQ ID NO:41: SEQUENCE CHARACTERISTICS: LENGTH: 32 amino acids TYPE: amino acid TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:41: Gly Pro Gln His Leu Pro Leu Pro Cys Arg Asn Leu Ser Gly Asn Pro 1 5 10 Phe Glu Cys Asp Cys Gly Leu Ala Trp Leu Pro Arg Trp Ala Glu Glu 25 INFORMATION FOR SEQ ID NO:42: SEQUENCE CHARACTERISTICS: LENGTH: 32 amino acids TYPE: amino acid TOPOLOGY: linear S(ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:42: Gln Pro Asn Trp Asp Met Arg Asp Gly Phe Asp Ile Ser Gly Asn Pro 1 5 10 Trp Ile Cys Asp Gin Asn Leu Ser Asp Leu Tyr Arg Trp Leu Gin Ala 25 S INFORMATION FOR SEQ ID NO:43: SEQUENCE CHARACTERISTICS: LENGTH: 32 amino acids TYPE: amino acid TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:43: Thr Val Gin Gly Leu Ser Leu Gin Glu Leu Val Leu Ser Gly Asn Pro 1 5 10 Leu His Cys Ser Cys Ala Leu Arg Trp Leu Gln Arg Trp Glu Glu Glu 25 INFORMATION FOR SEQ ID NO:44: SEQUENCE CHARACTERISTICS: LENGTH: 32 amino acids TYPE: amino acid TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:44: Phe Asp His Leu Pro Gin Leu Gin Thr Leu Asp Val Thr Gin Asn Pro 1 5 10 Trp His Cys Asp Cys Ser Leu Thr Tyr Leu Arg Leu Trp Leu Glu Asp 25 INFORMATION FOR SEQ ID SEQUENCE CHARACTERISTICS: LENGTH: 32 amino acids TYPE: amino acid TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID Phe Phe Gly Ser His Leu Leu Pro Phe Ala Phe Leu His Gly Asn Pro 1 5 10 Trp Leu Cys Asn Cys Glu Ile Leu Tyr Phe Arg Arg Trp Leu Gln Asp 25 INFORMATION FOR SEQ ID NO:46: SEQUENCE CHARACTERISTICS: LENGTH: 32 amino acids TYPE: amino acid TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:46: Leu Asp Ala Leu Pro Ala Leu Arg Thr Ala His Leu Gly Ala Asn Pro 1 5 10 Trp Arg Cys Asp Cys Arg Leu Val Pro Leu Arg Ala Trp Leu Ala Gly 25 INFORMATION FOR SEQ ID NO:47: SEQUENCE CHARACTERISTICS: LENGTH: 32 amino acids TYPE: amino acid TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:47: Leu Asn Arg Thr Met Lys Trp Arg Ser Val Lys Leu Ser Gly Asn Pro 1 5 10 Trp Met Cys Asp Cys Thr Ala Lys Pro Leu Leu Leu Phe Thr Gin Asp 25 INFORMATION FOR SEQ ID NO:48: SEQUENCE CHARACTERISTICS: LENGTH: 32 amino acids TYPE: amino acid TOPOLOGY: linear (ii) MOLECULE TYPE: peptide S(xi) SEQUENCE DESCRIPTION: SEQ ID NO:48: Phe Glu Asp Leu Lys Ser Leu Thr His Ile Ala Leu Gly Ser Asn Pro o :1 5 10 Leu Tyr Cys Asp Cys Gly Leu Lys Trp Phe Ser Asp Trp Ile Lys Leu 25 INFORMATION FOR SEQ ID NO:49: SEQUENCE CHARACTERISTICS: LENGTH: 15 amino acids TYPE: amino acid TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:49: Leu Leu Ser Gly Asn Pro Trp Cys Asp Cys Leu Trp Leu Arg Trp 1 5 10 INFORMATION FOR SEQ ID SEQUENCE CHARACTERISTICS: LENGTH: 35 amino acids TYPE: amino acid TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID Thr Ala Thr Arg Trp Asp Phe Gly Asp Gly Ser Ala Glu Val Asp Ala 1 5 10 Ala Gly Pro Ala Ala Ser His Arg Tyr Val Leu Pro Gly Arg Tyr His 25 Val Thr Ala INFORMATION FOR SEQ ID NO:51: SEQUENCE CHARACTERISTICS: LENGTH: 35 amino acids TYPE: amino acid TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:51: e e Val Leu Tyr Thr Trp Asp Phe Gly Asp Gly Ser Pro Val Leu Thr Gin S1 5 10 Ser Gln Pro Ala Ala Asn His Thr Tyr Ala Ser Arg Gly Thr Tyr His 20 25 S* Val Arg Leu INFORMATION FOR SEQ ID NO:52: SEQUENCE CHARACTERISTICS: LENGTH: 35 amino acids TYPE: amino acid TOPOLOGY: linear (ii) MOLECULE TYPE: peptide

CC

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:52: Val Ala Tyr His Trp Asp Phe Gly Asp Gly Ser Pro Gly Gin Asp Thr 1 5 10 15 10 Asp Glu Pro Arg Ala Glu His Ser Tyr Leu Arg Pro Gly Asp Tyr Arg 25 Val Gin Val INFORMATION FOR SEQ ID NO:53: SEQUENCE CHARACTERISTICS: LENGTH: 35 amino acids TYPE: amino acid TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:53: Leu Ser Tyr Thr Trp Asp Phe Gly Asp Ser Ser Gly Thr Leu Ile Ser 1 5 10 15 Arg Ala Pro Val Val Thr His Thr Tyr Leu Glu Pro Gly Pro Val Thr 25 Ala Gin Val INFORMATION FOR SEQ ID NO:54: SEQUENCE

CHARACTERISTICS:

LENGTH: 35 amino acids TYPE: amino acid TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:54: Leu Ser Tyr Thr Trp Asp Phe Gly Asp Ser Thr Gly Thr Leu Ile Ser 1 5 10 Arg Ala Leu Thr Val Thr His Thr Tyr Leu Glu Ser Gly Pro Val Thr 25 Ala Gin Val INFORMATION FOR SEQ ID SEQUENCE

CHARACTERISTICS:

LENGTH: 22 amino acids TYPE: amino acid TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID Tyr Thr Trp Asp Phe Gly Asp Gly Ser Leu Pro Ala His Thr Tyr Leu 1 5 10 Pro Gly Tyr Val Gin Val INFORMATION FOR SEQ ID NO:56: SEQUENCE

CHARACTERISTICS:

LENGTH: 17 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:56: ATCTCCTCGC

CCGCCAG

17 INFORMATION FOR SEQ ID NO:57: SEQUENCE

CHARACTERISTICS:

LENGTH: 17 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) .0 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:57: AGATGTGCTT GTCAAAG 17 INFORMATION FOR SEQ ID NO:58: SEQUENCE

CHARACTERISTICS:

LENGTH: 17 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:58: TGTTGTCCAG

CCAGTTG

17

Claims (38)

1. Isolated nucleic acid encoding human PKD1 polypeptide.

2. Isolated nucleic acid according to claim 1, wherein said nucleic acid is DNA comprising the sequence set forth in SEQ ID NO:2.

3. Isolated nucleic acid according to claim 1, wherein said nucleic acid is RNA.

4. Isolated nucleic acid according to claim 1, wherein said nucleic acid is cDNA comprising the sequence set forth in SEQ ID NO:4. Isolated nucleic acid that hybridizes under stringent conditions to the nucleic acid of claim 1.

6. Isolated nucleic acid according to claim comprising the sequence set forth in SEQ ID NO:3.

7. Isolated polypeptide encoded by the nucleic acid of claim 1.

8. Isolated polypeptide according to claim 7 :comprising the amino acid sequence set forth in SEQ ID

9. A vector comprising the isolated nucleic acid of claim 1.

10. A vector according to claim 9 further comprising a transcriptional regulatory element operably linked to said nucleic acid, said element having the ability to 169 direct the expression of genes of prokaryotic or eukaryotic cells and their viruses or combinations thereof.

11. A host cell comprising the vector of claim 9.

12. A method for producing PKD1 protein, which comprises: culturing the host cell of claim 11 in a medium and under conditions suitable for expression of said protein, and isolating said expressed protein.

13. Isolated human PKD1 gene, comprising the DNA sequence set forth in SEQ ID NO:2 having modifications selected from the group consisitng of: transitions, transversions, deletions, and insertions.

14. The gene of claim 13, comprising a DNA sequence whose presence in one or more copies in the genome of a subject is associated with adult-onset polycystic kidney disease in said subject. A recombinant vector comprising the DNA sequence of claim 13.

16. The vector of claim 15 further comprising a transcriptional regulatory element operably linked to said DNA sequence, said element having the ability to direct the expression of genes of prokaryotic or eukaryotic cells and their viruses or combinations hereof.

17. A host cell comprising the vector of claim

18. A method for producing mutant PKD1 protein, which comprises: 170 culturing the host cell of claim 17 in a medium and under conditions suitable for expression of said protein, and isolating said expressed protein.

19. An isolated nucleic acid comprising: 5'-AGGACCTGTCCAGGCATC-3' (SEQ ID An isolated nucleic acid comprising: 5'-GCGCTTTGCAGACGGTAGGCG-3' (SEQ ID NO:14).

21. An isolated nucleic acid comprising: 5'-AGGTCAACGTGGGCCTCCAAGTAGT-3' (SEQ ID NO:13).

22. An isolated nucleic acid comprising: 5'-AGCGCAACTACTTGGAGGCCC-3' (SEQ ID

23. A diagnostic method for screening human subjects to identify PKD1 carriers, which comprises the steps of: obtaining a sample of biological material from said subject; and assaying for the presence of mutant PKDI genes or their protein products in said biological material.

24. The method of claim 23 wherein said biological material comprises nucleic acid, and said assaying comprises: selectively amplifying the authentic PKD1 gene, or fragments thereof, from said biological material, and detecting the presence of normal and mutant PKD1 genes using an analytical method selected from the group consisting of: restriction enzyme digestion, direct S. 10 DNA sequencing, hybridization with sequence-specific oligonucleotides, single-stranded conformational polymorphism analysis, denaturating gradient gel electrophoresis (DDGE), two-dimensional gel electrophoresis, and combinations thereof. The method of claim 24 wherein said amplifying is performed in the presence of at least one oligonucleotide selected from the-group consisting of 5'-AGGACCTGTCCAGGCATC-3' (SEQ ID 5'-GCGCTTTGCAGACGGTAGGCG-3' (SEQ ID NO:14), 5'-AGGTCAACGTGGGCCTCCAAGTAGT-3' (SEQ ID NO:13), and 5'-AGCGCAACTACTTGGAGGCCC-3' (SEQ ID

26. The method of claim 23, wherein said assaying step comprises an immunoassay employing an antibody specific for said PKD1 gene product.

27. An isolated antibody directed against a peptide comprising the sequence (C)SRTPLRAKNKVHPSST (SEQ ID or immunogenic fragments thereof.

28. The antibody of claim 27 immunoreactive with a polypeptide encoded by the gene sequence set forth in SEQ ID NO:2.

29. An isolated antibody immunoreactive with a polypeptide encoded by the sequence set forth in SEQ ID NO:2.

30. An isolated antibody immunoreactive with a polypeptide comprising the amino acid sequence set forth in SEQ ID *oo.

31. A method for treating a disease condition having the characterisitics of APKD, which comprises administering to cells having defective PKD1 gene function a normal human PKD1 gene or fragments thereof, wherein said administration results in expression of therapeutically effective amounts of normal PKD1 protein or fragments thereof. 172

32. The method claim 31, wherein said normal human PKD1 gene comprises the DNA sequence of SEQ ID NO:2.

33. The method of claim 31, wherein said normal human PKD1 gene comprises the cDNA sequence of SEQ ID NO:4.

34. A method for treating a disease condition having the characterization of APKD, which comprises administering to cells having defective PKD1 gene function therapeutically effective amounts of a normal PKD1 protein or fragments thereof. The method of claim 34, wherein said PKD1 protein is encoded by the DNA sequence set forth in SEQ ID NO:2.

36. The method of claim 34, wherein said PKD1 protein is encoded by the cDNA sequence set forth in SEQ ID NO:4.

37. The method of claim 35, further comprising administering a polypeptide having an amino acid sequence set forth in SEQ ID

38. A composition for treating a disease condition having the characteristics of APKD, said composition comprising an isolated human PKD1 gene having the DNA sequence of SEQ ID NO:2, or fragments thereof, and a 5 Pharmaceutically acceptable carrier or diluent.

39. The composition of claim 38 comprising a vector into which said PKD1 gene is incorporated. The composition of claim 38, further comprising an isolated human PKD1 gene having the DNA sequence of SEQ ID NO:4 for fragments thereof. 173

41. A composition for treating a disease condition having the characteristics of APKD, said composition comprising a normal PKD1 protein encoded by the DNA sequence of SEQ ID NO:2, or fragments thereof, and a Pharmaceutically acceptable carrier or diluent.

42. The composition of claim 41 further comprising a polypeptide encoded by the DNA sequence of SEQ ID NO:4 or fragments thereof.

43. A unicellular or multicellular organism whose genome comprises a recombinant PKD1 gene or fragments thereof.

44. The organism of claim 43 wherein said PKD1 gene has the DNA sequence of SEQ ID NO:2 or fragments thereof. The organism of claim 43 wherein said PKD1 gene has the sequence of SEQ ID NO:4 or fragments thereof. DATED this 2nd day of July 2001 Genzyme Corporation AND Johns Hopkins University DAVIES COLLISON CAVE Patent Attorneys for the applicant *••go o **eo 174