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US20030129696A1 - Polynucleotides and polypeptides encoding receptors - Google Patents

Polynucleotides and polypeptides encoding receptors Download PDF

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US20030129696A1
US20030129696A1 US10/156,136 US15613602A US2003129696A1 US 20030129696 A1 US20030129696 A1 US 20030129696A1 US 15613602 A US15613602 A US 15613602A US 2003129696 A1 US2003129696 A1 US 2003129696A1
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Jian Ni
Craig Rosen
Reiner Gentz
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Priority to US11/041,419 priority patent/US20050176044A1/en
Priority to US11/832,019 priority patent/US20080058247A1/en
Priority to US12/431,986 priority patent/US20090208969A1/en
Priority to US12/952,967 priority patent/US20110151473A1/en
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    • C07K14/70503—Immunoglobulin superfamily
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    • C12N9/6489—Metalloendopeptidases (3.4.24)
    • C12N9/6491—Matrix metalloproteases [MMP's], e.g. interstitial collagenase (3.4.24.7); Stromelysins (3.4.24.17; 3.2.1.22); Matrilysin (3.4.24.23)
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    • C12N2799/021—Uses of viruses as vector for the expression of a heterologous nucleic acid
    • C12N2799/026—Uses of viruses as vector for the expression of a heterologous nucleic acid where the vector is derived from a baculovirus

Definitions

  • This invention relates to newly identified polynucleotides and the polypeptides encoded by them, the use of such polynucleotides and polypeptides, and their production. More particularly, the polynucleotides and polypeptides of the present invention relate to specific receptor families described in the specification and known in the art. The invention also relates to inhibiting or activating the action of such polynucleotides and polypeptides.
  • Receptor proteins are found on the membrane of the cells and are generally involved in signal transduction. There are many types of receptor proteins, and for convenience, these proteins are grouped in families based on similarity in structure and function.
  • the TM4SF superfamily of cell surface proteins also known as the tetraspan receptor superfamily, is comprised of at least seventeen individual gene products (these include CD9, CD20, CD37, CD53, CD63, CD81, CD82, A15, CO-029, Sm23, RDS, Uro B, Uro A, SAS, Rom-1, PETA3, and YKK8).
  • the TM4SF superfamily is the second largest group in the CD antigen superfamily.
  • Each member of the TM4SF superfamily can be characterized by several putative physical features including four highly conserved transmembrane domains, two divergent extracellular loops, and two short and highly divergent cytoplasmic tails.
  • TM4SF superfamily Expression patterns for members of the TM4SF superfamily tend to be rather broad and can vary widely between members.
  • the functional roles of TM4SF superfamily members are primarily associated with signal transduction events and pathways, but also include cell adhesion in platelets and other lymphocytic and non-lymphocytic cell lines, as well as cell motility, proliferation, and metastasis.
  • recent evidence suggests that a subset of the members of the TM4SF superfamily may function as potassium channel molecules.
  • CD20 One member of the TM4SF family, CD20, is a four membrane spanning domain cell surface phosphoprotein expressed exclusively on B lymphocytes. Although the precise functional role of CD20 has yet to be determined, it is thought to function primarily as a receptor during B-cell activation. Furthermore, a large number of experimental observations suggest several additional speculative roles for the CD20 molecule. For example, CD20-specific immunoprecipitation of biochemically cross-linked plasma membrane proteins suggests that CD20 assumes a multimeric structural conformation characteristic of other previously described membrane channel proteins. Further experimentation has revealed that expression of exogenous CD20 on the cell surface specifically increases Ca 2+ conductance across the plasma membrane.
  • CD20 complexes may function as B-cell specific Ca 2+ ion channels.
  • monoclonal antibodies raised against CD20 have been used to stimulate resting B-cells to transition out of the G0/G1 segment of the cell cycle. It has also been demonstrated that CD20 is associated with both serine and tyrosine kinases and, more specifically, that CD20 is associated, although not directly, with the Src family of tyrosine kinases including p56/531yn, p561ck, and p59fyn.
  • sialoadhesin molecules belongs to the Ig superfamily of receptor-like molecules.
  • the more than 100 members of the Ig superfamily are generally considered to engage in specific cell-cell interactions through which intercellular communication may occur.
  • intercellular communication may also be mediated through protein-carbohydrate interactions.
  • all members of the sialoadhesin family of the Ig superfamily are capable of mediating protein-sialic acid binding interactions.
  • sialoadhesin family including sialoadhesin, CD33, CD22, the myelin-associated glycoprotein (MAG), and the Schwann cell myelin protein (SMP).
  • MAG myelin-associated glycoprotein
  • SMP Schwann cell myelin protein
  • galectins are a family of the lectin superfamily of carbohydrate-binding proteins which have a high affinity for b-galactoside sugars. Although a large number of glycoproteins containing b-galactoside sugars are produced by the cell, only a few will bind to known galectins in vitro. Such apparent binding specificity suggests a highly specific functional role for the galectins.
  • Galectin 1 (conventionally termed LGALS1 for lectin, galactoside-binding, soluble ⁇ 1) is thought to specifically bind laminin, a highly polylactosaminated cellular glycoprotein, as well as the highly polylactosaminated lysosome-associated membrane proteins (LAMPs).
  • Galectin 1 has also been shown to bind specifically to a lactosamine-containing glycolipid found on olfactory neurons and to integrin a 7 b 1 on skeletal muscle cells.
  • Galectin 3 has also been observed to bind specifically to laminin, immunoglobulin E and its receptor, and bacterial lipopolysaccharides.
  • galectin 1 has been observed to modulate cell adhesion either positively or negatively. More specifically, galectin 1 appears to inhibit cell adhesion of skeletal muscle presumably by galectin 1-mediated disruption of laminin-integrin a 7 b 1 interactions. Alternatively, galectin 1 appears to promote cell adhesion in several non-skeletal muscle cell types examined presumably by a glycoconjugate cross-linking mechanism. Galectin 3 has also been observed to function in modulating cell-adhesion, as well as in the activation of certain immune cells by cross-linking IgE and IgE receptors.
  • galectins have been observed to be involved in the regulation of immune cell activity, as well as in such diverse processes as cell adhesion, proliferation, inflammation, autoimmunity, and metastasis of tumor cells.
  • a galectin-like antigen designated HOM-HD-21 was recently found to be highly expressed in a Hodgkin's Disease cDNA library.
  • PCTA-1 a novel galectin, termed PCTA-1, was identified as a specific cell surface marker on human prostate cancer cell lines and patient-derived carcinomas.
  • Galectins have also been found to function intracellularly as a component of ribonucleoprotein complexes.
  • galectins 1 and 3 have each been found to modulate T-cell growth and apoptosis by interaction with CD45 and possibly Bc12, respectively.
  • Ly6 superfamily A relatively new family of cell-surface proteins has been identified and termed the Ly6 superfamily.
  • the members of this family include murine and human,SCA-2, rat Ly-6 (also termed ThB), human CD59 [also known as protectin or membrane attack complex inhibition factor (MACIF)], and E48 antigen.
  • the determination of an initial functional role for SCA-2 may lie in an analysis of its expression profile with regard to the complex process of hematopoiesis.
  • SCA-2 is highly expressed in early thymic precusor cells. In turn, progeny of the intrathymic precusor population continue to express SCA-2, but only until the point of transition occurs from blast cell to small cell.
  • CD59 is a recently identified integral membrane protein which appears to be involved in the regulation of complement. Recent studies show that the CD59 antigen may prevent damage from complement C5b-9 and protect astrocytes during inflammatory and infectious disorders of the nervous system. Expression of recombinant human CD59 on porcine donor organs have been shown to prevent complement-mediated lysis and activation of endothelial cells that leads to hyperacute rejection. Recently, researchers at Alexion Pharmaceuticals (New Haven, Conn.) reported on the production of transgenic pigs which expressed human CD59. In these animals, xenogeneic organs were resistant to hyperacute rejection.
  • PNH is an acquired hematopoietic disorder characterized by complement-mediated hemolytic anemia, pancytopenia, and venous thrombosis. It is thought that retroviral gene therapy with this molecule could provide a treatment for PNH patients.
  • a final Ly6 superfamily member, the E48 antigen, is involved in intercellular adhesion between keratinocyte cells of the squamous epithelium. Such keratinocytes are attached to adjoining cells by large numbers of desmosomes, which are thought to play a role in the transition of transformed keratinocytes to metastatic tumor cells.
  • Treatment with a monoclonal antibody raised against the E48 antigen has been successful in the eradication of residual, postoperative squamous cell carcinoma cells of the upper aerodigestive tract in several in vivo models and, to some degree, in humans. (van Dongen, et al., “Progress in radioimmunotherapy of head and neck cancer,” Oncol. Rep.
  • a further example of a receptor family includes the prohibitin receptors.
  • the prohibitin gene product is expressed in a wide variety of tissues and has been implicated as a component of a number of anti-proliferative mechanisms.
  • the prohibitin gene encodes a 30 kD postsynthetically modified polypeptide located primarily in the mitochondria, but also may be associated with the IgM receptor on the B-cell plasma membrane.
  • the protein functionally inhibits DNA synthesis and entry into S phase of the cell cycle by an unknown mechanism.
  • prohibitin gene product is hypothesized to be involved in the maintenance of senescence and the prevention of cancer
  • somatic mutations in the prohibitin gene were present in a small number of breast cancers, no mutations were identified in any other breast, ovary, liver, and lung cancers examined.
  • the prohibitin gene has been mapped to human chromosome 17q12-21, the same region thought to contain the gene involved in sporadic breast cancer.
  • DNA sequence analysis of the prohibitin gene identified somatic mutation in 4 of 23 cases of sporadic breast cancer examined. Thus, prohibitin family members may be involved in the development of cancer.
  • the EGFR family of plasma membrane proteins are an integral component of normal cellular proliferation and in the pathogenesis of the cancerous state.
  • the family is relatively small and includes the EGFR, c-erbB-2, c-erbB-3, and others.
  • Various cancers are correlated with aberrant expression of one or more of these genes.
  • a number of ligands have been identified which bind to the EGFR-like receptors listed above including TGF-a, heparin-binding EGF, amphiregulin, criptoregulin, heregulin, and others.
  • EGF EGF
  • EGFR-related receptor EGFR-related receptor
  • the receptor molecule dimerizes activating its intracellular tyrosine kinase domain. This event results in the phosphorylation of specific tyrosine residues near the carboxy terminus of the receptor.
  • the diversity of signals able to be transduced through the relatively small number of EGFR-related receptor molecules is amplified considerably by the recent finding that EGFR-like receptor molecules can function when dimerized with other EGFR family members forming heterodimers.
  • EGFR-related family of integral membrane proteins have been implicated in the pathogenesis of a number of human disease-states. For example, a mutation in the EGFR itself appears to play an important role in the development of glioblastomas. (Sang et al., J. Neurosurg 82:841-846 (1995).) The EGFR gene is amplified or overexpressed in the majority of primary human glioblastomas. Although not conferring a distinct advantage on cell growth, an increase in EGFR expression was found to confer an increase in the ability of glioma cells to maintain anchorage-independent growth in soft agar especially in response to EGF and retinoic acid.
  • Anchorage-independent growth in vitro correlates highly with tumorigenicity in vivo, therefore, it is likely that cells which express abnormally high levels of EGFR in human glioblastoma cells may be involved in the high potential for these cells to cause tumors in vivo.
  • receptors described above there is a clear need for identifying and exploiting-novel members of the receptor families, such as those described above. Although structurally related, these receptors will likely possess diverse and multifaceted functions in a variety of cell and tissue types. Receptor type molecules should prove useful in target based screens for small molecules and other such pharmacologically valuable factors. Monoclonal antibodies raised against such receptors may prove useful as therapeutics in an anti-tumor, diagnostic, or other capacity. Furthermore, receptors described here may prove useful in an active or passive immunotherapeutical role in patients with cancer or other immunocompromised disease states.
  • the invention relates to receptor polypeptides and polynucleotides, as well as the methods for their production. Another aspect of the invention relates to methods for using such receptor polypeptides and polynucleotides. Such uses include the treatment of the specified diseases, among others. In still another aspect, the invention relates to methods to identify agonists and antagonists using the materials provided by the invention, and treating conditions associated with receptor imbalance with the identified compounds. Yet another aspect of the invention relates to diagnostic assays for detecting diseases associated with inappropriate receptor activity or levels.
  • Receptor refers, among others, to a polypeptide comprising the amino acid sequence set forth in SEQ ID NO: Y, or an allelic variant thereof.
  • Receptor Activity or “Biological Activity of the Receptor” refers to the metabolic or physiologic function of said receptor including similar activities or improved activities or these activities with decreased undesirable side-effects. Also included are antigenic and immunogenic activities of said receptor.
  • Receptor gene refers to a polynucleotide comprising the nucleotide sequence set forth in SEQ ID NO: X or allelic variants thereof and/or their complements.
  • SEQ ID NO: X comprises all or a substantial portion of the polynucleotide encoding each receptor of the invention.
  • the value X for the nucleotide sequence is an integer specified in Table 1.
  • This nucleotide sequence was translated into the receptor polypeptide identified in Table 1 as “SEQ ID NO: Y,” where the value of Y for each receptor polypeptide is an integer defined in Table 1.
  • the invention further provides a composition of matter comprising a nucleic acid molecule which comprises a human cDNA clone identified by a cDNA Clone ID (Identifier) in Table 1, which DNA molecule is contained in the material deposited with the American Type Culture Collection (“ATCC”) and given the ATCC Deposit Number shown in Table 1 for that cDNA clone.
  • ATCC American Type Culture Collection
  • the ATCC is located at American Type Culture Collection (ATCC), 12301 Park Lawn Drive, Rockville, Md. 20852, USA.
  • the deposit has been made under the terms of the Budapest Treaty on the international recognition of the deposit of micro-organisms for purposes of patent procedure. The strain will be irrevocably and without restriction or condition released to the public upon the issuance of a patent.
  • the deposit is provided merely as convenience to those of skill in the art and is not an admission that a deposit is required for enablement, such as that required under 35 U.S.C. ⁇ 112.
  • the nucleotide sequence of the polynucleotides contained in the deposited material, as well as the amino acid sequence of the polypeptide encoded thereby, are controlling in the event of any conflict with any description of sequences herein.
  • Antibodies as used herein includes polyclonal and monoclonal antibodies, chimeric, single chain, and humanized antibodies, as well as Fab fragments, including the products of an Fab or other immunoglobulin expression library.
  • isolated means altered “by the hand of man” from the natural state. If an “isolated” composition or substance occurs in nature, it has been changed or removed from its original environment, or both.
  • a polynucleotide or a polypeptide naturally present in a living animal is not “isolated,” but the same polynucleotide or polypeptide separated from the coexisting materials of its natural state is “isolated”, as the term is employed herein.
  • Polynucleotide generally refers to any polyribonucleotide or polydeoxribonucleotide, which may be unmodified RNA or DNA or modified RNA or DNA.
  • Polynucleotides include, without limitation single- and double-stranded DNA, DNA that is a mixture of single-and double-stranded regions, single-and double-stranded RNA, and RNA that is mixture of single-and double-stranded regions, hybrid molecules comprising DNA and RNA that may be single-stranded or, more typically, double-stranded or a mixture of single-and double-stranded regions.
  • polynucleotide refers to triple-stranded regions comprising RNA or DNA or both RNA and DNA.
  • the term polynucleotide also includes DNAs or RNAs containing one or more modified bases and DNAs or RNAs with backbones modified for stability or for other reasons.
  • Modified bases include, for example, tritylated bases and unusual bases such as inosine.
  • polynucleotide embraces chemically, enzymatically or metabolically modified forms of polynucleotides as typically found in nature, as well as the chemical forms of DNA and RNA characteristic of viruses and cells.
  • Polynucleotide also embraces relatively short polynucleotides, often referred to as oligonucleotides.
  • Polypeptide refers to any peptide or protein comprising two or more amino acids joined to each other by peptide bonds or modified peptide bonds, i.e., peptide isosteres. “Polypeptide” refers to both short chains, commonly referred to as peptides, oligopeptides or oligomers, and to longer chains, generally referred to as proteins. Polypeptides may contain amino acids other than the 20 gene-encoded amino acids. “Polypeptides” include amino acid sequences modified either by natural processes, such as posttranslational processing, or by chemical modification techniques which are well known in the art. Such modifications are well described in basic texts and in more detailed monographs, as well as in a voluminous research literature.
  • Modifications can occur anywhere in a polypeptide, including the peptide backbone, the amino acid side-chains and the amino or carboxyl termini. It will be appreciated that the same type of modification may be present in the same or varying degrees at several sites in a given polypeptide. Also, a given polypeptide may contain many types of modifications. Polypeptides may be branched as a result of ubiquitination, and they may be cyclic, with or without branching. Cyclic, branched and branched cyclic polypeptides may result from posttranslation natural processes or may be made by synthetic methods.
  • Modifications include acetylation, acylation, ADP-ribosylation, amidation, covalent attachment of flavin, covalent attachment of a heme moiety, covalent attachment of a nucleotide or nucleotide derivative, covalent attachment of a lipid or lipid derivative, covalent attachment of phosphotidylinositol, cross-linking, cyclization, disulfide bond formation, demethylation, formation of covalent cross-links, formation of cystine, formation of pyroglutamate, formylation, gamma-carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristoylation, oxidation, proteolytic processing, phosphorylation, prenylation, racemization, selenoylation, sulfation, transfer-RNA mediated addition of amino acids to proteins such as arginylation, and ubiquitination.
  • PROTEINS STRUCTURE AND MOLECULAR PROPERTIES, 2nd Ed., T. E. Creighton, W. H. Freeman and Company, New York, 1993 and Wold, F., Posttranslational Protein Modifications: Perspectives and Prospects, pgs. 1-12 in POSTTRANSLATIONAL COVALENT MODIFICATION OF PROTEINS, B. C.
  • Variant is a polynucleotide or polypeptide that differs from a reference polynucleotide or polypeptide respectively, but retains essential properties.
  • a typical variant of a polynucleotide differs in nucleotide sequence from another, reference polynucleotide. Changes in the nucleotide sequence of the variant may or may not alter the amino acid sequence of a polypeptide encoded by the reference polynucleotide. Nucleotide changes may result in amino acid substitutions, additions, deletions, fusions and truncations in the polypeptide encoded by the reference sequence, as discussed below.
  • a typical variant of a polypeptide differs in amino acid sequence from another, reference polypeptide. Generally, differences are limited so that the sequences of the reference polypeptide and the variant are closely similar overall and, in many regions, identical.
  • a variant and reference polypeptide may differ in amino acid sequence by one or more substitutions, additions, deletions in any combination.
  • a substituted or inserted amino acid residue may or may not be one encoded by the genetic code.
  • a variant of a polynucleotide or polypeptide may be a naturally occurring such as an allelic variant, or it may be a variant that is not known to occur naturally. Non-naturally occurring variants of polynucleotides and polypeptides may be made by mutagenesis techniques or by direct synthesis.
  • Identity is a measure of the identity of nucleotide sequences or amino acid sequences. In general, the sequences are aligned so that the highest order match is obtained. “Identity” per se has an art-recognized meaning and can be calculated using published techniques. (See, e.g.: COMPUTATIONAL MOLECULAR BIOLOGY, Lesk, A. M., ed., Oxford University Press, New York, 1988; BIOCOMPUTING: INFORMATICS AND GENOME PROJECTS, Smith, D. W., ed., Academic Press, New York, 1993; COMPUTER ANALYSIS OF SEQUENCE DATA, PART I, Griffin, A. M., and Griffin, H.
  • Preferred computer program methods to determine identity and similarity between two sequences include, but are not limited to, GCS program package (Devereux, J., et al., Nucleic Acids Research (1984) 12(1):387), BLASTP, BLASTN, FASTA (Atschul, S. F. et al., J Molec Biol (1990) 215:403.)
  • a polynucleotide having a nucleotide sequence having at least, for example, 95% “identity” to a reference nucleotide sequence of SEQ ID NO: X is intended that the nucleotide sequence of the polynucleotide is identical to the reference sequence except that the polynucleotide sequence may include up to five point mutations per each 100 nucleotides of the reference nucleotide sequence of SEQ ID NO: X.
  • a polynucleotide having a nucleotide sequence at least 95% identical to a reference nucleotide sequence up to 5% of the nucleotides in the reference sequence may be deleted or substituted with another nucleotide, or a number of nucleotides up to 5% of the total nucleotides in the reference sequence may be inserted into the reference sequence.
  • These mutations of the reference sequence may occur at the 5′ or 3′ terminal positions of the reference nucleotide sequence or anywhere between those terminal positions, interspersed either individually among nucleotides in the reference sequence or in one or more contiguous groups within the reference sequence.
  • a polypeptide having an amino acid sequence having at least, for example, 95% “identity” to a reference amino acid sequence of SEQ ID NO: Y is intended that the amino acid sequence of the polypeptide is identical to the reference sequence except that the polypeptide sequence may include up to five amino acid alterations per each 100 amino acids of the reference amino acid of SEQ ID NO: Y.
  • up to 5% of the amino acid residues in the reference sequence may be deleted or substituted with another amino acid, or a number of amino acids up to 5% of the total amino acid residues in the reference sequence may be inserted into the reference sequence.
  • These alterations of the reference sequence may occur at the amino or carboxy terminal positions of the reference amino acid sequence or anywhere between those terminal positions, interspersed either individually among residues in the reference sequence or in one or more contiguous groups within the reference sequence.
  • the present invention relates to receptor polypeptides (or receptor proteins).
  • the receptor polypeptides include the polypeptide of SEQ ID NO: Y; as well as polypeptides comprising the amino acid sequence of SEQ ID NO: Y; and polypeptides comprising the amino acid sequence which have at least 80% identity to that of SEQ ID NO: Y over its entire length, and still more preferably at least 90% identity, and even still more preferably at least 95% identity to SEQ ID NO: Y. Furthermore, those with at least 97-99% identity to SEQ ID NO: Y are highly preferred.
  • receptor polypeptides having the amino acid sequence which have at least 80% identity to the polypeptide having the amino acid sequence of SEQ ID NO: Y over its entire length, and still more preferably at least 90% identity, and even still more preferably at least 95% identity to SEQ ID NO: Y. Furthermore, those with at least 97-99% are highly preferred.
  • receptor polypeptides exhibit at least one biological activity of the receptor.
  • the receptor polypeptides may be in the form of the “mature” protein or may be a part of a larger protein such as a fusion protein. It is often advantageous to include an additional amino acid sequence which contains secretory or leader sequences, pro-sequences, sequences which aid in purification such as multiple histidine residues, or an additional sequence for stability during recombinant production.
  • fragments of the receptor polypeptides are also included in the invention.
  • a “fragment” is a polypeptide having an amino acid sequence that entirely is the same as part, but not all, of the amino acid sequence of the aforementioned receptor polypeptides.
  • fragments may be “free-standing,” or comprised within a larger polypeptide of which they form a part or region, most preferably as a single continuous region.
  • Representative examples of polypeptide fragments of the invention include, for example, fragments from about amino acid number 1-20, 21-40, 41-60, 61-80, 81-100, and 101 to the end of receptor polypeptide.
  • “about” includes the particularly recited ranges larger or smaller by several, 5, 4, 3, 2 or 1 amino acid at either extreme or at both extremes.
  • Preferred fragments include, for example, truncation polypeptides having the amino acid sequence of receptor polypeptides, except for deletion of a continuous series of residues that includes the amino terminus, or a continuous series of residues that includes the carboxyl terminus or deletion of two continuous series of residues, one including the amino terminus and one including the carboxyl terminus.
  • fragments characterized by structural or functional domains such as fragments -that comprise alpha-helix and alpha-helix forming regions, beta-sheet and beta-sheet-forming regions, turn and turn-forming regions, coil and coil-forming regions, hydrophilic regions, hydrophobic regions, alpha amphipathic regions, beta amphipathic regions, flexible regions, surface-forming regions, substrate binding region, and high antigenic index regions.
  • the “domains” of each receptor polypeptide are illustrated in the Figures. The Figures compare SEQ ID NO: Y to the closest know homologue. Identical amino acids shared between the two polypeptides are shaded, while conservative amino acid changes are boxed.
  • Biologically active fragments are those that mediate receptor activity, including those with a similar activity or an improved activity, or with a decreased undesirable activity. Also included are those that are antigenic or immunogenic in an animal, especially in a human.
  • variants are those that vary from the referents by conservative amino acid substitutions—i.e., those that substitute a residue with another of like characteristics. Typical such substitutions are among Ala, Val, Leu and Ile; among Ser and Thr; among the acidic residues Asp and Glu; among Asn and Gln; and among the basic residues Lys and Arg; or aromatic residues Phe and Tyr. Particularly preferred are variants in which several, 5-10, 1-5, or 1-2 amino acids are substituted, deleted, or added in any combination.
  • the receptor polypeptides of the invention can be prepared in any suitable manner.
  • Such polypeptides include isolated naturally occurring polypeptides, recombinantly produced polypeptides, synthetically produced polypeptides, or polypeptides produced by a combination of these methods. Means for preparing such polypeptides are well understood in the art.
  • Receptor polynucleotides include isolated polynucleotides which encode the receptor polypeptides and fragments, and polynucleotides closely related thereto. More specifically, a receptor polynucleotide of the invention includes a polynucleotide comprising the nucleotide sequence contained in SEQ ID NO: X encoding a receptor polypeptide of SEQ ID NO: Y, and polynucleotide having the particular sequence of SEQ ID NO: X.
  • Receptor polynucleotides further include a polynucleotide comprising a nucleotide sequence that has at least 80% identity over its entire length to a nucleotide sequence encoding the receptor polypeptide of SEQ ID NO: Y, and a polynucleotide comprising a nucleotide sequence that is at least 80% identical to that of SEQ ID NO: X over its entire length.
  • polynucleotides at least 90% identical are particularly preferred, and those with at least 95% are especially preferred.
  • those with at least 97% are highly preferred and those with at least 98-99% are most highly preferred, with at least 99% being the most preferred.
  • receptor polynucleotides are also included under receptor polynucleotides.
  • a nucleotide sequence which has sufficient identity to a nucleotide sequence contained in SEQ ID NO: X, or contained in the cDNA insert in the plasmid deposited with ATCC, to hybridize under conditions useable for amplification or for use as a probe or marker.
  • the receptor polynucleotide includes a nucleotide sequence having at least 80% identity to a nucleotide sequence encoding the receptor polypeptide expressed by the cDNA insert deposited at the ATCC, and a nucleotide sequence comprisings at least 15 contiguous nucleotides of such cDNA insert.
  • polynucleotides at least 90% identical are particularly preferred, and those with at least 95% are especially preferred. Furthermore, those with at least 97% are highly preferred and those with at least 98-99% are most highly preferred, with at least 99% being the most preferred.
  • the invention also provides polynucleotides which are complementary to all the above receptor polynucleotides.
  • the receptors of the invention are structurally related to other proteins of specified receptor families, as shown by the results in the Figures.
  • the cDNA sequence of SEQ ID NO: X encodes a polypeptide as described in Table 1 as SEQ ID NO: Y. Because the receptor polypeptides contain domains similar in structure to other receptor family members, the receptors of the present invention are expected to have, inter alia, similar biological functions/properties to their homologous polypeptides and polynucleotides, and their utility is obvious to anyone skilled in the art.
  • HMACR70 The novel full-length cDNA clone designated HMACR70 may be a member of the sialoadhesin family of the Ig superfamily of receptor-like molecules and a CD33 homologue. HMACR70 contains a 1497 nucleotide cDNA insert encoding a 315 amino acid ORF and was cloned from a GM-CSF-treated human macrophage cDNA library. The only additional cDNA libraries in the HGS database which include this clone are human eosinophils and possibly human gall bladder.
  • HMACR70 A BLAST analysis of the amino acid sequence of HMACR70 demonstrates that this clone exhibits approximately 50% identity and 69% similarity over a 300 amino acids stretch of a gene termed human differentiation antigen, and 38% identity and 62% similarity of the human myelin-associated glycoprotein precursor CD33 gene.
  • HMACR70 A more recent BLAST analysis confirms HMACR70's designation as a sialoadhesin family member.
  • HMACR70 is homologous to two recently identified sialoadhesin family members, human OB binding protein (OB) 1 and 2. (See, Genbank Accession No. U71382; see FIG. 1.) It is thought that OB-1 and OB-2 may bind leptin.
  • OB-1 and OB-2 may bind leptin.
  • HMACR70 as a sialoadhesin family member, may act to attenuate or even amplify intercellular routes of communication, including binding to leptin or modulating the activity of immune cells, such as macrophages.
  • any diseases affected by these processes could be treated by the polypeptide or fragment of HMACR70.
  • the cDNA clone HTEDK48 contains a 1849 nucleotide cDNA insert encoding a 245 amino acid ORF that was cloned from a human testes cDNA library.
  • the coding sequence of HTEDK48 (SEQ ID NO: 3) may be fused to other human proteins, such as 3-hydroxyacyl-CoA dehydrogenase.
  • BLAST analysis of the amino acid sequence of HTEDK48 demonstrates that this clone exhibits approximately 30% identity and 51% similarity over a 245 amino acid stretch of the CD82 molecule. Recent studies have shown that CD82 can associate with CD4 or CD8 and deliver costimulatory signals for the TCR/CD3 pathway.
  • CD82 has also been found to be involved in syncytium formation in HTLV-I-infected T-cells. And finally, in a recently published study in which the expression of the CD82 gene by tumors of the lung was examined retrospectively, it was reported that CD82 may be linked to the suppression of tumor metastasis of prostate cancer. The study also reported that decreased CD82 expression may be involved in malignant progression of such cancers. Thus, HTEDK48 may also be involved in the development of cancer.
  • HTEDK48 is homologous the rat leukocyte antigen, MRC OX-44, and the platelet endothelial tetraspan antigen -3 (PETA-3).
  • MRC OX-44 a member of a new family of cell surface proteins, appears to be involved in growth regulation.
  • Bellacosa, A., et al. “The Rat Leukocyte antigen MRC OX-44 is a Member of a New Family of Cell Surface Proteins which Appear to be Involved in Growth Regulation,” Mol. Cell. Bio.
  • HTEDK48 may function similar to MRC OX-44 or PETA-3 to affect growth of blood cells. Administering polypeptides or fragments of HTEDK48 may be an effective treatment of blood disorders.
  • the cDNA clone HPWAE25 contains a 1288 nucleotide cDNA insert encoding a 273 amino acid ORF that was cloned from a human pancreas tumor cDNA library, while clone HTPED39 represents a truncated cDNA sequence. This clone also appears in a number of other cDNA libraries constructed from a variety of human cell and tissue types including keratinocytes, ulcerative colitis, striatum depression, lymph node breast cancer, ovarian cancer, stage B2 prostate cancer, kidney medulla, and others.
  • Northern blot analysis of HLTAH80 also shows expression in a variety of human cell lines including U937, MM96, WM115, and MDAMB231.
  • a BLAST analysis of the amino acid sequence of HTPED39 demonstrates that this clone exhibits approximately 35% identity and 50% similarity over the entire length of the CD37 molecule.
  • the CD37 antigen is expressed on B cells and on a subpopulation of T cells, but not on pre-B or plasma cells. It has been reported that CD37 expression is downregulated in conjunction with B-cell activation, suggesting that CD37 may be involved in the processes which dictate the activation state of the B-cell.
  • HPWAE25 is also homologous to recently identified TM4SF members, NAG-2 and TALLA-1.
  • NAG-2 is thought to complex with integrins and other TM4SF proteins
  • TALLA-1 is a highly specific marker of T-cell acute lymphoblastic leukemia and neuroblastoma.
  • Tachibana I., et al., “NAG-2, A Novel Transmembrane-4 Superfamily (TM4SF) Protein that Complexs with Integrins and Other TM4SF Proteins,” J. Biol.
  • HPWAE25 may be involved the development of cancer, particularly leukemia, lymphoma, and neuroblastoma. HPWAE25 may be used as an effective treatment of these cancers, as well as a diagnostic marker.
  • a subfamily of TM4SF receptors include CD20 proteins.
  • a CD20-like cDNA clone was obtained from a human pancreas tumor cDNA library and contains a 1236 nucleotide insert which encodes a 250 amino acid ORF.
  • a BLAST analysis of the deduced amino acid sequence of HTPEF86 exhibits approximately 41% identity and 61% similarity to the CD20 gene, also known as B1 antigen. (See FIG. 4.) Expression of this gene is detected in only two additional HGS human cDNA libraries; amygdala depression and 9 week early stage human.
  • novel CD20-like molecule presented herein may also be involved in cell cycle activation.
  • Potential therapeutic and/or diagnostic applications for HTPEF86 may include such clinical presentations as juvenile rheumatoid arthritis, Graves' Disease, and a number of B-cell lymphomas or other lymphoid tumors.
  • the clone HSBBF02 contains a 1115 nucleotide cDNA insert encoding a 245 amino acid ORF and was cloned from an HSC 172 cell line cDNA library. This clone also appears in a number of other cDNA libraries constructed from a variety of human cell and tissue types including brain amygdala depression, endothelial cells, fetal liver and heart, osteoblasts, testes, and others.
  • a BLAST analysis of the amino acid sequence of HSBBF02 demonstrates that this clone exhibits approximately 64% identity and 80% similarity with the A15 molecule over a 131 amino acid stretch (A15 is composed of 244 amino acids).
  • a more recent BLAST search shows that HSBBF02 is similar to the TALLA-1 protein and may in fact be a closely related family member. (See FIG. 5.)
  • a second cDNA clone exhibits sequence similarity to the A15 molecule and TALLA-1. (See FIG. 6.)
  • This clone contains a 1662 nucleotide cDNA insert encoding a 253 amino acid ORF and was cloned from a human T-cell lymphoma cDNA library.
  • This clone also appears in a number of other cDNA libraries constructed from a variety of human cell and tissue types including B-cell lymphoma, corpus collosum, endometrial tumor, osteosarcoma, testes, and others.
  • Northern blot analysis of HLTAH80 also shows expression in a variety of human tissues including spleen, lymph node, thymus, PBLs, heart, and a particularly strong signal in skeletal muscle and pancreas.
  • a BLAST analysis of the amino acid sequence of HLTAH80 demonstrates that this clone exhibits approximately 35% identity and 55% similarity over the entire length of the A15 molecule.
  • A15 Since expression of A15 drops to undetectable levels when comparing immature T-cells to peripheral blood lymphocytes, it is thought that A15 may play a role in the development of T-cells. Furthermore, the MXS1(CCG-B7) gene which codes for A15 contains a number of triplet nucleotide repeats which have been associated with neuropsychiatric diseases such as Huntington's chorea, fragile X syndrome, and myotonic dystrophy. In addition, A15 appears to be expressed exclusively on T-cell acute lymphoblastic leukemia cell lines, including several derived from adult T-cell leukemia and those established by immortalization with human T-cell leukemia virus type 1 or Herpesvirus saimiri. Thus, clones HLTAH80 and/or HSBBF02 may also be involved in diseases caused by the expansion of repeats or chromosomal instability.
  • the cDNA clone HTPBA27 contains a 1345 nucleotide cDNA insert encoding a 238 amino acid ORF and was cloned from a human tumor pancreas cDNA library. This clone also appears in a number of other cDNA libraries constructed from a variety of human cell and tissue types including cerebellum, breast lymph node, osteosarcoma, adult testes, RS4;11 bone marrow cell line, microvascular endothelial cells, and others.
  • a BLAST analysis of the amino acid sequence of HTPBA27 demonstrates that this clone exhibits approximately 40% identity and 64% similarity with a glycoprotein termed CD53 over its entire length.
  • CD53 is thought to be involved in thymopoiesis, since rat CD53 can be detected on immature CD4-8-thymocytes and the functionally mature single-positive subset, but cannot be detected on the intermediate CD4+8+ thymocytic subset of cells.
  • the CD53 molecule has also been implicated as a component of signal transduction pathways in B cells, monocytes and granulocytes, rat macrophages, NK, and T cells.
  • HTPBA27 was recently confirmed as a TM4SF receptor.
  • HTPBA27 A Novel Transmembrane-4 Superfamily (TM4SF) Protein that with Integrins and Other TM4SF Proteins,” J. Biol. Chem., 272:29181-29189 (1997).)
  • NAG-2 A Novel Transmembrane-4 Superfamily (TM4SF) Protein that with Integrins and Other TM4SF Proteins
  • HTPBA27 polypeptide NAG-2 this group confirmed HTPBA27's status as a TM4SF receptor by showing that NAG-2 complexes with integrin and other TM4SF receptors.
  • diseases caused by the failure of HTPBA27 to complex with integrin and other TM4SF receptors can be treated by administering HTPBA27.
  • HTPBA27 can also be used to diagnose these diseases.
  • the cDNA clone HAIDQ59 contains cDNA insert encoding a 221 amino acid ORF that was cloned from a human epithelial cell induced with TNFa and INF cDNA library.
  • the 5′ end of HAIDQ59 is represented by the SEQ ID NO: 9, while the 3′ end is represented by SEQ ID NO: 10.
  • This clone appears in only two additional cDNA libraries in the HGS database. These two libraries were constructed from the human Jurkat T-cell line and human microvascular endothelial cells.
  • a BLAST analysis of the amino acid sequence of HAIDQ59 demonstrates that this clone exhibits approximately 53% identity and 69% similarity over 226 amino acids of the CD9 TM4SF molecule.
  • the cDNA clone HHFEK40 contains a 936 nucleotide cDNA insert encoding a 252 amino acid ORF and was cloned from a human fetal heart cDNA library. This clone appears once in the human fetal heart cDNA library and possibly in a hemangiopericytoma cDNA library.
  • a BLAST analysis of the amino acid sequence of HHFEK40 demonstrated that this clone exhibits approximately 60% identity and 75% similarity over the entire length of a molecule designated PETA-3. (See FIG. 9.) PETA-3 was originally identified as a novel human platelet surface glycoprotein termed gp27.
  • HHFEK40 may function similar to PETA-3 to affect growth of blood cells. Administering polypeptides or fragments of HHFEK40 may be an effective treatment of blood disorders.
  • the cDNA clone HGBGV89 contains a 738 nucleotide cDNA insert encoding a 197 amino acid ORF and was cloned from a human gall bladder cDNA library. The only two additional appearances of this clone in the HGS database are in a normalized fetal liver cDNA library and in a fetal liver/spleen cDNA library.
  • the cDNA clone HUVBB80 contains a 1071 nucleotide cDNA insert encoding a 201 amino acid ORF and was cloned from a human umbilical vein cDNA library.
  • the L6 cell surface antigen is highly expressed on lung, breast, colon, and ovarian carcinomas. Promising results of phase 1 clinical studies have been reported with an anti-L6 monoclonal antibody, or its humanized counterpart, suggesting that the L6 antigen may be an attractive target for monoclonal antibody-based cancer therapy.
  • TM4SF superfamily such as those described herein. Although structurally related, these factors will likely possess diverse and multifaceted functions in a variety of cell and tissue types. Receptor type molecules, such as the novel potential members of the TM4SF superfamily detailed here, should prove useful in target based screens for small molecules and other such pharmacologically valuable factors. Monoclonal antibodies raised against such factors may prove useful as therapeutics in an anti-tumor, diagnostic, or other capacity. Furthermore, factors such as the nine novel TM4SF superfamily-like molecules described here may prove useful in an active or passive immunotherapeutical role in patients with cancer or other immunocompromised disease states.
  • clone HJACE54 also called galectin 11, exhibits significant sequence identity to the rat galectin 5, the chicken galectin 3 gene, and the human galectin 8 genes.
  • the galectin 11 cDNA clone contains an 865 nucleotide insert which encodes a 133 amino acid ORF.
  • the clone was obtained from a Jurkat T-cell G1 phase cDNA library.
  • a BLAST analysis of the deduced amino acid sequence of HJACE54 demonstrates approximately 35% identity and 57% similarity to the amino acid sequence of the rat galectin 5 gene.
  • Expression of galectin 11 is quite limited in the HGS database. In fact, the only two additional ESTs in the HGS database which contain the HJACE54 sequence were found in human neutrophil and human infant adrenal gland cDNA libraries. Northern blot analyses have not been performed to examine expression patterns of the galectin 11 gene.
  • galectin 1 has been observed to modulate cell adhesion either positively or negatively. More specifically, galectin 1 appears to inhibit cell adhesion of skeletal muscle presumably by galectin 1-mediated disruption of laminin-integrin a 7 b 1 interactions. Alternatively, galectin 1 appears to promote cell adhesion in several non-skeletal muscle cell types examined presumably by a glycoconjugate cross-linking mechanism. Galectin 3 has also been observed to function in modulating cell-adhesion, as well as in the activation of certain immune cells by cross-linking IgE and IgE receptors.
  • galectins have been observed to be involved in the regulation of immune cell activity, as well as in such diverse processes as cell adhesion, proliferation, inflammation, autoimmunity, and metastasis of tumor cells.
  • a galectin-like antigen designated HOM-HD-21 was recently found to be highly expressed in a Hodgkin's Disease cDNA library.
  • a novel galectin, termed PCTA-1 was identified as a specific cell surface marker on human prostate cancer cell lines and patient-derived carcinomas.
  • Galectins have also been found to function intracellularly as a component of ribonucleoprotein complexes.
  • galectins 1 and 3 have each been found to modulate T-cell growth and apoptosis by interaction with CD45 and possibly Bc12, respectively.
  • the discovery of a novel galectin, such as that encoded by HJACE54, is likely to be a valuable asset both diagnostically and therapeutically.
  • Clone HROAD63 contains a 441 nucleotide cDNA which encodes a 70 amino acid polypeptide.
  • This novel clone exhibits significant sequence identity to several members of a relatively new family of cell-surface proteins termed the Ly6 superfamily. These members include murine and human SCA-2, rat Ly-6 (also termed ThB), and human CD59 [also known as protectin or membrane attack complex inhibition factor (MACIF)].
  • the novel E48 splice variant was obtained from the HGS human stomach cDNA library.
  • the clone is present in only a limited number of other HGS cDNA libraries including kidney cancer, keratinocyte, and tongue.
  • An alignment of the nucleotide sequences of the human E48 and HROAD63 cDNAs demonstrates that the initial 168 and 178 nucleotides of E48 and HROAD63, respectively, are identical, with the exception of an additional 10 nucleotides of sequence at the extreme 5′ end of the HROAD63 sequence.
  • the sequence of the two clones is also identical for an additional 229 nucleotides including the 3′ end of the coding sequences and the entire 3′ untranslated regions.
  • nucleotide sequence in this region of the clones is the deletion of a single thymidine residue in the 3′ UTR of the E48 cDNA.
  • the major difference between the two nucleotide sequences is a 329 nucleotide deletion from the HROAD63 sequence. This deletion causes a shift in the HROAD63 reading frame and encompasses the translational stop signal used in the E48 clone.
  • the carboxy terminal sequence of HROAD63 is radically altered with regard to that of E48 (as illustrated in FIG. 13 by the obvious differences between amino acids 56-128 of E48 and 56-70 of HROAD63 in the amino acid alignment).
  • HROAD63 may also be involved in blood disorders, as seen with its homologues SCA-2 and CD59.
  • a novel prohibitin cDNA clone presented herein was originally identified in a human bone marrow cell line (RS4;11) cDNA library.
  • the clone contains a 1066 nucleotide insert which encodes a 299 amino acid polypeptide.
  • BLAST and BestFit analyses of the predicted amino acid sequence of HMWGS46 demonstrate a highly significant sequence identity to a murine protein termed IgM B-cell receptor associated protein (BAP)-37 (Genbank accession number X78683).
  • BAP B-cell receptor associated protein
  • HMWGS46 and BAP-37 exhibit at least 87% identical.
  • the HMWGS46 clone also exhibits approximately 49% sequence identity and 85% sequence similarity to a human gene designated prohibitin.
  • the HMWGS46 cDNA appears in a substantial number of HGS human cDNA libraries in addition to the bone marrow cell line cDNA library from which it was cloned.
  • Some of the cDNA libraries in which this clone appears include keratinocytes, induced endothelial cells, activated neutrophils, synovial sarcoma, colon carcinoma cell line, Jurkat cell line membrane bound polysomes, epileptic frontal cortex, primary dendritic cells, and a number of others.
  • the novel gene related to prohibitin and BAP-37 may prove quite useful as a diagnostic for tumorigenesis, as well as a target for therapeutic intervention of such an event.
  • a novel gene, such as HMWGS46 may prove quite useful as a diagnostic for tumorigenesis, as well as a target for therapeutic intervention of such an event.
  • a human cDNA clone encoding a novel epidermal growth factor receptor (EGFR)-like molecule is also disclosed.
  • the novel EGFR-like cDNA clone presented herein was originally identified in an activated human neutrophil cDNA library.
  • the clone contains a 704 nucleotide insert which encodes a 168 amino acid polypeptide.
  • a BLAST analysis of the predicted amino acid sequence of HNFGW06 demonstrates that this novel clone exhibits approximately 85% identity and 90% similarity to a protein designated epidermal growth factor receptor-related protein [Homo sapiens]. (See FIG. 15.)
  • the expression profile of the HNFGW06 clone in the HGS database indicates the existence of a fairly highly restricted expression pattern.
  • synovial sarcoma smooth muscle, placenta, and possibly primary dendritic cells.
  • HNFGW06 may lead to a number of exciting possibilities for therapeutic and/or diagnostic treatments or reagents.
  • HNFGW06 may be involved in the onset of human breast cancers as well.
  • TGF-a acts through binding to the EGFR
  • HNFGW06 may also play a role in a variety of gastric processes including regulation of acid secretion, regulation of mucous cell growth, and protection against ethanol- and aspirin-induced injury to gastric tissues.
  • Polynucleotides of the present invention encoding a receptor may be obtained using standard cloning and screening, from a cDNA library derived from mRNA in cells specified in Table 1 using the expressed sequence tag (EST) analysis (Adams, M. D., et al. Science (1991) 252:1651-1656; Adams, M. D. et al., Nature, (1992) 355:632-634; Adams, M. D., et al., Nature (1995) 377 Supp:3-174.) Polynucleotides of the invention can also be obtained from natural sources such as genomic DNA libraries or can be synthesized using well known and commercially available techniques.
  • EST expressed sequence tag
  • the nucleotide sequence encoding a receptor polypeptide of SEQ ID NO: Y may be identical to the polynucleotide encoding SEQ ID NO: Y, or it may be a sequence, which as a result of the redundancy (degeneracy) of the genetic code, also encodes the polypeptide of SEQ ID NO: Y.
  • the polynucleotide may include the coding sequence for the mature polypeptide or a fragment thereof, by itself; the coding sequence for the mature polypeptide or fragment in reading frame with other coding sequences, such as those encoding a leader or secretory sequence, a pre-, or pro-or prepro-protein sequence, or other fusion peptide portions.
  • a marker sequence which facilitates purification of the fused polypeptide can be encoded.
  • the marker sequence is a hexa-histidine peptide, as provided in the pQE vector (Qiagen, Inc.) and described in Gentz et al., Proc Natl Acad Sci USA (1989) 86:821-824, or is an HA tag.
  • the polynucleotide may also contain non-coding 5′ and 3′ sequences, such as transcribed, non-translated sequences, splicing and polyadenylation signals, ribosome binding sites and sequences that stabilize mRNA.
  • Further preferred embodiments are polynucleotides encoding receptor variants comprising the amino acid sequence of receptor polypeptide of Table 1 (SEQ ID NO: Y) in which several, 5-10, 1-5, 1-3, 1-2 or 1 amino acid residues are substituted, deleted or added, in any combination.
  • the present invention further relates to polynucleotides that hybridize to the herein above-described sequences.
  • the present invention especially relates to polynucleotides which hybridize under stringent conditions to the herein above-described polynucleotides.
  • stringent conditions means hybridization will occur only if there is at least 80%, and preferably at least 90%, and more preferably at least 95%, yet even more preferably 97-99% identity between the sequences.
  • Polynucleotides of the invention which are identical or sufficiently identical to a nucleotide sequence contained in SEQ ID NO: X or a fragment thereof, or to the cDNA insert in the plasmid deposited at the ATCC, or a fragment thereof, may be used as hybridization probes for cDNA and genomic DNA, to isolate full-length cDNAs and genomic clones encoding the receptor and to isolate cDNA and genomic clones of other genes (including genes encoding homologs and orthologs) that have a high sequence similarity to the receptor gene.
  • Such hybridization techniques are known to those of skill in the art.
  • these nucleotide sequences are 80% identical, preferably 90% identical, more preferably 95% identical to that of the referent.
  • the probes generally will comprise at least 15 nucleotides. Preferably, such probes will have at least 30 nucleotides and may have at least 50 nucleotides. Particularly preferred probes will range between 30 and 50 nucleotides.
  • to obtain a polynucleotide encoding the receptor polypeptide, including homologs and orthologs from other species comprises the steps of screening an appropriate library under stringent hybridization conditions with a labeled probe having the SEQ ID NO: X or a fragment thereof; and isolating full-length cDNA and genomic clones containing said polynucleotide sequence.
  • stringent hybridization conditions are as defined above or, alternatively, conditions under overnight incubation at 42° C.
  • polynucleotides and polypeptides of the present invention may be employed as research reagents and materials for discovery of treatments and diagnostics to animal and human disease.
  • the present invention also relates to vectors which comprise a polynucleotide or polynucleotides of the present invention, and host cells which are genetically engineered with vectors of the invention and to the production of polypeptides of the invention by recombinant techniques.
  • Cell-free translation systems can also be employed to produce such proteins using RNAs derived from the DNA constructs of the present invention.
  • host cells can be genetically engineered to incorporate expression systems or portions thereof for polynucleotides of the present invention.
  • Introduction of polynucleotides into host cells can be effected by methods described in many standard laboratory manuals, such as Davis et al., BASIC METHODS IN MOLECULAR BIOLOGY (1986) and Sambrook et al., MOLECULAR CLONING: A LABORATORY MANUAL, 2nd Ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1989) such as calcium phosphate transfection, DEAE-dextran mediated transfection, transvection, microinjection, cationic lipid-mediated transfection, electroporation, transduction, scrape loading, ballistic introduction or infection.
  • Representative examples of appropriate hosts include bacterial cells, such as streptococci, staphylococci, E. coli , Streptomyces and Bacillus subtilis cells; fungal cells, such as yeast cells and Aspergillus cells; insect cells such as Drosophila S2 and Spodoptera Sf9 cells; animal cells such as CHO, COS, HeLa, C127, 3T3, BHK, HEK 293 and Bowes melanoma cells; and plant cells.
  • bacterial cells such as streptococci, staphylococci, E. coli , Streptomyces and Bacillus subtilis cells
  • fungal cells such as yeast cells and Aspergillus cells
  • insect cells such as Drosophila S2 and Spodoptera Sf9 cells
  • animal cells such as CHO, COS, HeLa, C127, 3T3, BHK, HEK 293 and Bowes melanoma cells
  • plant cells include bacterial cells, such as streptococci, staphyloc
  • a great variety of expression systems can be used.
  • Such systems include, among others, chromosomal, episomal and virus-derived systems, e.g., vectors derived from bacterial plasmids, from bacteriophage, from transposons, from yeast episomes, from insertion elements, from yeast chromosomal elements, from viruses such as baculoviruses, papova viruses, such as SV40, vaccinia viruses, adenoviruses, fowl pox viruses, pseudorabies viruses and retroviruses, and vectors derived from combinations thereof, such as those derived from plasmid and bacteriophage genetic elements, such as cosmids and phagemids.
  • the expression systems may contain control regions that regulate as well as engender expression.
  • any system or vector suitable to maintain, propagate or express polynucleotides to produce a polypeptide in a host may be used.
  • the appropriate nucleotide sequence may be inserted into an expression system by any of a variety of well-known and routine techniques, such as, for example, those set forth in Sambrook et al., MOLECULAR CLONING, A LABORATORY MANUAL (supra).
  • secretion signals may be incorporated into the desired polypeptide. These signals may be endogenous to the polypeptide or they may be heterologous signals.
  • the receptor polypeptide is to be expressed for use in screening assays, generally, it is preferred that the polypeptide be produced at the surface of the cell. In this event, the cells may be harvested prior to use in the screening assay. If the receptor polypeptide is secreted into the medium, the medium can be recovered in order to recover and purify the polypeptide; if produced intracellularly, the cells must first be lysed before the polypeptide is recovered.
  • Receptor polypeptides can be recovered and purified from recombinant cell cultures by well-known methods including ammonium sulfate or ethanol precipitation, acid extraction, anion or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxylapatite chromatography and lectin chromatography. Most preferably, high performance liquid chromatography is employed for purification. Well known techniques for refolding proteins may be employed to regenerate active conformation when the polypeptide is denatured during isolation and or purification.
  • This invention also relates to the use of receptor polynucleotides or polypeptides for use as diagnostic reagents. Detection of a mutated form of the receptor gene associated with a dysfunction will provide a diagnostic tool that can add to or define a diagnosis of a disease or susceptibility to a disease which results from under-expression, over-expression or altered expression of the receptor. Individuals carrying mutations in the receptor gene may be detected at the DNA level by a variety of techniques.
  • Nucleic acids for diagnosis may be obtained from a subject's cells, such as from blood, urine, saliva, tissue biopsy or autopsy material.
  • the genomic DNA may be used directly for detection or may be amplified enzymatically by using PCR or other amplification techniques prior to analysis.
  • RNA or cDNA may also be used in similar fashion. Deletions and insertions can be detected by a change in size of the amplified product in comparison to the normal genotype. Point mutations can be identified by hybridizing amplified DNA to labeled receptor nucleotide sequences. Perfectly matched sequences can be distinguished from mismatched duplexes by RNase digestion or by differences in melting temperatures.
  • DNA sequence differences may also be detected by alterations in electrophoretic mobility of DNA fragments in gels, with or without denaturing agents, or by direct DNA sequencing.
  • Sequence changes at specific locations may also be revealed by nuclease protection assays, such as RNase and S1 protection or the chemical cleavage method.
  • nuclease protection assays such as RNase and S1 protection or the chemical cleavage method.
  • an array of oligonucleotides probes comprising receptor nucleotide sequence or fragments thereof can be constructed to conduct efficient screening of e.g., genetic mutations.
  • the diagnostic assays offer a process for diagnosing or determining a susceptibility to specific diseases through detection of mutation in the receptor gene by the methods described.
  • specific diseases can be diagnosed by methods comprising determining from a sample derived from a subject an abnormally decreased or increased level of receptor polypeptide or receptor mRNA. Decreased or increased expression can be measured at the RNA level using any of the methods well known in the art for the quantitation of polynucleotides, such as, for example, PCR, RT-PCR, RNase protection, Northern blotting and other hybridization methods.
  • Assay techniques that can be used to determine levels of a protein in a sample derived from a host are well-known to those of skill in the art. Such assay methods include radioimmunoassays, competitive-binding assays, Western Blot analysis and ELISA assays.
  • the present invention relates to a diagnostic kit for a disease or susceptibility to a disease which comprises:
  • a receptor polynucleotide preferably the nucleotide sequence of SEQ ID NO: X, or a fragment thereof;
  • a receptor polypeptide preferably the polypeptide of SEQ ID NO: Y, or a fragment thereof; or
  • the nucleotide sequences of the present invention are also valuable for chromosome identification.
  • the sequence is specifically targeted to and can hybridize with a particular location on an individual human chromosome.
  • the mapping of relevant sequences to chromosomes according to the present invention is an important first step in correlating those sequences with gene associated disease. Once a sequence has been mapped to a precise chromosomal location, the physical position of the sequence on the chromosome can be correlated with genetic map data. Such data are found, for example, in V. McKusick, Mendelian Inheritance in Man (available on line through Johns Hopkins University Welch Medical Library). The relationship between genes and diseases that have been mapped to the same chromosomal region are then identified through linkage analysis (coinheritance of physically adjacent genes).
  • the differences in the cDNA or genomic sequence between affected and unaffected individuals can also be determined. If a mutation is observed in some or all of the affected individuals but not in any normal individuals, then the mutation is likely to be the causative agent of the disease.
  • polypeptides-of the invention or their fragments or analogs thereof, or cells expressing them can also be used as immunogens to produce antibodies immunospecific for the receptor polypeptides.
  • immunospecific means that the antibodies have substantially greater affinity for the polypeptides of the invention than their affinity for other related polypeptides in the prior art.
  • Antibodies generated against the receptor polypeptides can be obtained by administering the polypeptides or epitope-bearing fragments, analogs or cells to an animal, preferably a nonhuman, using routine protocols.
  • an animal preferably a nonhuman
  • any technique which provides antibodies produced by continuous cell line cultures can be used. Examples include the hybridoma technique (Kohler, G.
  • the above-described antibodies may be employed to isolate or to identify clones expressing the polypeptide or to purify the polypeptides by affinity chromatography.
  • Antibodies against receptor polypeptides may also be employed to treat diseases.
  • Another aspect of the invention relates to a method for inducing an immunological response in a mammal which comprises inoculating the mammal with a receptor polypeptide, or a fragment thereof, adequate to produce antibody and/or T cell immune response to protect said animal from a disease.
  • Yet another aspect of the invention relates to a method of inducing immunological response in a mammal which comprises, delivering a receptor polypeptide via a vector directing expression of the receptor polynucleotide in vivo in order to induce such an immunological response to produce antibody to protect said animal from diseases.
  • composition which, when introduced into a mammalian host, induces an immunological response in that mammal to a receptor polypeptide wherein the composition comprises a receptor polypeptide or receptor gene.
  • the vaccine formulation may further comprise a suitable carrier. Since a receptor polypeptide may be broken down in the stomach, it is preferably administered parenterally (including subcutaneous, intramuscular, intravenous, intradermal etc. injection).
  • Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation instonic with the blood of the recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents or thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials and may be stored in a freeze-dried condition requiring only the addition of the sterile liquid carrier immediately prior to use.
  • the vaccine formulation may also include adjuvant systems for enhancing the immunogenicity of the formulation, such as oil-in water systems and other systems known in the art. The dosage will depend on the specific activity of the vaccine and can be readily determined by routine experimentation.
  • the receptor polypeptide of the present invention may be employed in a screening process for compounds which bind the receptor and which activate (agonists) or inhibit activation of (antagonists) the receptor polypeptide of the present invention.
  • polypeptides of the invention may also be used to assess the binding of small molecule substrates and ligands in, for example, cells, cell-free preparations, chemical libraries, and natural product mixtures. These substrates and ligands may be natural substrates and ligands or may be structural or functional mimetics. See Coligan et al., Current Protocols in Immunology 1(2):Chapter 5 (1991).
  • the receptor polypeptides are responsible for many biological functions, including many pathologies. Accordingly, it is desirous to find compounds and drugs which stimulate the receptor on the one hand and which can inhibit the function of the receptor on the other hand. In general, agonists are employed for therapeutic and prophylactic purposes for such conditions and diseases. Antagonists may be employed for a variety of therapeutic and prophylactic purposes for such conditions and diseases.
  • such screening procedures involve producing appropriate cells which express the receptor-polypeptide of the present invention on the surface thereof.
  • Such cells include cells from mammals, yeast, Drosophila or E. coli .
  • Cells expressing the receptor (or cell membrane containing the expressed receptor) are then contacted with a test compound to observe binding, or stimulation or inhibition of a functional response.
  • the assays may simply test binding of a candidate compound wherein adherence to the cells bearing the receptor is detected by means of a label directly or indirectly associated with the candidate compound or in an assay involving competition with a labeled competitor. Further, these assays may test whether the candidate compound results in a signal generated by activation of the receptor, using detection systems appropriate to the cells bearing the receptor at their surfaces. Inhibitors of activation are generally assayed in the presence of a known agonist and the effect on activation by the agonist by the presence of the candidate compound is observed.
  • the assays may simply comprise the steps of mixing a candidate compound with a solution containing a receptor polypeptide to form a mixture, measuring receptor activity in the mixture, and comparing the receptor activity of the mixture to a standard.
  • the receptor cDNA, protein and antibodies to the protein may also be used to configure assays for detecting the effect of added compounds on the production of receptor mRNA and protein in cells.
  • an ELISA may be constructed for measuring secreted or cell associated levels of receptor protein using monoclonal and polyclonal antibodies by standard methods known in the art, and this can be used to discover agents which may inhibit or enhance the production of the receptor (also called antagonist or agonist, respectively) from suitably manipulated cells or tissues. Standard methods for conducting screening assays are well understood in the art.
  • Examples of potential receptor antagonists include antibodies or, in some cases, oligonucleotides or proteins which are closely related to the ligand of the receptor, e.g., a fragment of the ligand, or small molecules which bind to the receptor but do not elicit a response, so that the activity of the receptor is prevented.
  • the present invention relates to a screening kit for identifying agonists, antagonists, ligands, receptors, substrates, enzymes, etc. for receptor polypeptides; or compounds which decrease or enhance the production of receptor, which comprises:
  • This invention provides methods of treating an abnormal conditions related to both an excess of and insufficient amounts of receptor activity.
  • One approach comprises administering to a subject an inhibitor compound (antagonist) as described along with a pharmaceutically acceptable carrier in an amount effective to inhibit activation by blocking the binding of ligands to the receptor or by inhibiting a second signal, and thereby alleviating the abnormal condition.
  • soluble forms of the receptor polypeptides still capable of binding the ligand in competition with endogenous receptor may be administered.
  • Typical embodiments of such competitors comprise fragments of the receptor polypeptide.
  • expression of the gene encoding endogenous receptor can be inhibited using expression blocking techniques.
  • Known such techniques involve the use of antisense sequences, either internally generated or separately administered.
  • antisense sequences either internally generated or separately administered.
  • oligonucleotides which form triple helices with the gene can be supplied.
  • oligomers can be administered per se or the relevant oligomers can be expressed in vivo.
  • a therapeutically effective amount of a compound which activates the receptor i.e., an agonist as described above
  • a pharmaceutically acceptable carrier i.e., a pharmaceutically acceptable carrier
  • gene therapy may be employed to effect the endogenous production of the receptor by the relevant cells in the subject.
  • a polynucleotide of the invention may be engineered for expression in a replication defective retroviral vector, as discussed above.
  • the retroviral expression construct may then be isolated and introduced into a packaging cell transduced with a retroviral plasmid vector containing RNA encoding a polypeptide of the present invention such that the packaging cell now produces infectious viral particles containing the gene of interest.
  • These producer cells may be administered to a subject for engineering cells in vivo and expression of the polypeptide in vivo.
  • gene therapy see Chapter 20, Gene Therapy and other Molecular Genetic-based Therapeutic Approaches, (and references cited therein) in Human Molecular Genetics, T Strachan and A P Read, BIOS Scientific Publishers Ltd (1996).
  • Peptides such as the soluble form of receptor polypeptides, and agonists and antagonist peptides or small molecules, may be formulated in combination with a suitable pharmaceutical carrier.
  • suitable pharmaceutical carrier include but are not limited to, saline, buffered saline, dextrose, water, glycerol, ethanol, and combinations thereof. Formulation should suit the mode of administration, and is well within the skill of the art.
  • the invention further relates to pharmaceutical packs and kits comprising one or more containers filled with one or more of the ingredients of the aforementioned compositions of the invention.
  • Polypeptides and other compounds of the present invention may be employed alone or in conjunction with other compounds, such as therapeutic compounds.
  • Preferred forms of systemic administration of the pharmaceutical compositions include injection, typically by intravenous injection. Other injection routes, such as subcutaneous, intramuscular, or intraperitoneal, can be used. Alternative means for systemic administration include transmucosal and transdermal administration using penetrants such as bile salts or fusidic acids or other detergents.
  • oral administration may also be possible. Administration of these compounds may also be topical and/or localized, in the form of salves, pastes, gels and the like.
  • the dosage range required depends on the choice of peptide, the route of administration, the nature of the formulation, the nature of the subject's condition, and the judgment of the attending practitioner. Suitable dosages, however, are in the range of 0.1-100 ⁇ g/kg of subject. Wide variations in the needed dosage, however, are to be expected in view of the variety of compounds available and the differing efficiencies of various routes of administration. For example, oral administration would be expected to require higher dosages than administration by intravenous injection. Variations in these dosage levels can be adjusted using standard empirical routines for optimization, as is well understood in the art.
  • Polypeptides used in treatment can also be generated endogenously in the subject, in treatment modalities often referred to as “gene therapy” as described above.
  • cells from a subject may be engineered with a polynucleotide, such as a DNA or RNA, to encode a polypeptide ex vivo, and for example, by the use of a retroviral plasmid vector. The cells are then introduced into the subject.
  • a polynucleotide such as a DNA or RNA

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Abstract

Receptor polypeptides and polynucleotides and methods for producing such polypeptides by recombinant techniques are disclosed. Also disclosed are methods for utilizing receptor polypeptides and polynucleotides in the design of protocols for the treatment of diseases and diagnostic assays for such conditions.

Description

    FIELD OF INVENTION
  • This invention relates to newly identified polynucleotides and the polypeptides encoded by them, the use of such polynucleotides and polypeptides, and their production. More particularly, the polynucleotides and polypeptides of the present invention relate to specific receptor families described in the specification and known in the art. The invention also relates to inhibiting or activating the action of such polynucleotides and polypeptides. [0001]
  • This application claims benefit of 35 U.S.C. section 119(e) based on copending U.S. Provisional Application Serial Nos. 60/034,204, filed Jan. 21, 1997 And 60/034,205, filed Jan. 21, 1997.[0002]
    • BACKGROUND OF THE INVENTION
  • Receptor proteins are found on the membrane of the cells and are generally involved in signal transduction. There are many types of receptor proteins, and for convenience, these proteins are grouped in families based on similarity in structure and function. [0003]
  • For example, the TM4SF superfamily of cell surface proteins, also known as the tetraspan receptor superfamily, is comprised of at least seventeen individual gene products (these include CD9, CD20, CD37, CD53, CD63, CD81, CD82, A15, CO-029, Sm23, RDS, Uro B, Uro A, SAS, Rom-1, PETA3, and YKK8). The TM4SF superfamily is the second largest group in the CD antigen superfamily. Each member of the TM4SF superfamily can be characterized by several putative physical features including four highly conserved transmembrane domains, two divergent extracellular loops, and two short and highly divergent cytoplasmic tails. Expression patterns for members of the TM4SF superfamily tend to be rather broad and can vary widely between members. The functional roles of TM4SF superfamily members are primarily associated with signal transduction events and pathways, but also include cell adhesion in platelets and other lymphocytic and non-lymphocytic cell lines, as well as cell motility, proliferation, and metastasis. In addition, recent evidence suggests that a subset of the members of the TM4SF superfamily may function as potassium channel molecules. [0004]
  • One member of the TM4SF family, CD20, is a four membrane spanning domain cell surface phosphoprotein expressed exclusively on B lymphocytes. Although the precise functional role of CD20 has yet to be determined, it is thought to function primarily as a receptor during B-cell activation. Furthermore, a large number of experimental observations suggest several additional speculative roles for the CD20 molecule. For example, CD20-specific immunoprecipitation of biochemically cross-linked plasma membrane proteins suggests that CD20 assumes a multimeric structural conformation characteristic of other previously described membrane channel proteins. Further experimentation has revealed that expression of exogenous CD20 on the cell surface specifically increases Ca[0005] 2+ conductance across the plasma membrane. Together, these results suggest that CD20 complexes may function as B-cell specific Ca2+ ion channels. In addition, monoclonal antibodies raised against CD20 have been used to stimulate resting B-cells to transition out of the G0/G1 segment of the cell cycle. It has also been demonstrated that CD20 is associated with both serine and tyrosine kinases and, more specifically, that CD20 is associated, although not directly, with the Src family of tyrosine kinases including p56/531yn, p561ck, and p59fyn.
  • A second example of a receptor subfamily, called sialoadhesin molecules, belongs to the Ig superfamily of receptor-like molecules. The more than 100 members of the Ig superfamily are generally considered to engage in specific cell-cell interactions through which intercellular communication may occur. In addition to classical protein-protein interactions, intercellular communication may also be mediated through protein-carbohydrate interactions. In fact, all members of the sialoadhesin family of the Ig superfamily are capable of mediating protein-sialic acid binding interactions. To date, only a small number of proteins have been assigned to the sialoadhesin family including sialoadhesin, CD33, CD22, the myelin-associated glycoprotein (MAG), and the Schwann cell myelin protein (SMP). Each of these proteins is expressed in a restricted subset of cell types. For example, CD22 and CD33 are expressed exclusively by B-lymphocytes and cells of the myelomonocytic lineage, respectively. [0006]
  • Similarly, galectins are a family of the lectin superfamily of carbohydrate-binding proteins which have a high affinity for b-galactoside sugars. Although a large number of glycoproteins containing b-galactoside sugars are produced by the cell, only a few will bind to known galectins in vitro. Such apparent binding specificity suggests a highly specific functional role for the galectins. Galectin 1 (conventionally termed LGALS1 for lectin, galactoside-binding, soluble −1) is thought to specifically bind laminin, a highly polylactosaminated cellular glycoprotein, as well as the highly polylactosaminated lysosome-associated membrane proteins (LAMPs). Galectin 1 has also been shown to bind specifically to a lactosamine-containing glycolipid found on olfactory neurons and to integrin a[0007] 7b1 on skeletal muscle cells. Galectin 3 has also been observed to bind specifically to laminin, immunoglobulin E and its receptor, and bacterial lipopolysaccharides.
  • Various galectins have been shown to function in the mechanisms of intercellular communication. For example, depending on cell type, [0008] galectin 1 has been observed to modulate cell adhesion either positively or negatively. More specifically, galectin 1 appears to inhibit cell adhesion of skeletal muscle presumably by galectin 1-mediated disruption of laminin-integrin a7b1 interactions. Alternatively, galectin 1 appears to promote cell adhesion in several non-skeletal muscle cell types examined presumably by a glycoconjugate cross-linking mechanism. Galectin 3 has also been observed to function in modulating cell-adhesion, as well as in the activation of certain immune cells by cross-linking IgE and IgE receptors. In addition, galectins have been observed to be involved in the regulation of immune cell activity, as well as in such diverse processes as cell adhesion, proliferation, inflammation, autoimmunity, and metastasis of tumor cells. Furthermore, a galectin-like antigen designated HOM-HD-21 was recently found to be highly expressed in a Hodgkin's Disease cDNA library. Very recently, a novel galectin, termed PCTA-1, was identified as a specific cell surface marker on human prostate cancer cell lines and patient-derived carcinomas. Galectins have also been found to function intracellularly as a component of ribonucleoprotein complexes. Finally, galectins 1 and 3 have each been found to modulate T-cell growth and apoptosis by interaction with CD45 and possibly Bc12, respectively.
  • A relatively new family of cell-surface proteins has been identified and termed the Ly6 superfamily. The members of this family include murine and human,SCA-2, rat Ly-6 (also termed ThB), human CD59 [also known as protectin or membrane attack complex inhibition factor (MACIF)], and E48 antigen. The determination of an initial functional role for SCA-2 may lie in an analysis of its expression profile with regard to the complex process of hematopoiesis. SCA-2 is highly expressed in early thymic precusor cells. In turn, progeny of the intrathymic precusor population continue to express SCA-2, but only until the point of transition occurs from blast cell to small cell. Further experimental evidence demonstrates that mature thymocytes and peripheral T-cells do not express detectable levels of SCA-2, whereas mature, peripheral B-cells do continue to express SCA-2. As a result, it seems very likely that SCA-2 plays an important role in thymocyte maturation and differentiation. A plausible explanation for this functional hypothesis is that SCA-2 may act as a receptor for a unknown cytokine which regulates thymocyte maturation and differentiation. [0009]
  • In addition, CD59 is a recently identified integral membrane protein which appears to be involved in the regulation of complement. Recent studies show that the CD59 antigen may prevent damage from complement C5b-9 and protect astrocytes during inflammatory and infectious disorders of the nervous system. Expression of recombinant human CD59 on porcine donor organs have been shown to prevent complement-mediated lysis and activation of endothelial cells that leads to hyperacute rejection. Recently, researchers at Alexion Pharmaceuticals (New Haven, Conn.) reported on the production of transgenic pigs which expressed human CD59. In these animals, xenogeneic organs were resistant to hyperacute rejection. (Fodor, et al., “Expression of a functional human complement inhibitor in a transgenic pig as a model for the prevention of xenogeneic hyperacute organ rejection,” Proc. Natl. Acad. Sci., 91:1153-11157 (1994).) The same company also reported that expression of recombinant transmembrane CD59 in paroxysmal nocturnal hemoglobinuria (PNH) B-cells confers resistance to human complement. (Rother et al., “Expression of recombinant transmembrane CD59 in paroxysmal nocturnal hemoglobinuria B-cells confers resistance to human complement,” Blood, 84:2604-2611 (1994).) PNH is an acquired hematopoietic disorder characterized by complement-mediated hemolytic anemia, pancytopenia, and venous thrombosis. It is thought that retroviral gene therapy with this molecule could provide a treatment for PNH patients. [0010]
  • A final Ly6 superfamily member, the E48 antigen, is involved in intercellular adhesion between keratinocyte cells of the squamous epithelium. Such keratinocytes are attached to adjoining cells by large numbers of desmosomes, which are thought to play a role in the transition of transformed keratinocytes to metastatic tumor cells. Treatment with a monoclonal antibody raised against the E48 antigen has been successful in the eradication of residual, postoperative squamous cell carcinoma cells of the upper aerodigestive tract in several in vivo models and, to some degree, in humans. (van Dongen, et al., “Progress in radioimmunotherapy of head and neck cancer,” Oncol. Rep. 1:259-264 (1994).) The gene encoding the E48 antigen has been mapped to the q24-qter region of human chromosome 8. Interestingly, a number of human diseases have been mapped to this region of chromosome 8 including Langer-Giedion syndrome, brachio-otorhinolaryngeal syndrome, trichorhinolaryngeal syndrome, and epiderrnolysis bullosa simplex. [0011]
  • A further example of a receptor family includes the prohibitin receptors. The prohibitin gene product is expressed in a wide variety of tissues and has been implicated as a component of a number of anti-proliferative mechanisms. The prohibitin gene encodes a 30 kD postsynthetically modified polypeptide located primarily in the mitochondria, but also may be associated with the IgM receptor on the B-cell plasma membrane. The protein functionally inhibits DNA synthesis and entry into S phase of the cell cycle by an unknown mechanism. Interestingly, although the prohibitin gene product is hypothesized to be involved in the maintenance of senescence and the prevention of cancer, one study found that, although somatic mutations in the prohibitin gene were present in a small number of breast cancers, no mutations were identified in any other breast, ovary, liver, and lung cancers examined. (Sato et al., Genomics 17:762-764 (1993).) However, the prohibitin gene has been mapped to human chromosome 17q12-21, the same region thought to contain the gene involved in sporadic breast cancer. Furthermore, DNA sequence analysis of the prohibitin gene identified somatic mutation in 4 of 23 cases of sporadic breast cancer examined. Thus, prohibitin family members may be involved in the development of cancer. [0012]
  • Moreover, the EGFR family of plasma membrane proteins are an integral component of normal cellular proliferation and in the pathogenesis of the cancerous state. The family is relatively small and includes the EGFR, c-erbB-2, c-erbB-3, and others. Various cancers are correlated with aberrant expression of one or more of these genes. A number of ligands have been identified which bind to the EGFR-like receptors listed above including TGF-a, heparin-binding EGF, amphiregulin, criptoregulin, heregulin, and others. A large fraction of adenocarcinomas examined to date, especially those of the breast, colon, and pancreas, are typified by the amplification or overexpression of the c-erbB-2 gene. EGF, or an analogous ligand, initiates the cellular growth factor response by binding to the EGFR, or EGFR-related, receptor. Following the binding event, the receptor molecule dimerizes activating its intracellular tyrosine kinase domain. This event results in the phosphorylation of specific tyrosine residues near the carboxy terminus of the receptor. The diversity of signals able to be transduced through the relatively small number of EGFR-related receptor molecules is amplified considerably by the recent finding that EGFR-like receptor molecules can function when dimerized with other EGFR family members forming heterodimers. [0013]
  • Members of the EGFR-related family of integral membrane proteins have been implicated in the pathogenesis of a number of human disease-states. For example, a mutation in the EGFR itself appears to play an important role in the development of glioblastomas. (Sang et al., J. Neurosurg 82:841-846 (1995).) The EGFR gene is amplified or overexpressed in the majority of primary human glioblastomas. Although not conferring a distinct advantage on cell growth, an increase in EGFR expression was found to confer an increase in the ability of glioma cells to maintain anchorage-independent growth in soft agar especially in response to EGF and retinoic acid. Anchorage-independent growth in vitro correlates highly with tumorigenicity in vivo, therefore, it is likely that cells which express abnormally high levels of EGFR in human glioblastoma cells may be involved in the high potential for these cells to cause tumors in vivo. [0014]
  • Moreover, overexpression or amplification of c-erbB-2 has been reported to be involved in a high number adenocarcinomas, particularly of the breast, colon, and pancreas, and in a small proportion of ovarian carcinomas. [0015]
  • Thus, there is a clear need for identifying and exploiting-novel members of the receptor families, such as those described above. Although structurally related, these receptors will likely possess diverse and multifaceted functions in a variety of cell and tissue types. Receptor type molecules should prove useful in target based screens for small molecules and other such pharmacologically valuable factors. Monoclonal antibodies raised against such receptors may prove useful as therapeutics in an anti-tumor, diagnostic, or other capacity. Furthermore, receptors described here may prove useful in an active or passive immunotherapeutical role in patients with cancer or other immunocompromised disease states. [0016]
    • SUMMARY OF THE INVENTION
  • In one aspect, the invention relates to receptor polypeptides and polynucleotides, as well as the methods for their production. Another aspect of the invention relates to methods for using such receptor polypeptides and polynucleotides. Such uses include the treatment of the specified diseases, among others. In still another aspect, the invention relates to methods to identify agonists and antagonists using the materials provided by the invention, and treating conditions associated with receptor imbalance with the identified compounds. Yet another aspect of the invention relates to diagnostic assays for detecting diseases associated with inappropriate receptor activity or levels.[0017]
    • DESCRIPTION OF THE INVENTION
  • Definitions [0018]
  • The following definitions are provided to facilitate understanding of certain terms used frequently herein. [0019]
  • “Receptor” refers, among others, to a polypeptide comprising the amino acid sequence set forth in SEQ ID NO: Y, or an allelic variant thereof. [0020]
  • “Receptor Activity” or “Biological Activity of the Receptor” refers to the metabolic or physiologic function of said receptor including similar activities or improved activities or these activities with decreased undesirable side-effects. Also included are antigenic and immunogenic activities of said receptor. [0021]
  • “Receptor gene” refers to a polynucleotide comprising the nucleotide sequence set forth in SEQ ID NO: X or allelic variants thereof and/or their complements. [0022]
  • “SEQ ID NO: X” comprises all or a substantial portion of the polynucleotide encoding each receptor of the invention. The value X for the nucleotide sequence is an integer specified in Table 1. This nucleotide sequence was translated into the receptor polypeptide identified in Table 1 as “SEQ ID NO: Y,” where the value of Y for each receptor polypeptide is an integer defined in Table 1. [0023]
  • The invention further provides a composition of matter comprising a nucleic acid molecule which comprises a human cDNA clone identified by a cDNA Clone ID (Identifier) in Table 1, which DNA molecule is contained in the material deposited with the American Type Culture Collection (“ATCC”) and given the ATCC Deposit Number shown in Table 1 for that cDNA clone. The ATCC is located at American Type Culture Collection (ATCC), 12301 Park Lawn Drive, Rockville, Md. 20852, USA. The deposit has been made under the terms of the Budapest Treaty on the international recognition of the deposit of micro-organisms for purposes of patent procedure. The strain will be irrevocably and without restriction or condition released to the public upon the issuance of a patent. The deposit is provided merely as convenience to those of skill in the art and is not an admission that a deposit is required for enablement, such as that required under 35 U.S.C. §112. The nucleotide sequence of the polynucleotides contained in the deposited material, as well as the amino acid sequence of the polypeptide encoded thereby, are controlling in the event of any conflict with any description of sequences herein. [0024]
  • “Antibodies” as used herein includes polyclonal and monoclonal antibodies, chimeric, single chain, and humanized antibodies, as well as Fab fragments, including the products of an Fab or other immunoglobulin expression library. [0025]
  • “Isolated” means altered “by the hand of man” from the natural state. If an “isolated” composition or substance occurs in nature, it has been changed or removed from its original environment, or both. For example, a polynucleotide or a polypeptide naturally present in a living animal is not “isolated,” but the same polynucleotide or polypeptide separated from the coexisting materials of its natural state is “isolated”, as the term is employed herein. [0026]
  • “Polynucleotide” generally refers to any polyribonucleotide or polydeoxribonucleotide, which may be unmodified RNA or DNA or modified RNA or DNA. “Polynucleotides” include, without limitation single- and double-stranded DNA, DNA that is a mixture of single-and double-stranded regions, single-and double-stranded RNA, and RNA that is mixture of single-and double-stranded regions, hybrid molecules comprising DNA and RNA that may be single-stranded or, more typically, double-stranded or a mixture of single-and double-stranded regions. In addition, “polynucleotide” refers to triple-stranded regions comprising RNA or DNA or both RNA and DNA. The term polynucleotide also includes DNAs or RNAs containing one or more modified bases and DNAs or RNAs with backbones modified for stability or for other reasons. “Modified” bases include, for example, tritylated bases and unusual bases such as inosine. A variety of modifications has been made to DNA and RNA; thus, “polynucleotide” embraces chemically, enzymatically or metabolically modified forms of polynucleotides as typically found in nature, as well as the chemical forms of DNA and RNA characteristic of viruses and cells. “Polynucleotide” also embraces relatively short polynucleotides, often referred to as oligonucleotides. [0027]
  • “Polypeptide” refers to any peptide or protein comprising two or more amino acids joined to each other by peptide bonds or modified peptide bonds, i.e., peptide isosteres. “Polypeptide” refers to both short chains, commonly referred to as peptides, oligopeptides or oligomers, and to longer chains, generally referred to as proteins. Polypeptides may contain amino acids other than the 20 gene-encoded amino acids. “Polypeptides” include amino acid sequences modified either by natural processes, such as posttranslational processing, or by chemical modification techniques which are well known in the art. Such modifications are well described in basic texts and in more detailed monographs, as well as in a voluminous research literature. Modifications can occur anywhere in a polypeptide, including the peptide backbone, the amino acid side-chains and the amino or carboxyl termini. It will be appreciated that the same type of modification may be present in the same or varying degrees at several sites in a given polypeptide. Also, a given polypeptide may contain many types of modifications. Polypeptides may be branched as a result of ubiquitination, and they may be cyclic, with or without branching. Cyclic, branched and branched cyclic polypeptides may result from posttranslation natural processes or may be made by synthetic methods. Modifications include acetylation, acylation, ADP-ribosylation, amidation, covalent attachment of flavin, covalent attachment of a heme moiety, covalent attachment of a nucleotide or nucleotide derivative, covalent attachment of a lipid or lipid derivative, covalent attachment of phosphotidylinositol, cross-linking, cyclization, disulfide bond formation, demethylation, formation of covalent cross-links, formation of cystine, formation of pyroglutamate, formylation, gamma-carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristoylation, oxidation, proteolytic processing, phosphorylation, prenylation, racemization, selenoylation, sulfation, transfer-RNA mediated addition of amino acids to proteins such as arginylation, and ubiquitination. (See, for instance, PROTEINS—STRUCTURE AND MOLECULAR PROPERTIES, 2nd Ed., T. E. Creighton, W. H. Freeman and Company, New York, 1993 and Wold, F., Posttranslational Protein Modifications: Perspectives and Prospects, pgs. 1-12 in POSTTRANSLATIONAL COVALENT MODIFICATION OF PROTEINS, B. C. Johnson, Ed., Academic Press, New York, 1983; Seifter et al., “Analysis for protein modifications and nonprotein cofactors”, Meth Enzymol (1990) 182:626-646 and Rattan et al., “Protein Synthesis: Posttranslational Modifications and Aging”, Ann NY Acad Sci (1992) 663:48-62.) [0028]
  • “Variant” as the term is used herein, is a polynucleotide or polypeptide that differs from a reference polynucleotide or polypeptide respectively, but retains essential properties. A typical variant of a polynucleotide differs in nucleotide sequence from another, reference polynucleotide. Changes in the nucleotide sequence of the variant may or may not alter the amino acid sequence of a polypeptide encoded by the reference polynucleotide. Nucleotide changes may result in amino acid substitutions, additions, deletions, fusions and truncations in the polypeptide encoded by the reference sequence, as discussed below. A typical variant of a polypeptide differs in amino acid sequence from another, reference polypeptide. Generally, differences are limited so that the sequences of the reference polypeptide and the variant are closely similar overall and, in many regions, identical. A variant and reference polypeptide may differ in amino acid sequence by one or more substitutions, additions, deletions in any combination. A substituted or inserted amino acid residue may or may not be one encoded by the genetic code. A variant of a polynucleotide or polypeptide may be a naturally occurring such as an allelic variant, or it may be a variant that is not known to occur naturally. Non-naturally occurring variants of polynucleotides and polypeptides may be made by mutagenesis techniques or by direct synthesis. [0029]
  • “Identity” is a measure of the identity of nucleotide sequences or amino acid sequences. In general, the sequences are aligned so that the highest order match is obtained. “Identity” per se has an art-recognized meaning and can be calculated using published techniques. (See, e.g.: COMPUTATIONAL MOLECULAR BIOLOGY, Lesk, A. M., ed., Oxford University Press, New York, 1988; BIOCOMPUTING: INFORMATICS AND GENOME PROJECTS, Smith, D. W., ed., Academic Press, New York, 1993; COMPUTER ANALYSIS OF SEQUENCE DATA, PART I, Griffin, A. M., and Griffin, H. G., eds., Humana Press, New Jersey, 1994; SEQUENCE ANALYSIS IN MOLECULAR BIOLOGY, von Heinje, G., Academic Press, 1987; and SEQUENCE ANALYSIS PRIMER, Gribskov, M. and Devereux, J., eds., M Stockton Press, New York, 1991.) While there exist a number of methods to measure identity between two polynucleotide or polypeptide sequences, the term “identity” is well known to skilled artisans. (Carillo, H., and Lipton, D., SIAM J Applied Math (1988) 48:1073.) Methods commonly employed to determine identity or similarity between two sequences include, but are not limited to, those disclosed in Guide to Huge Computers, Martin J. Bishop, ed., Academic Press, San Diego, 1994, and Carillo, H., and Lipton, D., SIAM J Applied Math (1988) 48:1073. Methods to determine identity and similarity are codified in computer programs. Preferred computer program methods to determine identity and similarity between two sequences include, but are not limited to, GCS program package (Devereux, J., et al., Nucleic Acids Research (1984) 12(1):387), BLASTP, BLASTN, FASTA (Atschul, S. F. et al., J Molec Biol (1990) 215:403.) [0030]
  • As an illustration, by a polynucleotide having a nucleotide sequence having at least, for example, 95% “identity” to a reference nucleotide sequence of SEQ ID NO: X is intended that the nucleotide sequence of the polynucleotide is identical to the reference sequence except that the polynucleotide sequence may include up to five point mutations per each 100 nucleotides of the reference nucleotide sequence of SEQ ID NO: X. In other words, to obtain a polynucleotide having a nucleotide sequence at least 95% identical to a reference nucleotide sequence, up to 5% of the nucleotides in the reference sequence may be deleted or substituted with another nucleotide, or a number of nucleotides up to 5% of the total nucleotides in the reference sequence may be inserted into the reference sequence. These mutations of the reference sequence may occur at the 5′ or 3′ terminal positions of the reference nucleotide sequence or anywhere between those terminal positions, interspersed either individually among nucleotides in the reference sequence or in one or more contiguous groups within the reference sequence. [0031]
  • Similarly, by a polypeptide having an amino acid sequence having at least, for example, 95% “identity” to a reference amino acid sequence of SEQ ID NO: Y is intended that the amino acid sequence of the polypeptide is identical to the reference sequence except that the polypeptide sequence may include up to five amino acid alterations per each 100 amino acids of the reference amino acid of SEQ ID NO: Y. In other words, to obtain a polypeptide having an amino acid sequence at least 95% identical to a reference amino acid sequence, up to 5% of the amino acid residues in the reference sequence may be deleted or substituted with another amino acid, or a number of amino acids up to 5% of the total amino acid residues in the reference sequence may be inserted into the reference sequence. These alterations of the reference sequence may occur at the amino or carboxy terminal positions of the reference amino acid sequence or anywhere between those terminal positions, interspersed either individually among residues in the reference sequence or in one or more contiguous groups within the reference sequence. [0032]
  • Polypeptides of the Invention [0033]
  • In one aspect, the present invention relates to receptor polypeptides (or receptor proteins). The receptor polypeptides include the polypeptide of SEQ ID NO: Y; as well as polypeptides comprising the amino acid sequence of SEQ ID NO: Y; and polypeptides comprising the amino acid sequence which have at least 80% identity to that of SEQ ID NO: Y over its entire length, and still more preferably at least 90% identity, and even still more preferably at least 95% identity to SEQ ID NO: Y. Furthermore, those with at least 97-99% identity to SEQ ID NO: Y are highly preferred. Also included within receptor polypeptides are polypeptides having the amino acid sequence which have at least 80% identity to the polypeptide having the amino acid sequence of SEQ ID NO: Y over its entire length, and still more preferably at least 90% identity, and even still more preferably at least 95% identity to SEQ ID NO: Y. Furthermore, those with at least 97-99% are highly preferred. Preferably receptor polypeptides exhibit at least one biological activity of the receptor. [0034]
  • The receptor polypeptides may be in the form of the “mature” protein or may be a part of a larger protein such as a fusion protein. It is often advantageous to include an additional amino acid sequence which contains secretory or leader sequences, pro-sequences, sequences which aid in purification such as multiple histidine residues, or an additional sequence for stability during recombinant production. [0035]
  • Fragments of the receptor polypeptides are also included in the invention. A “fragment” is a polypeptide having an amino acid sequence that entirely is the same as part, but not all, of the amino acid sequence of the aforementioned receptor polypeptides. As with receptor polypeptides, fragments may be “free-standing,” or comprised within a larger polypeptide of which they form a part or region, most preferably as a single continuous region. Representative examples of polypeptide fragments of the invention, include, for example, fragments from about amino acid number 1-20, 21-40, 41-60, 61-80, 81-100, and 101 to the end of receptor polypeptide. In this context “about” includes the particularly recited ranges larger or smaller by several, 5, 4, 3, 2 or 1 amino acid at either extreme or at both extremes. [0036]
  • Preferred fragments include, for example, truncation polypeptides having the amino acid sequence of receptor polypeptides, except for deletion of a continuous series of residues that includes the amino terminus, or a continuous series of residues that includes the carboxyl terminus or deletion of two continuous series of residues, one including the amino terminus and one including the carboxyl terminus. [0037]
  • Also preferred are fragments characterized by structural or functional domains, such as fragments -that comprise alpha-helix and alpha-helix forming regions, beta-sheet and beta-sheet-forming regions, turn and turn-forming regions, coil and coil-forming regions, hydrophilic regions, hydrophobic regions, alpha amphipathic regions, beta amphipathic regions, flexible regions, surface-forming regions, substrate binding region, and high antigenic index regions. The “domains” of each receptor polypeptide are illustrated in the Figures. The Figures compare SEQ ID NO: Y to the closest know homologue. Identical amino acids shared between the two polypeptides are shaded, while conservative amino acid changes are boxed. By examining the regions or amino acids shaded and/or boxed, the skilled artisan can readily identify conserved domains between the two polypeptides. The amino acids sequences of SEQ ID NO: Y falling within these conserved domains are “fragments” and are specifically contemplated by the present invention. Especially preferred is the extracellular domains of a receptor of the invention. Soluble extracellular domains have antagonist activity mediated by competition with a receptor ligand. [0038]
  • Other preferred fragments are biologically active fragments. Biologically active fragments are those that mediate receptor activity, including those with a similar activity or an improved activity, or with a decreased undesirable activity. Also included are those that are antigenic or immunogenic in an animal, especially in a human. [0039]
  • Preferably, all of these polypeptide fragments retain a biological activity of the receptor, including antigenic activity. Variants of the defined sequence and fragments also form part of the present invention. Preferred variants are those that vary from the referents by conservative amino acid substitutions—i.e., those that substitute a residue with another of like characteristics. Typical such substitutions are among Ala, Val, Leu and Ile; among Ser and Thr; among the acidic residues Asp and Glu; among Asn and Gln; and among the basic residues Lys and Arg; or aromatic residues Phe and Tyr. Particularly preferred are variants in which several, 5-10, 1-5, or 1-2 amino acids are substituted, deleted, or added in any combination. [0040]
  • The receptor polypeptides of the invention can be prepared in any suitable manner. Such polypeptides include isolated naturally occurring polypeptides, recombinantly produced polypeptides, synthetically produced polypeptides, or polypeptides produced by a combination of these methods. Means for preparing such polypeptides are well understood in the art. [0041]
  • Polynucleotides of the Invention [0042]
  • Another aspect of the invention relates to receptor polynucleotides. Receptor polynucleotides include isolated polynucleotides which encode the receptor polypeptides and fragments, and polynucleotides closely related thereto. More specifically, a receptor polynucleotide of the invention includes a polynucleotide comprising the nucleotide sequence contained in SEQ ID NO: X encoding a receptor polypeptide of SEQ ID NO: Y, and polynucleotide having the particular sequence of SEQ ID NO: X. [0043]
  • Receptor polynucleotides further include a polynucleotide comprising a nucleotide sequence that has at least 80% identity over its entire length to a nucleotide sequence encoding the receptor polypeptide of SEQ ID NO: Y, and a polynucleotide comprising a nucleotide sequence that is at least 80% identical to that of SEQ ID NO: X over its entire length. In this regard, polynucleotides at least 90% identical are particularly preferred, and those with at least 95% are especially preferred. Furthermore, those with at least 97% are highly preferred and those with at least 98-99% are most highly preferred, with at least 99% being the most preferred. Also included under receptor polynucleotides are a nucleotide sequence which has sufficient identity to a nucleotide sequence contained in SEQ ID NO: X, or contained in the cDNA insert in the plasmid deposited with ATCC, to hybridize under conditions useable for amplification or for use as a probe or marker. Moreover, the receptor polynucleotide includes a nucleotide sequence having at least 80% identity to a nucleotide sequence encoding the receptor polypeptide expressed by the cDNA insert deposited at the ATCC, and a nucleotide sequence comprisings at least 15 contiguous nucleotides of such cDNA insert. In this regard, polynucleotides at least 90% identical are particularly preferred, and those with at least 95% are especially preferred. Furthermore, those with at least 97% are highly preferred and those with at least 98-99% are most highly preferred, with at least 99% being the most preferred. The invention also provides polynucleotides which are complementary to all the above receptor polynucleotides. [0044]
  • The receptors of the invention are structurally related to other proteins of specified receptor families, as shown by the results in the Figures. The cDNA sequence of SEQ ID NO: X encodes a polypeptide as described in Table 1 as SEQ ID NO: Y. Because the receptor polypeptides contain domains similar in structure to other receptor family members, the receptors of the present invention are expected to have, inter alia, similar biological functions/properties to their homologous polypeptides and polynucleotides, and their utility is obvious to anyone skilled in the art. [0045]
    TABLE 1
    Clone ID SEQ ID SEQ ID ATCC ATCC Receptor
    Name NO:X NO:Y Deposit No. Deposit Date Family Homology
    HMACR70
    1 18 209054 May 16, 1997 Ig Sialoadhesin
    ##### Jan. 21, 1998 OB-1
    HTEDK48 209054 May 16, 1997 TM4SF MRC-OX44
    PETA-3
    1-1849 bp 2
    160-900 bp 3 19
    HTPED39 4 20 209054 May 16, 1997 TM4SF NAG-2
    HPWAE25 ##### Jan. 21, 1998 TALLA-1
    HTPEF86 5 21 209053 May 16, 1997 TM4SF CD20
    B1 Antigen
    HSBBF02 6 22 209054 May 16, 1997 TM4SF TALLA-1
    HLTAH80 7 23 97242 Aug. 2, 1995 TM4SF TALLA-1
    209054 May 16, 1997
    HTPBA27 8 24 97242 Aug. 2, 1995 TM4SF NAG-2
    209054 May 16, 1997
    HAIDQ59 209054 May 16, 1997 TM4SF CD9
    Antigen
    5' 9 25
    Sequence
    3' 10
    Sequence
    HHFEK40
    11 26 209054 May 16, 1997 TM4SF PETA-3
    HGBGV89 12 27 209125 Jun. 9, 1997 TM4SF L6H
    209054 May 16, 1997
    HUVBB80 13 28 209054 May 16, 1997 TM4SF L6
    HJACE54 14 29 209053 May 16, 1997 Lectin Galectin-3
    Galectin-5
    Galectin-8
    HROAD63 15 30 209053 May 16, 1997 Ly6 E48 splice
    variant
    HMWGS4 16 31 209053 May 16, 1997 Prohibitin BAP-37
    6
    HNFGW06 17 32 209053 May 16, 1997 EGFR EGFR
  • The novel full-length cDNA clone designated HMACR70 may be a member of the sialoadhesin family of the Ig superfamily of receptor-like molecules and a CD33 homologue. HMACR70 contains a 1497 nucleotide cDNA insert encoding a 315 amino acid ORF and was cloned from a GM-CSF-treated human macrophage cDNA library. The only additional cDNA libraries in the HGS database which include this clone are human eosinophils and possibly human gall bladder. A BLAST analysis of the amino acid sequence of HMACR70 demonstrates that this clone exhibits approximately 50% identity and 69% similarity over a 300 amino acids stretch of a gene termed human differentiation antigen, and 38% identity and 62% similarity of the human myelin-associated glycoprotein precursor CD33 gene. [0046]
  • A more recent BLAST analysis confirms HMACR70's designation as a sialoadhesin family member. HMACR70 is homologous to two recently identified sialoadhesin family members, human OB binding protein (OB) 1 and 2. (See, Genbank Accession No. U71382; see FIG. 1.) It is thought that OB-1 and OB-2 may bind leptin. Thus, HMACR70, as a sialoadhesin family member, may act to attenuate or even amplify intercellular routes of communication, including binding to leptin or modulating the activity of immune cells, such as macrophages. Clearly, any diseases affected by these processes could be treated by the polypeptide or fragment of HMACR70. [0047]
  • The full-length nucleotide sequences of ten novel human cDNA clones which potentially belong to the TM4SF superfamily are disclosed in the table above and will be addressed sequentially. [0048]
  • The cDNA clone HTEDK48 contains a 1849 nucleotide cDNA insert encoding a 245 amino acid ORF that was cloned from a human testes cDNA library. The coding sequence of HTEDK48 (SEQ ID NO: 3) may be fused to other human proteins, such as 3-hydroxyacyl-CoA dehydrogenase. BLAST analysis of the amino acid sequence of HTEDK48 demonstrates that this clone exhibits approximately 30% identity and 51% similarity over a 245 amino acid stretch of the CD82 molecule. Recent studies have shown that CD82 can associate with CD4 or CD8 and deliver costimulatory signals for the TCR/CD3 pathway. CD82 has also been found to be involved in syncytium formation in HTLV-I-infected T-cells. And finally, in a recently published study in which the expression of the CD82 gene by tumors of the lung was examined retrospectively, it was reported that CD82 may be linked to the suppression of tumor metastasis of prostate cancer. The study also reported that decreased CD82 expression may be involved in malignant progression of such cancers. Thus, HTEDK48 may also be involved in the development of cancer. [0049]
  • A more recent BLAST analysis shows that HTEDK48 is homologous the rat leukocyte antigen, MRC OX-44, and the platelet endothelial tetraspan antigen -3 (PETA-3). (See FIG. 2X.) MRC OX-44, a member of a new family of cell surface proteins, appears to be involved in growth regulation. (See, Bellacosa, A., et al., “The Rat Leukocyte antigen MRC OX-44 is a Member of a New Family of Cell Surface Proteins which Appear to be Involved in Growth Regulation,” Mol. Cell. Bio. 11: 2864-2872 (1991).) Similarly, PETA-3 has been located to platelet endothelial cells, and an anti-PETA-3 antigen monoclonal antibody can stimulate platelet aggregation and mediator release. (See, Fitter, S., “Molecular Cloning of cDNA Encoding a Novel Platelet-Endothelial Cell Tetra-Span Antigen, PETA-3,” Blood, 86(4):1348-1355 (1995).) Thus, HTEDK48 may function similar to MRC OX-44 or PETA-3 to affect growth of blood cells. Administering polypeptides or fragments of HTEDK48 may be an effective treatment of blood disorders. [0050]
  • The cDNA clone HPWAE25 contains a 1288 nucleotide cDNA insert encoding a 273 amino acid ORF that was cloned from a human pancreas tumor cDNA library, while clone HTPED39 represents a truncated cDNA sequence. This clone also appears in a number of other cDNA libraries constructed from a variety of human cell and tissue types including keratinocytes, ulcerative colitis, striatum depression, lymph node breast cancer, ovarian cancer, stage B2 prostate cancer, kidney medulla, and others. Northern blot analysis of HLTAH80 also shows expression in a variety of human cell lines including U937, MM96, WM115, and MDAMB231. A BLAST analysis of the amino acid sequence of HTPED39 demonstrates that this clone exhibits approximately 35% identity and 50% similarity over the entire length of the CD37 molecule. The CD37 antigen is expressed on B cells and on a subpopulation of T cells, but not on pre-B or plasma cells. It has been reported that CD37 expression is downregulated in conjunction with B-cell activation, suggesting that CD37 may be involved in the processes which dictate the activation state of the B-cell. [0051]
  • Moreover, HPWAE25 is also homologous to recently identified TM4SF members, NAG-2 and TALLA-1. (See FIG. 3.) NAG-2 is thought to complex with integrins and other TM4SF proteins, while TALLA-1 is a highly specific marker of T-cell acute lymphoblastic leukemia and neuroblastoma. (See, Tachibana, I., et al., “NAG-2, A Novel Transmembrane-4 Superfamily (TM4SF) Protein that Complexs with Integrins and Other TM4SF Proteins,” J. Biol. Chem., 272:29181-29189 (1997); Takagi, S., “Identification of a Higly Specific Surface Marker of T-cell Acute Lymphoblastic Leukemia and Neuroblastoma as a New Member of the [0052] Transmembrane 4 Superfamily,” Int. J. Cancer 61(5):706-715 (1995).) Thus, HPWAE25 may be involved the development of cancer, particularly leukemia, lymphoma, and neuroblastoma. HPWAE25 may be used as an effective treatment of these cancers, as well as a diagnostic marker.
  • A subfamily of TM4SF receptors include CD20 proteins. A CD20-like cDNA clone was obtained from a human pancreas tumor cDNA library and contains a 1236 nucleotide insert which encodes a 250 amino acid ORF. A BLAST analysis of the deduced amino acid sequence of HTPEF86 exhibits approximately 41% identity and 61% similarity to the CD20 gene, also known as B1 antigen. (See FIG. 4.) Expression of this gene is detected in only two additional HGS human cDNA libraries; amygdala depression and 9 week early stage human. Although the precise functional role of CD20 has yet to be determined, it is clear that CD20 plays a key role in the regulation of B-cell activation. Based primarily on sequence identity, the novel CD20-like molecule presented herein may also be involved in cell cycle activation. Potential therapeutic and/or diagnostic applications for HTPEF86 may include such clinical presentations as juvenile rheumatoid arthritis, Graves' Disease, and a number of B-cell lymphomas or other lymphoid tumors. [0053]
  • The clone HSBBF02 contains a 1115 nucleotide cDNA insert encoding a 245 amino acid ORF and was cloned from an HSC 172 cell line cDNA library. This clone also appears in a number of other cDNA libraries constructed from a variety of human cell and tissue types including brain amygdala depression, endothelial cells, fetal liver and heart, osteoblasts, testes, and others. A BLAST analysis of the amino acid sequence of HSBBF02 demonstrates that this clone exhibits approximately 64% identity and 80% similarity with the A15 molecule over a 131 amino acid stretch (A15 is composed of 244 amino acids). A more recent BLAST search shows that HSBBF02 is similar to the TALLA-1 protein and may in fact be a closely related family member. (See FIG. 5.) [0054]
  • In addition, a second cDNA clone, designated HLTAH80, exhibits sequence similarity to the A15 molecule and TALLA-1. (See FIG. 6.) This clone contains a 1662 nucleotide cDNA insert encoding a 253 amino acid ORF and was cloned from a human T-cell lymphoma cDNA library. This clone also appears in a number of other cDNA libraries constructed from a variety of human cell and tissue types including B-cell lymphoma, corpus collosum, endometrial tumor, osteosarcoma, testes, and others. Northern blot analysis of HLTAH80 also shows expression in a variety of human tissues including spleen, lymph node, thymus, PBLs, heart, and a particularly strong signal in skeletal muscle and pancreas. A BLAST analysis of the amino acid sequence of HLTAH80 demonstrates that this clone exhibits approximately 35% identity and 55% similarity over the entire length of the A15 molecule. [0055]
  • Since expression of A15 drops to undetectable levels when comparing immature T-cells to peripheral blood lymphocytes, it is thought that A15 may play a role in the development of T-cells. Furthermore, the MXS1(CCG-B7) gene which codes for A15 contains a number of triplet nucleotide repeats which have been associated with neuropsychiatric diseases such as Huntington's chorea, fragile X syndrome, and myotonic dystrophy. In addition, A15 appears to be expressed exclusively on T-cell acute lymphoblastic leukemia cell lines, including several derived from adult T-cell leukemia and those established by immortalization with human T-cell [0056] leukemia virus type 1 or Herpesvirus saimiri. Thus, clones HLTAH80 and/or HSBBF02 may also be involved in diseases caused by the expansion of repeats or chromosomal instability.
  • The cDNA clone HTPBA27 contains a 1345 nucleotide cDNA insert encoding a 238 amino acid ORF and was cloned from a human tumor pancreas cDNA library. This clone also appears in a number of other cDNA libraries constructed from a variety of human cell and tissue types including cerebellum, breast lymph node, osteosarcoma, adult testes, RS4;11 bone marrow cell line, microvascular endothelial cells, and others. A BLAST analysis of the amino acid sequence of HTPBA27 demonstrates that this clone exhibits approximately 40% identity and 64% similarity with a glycoprotein termed CD53 over its entire length. CD53 is thought to be involved in thymopoiesis, since rat CD53 can be detected on immature CD4-8-thymocytes and the functionally mature single-positive subset, but cannot be detected on the intermediate CD4+8+ thymocytic subset of cells. The CD53 molecule has also been implicated as a component of signal transduction pathways in B cells, monocytes and granulocytes, rat macrophages, NK, and T cells. Moreover, as illustrated in FIG. 7, HTPBA27 was recently confirmed as a TM4SF receptor. (See, Tachibana, I., et al., “NAG-2, A Novel Transmembrane-4 Superfamily (TM4SF) Protein that with Integrins and Other TM4SF Proteins,” J. Biol. Chem., 272:29181-29189 (1997).) Calling the HTPBA27 polypeptide NAG-2, this group confirmed HTPBA27's status as a TM4SF receptor by showing that NAG-2 complexes with integrin and other TM4SF receptors. Thus, diseases caused by the failure of HTPBA27 to complex with integrin and other TM4SF receptors can be treated by administering HTPBA27. HTPBA27 can also be used to diagnose these diseases. [0057]
  • The cDNA clone HAIDQ59 contains cDNA insert encoding a 221 amino acid ORF that was cloned from a human epithelial cell induced with TNFa and INF cDNA library. The 5′ end of HAIDQ59 is represented by the SEQ ID NO: 9, while the 3′ end is represented by SEQ ID NO: 10. This clone appears in only two additional cDNA libraries in the HGS database. These two libraries were constructed from the human Jurkat T-cell line and human microvascular endothelial cells. A BLAST analysis of the amino acid sequence of HAIDQ59 demonstrates that this clone exhibits approximately 53% identity and 69% similarity over 226 amino acids of the CD9 TM4SF molecule. (See FIG. 8.) It has been demonstrated that the CD9 molecule is involved in signal transduction pathways in platelets, as well as in cell adhesion in both platelets and pre-B-cell lines. Intriguingly, a monoclonal antibody (vpg15), which recognizes the feline homologue of CD9, has been shown to block infection by feline immunodeficiency virus (FIV). Furthermore, a recent study shows that cells expressing high levels of CD9 exhibited suppressed cell motility. Thus, HAIDQ59 may also be involved in signal transduction of blood cells. [0058]
  • The cDNA clone HHFEK40 contains a 936 nucleotide cDNA insert encoding a 252 amino acid ORF and was cloned from a human fetal heart cDNA library. This clone appears once in the human fetal heart cDNA library and possibly in a hemangiopericytoma cDNA library. A BLAST analysis of the amino acid sequence of HHFEK40 demonstrated that this clone exhibits approximately 60% identity and 75% similarity over the entire length of a molecule designated PETA-3. (See FIG. 9.) PETA-3 was originally identified as a novel human platelet surface glycoprotein termed gp27. Although PETA-3 is present in low abundance on the platelet surface, an anti-PETA-3 monoclonal antibody can stimulate platelet aggregation and mediator release. Thus, HHFEK40 may function similar to PETA-3 to affect growth of blood cells. Administering polypeptides or fragments of HHFEK40 may be an effective treatment of blood disorders. [0059]
  • The cDNA clone HGBGV89 contains a 738 nucleotide cDNA insert encoding a 197 amino acid ORF and was cloned from a human gall bladder cDNA library. The only two additional appearances of this clone in the HGS database are in a normalized fetal liver cDNA library and in a fetal liver/spleen cDNA library. The cDNA clone HUVBB80 contains a 1071 nucleotide cDNA insert encoding a 201 amino acid ORF and was cloned from a human umbilical vein cDNA library. This clone appears in several additional cDNA libraries in the HGS database including prostate BPH, thyroid, and fetal liver/spleen. BLAST analyses of the amino acid sequences of HGBGV89 and HUVBB80 demonstrate that these clones exhibit approximately 49% identity and 65% similarity and 47% identity and 68% similarity, respectively, over the entire length of a molecule designated L6 surface protein or human tumor-associated antigen L6. (See FIGS. 10 & 11.) Moreover, another group has confirmed the TM4SF receptor homology of HGBGV89 by describing the protein as a putative transmembrane protein L6H. (See Genbank Accession No 2587054; see FIG. 10.) The L6 cell surface antigen is highly expressed on lung, breast, colon, and ovarian carcinomas. Promising results of [0060] phase 1 clinical studies have been reported with an anti-L6 monoclonal antibody, or its humanized counterpart, suggesting that the L6 antigen may be an attractive target for monoclonal antibody-based cancer therapy.
  • In summary, there is a clear need for identifying and exploiting novel members of the TM4SF superfamily such as those described herein. Although structurally related, these factors will likely possess diverse and multifaceted functions in a variety of cell and tissue types. Receptor type molecules, such as the novel potential members of the TM4SF superfamily detailed here, should prove useful in target based screens for small molecules and other such pharmacologically valuable factors. Monoclonal antibodies raised against such factors may prove useful as therapeutics in an anti-tumor, diagnostic, or other capacity. Furthermore, factors such as the nine novel TM4SF superfamily-like molecules described here may prove useful in an active or passive immunotherapeutical role in patients with cancer or other immunocompromised disease states. [0061]
  • Besides TM4SF receptors, receptors from other families are also described. For example, clone HJACE54, also called [0062] galectin 11, exhibits significant sequence identity to the rat galectin 5, the chicken galectin 3 gene, and the human galectin 8 genes. (See FIG. 12.) The galectin 11 cDNA clone contains an 865 nucleotide insert which encodes a 133 amino acid ORF. The clone was obtained from a Jurkat T-cell G1 phase cDNA library. A BLAST analysis of the deduced amino acid sequence of HJACE54 demonstrates approximately 35% identity and 57% similarity to the amino acid sequence of the rat galectin 5 gene. Expression of galectin 11 is quite limited in the HGS database. In fact, the only two additional ESTs in the HGS database which contain the HJACE54 sequence were found in human neutrophil and human infant adrenal gland cDNA libraries. Northern blot analyses have not been performed to examine expression patterns of the galectin 11 gene.
  • Various galectins have been shown to function in the mechanisms of intercellular communication. For example, depending on cell type, [0063] galectin 1 has been observed to modulate cell adhesion either positively or negatively. More specifically, galectin 1 appears to inhibit cell adhesion of skeletal muscle presumably by galectin 1-mediated disruption of laminin-integrin a7b1 interactions. Alternatively, galectin 1 appears to promote cell adhesion in several non-skeletal muscle cell types examined presumably by a glycoconjugate cross-linking mechanism. Galectin 3 has also been observed to function in modulating cell-adhesion, as well as in the activation of certain immune cells by cross-linking IgE and IgE receptors. In addition, galectins have been observed to be involved in the regulation of immune cell activity, as well as in such diverse processes as cell adhesion, proliferation, inflammation, autoimmunity, and metastasis of tumor cells. Furthermore, a galectin-like antigen designated HOM-HD-21 was recently found to be highly expressed in a Hodgkin's Disease cDNA library. Very recently, a novel galectin, termed PCTA-1, was identified as a specific cell surface marker on human prostate cancer cell lines and patient-derived carcinomas. Galectins have also been found to function intracellularly as a component of ribonucleoprotein complexes. Finally, galectins 1 and 3 have each been found to modulate T-cell growth and apoptosis by interaction with CD45 and possibly Bc12, respectively. As a result, the discovery of a novel galectin, such as that encoded by HJACE54, is likely to be a valuable asset both diagnostically and therapeutically.
  • Additionally, a full-length nucleotide sequence of a novel human cDNA clone which encodes an apparent splice variant of the previously described human E48 antigen has recently been determined. (See FIG. 13.) Clone HROAD63 contains a 441 nucleotide cDNA which encodes a 70 amino acid polypeptide. This novel clone exhibits significant sequence identity to several members of a relatively new family of cell-surface proteins termed the Ly6 superfamily. These members include murine and human SCA-2, rat Ly-6 (also termed ThB), and human CD59 [also known as protectin or membrane attack complex inhibition factor (MACIF)]. The novel E48 splice variant was obtained from the HGS human stomach cDNA library. The clone is present in only a limited number of other HGS cDNA libraries including kidney cancer, keratinocyte, and tongue. An alignment of the nucleotide sequences of the human E48 and HROAD63 cDNAs demonstrates that the initial 168 and 178 nucleotides of E48 and HROAD63, respectively, are identical, with the exception of an additional 10 nucleotides of sequence at the extreme 5′ end of the HROAD63 sequence. The sequence of the two clones is also identical for an additional 229 nucleotides including the 3′ end of the coding sequences and the entire 3′ untranslated regions. The only divergence of nucleotide sequence in this region of the clones is the deletion of a single thymidine residue in the 3′ UTR of the E48 cDNA. The major difference between the two nucleotide sequences is a 329 nucleotide deletion from the HROAD63 sequence. This deletion causes a shift in the HROAD63 reading frame and encompasses the translational stop signal used in the E48 clone. As a result, the carboxy terminal sequence of HROAD63 is radically altered with regard to that of E48 (as illustrated in FIG. 13 by the obvious differences between amino acids 56-128 of E48 and 56-70 of HROAD63 in the amino acid alignment). The clinical presentation of disorders, including abnormal skin and hair phenotypes, may be attributed, at least in part, to a non-functional Ly6 superfamily member such as E48 or HROAD63. HROAD63 may also be involved in blood disorders, as seen with its homologues SCA-2 and CD59. [0064]
  • A novel prohibitin cDNA clone presented herein was originally identified in a human bone marrow cell line (RS4;11) cDNA library. The clone contains a 1066 nucleotide insert which encodes a 299 amino acid polypeptide. BLAST and BestFit analyses of the predicted amino acid sequence of HMWGS46 demonstrate a highly significant sequence identity to a murine protein termed IgM B-cell receptor associated protein (BAP)-37 (Genbank accession number X78683). The HMWGS46 amino acid sequence exhibits nearly perfect identity and similarity over the entire length of the murine BAP-37 sequence. (See FIG. 14.) In addition, the full-length nucleotide sequences of HMWGS46 and BAP-37 exhibit at least 87% identical. The HMWGS46 clone also exhibits approximately 49% sequence identity and 85% sequence similarity to a human gene designated prohibitin. Finally, the HMWGS46 cDNA appears in a substantial number of HGS human cDNA libraries in addition to the bone marrow cell line cDNA library from which it was cloned. Some of the cDNA libraries in which this clone appears include keratinocytes, induced endothelial cells, activated neutrophils, synovial sarcoma, colon carcinoma cell line, Jurkat cell line membrane bound polysomes, epileptic frontal cortex, primary dendritic cells, and a number of others. The novel gene related to prohibitin and BAP-37 may prove quite useful as a diagnostic for tumorigenesis, as well as a target for therapeutic intervention of such an event. Thus, although the precise functional role of the prohibitin family members are less than clear, it is quite likely that such homologues are involved in such complex processes as development, senescence, and tumor suppression. Therefore a novel gene, such as HMWGS46, may prove quite useful as a diagnostic for tumorigenesis, as well as a target for therapeutic intervention of such an event. [0065]
  • A human cDNA clone encoding a novel epidermal growth factor receptor (EGFR)-like molecule is also disclosed. The novel EGFR-like cDNA clone presented herein was originally identified in an activated human neutrophil cDNA library. The clone contains a 704 nucleotide insert which encodes a 168 amino acid polypeptide. A BLAST analysis of the predicted amino acid sequence of HNFGW06 demonstrates that this novel clone exhibits approximately 85% identity and 90% similarity to a protein designated epidermal growth factor receptor-related protein [Homo sapiens]. (See FIG. 15.) The expression profile of the HNFGW06 clone in the HGS database indicates the existence of a fairly highly restricted expression pattern. In addition to the activated neutrophil library from which this clone was obtained, it also appears in the following HGS human cDNA libraries: synovial sarcoma, smooth muscle, placenta, and possibly primary dendritic cells. [0066]
  • The novel EGFR-like cDNA clone HNFGW06 may lead to a number of exciting possibilities for therapeutic and/or diagnostic treatments or reagents. For example, HNFGW06 may be involved in the onset of human breast cancers as well. In addition, due to the fact that TGF-a acts through binding to the EGFR, it is possible that HNFGW06 may also play a role in a variety of gastric processes including regulation of acid secretion, regulation of mucous cell growth, and protection against ethanol- and aspirin-induced injury to gastric tissues. [0067]
    • GENERATING POLYNUCLEOTIDES
  • Polynucleotides of the present invention encoding a receptor may be obtained using standard cloning and screening, from a cDNA library derived from mRNA in cells specified in Table 1 using the expressed sequence tag (EST) analysis (Adams, M. D., et al. Science (1991) 252:1651-1656; Adams, M. D. et al., Nature, (1992) 355:632-634; Adams, M. D., et al., Nature (1995) 377 Supp:3-174.) Polynucleotides of the invention can also be obtained from natural sources such as genomic DNA libraries or can be synthesized using well known and commercially available techniques. [0068]
  • The nucleotide sequence encoding a receptor polypeptide of SEQ ID NO: Y may be identical to the polynucleotide encoding SEQ ID NO: Y, or it may be a sequence, which as a result of the redundancy (degeneracy) of the genetic code, also encodes the polypeptide of SEQ ID NO: Y. [0069]
  • When the polynucleotides of the invention are used for the recombinant production of a receptor polypeptide, the polynucleotide may include the coding sequence for the mature polypeptide or a fragment thereof, by itself; the coding sequence for the mature polypeptide or fragment in reading frame with other coding sequences, such as those encoding a leader or secretory sequence, a pre-, or pro-or prepro-protein sequence, or other fusion peptide portions. For example, a marker sequence which facilitates purification of the fused polypeptide can be encoded. In certain preferred embodiments of this aspect of the invention, the marker sequence is a hexa-histidine peptide, as provided in the pQE vector (Qiagen, Inc.) and described in Gentz et al., Proc Natl Acad Sci USA (1989) 86:821-824, or is an HA tag. The polynucleotide may also contain non-coding 5′ and 3′ sequences, such as transcribed, non-translated sequences, splicing and polyadenylation signals, ribosome binding sites and sequences that stabilize mRNA. [0070]
  • Further preferred embodiments are polynucleotides encoding receptor variants comprising the amino acid sequence of receptor polypeptide of Table 1 (SEQ ID NO: Y) in which several, 5-10, 1-5, 1-3, 1-2 or 1 amino acid residues are substituted, deleted or added, in any combination. [0071]
  • The present invention further relates to polynucleotides that hybridize to the herein above-described sequences. In this regard, the present invention especially relates to polynucleotides which hybridize under stringent conditions to the herein above-described polynucleotides. As herein used, the term “stringent conditions” means hybridization will occur only if there is at least 80%, and preferably at least 90%, and more preferably at least 95%, yet even more preferably 97-99% identity between the sequences. [0072]
  • Polynucleotides of the invention, which are identical or sufficiently identical to a nucleotide sequence contained in SEQ ID NO: X or a fragment thereof, or to the cDNA insert in the plasmid deposited at the ATCC, or a fragment thereof, may be used as hybridization probes for cDNA and genomic DNA, to isolate full-length cDNAs and genomic clones encoding the receptor and to isolate cDNA and genomic clones of other genes (including genes encoding homologs and orthologs) that have a high sequence similarity to the receptor gene. Such hybridization techniques are known to those of skill in the art. Typically these nucleotide sequences are 80% identical, preferably 90% identical, more preferably 95% identical to that of the referent. The probes generally will comprise at least 15 nucleotides. Preferably, such probes will have at least 30 nucleotides and may have at least 50 nucleotides. Particularly preferred probes will range between 30 and 50 nucleotides. [0073]
  • In one embodiment, to obtain a polynucleotide encoding the receptor polypeptide, including homologs and orthologs from other species, comprises the steps of screening an appropriate library under stringent hybridization conditions with a labeled probe having the SEQ ID NO: X or a fragment thereof; and isolating full-length cDNA and genomic clones containing said polynucleotide sequence. Such hybridization techniques are well known to those of skill in the art. Stringent hybridization conditions are as defined above or, alternatively, conditions under overnight incubation at 42° C. in a solution comprising: 50% formamide, 5×SSC (150 mM NaCl, 15 mM trisodium citrate), 50 mM sodium phosphate (pH7.6), 5× Denhardt's solution, 10% dextran sulfate, and 20 microgram/ml denatured, sheared salmon sperm DNA, followed by washing the filters in 0.1×SSC at about 65° C. The polynucleotides and polypeptides of the present invention may be employed as research reagents and materials for discovery of treatments and diagnostics to animal and human disease. [0074]
  • Vectors, Host Cells, Expression [0075]
  • The present invention also relates to vectors which comprise a polynucleotide or polynucleotides of the present invention, and host cells which are genetically engineered with vectors of the invention and to the production of polypeptides of the invention by recombinant techniques. Cell-free translation systems can also be employed to produce such proteins using RNAs derived from the DNA constructs of the present invention. [0076]
  • For recombinant production, host cells can be genetically engineered to incorporate expression systems or portions thereof for polynucleotides of the present invention. Introduction of polynucleotides into host cells can be effected by methods described in many standard laboratory manuals, such as Davis et al., BASIC METHODS IN MOLECULAR BIOLOGY (1986) and Sambrook et al., MOLECULAR CLONING: A LABORATORY MANUAL, 2nd Ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1989) such as calcium phosphate transfection, DEAE-dextran mediated transfection, transvection, microinjection, cationic lipid-mediated transfection, electroporation, transduction, scrape loading, ballistic introduction or infection. [0077]
  • Representative examples of appropriate hosts include bacterial cells, such as streptococci, staphylococci, [0078] E. coli, Streptomyces and Bacillus subtilis cells; fungal cells, such as yeast cells and Aspergillus cells; insect cells such as Drosophila S2 and Spodoptera Sf9 cells; animal cells such as CHO, COS, HeLa, C127, 3T3, BHK, HEK 293 and Bowes melanoma cells; and plant cells.
  • A great variety of expression systems can be used. Such systems include, among others, chromosomal, episomal and virus-derived systems, e.g., vectors derived from bacterial plasmids, from bacteriophage, from transposons, from yeast episomes, from insertion elements, from yeast chromosomal elements, from viruses such as baculoviruses, papova viruses, such as SV40, vaccinia viruses, adenoviruses, fowl pox viruses, pseudorabies viruses and retroviruses, and vectors derived from combinations thereof, such as those derived from plasmid and bacteriophage genetic elements, such as cosmids and phagemids. The expression systems may contain control regions that regulate as well as engender expression. Generally, any system or vector suitable to maintain, propagate or express polynucleotides to produce a polypeptide in a host may be used. The appropriate nucleotide sequence may be inserted into an expression system by any of a variety of well-known and routine techniques, such as, for example, those set forth in Sambrook et al., MOLECULAR CLONING, A LABORATORY MANUAL (supra). [0079]
  • For secretion of the translated protein into the lumen of the endoplasmic reticulum, into the periplasmic space or into the extracellular environment, appropriate secretion signals may be incorporated into the desired polypeptide. These signals may be endogenous to the polypeptide or they may be heterologous signals. [0080]
  • If the receptor polypeptide is to be expressed for use in screening assays, generally, it is preferred that the polypeptide be produced at the surface of the cell. In this event, the cells may be harvested prior to use in the screening assay. If the receptor polypeptide is secreted into the medium, the medium can be recovered in order to recover and purify the polypeptide; if produced intracellularly, the cells must first be lysed before the polypeptide is recovered. [0081]
  • Receptor polypeptides can be recovered and purified from recombinant cell cultures by well-known methods including ammonium sulfate or ethanol precipitation, acid extraction, anion or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxylapatite chromatography and lectin chromatography. Most preferably, high performance liquid chromatography is employed for purification. Well known techniques for refolding proteins may be employed to regenerate active conformation when the polypeptide is denatured during isolation and or purification. [0082]
  • Diagnostic Assays [0083]
  • This invention also relates to the use of receptor polynucleotides or polypeptides for use as diagnostic reagents. Detection of a mutated form of the receptor gene associated with a dysfunction will provide a diagnostic tool that can add to or define a diagnosis of a disease or susceptibility to a disease which results from under-expression, over-expression or altered expression of the receptor. Individuals carrying mutations in the receptor gene may be detected at the DNA level by a variety of techniques. [0084]
  • Nucleic acids for diagnosis may be obtained from a subject's cells, such as from blood, urine, saliva, tissue biopsy or autopsy material. The genomic DNA may be used directly for detection or may be amplified enzymatically by using PCR or other amplification techniques prior to analysis. RNA or cDNA may also be used in similar fashion. Deletions and insertions can be detected by a change in size of the amplified product in comparison to the normal genotype. Point mutations can be identified by hybridizing amplified DNA to labeled receptor nucleotide sequences. Perfectly matched sequences can be distinguished from mismatched duplexes by RNase digestion or by differences in melting temperatures. DNA sequence differences may also be detected by alterations in electrophoretic mobility of DNA fragments in gels, with or without denaturing agents, or by direct DNA sequencing. (See, e.g., Myers et al., Science (1985) 230:1242.) Sequence changes at specific locations may also be revealed by nuclease protection assays, such as RNase and S1 protection or the chemical cleavage method. (See Cotton et al., Proc Natl Acad Sci USA (1985) 85: 4397-4401.) In another embodiment, an array of oligonucleotides probes comprising receptor nucleotide sequence or fragments thereof can be constructed to conduct efficient screening of e.g., genetic mutations. Array technology methods are well known and have general applicability and can be used to address a variety of questions in molecular genetics including gene expression, genetic linkage, and genetic variability. (See for example: M. Chee et al., Science, Vol 274, pp 610-613 (1996).) [0085]
  • The diagnostic assays offer a process for diagnosing or determining a susceptibility to specific diseases through detection of mutation in the receptor gene by the methods described. [0086]
  • In addition, specific diseases can be diagnosed by methods comprising determining from a sample derived from a subject an abnormally decreased or increased level of receptor polypeptide or receptor mRNA. Decreased or increased expression can be measured at the RNA level using any of the methods well known in the art for the quantitation of polynucleotides, such as, for example, PCR, RT-PCR, RNase protection, Northern blotting and other hybridization methods. Assay techniques that can be used to determine levels of a protein in a sample derived from a host are well-known to those of skill in the art. Such assay methods include radioimmunoassays, competitive-binding assays, Western Blot analysis and ELISA assays. [0087]
  • Thus in another aspect, the present invention relates to a diagnostic kit for a disease or susceptibility to a disease which comprises: [0088]
  • (a) a receptor polynucleotide, preferably the nucleotide sequence of SEQ ID NO: X, or a fragment thereof; [0089]
  • (b) a nucleotide sequence complementary to that of (a); [0090]
  • (c) a receptor polypeptide, preferably the polypeptide of SEQ ID NO: Y, or a fragment thereof; or [0091]
  • (d) an antibody to a receptor polypeptide, preferably to the polypeptide of SEQ ID NO: Y. [0092]
  • It will be appreciated that in any such kit, (a), (b), (c) or (d) may comprise a substantial component. [0093]
  • Chromosome Assays [0094]
  • The nucleotide sequences of the present invention are also valuable for chromosome identification. The sequence is specifically targeted to and can hybridize with a particular location on an individual human chromosome. The mapping of relevant sequences to chromosomes according to the present invention is an important first step in correlating those sequences with gene associated disease. Once a sequence has been mapped to a precise chromosomal location, the physical position of the sequence on the chromosome can be correlated with genetic map data. Such data are found, for example, in V. McKusick, Mendelian Inheritance in Man (available on line through Johns Hopkins University Welch Medical Library). The relationship between genes and diseases that have been mapped to the same chromosomal region are then identified through linkage analysis (coinheritance of physically adjacent genes). [0095]
  • The differences in the cDNA or genomic sequence between affected and unaffected individuals can also be determined. If a mutation is observed in some or all of the affected individuals but not in any normal individuals, then the mutation is likely to be the causative agent of the disease. [0096]
  • Antibodies [0097]
  • The polypeptides-of the invention or their fragments or analogs thereof, or cells expressing them can also be used as immunogens to produce antibodies immunospecific for the receptor polypeptides. The term “immunospecific” means that the antibodies have substantially greater affinity for the polypeptides of the invention than their affinity for other related polypeptides in the prior art. [0098]
  • Antibodies generated against the receptor polypeptides can be obtained by administering the polypeptides or epitope-bearing fragments, analogs or cells to an animal, preferably a nonhuman, using routine protocols. For preparation of monoclonal antibodies, any technique which provides antibodies produced by continuous cell line cultures can be used. Examples include the hybridoma technique (Kohler, G. and Milstein, C., Nature (1975) 256:495-497), the trioma technique, the human B-cell hybridoma technique (Kozbor et al., Immunology Today (1983) 4:72) and the EBV-hybridoma technique (Cole et al., MONOCLONAL ANTIBODIES AND CANCER THERAPY, pp. 77-96, Alan R. Liss, Inc., 1985). [0099]
  • Techniques for the production of single chain antibodies (U.S. Pat. No. 4,946,778) can also be adapted to produce single chain antibodies to polypeptides of this invention. Also, transgenic mice, or other organisms including other mammals, may be used to express humanized antibodies. [0100]
  • The above-described antibodies may be employed to isolate or to identify clones expressing the polypeptide or to purify the polypeptides by affinity chromatography. Antibodies against receptor polypeptides may also be employed to treat diseases. [0101]
  • Vaccines [0102]
  • Another aspect of the invention relates to a method for inducing an immunological response in a mammal which comprises inoculating the mammal with a receptor polypeptide, or a fragment thereof, adequate to produce antibody and/or T cell immune response to protect said animal from a disease. Yet another aspect of the invention relates to a method of inducing immunological response in a mammal which comprises, delivering a receptor polypeptide via a vector directing expression of the receptor polynucleotide in vivo in order to induce such an immunological response to produce antibody to protect said animal from diseases. [0103]
  • Further aspect of the invention relates to an immunological/vaccine formulation (composition) which, when introduced into a mammalian host, induces an immunological response in that mammal to a receptor polypeptide wherein the composition comprises a receptor polypeptide or receptor gene. The vaccine formulation may further comprise a suitable carrier. Since a receptor polypeptide may be broken down in the stomach, it is preferably administered parenterally (including subcutaneous, intramuscular, intravenous, intradermal etc. injection). Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation instonic with the blood of the recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents or thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials and may be stored in a freeze-dried condition requiring only the addition of the sterile liquid carrier immediately prior to use. The vaccine formulation may also include adjuvant systems for enhancing the immunogenicity of the formulation, such as oil-in water systems and other systems known in the art. The dosage will depend on the specific activity of the vaccine and can be readily determined by routine experimentation. [0104]
  • Screening Assays [0105]
  • The receptor polypeptide of the present invention may be employed in a screening process for compounds which bind the receptor and which activate (agonists) or inhibit activation of (antagonists) the receptor polypeptide of the present invention. Thus, polypeptides of the invention may also be used to assess the binding of small molecule substrates and ligands in, for example, cells, cell-free preparations, chemical libraries, and natural product mixtures. These substrates and ligands may be natural substrates and ligands or may be structural or functional mimetics. See Coligan et al., Current Protocols in Immunology 1(2):Chapter 5 (1991). [0106]
  • The receptor polypeptides are responsible for many biological functions, including many pathologies. Accordingly, it is desirous to find compounds and drugs which stimulate the receptor on the one hand and which can inhibit the function of the receptor on the other hand. In general, agonists are employed for therapeutic and prophylactic purposes for such conditions and diseases. Antagonists may be employed for a variety of therapeutic and prophylactic purposes for such conditions and diseases. [0107]
  • In general, such screening procedures involve producing appropriate cells which express the receptor-polypeptide of the present invention on the surface thereof. Such cells include cells from mammals, yeast, Drosophila or [0108] E. coli. Cells expressing the receptor (or cell membrane containing the expressed receptor) are then contacted with a test compound to observe binding, or stimulation or inhibition of a functional response.
  • The assays may simply test binding of a candidate compound wherein adherence to the cells bearing the receptor is detected by means of a label directly or indirectly associated with the candidate compound or in an assay involving competition with a labeled competitor. Further, these assays may test whether the candidate compound results in a signal generated by activation of the receptor, using detection systems appropriate to the cells bearing the receptor at their surfaces. Inhibitors of activation are generally assayed in the presence of a known agonist and the effect on activation by the agonist by the presence of the candidate compound is observed. [0109]
  • Further, the assays may simply comprise the steps of mixing a candidate compound with a solution containing a receptor polypeptide to form a mixture, measuring receptor activity in the mixture, and comparing the receptor activity of the mixture to a standard. [0110]
  • The receptor cDNA, protein and antibodies to the protein may also be used to configure assays for detecting the effect of added compounds on the production of receptor mRNA and protein in cells. For example, an ELISA may be constructed for measuring secreted or cell associated levels of receptor protein using monoclonal and polyclonal antibodies by standard methods known in the art, and this can be used to discover agents which may inhibit or enhance the production of the receptor (also called antagonist or agonist, respectively) from suitably manipulated cells or tissues. Standard methods for conducting screening assays are well understood in the art. [0111]
  • Examples of potential receptor antagonists include antibodies or, in some cases, oligonucleotides or proteins which are closely related to the ligand of the receptor, e.g., a fragment of the ligand, or small molecules which bind to the receptor but do not elicit a response, so that the activity of the receptor is prevented. [0112]
  • Thus in another aspect, the present invention relates to a screening kit for identifying agonists, antagonists, ligands, receptors, substrates, enzymes, etc. for receptor polypeptides; or compounds which decrease or enhance the production of receptor, which comprises: [0113]
  • (a) a receptor polypeptide, preferably that of SEQ ID NO: Y; [0114]
  • (b) a recombinant cell expressing a receptor polypeptide, preferably that of SEQ ID NO: Y; [0115]
  • (c) a cell membrane expressing a receptor polypeptide; preferably that of SEQ ID NO: Y; or [0116]
  • (d) antibody to a receptor polypeptide, preferably that of SEQ ID NO: Y. [0117]
  • It will be appreciated that in any such kit, (a), (b), (c) or (d) may comprise a substantial component. [0118]
  • Prophylactic and Therapeutic Methods [0119]
  • This invention provides methods of treating an abnormal conditions related to both an excess of and insufficient amounts of receptor activity. [0120]
  • If the activity of the receptor is in excess, several approaches are available. One approach comprises administering to a subject an inhibitor compound (antagonist) as described along with a pharmaceutically acceptable carrier in an amount effective to inhibit activation by blocking the binding of ligands to the receptor or by inhibiting a second signal, and thereby alleviating the abnormal condition. [0121]
  • In another approach, soluble forms of the receptor polypeptides still capable of binding the ligand in competition with endogenous receptor may be administered. Typical embodiments of such competitors comprise fragments of the receptor polypeptide. [0122]
  • In still another approach, expression of the gene encoding endogenous receptor can be inhibited using expression blocking techniques. Known such techniques involve the use of antisense sequences, either internally generated or separately administered. (See, for example, O'Connor, J Neurochem (1991) 56:560 in Oligodeoxynucleotides as Antisense Inhibitors of Gene Expression, CRC Press, Boca Raton, Fla. (1988).) Alternatively, oligonucleotides which form triple helices with the gene can be supplied. (See, for example, Lee et al., Nucleic Acids Res (1979) 6:3073; Cooney et al., Science (1988) 241:456; Dervan et al., Science (1991) 251:1360.) These oligomers can be administered per se or the relevant oligomers can be expressed in vivo. [0123]
  • For treating abnormal conditions related to an under-expression of the receptor and its activity, several approaches are also available. One approach comprises administering to a subject a therapeutically effective amount of a compound which activates the receptor, i.e., an agonist as described above, in combination with a pharmaceutically acceptable carrier, to thereby alleviate the abnormal condition. Alternatively, gene therapy may be employed to effect the endogenous production of the receptor by the relevant cells in the subject. For example, a polynucleotide of the invention may be engineered for expression in a replication defective retroviral vector, as discussed above. The retroviral expression construct may then be isolated and introduced into a packaging cell transduced with a retroviral plasmid vector containing RNA encoding a polypeptide of the present invention such that the packaging cell now produces infectious viral particles containing the gene of interest. These producer cells may be administered to a subject for engineering cells in vivo and expression of the polypeptide in vivo. For overview of gene therapy, see [0124] Chapter 20, Gene Therapy and other Molecular Genetic-based Therapeutic Approaches, (and references cited therein) in Human Molecular Genetics, T Strachan and A P Read, BIOS Scientific Publishers Ltd (1996).
  • Formulation and Administration [0125]
  • Peptides, such as the soluble form of receptor polypeptides, and agonists and antagonist peptides or small molecules, may be formulated in combination with a suitable pharmaceutical carrier. Such formulations comprise a therapeutically effective amount of the polypeptide or compound, and a pharmaceutically acceptable carrier or excipient. Such carriers include but are not limited to, saline, buffered saline, dextrose, water, glycerol, ethanol, and combinations thereof. Formulation should suit the mode of administration, and is well within the skill of the art. The invention further relates to pharmaceutical packs and kits comprising one or more containers filled with one or more of the ingredients of the aforementioned compositions of the invention. [0126]
  • Polypeptides and other compounds of the present invention may be employed alone or in conjunction with other compounds, such as therapeutic compounds. Preferred forms of systemic administration of the pharmaceutical compositions include injection, typically by intravenous injection. Other injection routes, such as subcutaneous, intramuscular, or intraperitoneal, can be used. Alternative means for systemic administration include transmucosal and transdermal administration using penetrants such as bile salts or fusidic acids or other detergents. In addition, if properly formulated in enteric or encapsulated formulations, oral administration may also be possible. Administration of these compounds may also be topical and/or localized, in the form of salves, pastes, gels and the like. [0127]
  • The dosage range required depends on the choice of peptide, the route of administration, the nature of the formulation, the nature of the subject's condition, and the judgment of the attending practitioner. Suitable dosages, however, are in the range of 0.1-100 μg/kg of subject. Wide variations in the needed dosage, however, are to be expected in view of the variety of compounds available and the differing efficiencies of various routes of administration. For example, oral administration would be expected to require higher dosages than administration by intravenous injection. Variations in these dosage levels can be adjusted using standard empirical routines for optimization, as is well understood in the art. [0128]
  • Polypeptides used in treatment can also be generated endogenously in the subject, in treatment modalities often referred to as “gene therapy” as described above. Thus, for example, cells from a subject may be engineered with a polynucleotide, such as a DNA or RNA, to encode a polypeptide ex vivo, and for example, by the use of a retroviral plasmid vector. The cells are then introduced into the subject. [0129]
  • All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth. [0130]
    HMACR70
    GCAGTTCCTCAGACAAGAACCCTCAGCAACAGACGTTCCCTCGCGGCCCTGGCACCTCCAACCCCAGATATGCTGCTCCTGCTGCTGTG
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 90
    CCTCAAGCACTCTCTTCTTGGCACTCCTTGTCTGCAACGCAGCGCCCGGACCGTGGAGGTTGGCGTCTATACGACGACGACGACGACCAC
    (SEQ ID NO:18)
                                                                          M  L  L  L  L  L  L
    CCCCTCCTCTCCGGCAGGCACACCCTCCAACCACACAAGACTAACCGCAAGGATTACTCCCTCACCATGCAGAGTTCCCTGACCGTGCAA
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 180
    GGGGACGAGACCCCCTCCCTCTCCCACCTTCCTGTCTTCTCATTCGCCTTCCTAATCACCGACTGCTACGTCTCAACGCACTGGACGTT
     P  L  L  W  C  R  S  R  V  S  G  O  K  S  H  R  K  D  Y  S  L  T  M  O  S  S  V  T  V  O
    CAGGCCATCTCTCTCCATCTGCGCTCCTCCTTCTCCTACCCACTGGACACCCAGACTGACTCTGACCCAGTTCATGCCTACTCCTTCCCG
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 270
    CTCCCCTACACACAGGTACACCCCACGACCAAGAGCATCGCTCACCTCTCGGTCTCACTCACACTGCCTCAAGTACCCATGACCAACCCC
     S  G  M  C  V  H  V  R  C  S  F  S  Y  P  V  D  O  T  D  S  D  P  V  H  G  Y  W  F  R
    GCAGGCAATCATATAACCTGGAAGCCTCCACTCCCCACAAACAACCCACCTTGGCCAGTGCAGCACGAAACTCGCCACCCATTCCACCTC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 360
    CGTCCCTTACTATATTCCACCTTCCCACGTCACCGCTCTTTCTTCCCTCCAACCCCTCACGTCCTCCTTTCAGCCCTCGCTAACGTCCAC
     A  G  N  D  I  S  W  K  A  P  V  A  T  N  N  P  A  W  A  V  G  E  E  T  R  O  R  F  H  L
    CTTGCCGACCCACAGACCAAAAATTCCACCCTCACCATCACAGATGCCAGAATCACTGATGCGGGGACATACTTCTTTCGTATGCACAAA
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 450
    GAACCCCTGCCTCTCTCCTTTTTAACCTCGGACTCGTACTCTCTACCCTCTTACTCACTACCCCCTCTATCAAGAAACCATACCTCTTT
     L  G  O  P  Q  T  K  N  C  T  L  S  I  R  D  A  R  M  S  D  A  C  R  Y  F  F  R  P  M  E  K
    CGAAATATAAAATGCAATTATAAATATGACCACCTCTCTGTGAACCTCACATACCCTCCTCACAACTTGACTCTCACTCTCTTCCAAGGA
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 540
    CCTTTATATTTTACCTTAATATTTATACTGGTCCAGAGACACTTCCACTCTATGGCAGGACTCTTGAACTGACACTCACACAAGGTTCCT
     G  N  I  K  W  N  Y  K  Y  D  O  L  S  V  H  V  T  Y  P  P  O  N  L  F  V  F  V  F  O  C
    GAAGGCACACCATCCACAGCTCTGCCCAACACCTCATCTCTTTCACTCCTAGAGCGCCAGTCTCTGCCCTFCCTCTCTGCTGTTCACACC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 630
    CTTCCGTGTCCTAGGTGTCGACACCCCTTCTCCACTACAGAAAGTCACGATCTCCCGGTCACACACGCGAACCAGACACGACAACTGTCC
     E  G  T  A  S  T  A  L  C  N  S  S  S  L  S  V  L  E  G  O  S  L  R  L  V  C  A  V  D  S
    AATCCCCCTGCCAGCCTGACCTGGACCTGCAGCAGTCTCACCCTCTACCCCTCACAGCCCTCAAACCCTCTCGTACTGCACCTCCAACTC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 720
    TTAGCGCGACGGTCCCACTCGACCTGGACCTCCTCACACTGCGACATCCGGAGTCTCCGGAGTTTGCCACACCATGACCTCGACCTTCAC
     N  P  P  A  R  L  S  W  T  W  R  S  L  F  L  Y  P  S  O  P  S  N  P  L  V  L  E  L  O  V
    CACCTCGGCGATGAAGGCGAATTCACCTGTCCAGCTCACAACTCTCTCGCTTCCCACCACCFTTCCCTCAACCTCTCCCTCCAACAGGAC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 810
    GTCGACCCCCTACTTCCCCTTAACTGCACACCTCGACTCTTCACACACCCAACCGTCCTCCAAACCGACTTCCACACCCACGFFGTCCTC
     H  L  G  D  E  G  E  F  T  C  R  A  O  N  S  L  C  S  O  H  V  S  L  N  L  S  L  O  O  E
    TACACAGCCAAAATCAACCCTCTATCACCACFCTTCCTGCCCCCCGTCGGCCCAACTCCACCCACACCCCTCCTCTTCCTCTCCTTCTGT
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 900
    ATCTCFCCGTTTTACTTCGCACATACTCCTCACAACGACCCCCGCCAGCCCCCTTCACCTCGGTGTCCCGACCACAACGACAGGAACACA
      Y  T  G  K  M  K  P  V  S  G  V  L  L  G  A  V  C  C  T  G  A  T  A  L  V  F  L  S  F  C
    GTCATCTTCATFGFACTCACGTCCTCCACGAACAAATCCGCAAGACCACCAGCCCACGTGCCACACATAGCCAFCAAGGATGCAAACACC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 990
    CACTAGAACTAACATCACTCCAGGACCTCCTTCTTTAGCCCTTCTCCTCCTCCCCTGCACCCTCTCTATCCCTACTTCCTACCTTTCTCC
     V  I  F  I  V  V  R  S  C  R  K  K  S  A  R  P  A  A  O  V  C  O  I  C  P  I  K  D  A  N  T
    ATTCACGCGCTCAGCCTCTCAGGGTAACTGGATGAGTCCTCCGCACAFGATAACCCCCGACACCATCCCCTCCCTCCCCACTCCCTCAGC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 1080
    TAACTCCCCGAGTCGCAGAGTCCCATTGACCTACTCAGCACCCCTCTACTATTCGCCCCFGTCCTACCCCACCCACCCCTGAGCCAGTCC
      I  O  C  L  S  L  S  C
    HMACR70
    (SEQ ID NO:1)
    CGAGGAAAGACAGATCCCACTATGCACCCCTCACCTTTCATAAGCCGGAGCCTCACCACCTATCCAGGTCAAGAACCCATGAG
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 1170
    CCTCCTTTCTCTCTACGCTCATACCTGCCCAGTCCAAACTATTCCCCCTCGGAGTCCTGGATAGGTCCAGTTCTTCGGT
    TACTCAGACATCAACATCCCCAAGTAAGAAAATGCACACCCTCGGGCTTGTTTCAGGGTTCACCACCCCTCCAGCAAACGAGTT
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 1260
    ATCAGfCTCTAGTTCTAGGGGTTCATTCTTTTACCTCTCCGAGCCCGAACAAACTCCCAAGTGCTCGCGAGCTCCTTTCCTCAGACTCCG
    TCATTCCAGTACAATTAGCACCCCTCAATGCTGTGCAACAAGACATCACAACTTATTCCTCTTCTCTAACTGAAAATGCATGCCTGT
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 1350
    ACTAAGGTCATCTTAATCCTCGGGAGTTACCACACGTGGTTCTGTAGTCTTGAATAAGGAGAACAGATTCACTTTTACGTACGGACTACT
    CCAAACTCTCCCTTTCCCCATCCAATCGGTCCACACTCCCCGCCCTGGCCTCTGTACCCACGATTCTCCTCTGTACTTCTCTAAGGATGA
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 1440
    GGTTTGAGAGGGAAAGGGGTAGGTTAGCCAGGTGTGAGGGGCGGGACCGGAGACATGGGTGGTAAGAGGAGACATGAAGAGATTCCTACT
    CTACTTTAGATTCCGAATATAGTGAGATTGTAACGTGAAAAAAAAAAAAAAAAAAAA
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|+→ 1497
    GATGAAATCTAAGGCTTATATCACTCTAACATTGCACTTTTTTTTTTTTTTTTTTTT
    HTEDK48
    (SEQ ID NO:3)
    CCCCACCACTCCACAACCATCACGCAGCCACCACACACAGCCCCACAGCAACTCACCATTCCCCCCCCTTCCTCAGGGATCCCTT
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 90
    GGCCTACTCCCTCCCTCCTGTCTCTCCCCCTCTCCTTCACTCCTAACCCCCCCCAACCACTCTACCCATACTACA
    CCCAAACACTAGCCCACAGGTTCACCAACATGTTAACTTAAATCTTCCGCTCCCCCACTCTCTTCACCATCGCTGAAATCC
    (SEQ ID NO:19)
                                                                          M  A  E  H  T  P
    TATTCTTCCTTGAACAAACTGTTATCTTTACTCAATCCCTTCCTGCCTCTCTCTCGCATCATCCTACTTCCCCTCCCCATTCCTCCT
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 270
    ATAACAACCAACTTCTTTCACAATACAAATCACTTACCCAACCACCCACACACACCCTACTACCATCAACCCCACCCGTAACCACCATTT
     Y  S  S  L  K  K  L  L  S  L  L  N  C  F  V  A  V  S  C  I  I  L  V  G  L  G  I  C  C  K
    TCTCCACGCGCCTCTCTGACGAATCTCCTCCCGCTCTCCTCCCCATACCTCCTTCACCTTCCCAACCTCTCCCTGCTCATGCCATCCATC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 360
    ACACCTCCCCCCACACACTCCTTACACCACCCCCACACCACCCCTATCCACCAAGTCCAACCCTTCGACACCCACCACTACCCTACCTAC
     C  G  C  A  S  L  T  N  V  L  C  L  S  S  A  Y  L  L  H  V  C  N  L  C  L  V  M  C  C
    ACCCTACTCCTTGCCTCTCCCCCGTCCTATCCACCCACTAAACACACCACACCCACCCTCTTCTTTTCCATCCTGTCAATCCTTATTCT
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 450
    TCCCATCACCAACCGACACCCCCCACCATACCTCCCTCATTTCTCTCGTCTCCCTCCCACAACAAAACCTACCACAGTTACCAATAACAC
     T  V  L  L  C  C  A  C  W  Y  C  A  T  K  E  S  R  C  T  L  L  T  C  I  L  S  M  V  I  V
    CTCATCATCCAACTTACACCTCCCACACTCCTCCTTCTTTTCTTTCCAATTCTTCCACATCTCCCCTTCCAACACACCTTCCTCACCCTC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 540
    CACTACTACCTTCAATTCTCCACCCTCTCACCACCAACAAAACAAACCTTAACAACCTCTACACCCCAACCTTCTCTCCAACCACTCCCAC
     L  I  M  E  V  T  A  A  T  V  V  L  L  F  F  P  I  V  C  O  V  A  L  E  N  T  F  G  V  T  L
    AGGAACAATTACACACCTTACAACCACCCATACCACTATTCTACACACTCCAACTTCCTCATCCACAACCTAAACTCCTCTCCCCTCAAT
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 630
    TCCTTCTTAATGTCTCCAATGTTGCTCGGTCTGCTGATAAGATGTGTCACCTTGAACCAGTACCTCTTCGATTTCACGACACCCCACTTA
     R  K  N  Y  R  C  Y  N  E  P  O  D  Y  S  T  G  W  N  L  V  M  E  K  L  K  C  C  C  V  N
    AACTACACACATTTTTCTCCCTCTTCCTTCCAAATCACAACCCCCCACACCTACCCCACCACTTCCTCTAAATCCATCCCAACTCTCTCC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 720
    TTCATCTCTCTAAAAACACCCACAACCAACCTTTACTCTTCCCCCCTCTCCATCCCCTCCTCAACCACATTTACCTACCCTTCACACACC
     N  Y  T  D  F  S  C  S  S  F  E  M  T  T  C  T  Y  P  R  S  C  C  K  S  C  S  V  S
    TGTGACGGACGCGATGTGTCTCCAAACGTCATCCACCAGAAGGGCTGTTTCCATAAACTCCTAAAAATCACCAAGACTCAGAGCTTCACC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 810
    ACACTCCCTCCCCTACACACACCTTTCCACTACCTCCTCTTCCCCACAAACCTATTTCACCATTTTTACTCCTTCTCACTCTCCAACTCC
     C  D  C  R  D  V  S  P  N  V  H  O  K  C  C  F  H  K  I  T  K  I  K  I  O  S  F  T
    CTCACTCCCACCTCTCTCCCACCTCCACTCATACACACCTCCCCCTCTCCCTATCTTCCCCACCCTCCTCTTCAACTCCTCCCCTAAACC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 900
    CACTCACCCTCCACACACCCTCCACCTCACTATCTCTCCACCCCCACACCCATACAACCCCTCCCACCACAACTTCACCACCCCATTTCC
     L  S  C  S  S  L  C  A  A  V  C  R  W  C  S  R  Y  V  A  D  A  C  L  E  I  L  A
    GATCCCCCCCCCTACCCCTCCCAAACTCCTCCCTTTACCACCCTCACCCACCACCCTCCCCTTCCTCCATCCTTTTAACCTTCCTCACCC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 990
    CTACCCCCCCCCATCCCCACCCTTTCACCACCCAAATCCTCCCACTCCCTCCTCCCACCCCAACCACCTACCAAAATTCCAACCACTCCC
    TCTCCCTCACACCACCTCTCCCTCAATCTCCATCCACCCCCACCTCCCACATCACCAACACATACAATCTTTCCCACCAACACTTCCTCC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 1080
    ACACCCACTCTCCTCCACACCCACTTACACCTACCTCCCCCTCCACCCTCTACTCCTTCTCTATCTTACAAACCCTCCTTCTCAACCACC
    HTEDK48
    (SEQ ID NO:2)
    TTCCACATTACAAGCATAGCTAATGCCACCACCACACAAGACCGATTCCCTCCCCTCCATTTCTTCAACCCACTGCCTCTCATCAAACTT
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 1117
    AACGTCTAATCTTCGTATCGATTACGCTGGTGCTCTGTTCTGGCTAAGCCACCGGACGTAAAGAAGTTCCGTCACGCACAGTACTTTGAA
    GTCGAGGTCATTAAAACACCAATCACCACCCACAAGACATTTCAATTTTTGGTAGACTTTAGCAAAACCCTACCAAAGCATCCTGTGGCT
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 1126
    CACCTCCAGTAATTTTGTGGTTACTGGTCGGTCTTCTGTAAACTTAGAAACCATCTGAAATCGTTTTGCCATGTTTCGTAGGACAAAGA
    TGCAAGGACACTCCTGGGTTTATTCTGAACCCCCTCCTCGTTCCA1ACCTCATCGAAGCAATCAGGCTCTATGAACGAGCCCCTCCTGGC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 1135
    ACGTTCCTGTGAGGACCCAAATAACACTTGGCGGAGGACCAAGGTATGCAGTACCTTCGTTAGTCGCACATACTTGCTCCCGCAGGACCC
    TTTCCCTGTGGGCTTCTCAGAAACGTTTCTGGAACTCCCACCACCCCCACTACAGTCCCAGCCAGAGCAATTGCATGGCCGGCCCACATT
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 1144
    AAAGCGACACCCGAAGACTCTTTCCAAACACCTTGAGGGTGGTGGGCGTCATGTCAGCGTCGGTCTCGTTAACGTACCGGCCGGGTCTAA
    GATATCCTGGATCTCTGCTTTTGATTAAAAGGTGACGCATCCAAAGAAGACATTGACACTGCTATGAAATTAGCAGCCGGTTACCCCATG
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 1530
    CTATACGACCTAGAGACCAAAACTAATTTTCCACTCCGTACGTTTCTTCTGTAACTGTCACGATACTTTAATCCTCGGCCAATGGGGTAC
    GGCCCATTTGAGCTTCTAGATTATGTCGGACTGGATACTACGAAGTTCATCGTG1GATGGGTCGCATCAAATGGATGCAGAGAACCCATTA
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 1620
    CCGCGTAAACTCGAAGATCTAATACAGCCTCACCTATCATGCTTCAAGTAGCACCTACCCACCGTACTTTACCTACGTCTCTTGGCTAAT
    CATCAGCCCAGCCCATCCTTAAATAAGCTG1GTACTCAGAGAACAAGTTCGGCAAGAAGACTCGACAAGGATTTTACAAATACAAGTGATGT
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 1171
    GTAGTCGGGTCGGGTAGGAATTTATTCGACCATCGTCTCTTGTTCAAGCCGTTCTTCTGACCTCTTCCTAAAATGTTTATGTTCACTACA
    GCAGCTTCTCCGGTTCTGAGAACAACACCTGAGAGCCCTTTCCACCCACTGCCCCCAGTGCCTGTGGTGAATGCTCTTTGGTCACACATTC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 160
    CGTCGAAGAGGCCAAGACTCTTCTTGTGGACTCTCGCGAAAGGTCGCTCACGGGGCTCACGGACACCCTTACGAGAAACCAGTCTGTAAC
    CCTCACACAGTACAGTTTAATAAATGTTCATTTTCATTGTAAAAAAAAA
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|+++→ 184
    GCAGTGTGTCATCTCAAATTATTTACACGTAAAACTAACATTTTYTTTT
    HPWAE25
    (SEQ ID NO:4)
    GGCCTCCCTCTCCCTCCCCACTCACTCCCAACACCCCCCACCTCTTTTCTCCTTTCTCCACGCTCACCACTTCCCTCTTTCACAAT
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 90
    CCCCACCCACACGGACCCCTCACVCACCCTTCTGCCCCCTCCACAAAACACCAAACACCTCCCACTCCTGAACCGACAAACTCTTC
    TCCCAACACCCCTCAACACCACCCACCATCCACTCCTTCACCTTCATTAACACCATCATGATCCTCTTCAATTTCCTCATCTTTCT
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 180
    ACCGTTCTCCGCACTTCTCCTCCCTCCTACCTCACCAACTCCAACTAATTCTCGTACTACTACCAGAACTTAAACCACTACAAAGACAC
    (SEQ ID NO:20)
                                M  G  C  P  S  F  I  K  T  M  M  I  L  P  N  L  L  I  P  L  C
    CCTCCACCCCTCTTCCCACTCCCCATCTCCCTGTCAATCCATCCCCCATCCTTTCTCAACATCTTCCCCCCACTCTCCTCCACTCCCATC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 270
    CCACGTCCCCACAACCCTCACCCCTACACCCACACTTACCTACCCCCTACCAAACACTTCTACAACCCCCCTCACACCACGTCACCCTAC
     G  A  A  L  L  A  V  C  W  V  S  I  D  C  A  S  P  L  K  P  C  P  L  S  S  S  A  M
    CACTTTGTCAACCTCCGCTACTTCCTCATCCCACCCCCCCTTCTCCTCTTTCCTCTTCCTTTCCTCGCCTCCTATCCTCCTAACACTCAC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 360
    CTCAAACACTTCCACCCCATCAACCACTACCCTCCCCCCCAACACCACAAACCACAACCAAACCACCCGACGATACCACCATTCTGACTC
     O  P  V  N  V  C  Y  P  L  I  A  A  C  V  V  V  P  A  L  C  P  L  C  C  Y  C  A  K  T  E
    AGCAACTGTCCCCTCCTCACCTTCTTCTTCATCCTCCTCCTCCTCTTCATTCCTCACCTTCCAGCTCCTCTCGTCCCCTTCCTCTACACC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 450
    TCCTTCACACCCGACCACTGCAACAACAACTAGGACCACCAGTACAACTAACCACTCCAACGTCCACCACACCACCGCAACCACATCTCC
     S  K  C  A  L  V  T  P  P  P  I  L  L  L  I  P  T  A  E  V  A  A  A  V  V  A  L  V  Y  T
    ACAATCCCTCACCACTTCCTCACCTTCCTCCTACTCCCTCCCATCAACAAACATTATCCTTCCCACCAACACTTCACTCAACTCTCCAAC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 540
    TCTTACCGACTCCTCAACCACTCCAACCACCATCACCCACCCTACTTCTTTCTAATACCAACCCTCCTTCTGAACTCAGTTCACACCTTC
     T  M  A  E  H  P  L  T  L  L  V  V  P  A  K  K  O  Y  C  S  O  E  D  P  T  O  V  W  N
    ACCACCATCAAACCCCTCAACTCCTCTCCCTTCACCAACTATACCCATTTTCAGCACTCACCCTACTTCAAACACAACACTCCCTTTCCC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 630
    TCCTCCTACTTTCCCCACTTCACCACACCCAACTCCTTCATATCCCTAAAACTCCTCACTCCCATCAACTTTCTCTTCTCACCCAAAGGC
     T  T  M  K  C  L  K  C  C  C  P  T  N  Y  T  D  P  E  D  S  P  Y  P  K  E  N  S  A  P
    CCATTCTCTTCCAATCACAACCTCACCAACACACCCAATCAAACCTCCACCAACCAAAACCCTCACCACCAAAAACTACACCCTTCCTTC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 720
    CCTAACACAACCTTACTCTTCCACTCCTTCTCTCCGTTACTTTCCACCTCCTTCCTTTTCCCACTCCTCCTTTTTCATCTCCCAACCAAC
     P  P  C  C  N  D  N  V  T  N  T  A  N  E  T  C  T  K  O  K  A  N  O  K  V  E  C  C  P
    AATCACCTTTTCTATCACATCCCAACTAATCCACTCACCCTCCCTGCTCTCCCACCTCCAATTCCCCCCCTCCACCTCCCTCCCATCAAT
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 810
    TTACTCCAAAACATACTCTACCCTTCATTACCTCACTCCCACCCACCACACCCTCCACCTTAACCCCCCCACCTCCACCCACCCTACTT
     N  D  L  L  Y  D  I  R  T  N  A  V  T  V  C  C  V  A  A  C  I  C  C  L  E  L  A  A  M  N
    TCTCTCCATCTATCTCTACTCCAATCTACAATAACTCCACTTCTCCCTCTCCCACTACTCCTCCCACATCCCAACTCTCAACACCCACCC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 900
    ACACACCTACATACACATCACCTTACATCTTATTCACCTCAACACCCACACCCTCATGACCACCCTCTACCCTTCACACTTCTCCCTCCC
     C  V  N  V  S  V  L  O  S  T  I  S  P  L  L  P  L  P  L  L  L  P  N  C  N  C  E  E  A  P
    TCCCAACCACCACTCATTCCCCCACCCCACACCATCTAACAATCTCACTTCCCCCACAATCCACCTCCCC TTTC TCCTCCACACTTCCCC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 990
    ACCGTTCCTCCTCACTAACCCCCTCCCCTCTCCTACATTCTTACACTCAACCCCCTCTTACCTCCACCCCAAACACCACCTCTCAACCCC
     W  O  A  A  V  C  C  C  O  R
    CTACATACCCACCACTCCTTTTACCCCATCCCTCACTTTCCTTCCATTCCTCCCTCCATCCCTGCCCCGCATTCCACACCCTCTAACCTA
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 1080
    GATCTATCCCTGGTGAGGAAAATCCGCTACGGACTGAAAGGAAGGTAACCACCCACCTACCCCACCCCCCGTAAGGTCTGGAGATTCCAT
    HPWAE25
    CCCAGTTCTCTTGCCCATTCCCCCACTCTATTAAACCCTTGATATGCCCCCTACCCCTAGTGGTCATCCCACTGCTCTACTGGCGCATGA
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 1170
    CGCTCAAGACAACCGCTAAGGGGCTCACATAATTTGCGAACTATACGGGGCATCCGAATCACCACTACGGTCACGAGATGACCCCCTACT
    GAGAAACGCATTTTATAGCCTCCCCATAAGTGAAATCAGCACAGCCTCTGGC1GGATGTCTACAACGCACTTCAAAATGCATAAACCTGT
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 1260
    CTCTTTCCGTAAAATATCCGACCCCTATTCACTTTAGTCCTCTCGGACACCCACCTACACATCTTCCGTGAAGTTTTACCTATTTGGACA
    TACAATGTTAAAAAAAAAAAAAAAAAAA
    ++++|++++|++++|++++|++++|++→ 1288
    ATCTTACAATTTTTTTTTTTTTTTTTTT
    HTPEP86
    AAAAAAAACAACCTCCCCACAGCAAACAAAACCAATACCATCAACAGAAGCCTCCCTGCTCCCACACCAACCATCAATTCCTTCA
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 90
    TTTTTTTTGTTCCAGGGGTGTCGTTTCTTTTCCTTATCCTAGTTCTCTATGCACCGACGACCGTCTCGTTCGTACTTAAGCTACTGAAGT
    (SEQ ID NO:21)
                                                                             M  N  S  M  T  S
    CCACTTCCCCTCCCCAATTCTCTCTTCGTCGTCCCACCCCACAATGCTTATCCTGTCACCCCACGAATTATGTCTCACGTCCCCCTT
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 180
    CGTCAACCCCACCCCTTAACACACAACCACCACCCTCCCCTCTTACCAATACCACACTGCGGTCCTTAATACAGACTCCACCCCCT
     A  V  P  V  A  N  S  V  L  V  V  A  P  H  N  C  Y  P  V  T  P  C  M  S  H  V  P  L
    CCAAACACCCACCCCCAACTCCACCTACTTCCTCCCAACCCACCTACTTTCCTCTCCAATCTCAATCCCCACCCTCTGCACAAACCTCTC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 270
    CCTTTCTCCCTCCCCCTTCACCTCCATCAACCACCCTTCCCTGCATCAAACCACACCTTACACTTACCCCTCCGACACCTCTTTCCACAC
     P  N  S  O  P  D  V  H  L  V  P  C  N  P  P  S  L  V  S  N  V  N  C  O  P  V  O  K  A  L
    AAACAACCCAAAACCTTGCCCCCCATCCACATCATCATTGCCCTGCCTCACATCCGCCTCCCCTCCATCATGCCCACGCTTCTCGTACGC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 360
    TTTCTTCCGTTTTCGAACCCCCCCTAGGTCTACTACTAACCGCACCGAGTCTAGCCCCAGCCCACCTACTACCCCTCCCAACACCATCCC
     K  E  C  K  T  L  C  A  I  O  I  I  I  I  C  L  A  H  I  G  L  C  S  I  M  A  T  V  L  V  C
    CAATACCTCTCTATTTCATTCTACCCACCCTTTCCCTTCTCGCCACCCTTCTCGTTTATCATTTCACGATCTCTCTCCCTCCCACCACA
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 450
    CTTATCCACACATAAACTAAGATCCCTCCCAAACCCAACACCCCTCCCAACACCAAATACTAAACTCC TACACAGACCCACCGTCCTCTT
     E  Y  L  S  I  S  F  Y  C  O  F  P  F  W  C  C  L  W  F  I  I  S  G  S  L  S  V  A  A  E
    AATCAGCCATATTCTTATTCCCTCCTGTCTCGCACTTTGCCCTTCAACATCGTCACTCCAATCTCCTCGCCACTTCCACTCATACTCTTC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 540
    TTAGTCCCTATAACAATAACCGACGACACACCCTCAAACCCGAACTTCTACCACTCACCTTACACCACACCTCAACCTCACTATCACAAC
     N  O  P  Y  S  Y  C  L  L  S  O  S  L  C  L  N  I  V  S  A  I  C  S  A  V  C  V  I  L  F
    ATCACAGATCTAACTATTCCCCACCCATATCCCTACCCCCACTATTATCCTTACCCCTCCGCTGTCAACCCTCCAATCGCGATTTCTCGC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 630
    TAGTCTCTACATTCATAACCGGTGCCTATACCCATGCCCCTCATAATACGAATCCCCACCCCACAC TTCGGACCTTACCCCTAAACACCC
     I  T  D  L  S  I  P  H  P  Y  A  Y  P  D  Y  Y  P  Y  A  W  C  V  N  P  C  M  A  I  S  G
    CTCCTCCTCCTCTTCTGCCTCCTGCAGTTTCCCATCGCATGCCCATCTTCCCACTTTGCCTCCCACTTCCTCTCCTCTCAATCAACCAAT
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 720
    CACCACGACCACAACACCGACGACCTCAAACCCTACCGTACGCCTACAACCGTGAAACCGACCCTCAACCACACGACACTTACTTCCTT
     V  L  L  V  T  C  L  L  E  F  C  T  A  C  A  S  S  H  F  C  C  D  L  V  C  C  O  S  S  N
    CTCACTCTCATCTATCCAAACATCTATCCACCAAACCCACTCATCACCCCACAACCCCTCACCTCACCACCAACTTATTCCACTCACATC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 810
    CACTCACACTACATACCTTTCTACATACCTCCTTTCCCTCACTACTCCCCTCTTCCCCACTCCACTCCTCCTYCAATAACCTCACTCT
     V  S  V  I  Y  P  N  Y  A  A  N  P  V  T  P  E  P  V  T  S  P  P  S  Y  S  S  E
    CAACCAAATAACTAACCCTACACATTCTCCAACCATCTTTCACTCCCACCAAAACAACTCCTCCTCCCTTTCTGCCCTTCCATAACCCAC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 900
    GTTCGTTTATTCATTCCCATCTCTAACACCTTCCTACAAACTCACCCTCCTTTTCTTCACCACCACCCAAACACCCCAACCTATTCCCTC
     O  A  N  K
    GTCCTTCCTCTTCTCACACCTCACCAAACCTCTCTCCCACTCTTTCTACTCTCACCTTCATTCTTCAATTCACTCTACCAAACCATCCTC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 990
    CACCAACCACAACACTCTCCACTCCTTTCCACACACCCTCACAAACATCACACTCCAACTAACAACTTAACTCACATCCTTTCCTACCAC
    TTTCTCTATCAACAACAACACACACATTTTAAACACATCTTAACCAACACCCACTCCCTACCCCACATCCATCACCACATATCTCCCCAT
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 1080
    AAACAGATACTTCTTCTTCTCTCTCTAAAATTTCTCTACAATTCCTTCTCCCTCACCCATCCCCTCTACCTACTCGTCTATACACCCCTA
    HTPEF86
    (SEQ ID NO:5)
    CCAGCCTCTGGGGCCTTGGCACACCCATTCGTGTGCTCTGCTGCATGTGAGCTTGTGGGTTAGAGGAACAAATATCTAGACATTCAATCT
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 1170
    GGTCGGAGACCCCGGAACCGTGTGGGTAAGCACACGAGACGACCGACACTCGAACACCCAATCTCCTTGTTTATACATCTCTAAGTTACA
    TCACTCTTTCAATTGTGCATTCATTTAATAAATAGATACTCAGCATTCAAAAAAAAAAAAAAAAAA
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|→ 1236
    AGTGAGAAAGTTAACACCTAAGTAAATTATTTATCTATGACTCGTAAGTTTTTTTTTTTTTTTTTT
    HSBBF02
    (SEQ ID NO:6)
    CACCACCAGCCTCTCCGCCTACTCATGGCCTCCCCCTCTCGCACACTGCACACTAAACCACTCATTACTTCTTTCAACACCGTTCTCCTA
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 190
    CTCCTCCTCCCAGACCCCGATCACTACCGCACCGGCACACCCTCTCACCTCTGATTTCCTCACTAATCAACAAAGTTCTCCCAACACCAT
    (SEQ ID NO:22)
                             M  A  S  P  S  R  R  L  O  T  K  P  V  I  T  C  F  K  S  V  L  L
    ATCTACACTTTTATTTTCTCCATCACTCCCCTTATCCTTCTTCCACTTCCCATTTCCCCCAACGTCAGGTCCACAATTACTTTTCTCTT
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 180
    TACATCTCAAAATAAAACACCTACTCACCCCAATACGAAGAACCTCAACCCTAAACCCCCTTCCACTCCCACCTCTTAATCAAAACACAA
     I  Y  T  F  F  W  I  T  G  V  I  L  L  A  V  G  I  W  C  K  V  S  L  E  N  T  F  S  L
    TTAAATCACAAGCCCACCAATCTCCCCTTCCTCCTCATTCCTACTCCTACCCTCATTATTCTTTTCCCCACCTTTCCTTCTTTTCCTACC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 270
    AATTTACTCTTCCGCTGCTTACACCCGAACCACCACTAACGATCACCATGGCACTAATAACAAAACCCGTGCAAACCAACAAAACGATGC
     L  N  E  K  A  T  N  V  P  F  V  L  I  A  T  G  T  V  I  I  L  L  C  T  T  C  G  F  A  T
    TCCCCACCTTCTCCATCCATGCTAAAACTCTATCCAATCTTTCTCACTCTCCTTTTTTTCGTCCAACTCCTCCCTCCCATCCTACCATTT
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 360
    ACGCCTCCAACACGTACCTACCATTTTCACATACCTTACAAACACTCAGAGCAAAAAAACCACCTTCACCACCGACGCTACCATCCTAAA
     C  R  A  S  A  W  M  L  K  L  T  A  M  F  L  T  L  V  F  L  V  E  L  V  A  A  I  V  G  F
    GTTTTCACACATCACATTAAGAACACCTTTAACAATAATTATGACAAGGCTTTCAACCAGTATAACTCTACAGCACATTATACAACCCAT
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 450
    CAAAACTCTCTACTCTAATTCTTGTCCAAATTCTTATTAATACTCTTCCGAAACTTCCTCATATTCACATCTCCTCTAATATCTTCCCTA
     V  F  R  H  E  I  K  N  S  F  K  N  N  T  E  K  A  L  K  O  T  N  S  T  C  D  T  R  S  H
    CCACTACACAACATCCAAAATACCTTGCATTGTTGTGCTGTCACCCATTATACACATTGGACACATACTAATTATTACTCACAAAAACGA
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 540
    CCTCATCTCTTCTACCTTTTATCCAACCTAACAACACCACACTCCCTAATATCTCTAACCTCTCTATCATTAATAATCACTCTTTTTCCT
     A  V  D  K  I  D  N  T  L  H  C  C  C  V  T  O  T  R  D  W  T  D  T  N  T  T  S  E  K  G
    TTTCCTAAGACTTCCTCTAAACTTGAAGATTCTACTCCACACACACATCCACACAAACTAAACAATCAACCTTCTTTTATAAACCTCATC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 630
    AAACCATTCTCAACCACATTTCAACTTCTAACATGACCTGTCTCTCTACCTCTGTTTCATTTCTTACTTCCAACAAAATATTTCCACTAC
     F  P  K  S  C  C  K  L  E  O  C  T  P  O  R  D  A  O  K  V  N  N  E  C  C  F  I  K  V  N
    ACCATTATACACTCAGAAATCCCACTCCTTCCACGAATTTCCTTTCCACTTCCTTCCTTCCAACTGATTCCAATCTTTCTCCCCTACTCC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 720
    TGCTAATATCTCACTCTTTACCCTCACCAACCTCCTTAAAGCAAACCTCAACCAACCAACCTTCACTAACCTTACAAAGACCCCATCACC
     T  I  I  E  S  E  M  D  G  V  V  A  G  I  S  F  G  V  A  C  F  G  L  I  G  I  F  L  A  Y  C
    CTCTCTCCTGCCATAACAAATAACCACTATGACATACTCTAACCCAATCTATCTCTCCCCCTATTCCTCTCTACCTTTAACCACATTTAC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 810
    CACAGACCACCCTATTCTTTATTCCTCATACTCTATCACATTCCCTTACATACACACCCCOATAACCACACATCCAAATTCCTCTAAATC
     L  S  R  A  I  T  N  N  O  Y  E  I  V
    GCTCCCCCCTCTCAATTACAAACTTGCTTCCCTCCACAACTCACAACACTACTTACTGATACACCAAAAAACTACACCACTAGCTTCATT
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 900
    CCACCCCGCACACTTAATCTTTCAACCAACCGACCTCTTGACTCTTCTCATCAATCACTATCTCCTTTTTTCATCTCCTCATCCAACTAA
    CAATCAACATCTATCTACACCTAAAACTACACCAATACCCTCATTCAATCAAGATCCCTCCTCCCACTCCCCTCATTCAATCAACATCTA
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 990
    CTTACTTCTACATACATCTCCATTTTCATCTCCTTATCCCACTAACTTACTTCTACCCACGAGCCTCACCCCACTAACTTACTTCTACAT
    TCTTTCCTATCTTCTAACTCCACCTTCTATCCCATTCATCTTACATCCTTCAAACCCTCTATCCCTCTCAAACACTCCAACACCTACTAA
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 1080
    ACAAACCATACAACATTCACCTCCAACATACCCTAACTACAATCTACCAACTTTCCGACATACCCACACTTTCTCACCTTCTCCATCATT
    HSBBF02
    ATTGTAAATGAAGTAAAAAAAAAAAAAAAAAAAAA
    ++++|++++|++++|++++|++++|++++|++++→ 115
    TAACATTTACTTTATTTTTTTTTTTTTTTTTTTTT
    HLTAH80
    (SEQ ID NO:7)
    CACGACCATTGCCGCTCTCTCGGPGAGCGCAGCCCCGCTCTCCGGGCCGGGCCTTCGCCGCCCACCGCCGCCATGGCCCAGTGCGGCATC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 90
    GTGCTCGTAACGGCGAGAGAGCCACTCGCGTCGGCGAGAGGCCCGGCCCGGAAGCGCCCGGTGGCCGCGCTACCCGGTCACGCCGTAG
    (SEQ ID NO:22)
                                                                             M  G  O  C  G
    ACCTCCTCCAAGACCCTCCTCCTCTTTCTCAACCTCATCTTCTCGCGGCCAGCTGCCATTTTATCCTATGTCGCAGCCTATGTCTTCATC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 180
    TCCAGGAGGTTCTCCCACCACCACAAAGACTTCGAGTACAACACCCCCCGTCCACCGTAAAATACGATACACCCTCGCATACACAAGTAG
     T  S  S  K  T  V  L  V  F  L  N  L  I  F  W  G  A  A  G  I  L  C  Y  V  G  A  Y  V  F  I
    ACTTATCATCACTATCACCACTTCTTTGAAGATGTGTACACCCTCATCCCTGCTCTACTCATCATACCTCTACCAGCCCTCCTTTTCATC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 270
    TCAATACTACTCATACTGCTGAACAAACTTCTACACATGTGCCAGTAGCGACGACATCACTACTATCCACATCCTCCGGACGAAAACTAG
     T  T  D  D  Y  D  H  P  P  E  D  V  V  T  L  I  P  A   V  V  A  V  C  A  L  L  P
    ATTCCCCTAATTGCCTCCTCTCCCACAATCCCCGAAAGTCGCTCTCGACTTCCCACGTTTGTCATCATCCTCCTCTTCGTTTTTGTCACA
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 360
    TAACCCGATTAACCCACCACACCCTGTTACCCCCTTTCAGCGACACCTCAACCCTGCAAACACTAGTACCACCACAACCAAAAACAGTGT
     I  C  L  C  C  C  A  T  I  R  E  S  R  C  C  L  A  T  P  V  L  L  L  V  P  V  T
    CAACTTGTTCTACTCCTTTTCCCATATCTTTACACACCAAAGCTCCAAAATCACCTTCATCGCACCATTCACAAAGTCTATAACACCTAC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 450
    CTTCAACAACATCACCAAAACCCTATACAAATCTC1CCTTTCCACCTTTTACTCCAACTACCGTCGTAACTCTTTCACATATlGCTCCATC
     E  V  V  V  V  V  L  D  T  V  T  R  A  K  V  E  N  E  V  O  R  S  I  O  K  V  T  K   T  Y
    AATCCAACCAACCCTCATCCTGCTACCCCGCCTATTCATTATGTACACACACAGCTCCATTGTTCTGCAATTCACAACTACTCAGACTCC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 540
    TTACCTTCGTTGCGACTACGACGATCGCCCCCATAACTAATACATCTCTCTGTCCACCTAACAACACCTTAACTCTTGATCAGTCTGACC
     N  C  T  N  P  D  A  A  S  R  A  I  D  T  V   D  R  D  L  H  C  C  C  H  N  T  S  D  W
    CAAAATACAGATTGCTTCAAACAAACCAAAAACCACACTCTCCCTCTTACCTCCTCCACACACACTGCCACCAATTCTAATCCCAGCCTG
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 630
    CTTTTATGTCTAACCAAGTTTCTTTGCTTTTTGCTCTCACACGCACAATCCACCACCTCTCTCTCACCCTCCTTAACATTACCGTCGCAC
     E  N  T  D  W  F  K  E  T  K  N  D  S  V  P  L  S  C  C  R  E  T  A  S  N  C  N  C  S  L
    CCCCACCCTTCCGACCTCTATCCTCACGGCTCTCACGCTCTACTTCTCAACAAGCTACAACAAATCATCATGCATGTGATCTGCGCCGCA
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 720
    CGCCTCCCAACCCTCCACATACCAC TCCCCACACTCCCAGATCAACACTTCTTCCATCTTCTTTACTACTACCTACACTAGACCCCGCCT
     A  H  P  S  D  L  T  A  E  C  C  E  A  L  V  V  K  K  L  O  E  I  T  I  M  H  V  I  W  A  A
    CTCGCATTTCCAGCTATTCACCTCCTGCGCATCCTCTGTCCTTCCATCCTCTTGTGCACAACCAGTAGAGATCCTGCTTACGACCTCTTC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 810
    CACCCTAAACCTCCATAACTCCACCACCCCTACGACACACCAACCTAGCACAACACGTCTTCCTCATCTCTAGGACCAATCCTCCACAAC
     L  A  P  A  A  I  O  L  L  G  M  L  C  A  C  I  V  L  C  R  R  S  R  D  P  A  T  E  L  P
    ATCACTGCCCCAACCTATCCATACTTCACAATCTCAAGCCTCACCTTTTTGCTCTTCTTCTGATTTCGAACCTCAATTCACCACGTCTCC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 900
    TACTGACCGCCTTGGATACGTATCAACTGTTAGAGTTCCGACTCGAAAAACCAGAACAACACTAAACCTTCCACTTAACTCGTCCACACC
     I  T  C  C  T  T  A
    TCCTCTGCCCCTCTCCAGTTCATTTAGTTAAAGCACATGTACACTCCTGTTGCACACACCACCTTCGCTTTTCATGTGCCCACCTACTTA
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 990
    ACCACAACCCCAGACCTCAACTAAATCAATTTCGTGTACATGTCACCACAACCTGTCTCGTCGAACCGAAAACTACACCCCTGCATGAAT
    CCTACTACCTCCCACTTTCTTTTTCCTTGTTCTACCTCACTCTTCATCCCCCTAACATTTTAACTACCATCGTCAACGTTCTAATTTCAC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 1080
    CGATCATCCACCCTCAAACAAAAACCAACAACATCCACTCACAAGTACGCCCATTCTAAAATTCATCCTACCACTTGCAACATTAAACTC
    HLTAH80
    AACCAATTGCGAGTCATGTACTGTG1GTAGAATTAAAGCAGGACACGAGCCTGCTTCTGTTACCTCCAAGTCGGTAACACGACTGATGCCGA
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 1170
    TTGCTTAACGCTCAGTACATCACACCATCTTAATTTCCTCCTGTGCTCCCACGAAGACAATGGACGTTCACCATTGTCCTCACTACGCCT
    AATGTCACCAGCTCCTTTCAGTCTGCACAGTGGACAACTCTTGCCCAAAGGTTTTTGGCGGCAGGAGGAGGAAACCAGCTTTCTCGTTAA
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 1260
    TTACAGTGGTCCAGGAAACTCAGAAGTGTCACCTCTTGAGAACCGGTTTCCAAAAACCCCCCTCCTCCTCCTTTGIGTCCAAAGACCAATT
    GGTTAACACCACATCCTGCCCCTCATTCCTGTCCTTTTAAAAAATATTTACTCTACTCCAATAAGATACCAGETCTACAAAATCACTAAA
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 1350
    CCAATGGGGGTCTACCACCGGCAGTAACCACAGCAAAATTTTTTATAAATGACATCAGGTTATTCTATCGTCGACATGTTTTACTGATTT
    ATAGATTGTACIGATCATATGGCGTATATCTTGCTTCATCTTCAAAATCAGAGACTGACCTTTGAAACTAGTCGTTTTTAATCAAAGTTGG
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 1440
    TATCTAACATCCTAGTATACCCCATATACAACCAAGTACAAGTTTTAGTCTCTCACTCCAAACTTTGATCACCAAAAATTACTTTCAACC
    CTTTATAGCAGGACTATAATGTATGCACTACTGTTTTAAAAGAATTAGTGTGAGTGTGTTTTTCTATGAATCAGCGCATTCATGGTAACT
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 1530
    GAAATATCCTCCTCATATTACATACGTGATGACAAAATTTTCTTAATCACACTCACACAAAAACATACTTACTCCGGTAAGTACCATTCA
    CTTAAGCTTGTTGCAAATAATCTACCCATGGAGACTACCAAAATAGTATGTAGATGTGATCTCAGTTGTAAATAGAAAAATCTAATTCAA
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 1620
    GAATTCGAACAACCTTTATTACATGGGTACATCTGATCCTTTTATCATACATCTACACTAGAGTCAACATTTATCTTTTTAGATTAACTT
    TAAACTCTGTATCAGCCCCCAACAAAAAAAAAAAAAAAAAAA
    ++++|++++|++++|++++|++++|++++|++++|++++|+→ 1662
    ATTTCAGACATACTCCGGGGTTGTTTTTTTTTTTTTTTTTTT
    HTPBA27
    (SEQ ID NO:8)
    CACCACCCCAGAGCTTCGCTTCCTTCCTCCCACCCACCACCTCCCTCCCCACTCCTCACCCTTCACCGACCCTCACCACCCCCTCCTC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 90
    CTGCTCCCCTCTCCAACCCCCAACGAACCACCCTCCCTCCTGCACCGACCCGTCACCACTCGGAACTCCCTCCCACTCCTCGCACCAG
    TCTTTCCTCTGGCCAGCCCACAACTCAAGCCCTCCCCCATCCCCCGCGCCTCCCTCCAGCCCCTCAACTACCTCATGTTCGCCTTCAACC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 180
    ACAAACCACACCCCTCCCCTCTTCACTTCCCCACCCCCTACCCCCCGCCCACCGACCTCCGGCACTTCATCCACTACAACCCGAACTTCC
    (SEQ ID NO:24)
                                 M  A  R  A  C  L  O  A  V  K  T  L  M  F  A  F  N
    TGTTCTTCTCCCTCCGAGCCTCTCCCCTCCTCCGTGTCGCCATCTGGCTCCCCCCCACACACCCGAGCTTCGCCACCCTGTCTTCTTCCT
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 270
    ACAACAACACCCACCCTCCCACACCGCACCACCCACAGCCCTACACCCACCCCCCGTGTCTCCCCTCCAACCCCTCCCACACAACAACCA
     L  F  F  W  L  C  C  C  C  V  L  C  V  C  I  W  L  A  A  T  O  G  S  F  A  T  L  S  S  S
    TCCCGTCCCTCTCGGCTCCCAACCTGCTCATCATCACCCCCCCCTTTGTCATGCCCATCCCCTTCCTCCCCTGCCTCGCTCCCATCAACC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 360
    ACGGCACCCACACCCCACGGTTGCACCAGTAGTACTGCCCGCCCAAACAGTACCCCTACCCCAACCACCCCACCGACCCACCCTACTTCC
     F  P  S  L  S  A  A  N  L  L  I  I  T  C  A  G  V  M  A  C   F  V  C  L  C  A  I  K
    AGAACAACTCCCTCCTGCTCACTTTCTTCCTCCTCCTCCTCCTCGTCTTCCTGCTCCACCCCACCATCCCCATCCTCTTCTTCCCCTACA
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 450
    TCTTCTTCACCGAGCACGAGTCAAACAACCACCACCACCACGACCACAACCACCACCTCCCCTCGTACCCCTACCACAAGAACCCCATCT
     E  N  K  C  L  L  L  T  F  G  L  L  L  L  L  V  F  L  L  E  A  T  T  A  I  L  F  G  A  T
    CCCACAACATTCACACCTATGCCCAGCAACACCTCAACAAACCCTTCCACCTCTACCGCACCCACCGCAACCTCGCCCTCACCAACCCCT
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 540
    CCCTCTTCTAACTCTCCATACCCCTCCTTCTCCACTTCTTTCCCAACCTCCACATCCCGTCCCTCCCCTTGCACCCCGACTCGTTGCCCA
     T  D  K  I  D  R  Y  A  O  O  D  L  K  K  G  L  H  L  Y  G  T  O  G  N  V  G  L  T  N  A
    CCACCATCATCCACACCCACTTCCCCTCCTCTGGCCTC TCCAACTACACTCACTGGTTCCACGTCTACAACGCCACCCGCCTACCTCACT
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 630
    CCTCGTAGTACCTCTCCCTCAACCCCACGACACCCCACACCTTCATCTGACTCACCAACCTCCACATGTTCCCCTCCCCCCATGCACTCA
     W  S  I  I  I  O  T  D  G  R  C  C  C  V  S  N  Y  T  D  W  F  E  V  T  N  A  T  R  V  P  D
    CCTGCTCCTTCCACTTCACTCACACCTCTCGCCTCCACCCCCCCCCCACCTGCTGGAACCCCCCCTCCTACCACACCCTCAACGTCTCCC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 720
    CCACCACCAACCTCAACTCACTCTCCACACCCCACCTCCCCCCCCCCTCCACCACCTTCCCCCCCACCATCCTCTCCCACTTCCACACCC
     S  C  C  L  E  G  S  E  S  C  C  L  H  A  P  C  T  W  W  K  A  P  C  T  E  T  V  K  V  W
    TTCAGGACAACCTGCTCCCTCTCGCCATCTTTCCCCTCTCCACCCCCCTCCTCCACATCCTCCCCCTCACCTTCCCCATCACCATGTACT
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 810
    AAGTCCTCTTGCACCACCGACACCCCTAGAAACCCCACACCTCCCCCGACCACCTCTAGGACCCGCACTCCAACCCGTACTCCTACATGA
     L  O  E  N  L  L  A   V  G  I  F  G  L  C  T  A  L  V   O  I  L   C  L  T  F  A  M  T  M   T
    CCCAACTCCTCAACCCACACACCTACTCCCCCTACCCCCCCCACCCCCCCCTTCTC TCCCAAAACCACCCCCACCCCCACATCCCCCCAC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 900
    CCCTTCACCACTTCCCTCTCTCCATCACCCCCATCCCCCCCCTCGCCCCCCAACACACGCTTTTCCTCCCCCTCCCCCTCTACCGCCCTC
     C  O  V  V  K   A  O  T  T  C  A
    CCACACCTCCTTTTCCCACCACCACCTTCCCTCTTCTCCCCCATCC TCCCACCAGCCACCCACCCACACGTCCCTCCACCCCCCCCAACC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 990
    CCTCTCCACCAAAACCCTCCTCCTCCAACCCACAACACCCCCTACCACCCTCCTCCCTCCCTCCCTCTCCACCCACCTCCCCCCCCTTCC
    CTCTTTCTCCAACCCCCTACCTCACCTCCC TTCACCCCCTCCCCACCCCCCCTCCCACCCCTCCCCACCTCCTCCCTCCCCAACCCACCC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 1080
    CACAAACACCTTCCCCCATCCACTCCACCCAACTCCCCCACCCCTCCCCCCCACCCTCCCCACCCCTCCACCACCCACCCCTTCCCTCCC
    HTPBA27
    CACCTGCCAGCGCCCTCCACCACTTTTTATATTTACCTATTCTCCAAAGCACTGTTCACACCGCAGCCACCC1GTGGCCCCCACCTTC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 1170
    CTCCCCACCCTCCCCCGAGGTCGTGAAAAATATAAATGCATAACAGGTTTCGTCACAAGTGTGCCCTCGGTCGCACACCCGCCGTCGAAC
    CTGGAAAACACGTTCGCGCTGGAGGACCCCCGTCTTGCCATCC7GCAGGTCGCCCCACTGGTCCTGGTGCTCCAGCCGCCGCCGTGGACC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 1260
    GACCTTTTGTGCAACCGCGAGCTCCTCGCCCCAGAACCCTAGGACCTCCACCGCTGACCAGGACCACGACGTCCGCCCCGCCACCTGC
    CCTCACCTAGATTCCATAGTGGGCCCGTCGGCCTCCTGGTCCATCTTAATAAAGTGTGAGGAGCAAAAAAAAAAAAAAAAAAAAA
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++→ 1345
    GGACTGGATGTAACGTATCACCCGGGCACCCCGACCACCAGGTAGAATTATTTCACACTGCTCGTTTTTTTTTTTTTTTTTTTTT
    HAIDQ59
    (SEQ ID NO:9)
    GCGCGCCGCCGGCCCGCAGCATGGCCCGCTTCCGCGCGGGCCTGCGCTCCATCAAGTACCTGCTGCTTGCCTTCAACCTGCTCTTCTCCCTC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 90
    CGCCGCGGCCCGGCGTCGTACCCCGCGAAGGCCCCCCCCGACGCCACCTAGTTCATGGACGACGAACCGAAGTTGCACGACAACACCCAC
    (SEQ ID NO:25)
                       M  C  R  F  R  G  C  L  R  C  I  K  Y  L  L  L  C  F  N  L  L  F  W  L
    CCTGGATCGCCCCTCATTGCTTTTGCACTATGCTTTCGGTTCCGAGCTGCCATAAACGAGTTATCATCACAGGACAAGTCCCCAGACTAT
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 180
    CGACCTAGCCCCCACTAACGAAAACCTCATACCAAACCCAAGCCTCCACCCTATTTCCTCAATAGTACTCTCCTCTTCACCCGTCTCATA
     A  G  S  A  V  A  G  G  L  W  F  R  G  C  C  A  I  K  E  L   S  S  E  C  K  S  P  E  T
    TTCTATCTCGCGCTCTATCTTCTCCTTCCACCCCGCCCCCTCATCATCCCCCTCCCCTTCTTCGGATCCTGCCCACCCATCCCGCACTCC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 270
    AACATACACCCCCACATACAACACCAACCTCCGCCCCGGCACTACTACCGCCACCCCAACAACCCTACGACGCCTCCGTACCCCCTCACC
     P  T  V  C  L  T  V  L  V   C  A  C  A  L  M  M   A   V  G  P  F  G  C  C  G  A  M  R  E  S
    CAATGTCTCCTTCCATCATTTTTTACCTGCCTCCTCCTCATATTTCCTGCTCAACTAACCACTCCAGTATTTGCTTTTATAGGCAAGCCG
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 360
    CTTACACACGAACCTACTAAAAAATCGACCGACGACCACTATAAACCACCACTTCATTCCTCACCTCATAAACGAAAATATCCGTTCCCC
     D  C  V   L  C  S  F  T  T  C  L  L  V  P  A  A  E  V  T  T  C  V  P  A  P  C  K  C
    CTACCTATCCGACATCTTCAGACCATCTATCAACAGGCTTACAATCATTACCTTAAACACAGGGGAAAAGGCAATCCCACACTCATCACC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 450
    CATCGATAGGC TGTACAAGTCTCCTACATACTTCTCCCAATGTTACTAATGCAATTTCTGTCCCCTTTTCCGTTACCCTCTCAGTACTGG
     V  A  I  R  H  V  C  T  M  T   E   E   A   T   N   CT   L   K   C  R   C   K   C   N   C   T   L   I   T
    TTCCACTCAACATTTCAGTGCTCTCCAAAACAAACCTCCCAACAGGTCCAACCTACATCCCCAAACCACCTTCTAGCACACAACAATTCC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 540
    AACCTCACTTCTAAACTCACCACACCTTTTCTTTCCAGCCTTGTCCAGCTTCCATCTACCCCTTTCCTCCAAGATCCTGTGTTCTTAACG
     P  H  S  T  P  C  C  C  C  K  E  S  S  E  C  V  C  P  T  C   P  K  E  L  L  C  N  K   N  O
    ATCCATGAAATTGACACCATAATCAGTGTTAACCTCCACCTCATTCCAATTCTCGCTATTCCAATTCCAGCTCTCACCATCTTTCCCATC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 630
    TAGCTACTTTAACTCTCCTATTACTCACAATTCGACCTCCAGTAACCTTAACACCCATAACCTTAACGTCCACACTCCTACAAACCCTAC
     I  D  E  I  E  T  I  I  S  V  K  L  G  L  I  G  L  I  G  I  V  G  I  G  I  A  G  L  T  I  F  G  M
    ATATTCAGCATGCTCCTCTCCTCTGCCATACCAAACTCACCAGATCTCATATGAACCTACTTCTACATCAAAATTCCAATCGAAAGCTTT
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 720
    TATAAGTCGTACCAGGAGACCACACGCTATGCTTTGACTCCTCTACACTATACTTCCATCAACATCTACTTTTAACCTTAGATTTCCAAA
     I  F  S  I  I   V  L  C  C  A  I  R  N  S  R  C  V  I
    CATACCAAATCTTC
    ++++|++++|+++→ 734
    CTATGCTTTACAAG
    HAIDQ59
    (SEQ ID NO:10)
    AGTGTTTATCCGACTAAAAAACTTTTAACACCTTTTTAGGCCAAATATTTTGGTCCTATACAAAACATCTAAATATGCTTTATTACTTTC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 90
    TCACAAATACCCTGATTTTTTGAAATTGTGGAAAATCCCCTTATAAAACCAGGATATGTTTTGTACATTATACGAAATAATGAAAC
    ATTTTCTGACCCTGCTGTAAACTACTGCAACCCTCACATCCCTCAAACCCACTTTTATGTCAAACTCTTCTCTTTCTCCAAATATAAGCA
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 180
    TAAAAGACTGGGACGACATTTGATGACGTTGGGAGTGTAGGGAGTTTCCCTGAAAATACAGTTTGAGAAGACAAAGAGGTTTATATTCCT
    AAAAACACTAAAGCAAGAGATCTCGCAGTTCAAAATTGTGGGAAAGAGAATTTCTATGCGCACTGTATCTATCAAATACCTCATACTTAC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 270
    TTTTTCTGATTTCGTTCTCTACACCGTCAACTTTTAACACCCTTTCTCTTAAACATACCCGTCACATAGATACTTTATGGACTATGAATG
    GTTTACATGTTTTCCTAACTTTTTGTATTTTTCTTGTATAGCCACCTAGAGAATTCTTCATAGATTAAGAACTACAGTTTTCACCACTTA
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 360
    CAAATCTACAAAAGGATTGAAAAACATAAAAAGAACATATCGCTGGATCTCTTAAGAACTATCTAATTCTTGATGTCAAAACTGGTGAAT
    ACATAAGTAAAACAAAGTCCTTCATAATTTAACCATTAGCATCTTTGGGCAAACCAAAATAAAGAAAACCATCTTCTCCTAGTTCTGTCT
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 450
    TGTATTCATTTTGTTTCACCAAGTATTAAAVTGCTAATCCTACAAACCCCTTTCCTTTTATTTCTTTTCGTAGAAGAGGATCAACACACA
    GGCCAACAGAAACAACTTAACCAAACAAAAATACTTATATATACACACAACAAAAATAATGTTCTTTTTATCCAAATCCCCTCTGAAAAT
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 540
    CCCGTTCTCTTTCTTCAATTCCTTTCTTTTTATCAATATATATCTCTCTTGTTTTTATTACAACAAAAATACCTTTACCCGACACTTTTA
    AAAATTTTCAATCTTTAAAAAAAAAAAAAAAAAAAAA
    ++++|++++|++++|++++|++++|++++|++++|+→ 577
    TTTTAAAAGTTACAAATTTTTTTTTTTTTTTTTTTTT
    HHFEK40
    (SEQ ID NO:26)
    TTCCCACGACCTCCCCCCCCTCCGCCCCTCCCCCCCCCCCCCACCCCCCCTCTCACTCTCTCTAGGCGCACTCCCTTGCCCCCTTCCGG
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 90
    AACCCGTCCTCCACGCCCGCCACCCCCCCACCCGCCGCCCCCCTCCCCGCCAGACTCAGAGACATCCGCGTCACGGAAGCGGCGAAGCCC
    ACCCCCTCCCACCGCCCACAACCCATGCCCCACTATAAGACTGACCACCACCACTGCCTCATCATCTACTTCAAGTATTTACTCTTTGTC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 180
    TCCGGGACCCTCCCCCCTCTTCCCTACCGCGTCATATTCTGACTCCTCCTCCTGACCGACTAGTAGATGAACTTCATAAATCAGAAACAG
    (SEQ ID NO:11)
                             M  A  H  Y  K  T  E  O  D  D  W  L  I  I  Y  L  K  Y  L  L  F  V
    TTCAACTTCTTCTTCTCGCTCGGGGCACCACCCGTCCTCGCTGTGGGCATCTCGACCCTGGTGCACAACACTGCCTACCTCAGCCTCCTC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 270
    AAGTTGAACAACAACACCCAGCCCCCTCCTCGGCAGGACCCACACCCGTAGACCTGGGACCACCTCTTCTCACCCATGCACTCGCAGGAC
     F  N  F  F  F  W  V  C  G  A  A  V  L  A  V  G  I  W  T  L  V  E  K  S  G  Y  L  S  V  L
    CCCTCCACCACCTTTGCCGCCTCCCCCTACATCCTCATCTTTGCGCCCCTACTTCTCATCCTCACCCGCTTCCTCCGCTTCCCTCCCATC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 360
    CCGAGGTCGTGGAAACCCCCCAGCCCCATGTAGCAGTACAAACCCCCGCATCAACAGTACCACTGGCCGAAGGACCCCAACCCACGGTAC
     A  S  S  T  F  A  A  S  A  T  G  L  F  A  C  V   L  V   N  V  T   G  F  L  C  F  G  A  I
    CTCTCGCACCCCAACCCCTGCCTCTCCACCTATTTCTCCCTGTTGCTCCTCATCTTCCTGCTTGAGCTCCTGCCGGGACTCCTCGCCCAT
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 450
    GAGACCCTCCCCTTCCCCACGCAGACGTGCATAAACACCGACAACCAGCACTACAAGCACCAACTCCACCACCGCCCTCACCACCGCGTA
     L  W  E  R  K  C  C  L  S  T  T  T  C  L  L  L  V  A  G  V  L  A  H
    CTGTATTACCAGAGCCTCACTGATCAACTCAACCACCACTTCAACCGGACTCTCCCTCAGAACTACGCGCAGCCGCACCACCCAGATCAC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 540
    CACATAATGCTCTCCCACTCACTACTTGACTTCGTCGTGAACTTGCCCTCACACCCACTCTTGATGCCCGTCCGCCTCGTCCGTCTAGTG
     V  Y  Y  C  R  L  S  C  E  L  K  C  H  L  H  G  T  L  A  E  N  Y  C  O  P  E  H  A  D  H
    CCCTCAGTCCACCCACTCCACCACGATTTCAACTCCTGCGCAAGCAACAGCTCACCCGACTGGCACCACACCACCTACATCCTCTTGCCC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 630
    CCGAGTCACCTGGCTGAGGTCGTCCTAAACTTCACCACCCCTTCCTTCTCCACTCCCCTCACCCTCCTGTCCTGCATGTACGACAACCCC
     A  S  V  C  R  L  C  C  C  F  K  C  C  C  S   N   S  S  A  N  C  H  S  T  T  I  L  L  R
    CAGGCCCAGGGCCGCCAGGTGCCCCACACCTGCTCCAACACACTCGTCGCCCCCTCCCGCCAGCGCGCCCACCCCTCCAACATCTATAAG
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 720
    CTCCCGCTCCCCCCGCTCCACGGCCTCTCCACCACCTTCTCTCACCACCGCCCGACGCCGGTCGCCCCCCTCCGCACCTTGTAGATATTC
     E  A  E  C  R  C  V  P  O  S  C  C  K  T  V  V  A  R  C  G  O  R  A  H  P  S  N  I  Y  K
    CTCCACGCACCCTGCCTCACCAACCTGCACCACTTCCTCCCCCACCACCTCCTCCTTATCCGCCCACTCGCCATCCCGCTCGCCTCCCTC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 910
    CACCTCCCTCCCACCCAGTGCTTCCACCTCCTCAACCACCGGCTCGTCGACCACCAATACCCCCGTCACCCGTACCCCCACCGGACCGAC
     V  E  G  G  C  L   T  K  L  E  C  F  L  A  D  H  L  L  L  M  G  A  V  C  C  V  A  C  L
    CAGATCTGCGCCATCCTTCTCACCTGCTGCTTCCACCACACGCTCCACCGCCATTTTTACTAATCGCAACCACCTCCTCTTCCAACTCCC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 900
    GTCTACACCCCCTACCAAGACTGGACGACGAACGTCCTCTCCGACGTCCCCGTAAAAATGATTACCCTTCGTGGAGGAGAAGGTTGACCC
     O  I  C  C  H   V   L   T   C   C   L   H   C  R   L   C  R   H   F   Y
    CCTCAACACAACATCTGGCACATGCCATCTCCAAGG
    ++++|++++|++++|++++|++++|++++|++++|→ 936
    GGACTTCTGTTGTACACCCTCTACGGTAGACGTTCC
    HGBGV89
    (SEQ ID NO:12)
    AGCTTACTTTCACTCACCCCCTCTCCTTCCTGACACCTCACCATGTGTACCCCAAAATGTGGGGCTCTGTGGGGCTCTCCCTCATTACC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 90
    TCGAATGAAAGTGAGTGGCGGACAGGAAGGACTGTGGAGTGGTACACATGCCCTTTTACACGGGCGACACACCCCGAGAGGGAGTAATGG
                                               M  C  T  C  K  C  A  R  C  V  C  L  S  L  I  T
    CTCTGCCTCCTCTCCATTCTGCCCAACCCCCTCCTGCTCCTACCTAATCCCCACACCTCCTCCACCAACACCAACCATCTCACCTTCCAA
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 180
    GAGACGGAGCACACCTAACACCGGTTGCGGGAGGACGACCATGGATTACCCCTCTCCACCACCTCGTTCTGGTTCCTACACTCCAACCTT
    (SEQ ID NO:27)
     L  C  L  V  C  I  V  A  N  A  L  L  L  V  P   N  O   E  T  S  W  T  N  T  N  H  L  S  L  C
    GTCTGCCTCATCCCCCGCTTCATTCCCCCCCCCCTAATCCTACTCTCTCCACCCATTCCACCCCTTCCCCCACCCCCCAACCCCTCCTCT
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 270
    CAGACCGAGTACCCGCCGAACTAACCCCCCCCGGATTACCATCACACACCTCCCTAACGTCCCCAACCCCCTCCCCCCTTCCCCACCACA
     V  W  L  M  C  C  F  C  C  C  L  M  V  L  C  P  C  A  A  V  R  A  C  C  K  C  C  C
    CCTCCTCCCTCCTCTCGAAACCCCTCCACCATCCTCCCCTCCCTCTTCTCCTCCCCCTTCCCCGTCCTTGCTCCCATCTACTCCCTCTCC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 360
    CCACGACCCACCACACCTTTCCCCACCTCCTACGACGCGACCCACAAGACCAGCCCCAACCCCCACCAACCACCCTACATCACCGACAGC
     G  A  G  C  C  G  N  R  C  R  M  L  R  S  V  F  S  S  A  F  G  V   L   C   A  G   T   C  L   S
    CTCTCTCCAGCTCCCCTCCCAAATCCACCCAGATCCTTAATCAACCCCCACTCCCCCTACCACTTCGAACACACCCCCCCACCTTACTTG
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 450
    CACACACCTCGACCCGACGCTTTACCTCCGTCTACCAATTACTTGCCCCTCACCCCCATCGTCAACCTTCTCTCCCCCCCTCCAATCAAC
     V  S  C  A  C  L   R   N  O   P   R   C   L   M   N   C   E   W   C   T   H   F   E   C  T   A   C   A   T   L
    CTCAACCCCACTCTATCCCATCCCTCCCACCCCCCCCCTCCCCTCCGCCCCTCCAATCTCACCCTCTTCTCCCTCCTCCTCCCCCCCTCC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 540
    CACTTCCCCTCACATACCCTACCCACCCTCCCCCCCCCACCCCACCACCCCACCTTACACTCCCACAACACCCACCACCACCCCCCCACC
     L  N  R  T  L  W  D  R  C   E  A  P  P  R  T   V  P  W  N  V   T  L  F  S  L  L  V  A  A  S
    TCCCTCCACATACTACTCTCTCCCATCCACCTCCTCAACCCCACCATTCCTCTCTTCTCCCCCCATTCCACCAAAAAACACCACACACCT
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 630
    ACCCACCTCTATCATCACACACCCTACCTCCACCACTTCCCCTCCTAACCACACAACACCCCCCTAACCTCCTTTTTTCTCCTCTCTCCA
     C  L  E  I  V  L  C  G   I  O  L  V  N  A  T  I  G  V  F  C  G  D  C   R   K   K   O  D  T   P
    CACTGAGGCTCCACTGACCGCCGGGTTACACCTCCTCCTTCCTCCACCCTCACTCCCTTCCTCCCTACAATAAACTCCTTTCCCCTCTCA
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 720
    GTGACTCCCACCTCACTCCCCCCCCAATCTCCACCACCAACCACCTCCCACTCACCCAACCACCCATCTTATTTCACCAAACCCCACACT
     H
    AAAAAAAAAAAAAAAAAC
    ++++|++++|++++|++→ 738
    TTTTTTTTTTTTTTTTTG
    HUVBB80
    (SEQ ID NO:13)
    GGCACGACAGATTCTCGCCTCCCCCTATATTCCAATTCCCCCTCTCCTCATCAATATCAACTCAACCCCTCTCACCCTCCAACTCCTTCT
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 90
    CCCTCCTCTCTAACAGCCGACGCCCATATAAGCTTAAGGGGCAGACCACTACTTATACTTCACTTCCCCACACTGGGACCTTCACCAAGA
    AACCACCCCAAAATCCCCTCTCCCAACTCTCCACCCTCCCTAACTTGTTTCCTCATTCCCCTTGCACTTTCCACTATAATCGTCAACATA
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 1180
    TTCGTCCCGTTTTACCCCAGAGCCTTCACACCTCCCACCGATTCAACAAACGACTAACCCCAACCTCAAACCTCATATTACCACTTCTAT
    (SEQ ID NO:28)
                 M  C  S  R  K  C  C  C  C  L  S  C  L  L  I   P  L  A  L  W  S  I  I  V  N
    TTATTCTATTTCCCCAATGCCCAAACTTCCTATCCATCCACCAATAAACTCACCAACTACCTGTCCTATTTTGAAGCAATCTCTTTCTCA
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 270
    AATAACATAAACCCCTTACCCCTTTCAACCATACCTACCTCCTTATTTCACTCCTTCATCCACACCATAAAACTTCCTTACACAAACACT
     L  L  Y  F  P  N  O  C  T  S  T  A  S  S  N  K  L  T  N  T  V  W  T  F  E  C  C  F  S
    GGCATCATCATGCTTATAGTAACAACAGTTCTTCTGGTACTGGAGAATAATAACAACTATAAATGTTCCCACACTGAAAACTGCAGCAAA
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 360
    CCCTAGTACTACCAATATCATTCTTCTCAACAACACCATCACCTCTTATTATTCTTCATATTTACAACCCTCTCACTTTTCACCTCCTTT
     G   I   N   M  L  I  V   T   T   V  L  L   V   L  E  N  N  N  N  Y   K   C   C   O  S  E  N  O  S  K
    AAATATCTCACACTGCTCTCAATTATCTTTTCTTCCCTCCCAATTCCTTTTTCTCCATACTGCCTCCTCATCTCTGCCTTGCCTCTTCTC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 450
    TTTATACACTCTGACCACACTTAATACAAAACAAGCCACCCTTAACCAAAAAGACCTATGACCGACCAGTACAGACCCAACCCAGAACAG
     K  Y  V  T  L  L  S  I  I  F  S  S  L  G  I  A  F  S  G  Y  C  L  V  I  S  A  L  G  L  V
    CAACGCCCATATTCCCCCACCCTTCATCGCTCCCACTATCCTTTTCAACCCACTCCTGCACCTTTCCTTACAGATTCTACCATATCGATT
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 540
    CTTCCCGCTATAACCCCCTCGCAACTACCCACCCTCATACGAAAACTTCCCTCACGACCTGCAAACCAATCTCTAAGATCCTATACCTAA
     O  C  P  V  C  R  T  L  C  C  W  E  T  A  F  E  C  T  A  C  R  F  L  T  C  S  S  I  W
    CAGTCCCTGCAACCTCCACATCTTGTCCACTCCAACATCATTTTATTTTCCATTCTCATAACCCTCACTGCCCTTCAACTCATCATCTCC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 630
    CTCACCCACCTTCCACCTCTACAACACCTCACCTTCTACTAAAATAAAACCTAAGACTATTCCCAGTCACCCCAAGTTCACTACTAGACC
     O  C  L  E  P  A  H  V  V  E  W  N  I  I  L  F  S  I  L  I  T   L   S  C  L  C  V  I  I  C
    CTCATCACACTACTCATCCAACTATCCAACATACTCTCTCCAACCTATTCACTCATCTTCCACCCTCCAATCATTTCAATAACCACAAAA
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 720
    CAGTACTCTCATCACTACCTTCATACCTTCTATCACACACCTTCCATAACTCACTACAACCTCCCACCTTACTAAACTTATTCCTGTTTT
     L  I  R  V  V   M  C   L   S   K   I   L   C   C   G   Y  S  V  I  F  O  P  C  I  I
    TGTTTTCCATTATCAACACATCCCCATCTATCTAAATATTATATCAACTCTCTTACACTTCACCCCAATATTCAAAATCATCCTCCTTTC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 810
    ACAAAACCTAATACTTCTCTACCCCTACATAGATTTATAATATACTTCACACAATCTCAACTCCCCTTATAACTTTTACTACCACCAAAC
    TGCATTTCCTCTTTATTTCTAAAAAATTTCCACTCCTCACTCCACATCCAACTATACCACCCTTCCATTTACTATCTTTTTTAACTAATA
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 900
    ACCTAAACCACAAATAAACATTTTTTAAACCTCACCACTGACCTCTACCTTCATATCCTCCCAACCTAAATCATACAAAAAATTCATTAT
    TCCATCACAAAC TTC4CAAATACTTCTCCCCTTTCATCAAACAAATCCATTTCCAACAATCTCTACTACCCAACTAAATAACAATATCAC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 990
    ACGTAGTCTTTGAAGTCTTTATGAACACCCCAAACTAGTTTCTTTACCTAAACGTTCTTACACATCATCCCTTCATTTATTCTTATACTC
    ACAAACCTTTATCCAATATCTATATTCCAACATTATTTAATATTCTCCAAAATTCCAAACACCCCAAAATTCTAACTCAAA
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|→ 1071
    TCTTTCCAAATACCTTATACATATAACCTTCTAATAAATTATAACACCTTTTAACCTTTCTCCCCTTTTAACATTCACTTT
    HJACE54
    (SEQ ID NO:14)
    TTTGTGGAGGCCAGCACAGACTACCCACCTCCACATCCTTTCCTCCTCATCACCCCCACCCTCCACCTCCCCTCCTCACATCCTCTTCCC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|
    AAACACCTCCCCTCCTCTCTCATCCCTCCACCTCTACCAAACCACGACTACTCCCCCTCCCACCTCCACCCCACGACTCTACGACAACGC
    (SEQ ID NO:29)
                                                     M  S  P  R  L  E  V  P  C  S  H  A  L  P
    CACCGTCTCTCCCCTCCCCACCTCATCATAGTACCCCCACTCCTCTTCCAACAGCCCAACCATTTTACTCTCACCCTCACCCACCACGCT
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 1180
    CTCCCACACACCCGACCCCTCCAGTACTATCATGCCCCTGACCACAACCTTCTCCCCTTCCTAAAATCAEACTCCCACTCCCTCCTCCGA
     O  G  L  S  P  C  D  V  I  V  R  C  L  V  L  C  E  R  K  H  F  T  V   S   L   R  D  O  A
    CCCCATGCTCCTCTGACAGTCACGGCCTCCTTCCCACACACAACTCTCCCGTGGATCTCCCGCTGCCCGCACAACAAAGTCATCTCACCC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 1270
    CCCCTACGAGCACACTCTCACTCCCCCACCAACCCTCTCTCTTCACACCCCACC TAGACCCCGACCCCCCTCTTCTTTCACTACACTCCC
     A  H   A   P   V  T   L   R   A  S   F  A   D  R  T  L  A  W  S  R   W  C  C   K   K   L  I  S  A
    CCCTTCCTGTTTTACGCCCAGACATTGTTTCACCTCCTCCTCCTCTTCCACCAGGCAGCCCTGAACCTGCCCCTCAATCCCCACCCCCTC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 1360
    GCCAACCAGAAAATCCGCCTCTCTAACAAACTCCACCACCAGCACAAGCTCCTCCCTCCCCAC TTCGACCCCCAGTTACCCCTCCCCCAC
     P  F  L  F  T   P   C  R   F  F   E   V   L   L   L   F   C  E  G  G   L   K   L  A  L  N  G  C  C  L
    CCCGCCACCACCATCAACCACCACGCCCTCCAGCAGCTCCCGCAGCTCCCCA7CACTCCAACTCTCCACCTCTACTCTCTCCACTCCTCA
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 450
    CCCCCCTGCTCCTACTTGCTCCTCCGGCACCTCCTCCACGCCCTCCAGCCCTAGTCACCTTCAGACCTCGACATCACACACCTCACCACT
     G  A  T  S  M  N  O  O  A  L  E  O  L  R  E  L  R  I  S  G  S  V  O  L  Y  C  V  H  S
    ACCATCCTTCCACCAAATACCCCACAAAACAACACTCACCCACTCCCCAGCCCCCCACTCTCCTCGCCTCATTAAACCATCCACCTGAAC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 540
    TCCTACCAAGGTCCTTTATGCCCTGTTTTGTTCTCAGTCCCTCACCCCTCCCCCCCTCACACGACGCCAGTAATTTCCTACCTGCACTTC
    AGCACCACATCACCCCCTCCTTCACCTCTGCCCTCACCAGACTCACTCTACACCACCTTTCCCCCTCACCCAACCCACAACACTCCAAAG
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 630
    TGGTCGTGTACTCCCCCACCAACTCGACACCCCACTCCTCTCACTCACATGTCCTCCAAACCCCCACTCCCTTCCCTCTTCTCACCTTTC
    CTTCCTCCAACTCTCCACCTTCCTCCACCACCACCCTCCCATATCCCTCCATGTGCCTTCACCCCCTCCACTCCACTCACACACCCAACT
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 720
    CAACCACCTTCACACGTCCAACCACCTCCTCCTCCCACCCTATACCCAGCTACACCCAACTCCCCCACCTCACCTCACTCTCTCCCTTCA
    CTTGTAGACTAACAAACATACTGCAAAATACAATCCCTTAAACAATGTCGTCATTTATTCTTTATTATTTATTTATTTCTCCTCAAATAA
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 810
    CAACATCTCATTCTTTCTATGACGTTTTATCTTACCGAATTTCTTACACCACTAAATAAGAAATAATAAATAAATAAAGACCACTTTATT
    ATAAATAACCTTATTTATTTAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++→ 865
    TATTTATTCCAATAAATAAATTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT
    HROAD63
    (SEQ ID NO:15)
    GCACGAGAGACGACATCAGAGATGAGGACAGCATTGCTGCTCCTTGCAGCCCTCCCTGTGGCTACAGGCCCAGCCCTTACCCTGCGCTGC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 90
    CGTGCTCTCTCCTGTAGTCTCTACTCCTGTCGTAACGACGAGGAACGTCCGCACCGACACCCATGTCCCGGTCGGGAATGCGACGCGACG
    (SEQ ID NO:30)
                          M  R  T  A  L  L  L  L  A  A  L  A  V  A  T  G  P  A  L  T  L  R  C
    CACGTGTGCACCAGCTCCAGCAACTGCAACCATTCTCTGGTCTGCCCCTGCCAGCTCTCGCTTCTGCAAGACCACGAACACACTGGAGCCT
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 180
    GTCCACACCTGGTCGAGGTCGTTGACGTTCCTAACACACCACACGGGCCGGTCGAGAGCGAACACCTTCTGGTGCTTGTGTCACCTCGGA
    H  V  C  T  S  S  S  N  O  K  H  S  V  V  C  P  A  S  S  R  G  C  K  T  T  N  T  V  E  P
    CTCACGCCTTCCCCCAAACTCTCCCACCAGCTCCACGTCCGCATGGAATCCTCATCACTTCGAGCACGCCCCACACACCCCACACAGCAT
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 270
    GACTCCCCAAGGGGCTTTCAGACCCTCCTCCACCTCCACCCGTACCTTACGACTACTGAACCTCGTCCGGGGTGTCTGGGGTG
    L  R  A  S  P  K  V  W  D  O  V  O  V  G  M  E  C
    GAACCCACCCCACACAGCATCCACCCCCCACCTCCATCCAACGTGGAGGACAGAAGCCCTGTCGATCCCCGGATTTCACACTCCTTCTCT
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 360
    CTTCGCTTCCGTGTCTCCTACGTCGGGGGTCGACGTACCTTCCACCTCCTGTCTTCGGCACACCTACGCGCCTAAACTCTCAGGAACACA
    TTTCTTGCCGTTTATTTTTCTACTCAAATCTCTACATGCAGATAAATGATTTAAACCACTAAAAAAAAAAAAAAAAAAAAA
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|→ 441
    AAACAACCGCAAATAAAAACATCACTTTAGAGATGTACCTCTATTTACTAAATTTGGTCATTTTTTTTTTTTTTTTTTTTT
    HMWGS46
    (SEQ ID NO:16)
    AGCGGGCCCGAACCCTCCTCTGAAGGGTGCAGTACCTAAGCCCGAGCGGGGTACACCCGCCCCGCCACCCCCTTCTCACCTCCAGTGCCC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 90
    TCGCCCGCCCTTGCCAGCACACTTCCCACGTCATCGATTCGGCCTCGCCCCATCTCCCCCCGCCCCTGGCGCAAGACTCCACCTCACGCC
    CCCCCCTCAAGATCAGACATGGCCCACAACTTGAACCACTTCGCCCCACCGCTCCCCCCCCCCCCCCCGGGCATGGGCACGCCCCTGAAG
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 180
    GGCCGGAGTTCTAGTCTGTACCGCCTCTTGAACTTCCTGAACCGCCCTGCCGACCGGCGCCCCCGCCCCCCGTACCCCTGCCCCGACTTC
    (SEQ ID NO:31)
                       M  A  C  N  L  K  D  L  A  G   R  L  P  A  G  P   R   G  M  G  T  A  L  K
    CTGTTGCTGCGGCCCCGCCCCGTGGCCTACCGTGTGCGCGAATCTGTCTTCACCCTGCAACCCGCCCACACACCCATCTTCTTCAATCCC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 270
    GACAACCACCCCCCCCCCCGCCACCCCATCCCACACGCGCTTACACACAACTCCCACGTTCCGCCCCTCTCTCCCTACAACAACTTACCC
     L  L  L  G  A  G  A    V  A  V  C  V  R  E  S  V  F  T  V   E   G  C   H  R   A  I  F  F  N  R
    ATCCCTGGACTCCAGCAGCACACTATCCTCCCCGACCGCCTTCACTTCACGATCCCTTCGTTCCAGTACCCCATTATCTATCACATTCGG
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 360
    TAGCCACCTCACCTCCTCCTGTCATAGGACCGGCTCCCCGAAGTGAACTCCTAGGCAACCAACCTCATGCGCTAATACATACTCTAACCC
     I  G  G  V  O  O  D  T  I  L  A  E  C  L  H  F  R  I  P  W  F  O  V  P  I  I  Y  D   I  R
    GCCAGACCTCGAAAAATCTCCTCCCCTACAGGCTCCAAACACCTACACATCGTCAATATCTCCCTCCGAGTCTTGTCTCCACCCAATGCT
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 450
    CCGTCTCCACCTTTTTACACCACCCCATCTCCGAGCTTTCTGGATCTCTACCACTTATACACCCACCCTCACAACACACCTCCCTTACCA
     A  R  P  R   K  I  S  S  P  T  C  S  K  D  L  C  M  V  N  S  L  R  V  L  S  R  P  N  A
    CAGGACCTTCCTACCATGTACCAGCGCCTAGCCCTGCACTACGACGAACGACTGTTGCCCTCCATTGTCAACCACCTCCTCAAGACTCTC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 540
    CTCCTCCAACCATCGTACATGCTCGCCCATCCCCACCTGATGCTCCTTCCTCACAACCCCACCTAACACTTCCTCCACCACTTCTCACAC
     C  E  L  P   S  M  T  C  R  L  C  L  D  V  E  E  R  V  L  P  S   V  N  E  V  L  K   S  V
    CTCCGCAACTTCAATCCCTCACAGCTCATCACCCACCGCCCCCACGTATCCCTCTTCATCCCCCCGCAGCTCACACACACCCCCAACGAC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 630
    CACCCCTTCAACTTACGCACTGTCGACTACTCCCTCCCCCGCGTCCATACCCACAACTACCCCCCCCTCCACTCTCTCTCCCCCTTCCTG
     V  A  K  F  N  A  S  O  L  I  T  O  R  A  O  V  S  L  L  R  R  E  L  T  E  R  A  K  D
    TTCAGCCTCATCCTGGATCATGTCGCCATCACAGACCTGAGCTTTAGCCGACAGTACACACCTGCTGTACAACCCAAACAACTCCCCCAG
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 720
    AAGTCGCAGTACGACCTACTACACCGCTACTCTCTCCACTCCAAATCCCCTCTCATCTCTCGACCACATCTTCGCTTTGTTCACCGGCTC
     F  S  L  I   L  D  C  V  A  I  T   E  L  S   F  S  R  E  V  T   A   A  V  E  A  K  C  V  A  O
    CACCAGCCCCACCGCCCCCAATTCTTGCTAGAAAAAGCAAAGCAGGAACAGCCCCACAAAATTCTGCACGCCCACCCTGAGCCCCAGCCT
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 810
    GTCCTCCCCCTCCCCCGCCTTAAGAACCATCTTTTTCGTTTCCTCCTTGTCCCCCTCTTTTAACACCTCCCCCTCCCACTCCCCCTCCCA
     O  E  A  O  R  A  C  F   L  V  E  K  A  K   C  E  C  R   C  K  I  V  C  A  E  C  E  A  E  A
    CCCAACATCCTTCCACAAGCACTCACCAACAACCCTGCC TACATCAAACTTCGCAACATTCGACCACCCCACAATATCTCCAACACCATC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 900
    CCGTTCTACCAACCTCTTCCTCACTCCTTCTTCCCACCGATCTACTTTGAACCGTTCTAACCTCCTCCGGTCTTATAGAGCTTCTGGTAG
     A   K   M  L  C  E  A  L  S  K  N  P   G  T  I  K  L  R  K   I  R  A  A  C  N  I  S  K  T
    CCCACATCACACAATCCTATCTATCTCACACCTGACAACCTTGTCCTCAACCTACAGCATCAAACTTTCACCACCCGAAGTCACAGCCTC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 990
    CGCTGTAGTGTCTTACCATAGATACACTCTCCACTGTTGCAACACGACTTGGATGTCCTACTTTCAAACTCGTCCCCTTCACTGTCCCAC
     A  T  S  C  N  R  I  T  L  T  A  D  N  L   V  L  N  L  C  D  E  S  F   T  R   C  S  C  S  L
    ATCAACGGTAAGAAATGAGCCTAGTCACCAACAACTCCACCCCCACAACAACTCCATCTCCTTCTCCACTTTTTGA
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|→ 1066
    TACTTCCCATTCTTTAGTCCCATCACTCCTTCTTCACGTCCCCGTCTTCTTCACCTAGALCAAGAGCTCAAAAACT
     K  C  K   K
    HNFGW06
    (SEQ ID NO:17)
    GGCACCAGATGACATCACTAAGTCCGATCTGCACAGAGCAGGCCAGCACCAACCACACAGGCTTCCTGCACATGCACTCCCACATCAA
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 90
    CCGTGCTCTACTGTAGTGATTCACCCGCTACACCTGTCTCCTCCCCTCCTCGTTGGTGTGTCCGAAGGACGTGTACCTGACCCTCTAGTT
    (SEQ ID NO:32)
                                                                              M  D  C  E  K
    GGGCCGCCCCTCCTGCATCCGCACCAACGGCACCTCTGAGATCACCACCCCGDAATACTGTCACTTCATGCACCGCTATTTCCATGAGGA
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 180
    CCCGGCCCGGACCACGTAGCCGTGCTTCCCCTCCACACTCTACTGCTGCCCCCTTATCACACTCAACTACGTCCCCATAAACGTACTCCT
     C  R  P  C   C  C  T  K  C  S  C  E  I  T  T  R  E  T  C  E  F  M  H  G  T  F   H  E  E
    ACCAACACTCTGCTCCCACGTCAGCCCACCCAGCCCTGGACTACTGCACCAGACCACGCTGCCCATCGCACCCTCCTCGCCCCCCCCCTC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 270
    TCGTTCTCACACGACGGTCCACTCCGCTCCCTCCCCACCTCATCACCTCCTCTCCTGCGACCCCTACCCTCCCACCACCCCCCCCCCCAG
     A  T   L  C  S  O  V   R  R  G  R  P  G  V  V  E  E  R  T  L  G  M  A  A  C  W  G  R  G  S
    ACCCACTCCCTCCCATCTCGCACCCTCACACTCAGCCTCCTTCTCCGCCCCTGACCACCATATGCCCATTCCCACCTCCACTCTTTTCGA
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 360
    TCCGTCACCCACTACACCCTCCCACTCTCACTCCCACCAACACCCCCCCACTCCTGGTATACCGCTAACGGTCCACCTCACAAAACCT
     R  T  P  S  H  V  G  A  S  D  S  G  C  F  W  G  A  E  H  H  N  P  I  P  R  C   T  V  L  D
    CAACCTGTCTTCGCCTCCTCCCTTCCTCAACCCTCACGTCCCAGATCAGTTTTACACGTCTCGCTGTCTCTTTTCCTACATCTTCCCTAA
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 450
    GTTCCACACAACCCCACCACGCAAGGACTTCCCACTCCACCCTCTACTCAAAATCTCCAGACCCACAGAGAAAAGCATGTACAACCCATT
     K    V   C   W   A   A   A   F   L   N   P   E   V   P   O  O  F   Y   R   S   G   C   L   F   S   Y   M  L   G   K
    CACCTCCTCAATGCCCCCGAACCCGACCCCTCTGATCCACACCCACCCCCACCCCTGCCCAAACCTTCCTCGCCCACCCTATGGTCCCTC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 540
    CTCCACCAGTTACCCGCCCTTGCCCTCCGCACACTACCTCTGGGTCCCCCTGCGCACCCCTTTCCAAGGACCCCGTCCCATACCACCCAC
     R  S   S   M  P  P   N  P  T  P  V  M  D   T  G  A  D  P  W  G  K  V  P  G  P  G  Y  G  R  S
    CAACCTCCCCAACACTACTCCTCCTGAACTGTCTCCATCAACGCCCCTCCCTGCTCTCTCCCTCCCCCACTGTCCCTCCACTGCCCTCCG
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++| 630
    CTTCCACGGCTTCTCATCACCACCACTTCACACACCTACTTCCGGCCACCGACCACACACCCAGCCCGTCACACCCACCTCACCCCACCC
     N  L  P  K   T   T   A   P   E   V   S   G
    TCTCTTCTCCCTCTTTTCAAATGACATCCCTCAACCGCACCTGCACGAACGTGCTCCCCCTCCCACCCTATCCC
    ++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|++++|+++→ 704
    ACACAACACCCACAAAAGTTTACTCTAGGCACTTCCCCTGGACCTCCTTCCACCACCCCGACCGTCCGATAGCC
  • [0131]
  • 1 63 1497 base pairs nucleic acid single linear DNA (genomic) 1 GCAGTTCCTG AGAGAAGAAC CCTGAGGAAC AGACGTTCCC TCGCGGCCCT GGCACCTCCA 60 ACCCCAGATA TGCTGCTGCT GCTGCTGCTG CCCCTGCTCT GGGGGAGGGA GAGGGTGGAA 120 GGACAGAAGA GTAACCGGAA GGATTACTCG CTGACGATGC AGAGTTCCGT GACCGTGCAA 180 GAGGGCATGT GTGTCCATGT GCGCTGCTCC TTCTCCTACC CAGTGGACAG CCAGACTGAC 240 TCTGACCCAG TTCATGGCTA CTGGTTCCGG GCAGGGAATG ATATAAGCTG GAAGGCTCCA 300 GTGGCCACAA ACAACCCAGC TTGGGCAGTG CAGGAGGAAA CTCGGGACCG ATTCCACCTC 360 CTTGGGGACC CACAGACCAA AAATTGCACC CTGAGCATCA GAGATGCCAG AATGAGTGAT 420 GCGGGGAGAT ACTTCTTTCG TATGGAGAAA GGAAATATAA AATGGAATTA TAAATATGAC 480 CAGCTCTCTG TGAACGTGAC ATACCCTCCT CAGAACTTGA CTGTGACTGT CTTCCAAGGA 540 GAAGGCACAG CATCCACAGC TCTGGGGAAC AGCTCATCTC TTTCAGTCCT AGAGGGCCAG 600 TCTCTGCGCT TGGTCTGTGC TGTTGACAGC AATCCCCCTG CCAGGCTGAG CTGGACCTGG 660 AGGAGTCTGA CCCTGTACCC CTCACAGCCC TCAAACCCTC TGGTACTGGA GCTGCAAGTG 720 CACCTGGGGG ATGAAGGGGA ATTCACCTGT CGAGCTCAGA ACTCTCTGGG TTCCCAGCAC 780 GTTTCCCTGA ACCTCTCCCT GCAACAGGAG TACACAGGCA AAATGAAGCC TGTATCAGGA 840 GTGTTGCTGG GGGCGGTCGG GGGAACTGGA GCCACAGCCC TGGTCTTCCT CTCCTTCTGT 900 GTCATCTTCA TTGTAGTGAG GTCCTGCAGG AAGAAATCGG CAAGACCAGC AGCGGACGTG 960 GGAGACATAG GCATGAAGGA TGCAAACACC ATTCAGGGGC TCAGCCTCTC AGGGTAACTG 1020 GATGAGTCCT GGGCAGATGA TAACCCCCGA CACCATGGCC TGGCTGCCCA CTCCCTCAGG 1080 GGAGGAAAGA GAGATCCCAG TATGCACCCC TCAGCTTTCA TAAGGGGGAG CCTCAGGACC 1140 TATCCAGGTC AAGAAGCCAC CAACAATGAG TACTCAGAGA TCAAGATCCC CAAGTAAGAA 1200 AATGCAGAGG CTCGGGCTTG TTTGAGGGTT CACGACCCCT CCAGCAAAGG AGTCTGAGGC 1260 TGATTCCAGT AGAATTAGCA GCCCTCAATG CTGTGCAACA AGACATCAGA ACTTATTCCT 1320 CTTGTCTAAC TGAAAATGCA TGCCTGATGA CCAAACTCTC CCTTTCCCCA TCCAATCGGT 1380 CCACACTCCC CGCCCTGGCC TCTGTACCCA CCATTCTCCT CTGTACTTCT CTAAGGATGA 1440 CTACTTTAGA TTCCGAATAT AGTGAGATTG TAACGTGAAA AAAAAAAAAA AAAAAAA 1497 1849 base pairs nucleic acid single linear DNA (genomic) 2 CGGCACGAGT GGACAACCAT CAGGGAGCCA GGACACAGAG GGGCAGAGCA AGTCAGCATT 60 GGCGCCCCTT CCTCAGATCC CTATCATCTT GGGAAACAGT AGCCCAGAGG TTCAGGAAGA 120 TGTTAACTTA AATGTTCGGG GTGCCCCAGT CTGTTCAGCA TGGCTGAAAT CCACACTCCG 180 TATTCTTCCT TGAAGAAACT GTTATCTTTA CTCAATGGCT TCGTGGCTGT GTCTGGCATC 240 ATCCTAGTTG GCCTGGGCAT TGGTGGTAAA TGTGGAGGGG CCTCTCTGAC GAATGTCCTC 300 GGGCTGTCCT CCGCATACCT CCTTCACGTT GGCAACCTGT GCCTGGTGAT GGGATGCATC 360 ACGGTACTGC TTGGCTGTGC CGGGTGGTAT GGAGCGACTA AAGAGAGCAG AGGCACGCTC 420 TTGTTTTGCA TCCTGTCAAT GGTTATTGTC CTCATCATGG AAGTTACAGC TGCCACAGTG 480 GTCCTTCTTT TCTTTCCAAT TGTTGGAGAT GTGGCCTTGG AACACACCTT CGTGACCCTG 540 AGGAAGAATT ACAGAGGTTA CAACGAGCCA GACGACTATT CTACACAGTG GAACTTGGTC 600 ATGGAGAAGC TAAAGTGCTG TGGGGTGAAT AACTACACAG ATTTTTCTGG CTCTTCCTTC 660 GAAATGACAA CGGGCCACAC CTACCCCAGG AGTTGCTGTA AATCCATCGG AAGTGTGTCC 720 TGTGACGGAC GCGATGTGTC TCCAAACGTC ATCCACCAGA AGGGCTGTTT CCATAAACTC 780 CTAAAAATCA CCAAGACTCA GAGCTTCACC CTGAGTGGGA GCTCTCTGGG AGCTGCAGTG 840 ATACAGAGGT GGGGGTCTCG CTATGTTGCG CAGGCTGGTC TTGAACTGCT GGCCTAAAGC 900 GATCCCCCCG CCTAGGCCTC CCAAAGTGCT GGGTTTACCA GCGTGAGCCA CCACGCTGGG 960 CTTCCTGCAT CCTTTTAAGG TTCCTGAGGG TCTGCCTGAG AGGAGCTGTC CCTGAATCTC 1020 CATGCAGCCC CACCTGCCAC ATCACCAAGA CATACAATCT TTGCCAGCAA CACTTCCTCC 1080 TTGCAGATTA CAAGCATAGC TAATGCCACC ACCAGACAAG ACCGATTCGC TGGCCTCCAT 1140 TTCTTCAACC CAGTGCCTGT CATGAAACTT GTGGAGGTCA TTAAAACACC AATGACCAGC 1200 CAGAAGACAT TTGAATCTTT GGTAGACTTT AGCAAAACCC TAGGAAAGCA TCCTGTTTCT 1260 TGCAAGGACA CTCCTGGGTT TATTGTGAAC CGCCTCCTGG TTCCATACCT CATGGAAGCA 1320 ATCAGGCTGT ATGAACGAGG GCCTCCTGGC TTTCCCTGTG GGCTTCTGAG AAAGGTTTCT 1380 GGAACTCCCA CCACCCCCAC TACAGTCCCA GCCAGAGCAA TTGCATGGCC GGCCCAGATT 1440 GATATCCTGG ATCTCTGCTT TTGATTAAAA GGTGACGCAT CCAAAGAAGA CATTGACACT 1500 GCTATGAAAT TAGGAGCCGG TTACCCCATG GGCCCATTTG AGCTTCTAGA TTATGTCGGA 1560 CTGGATACTA CGAAGTTCAT CGTGGATGGG TGGCATGAAA TGGATGCAGA GAACCCATTA 1620 CATCAGCCCA GCCCATCCTT AAATAAGCTG GTAGCAGAGA ACAAGTTCGG CAAGAAGACT 1680 GGAGAAGGAT TTTACAAATA CAAGTGATGT GCAGCTTCTC CGGTTCTGAG AAGAACACCT 1740 GAGAGCGCTT TCCAGCCAGT GCCCCGAGTG CCTGTGGGAA TGCTCTTTGG TCAGACATTC 1800 CCTCACACAG TACAGTTTAA TAAATGTGCA TTTTGATTGT AAAAAAAAA 1849 741 base pairs nucleic acid single linear DNA (genomic) 3 ATGGCTGAAA TCCACACTCC GTATTCTTCC TTGAAGAAAC TGTTATCTTT ACTCAATGGC 60 TTCGTGGCTG TGTCTGGCAT CATCCTAGTT GGCCTGGGCA TTGGTGGTAA ATGTGGAGGG 120 GCCTCTCTGA CGAATGTCCT CGGGCTGTCC TCCGCATACC TCCTTCACGT TGGCAACCTG 180 TGCCTGGTGA TGGGATGCAT CACGGTACTG CTTGGCTGTG CCGGGTGGTA TGGAGCGACT 240 AAAGAGAGCA GAGGCACGCT CTTGTTTTGC ATCCTGTCAA TGGTTATTGT CCTCATCATG 300 GAAGTTACAG CTGCCACAGT GGTCCTTCTT TTCTTTCCAA TTGTTGGAGA TGTGGCCTTG 360 GAACACACCT TCGTGACCCT GAGGAAGAAT TACAGAGGTT ACAACGAGCC AGACGACTAT 420 TCTACACAGT GGAACTTGGT CATGGAGAAG CTAAAGTGCT GTGGGGTGAA TAACTACACA 480 GATTTTTCTG GCTCTTCCTT CGAAATGACA ACGGGCCACA CCTACCCCAG GAGTTGCTGT 540 AAATCCATCG GAAGTGTGTC CTGTGACGGA CGCGATGTGT CTCCAAACGT CATCCACCAG 600 AAGGGCTGTT TCCATAAACT CCTAAAAATC ACCAAGACTC AGAGCTTCAC CCTGAGTGGG 660 AGCTCTCTGG GAGCTGCAGT GATACAGAGG TGGGGGTCTC GCTATGTTGC GCAGGCTGGT 720 CTTGAACTGC TGGCCTAAAG C 741 1288 base pairs nucleic acid single linear DNA (genomic) 4 GGCGTCCCTC TGCCTGCCCA CTCAGTGGCA ACACCCGGGA GCTGTTTTGT CCTTTGTGGA 60 GCCTCAGCAG TTCCCTCTTT CAGAACTCAC TGCCAAGAGC CCTGAACAGG AGCCACCATG 120 CAGTGCTTCA GCTTCATTAA GACCATGATG ATCCTCTTCA ATTTGCTCAT CTTTCTGTGT 180 GGTGCAGCCC TGTTGGCAGT GGGCATCTGG GTGTCAATCG ATGGGGCATC CTTTCTGAAG 240 ATCTTCGGGC CACTGTCGTC CAGTGCCATG CAGTTTGTCA ACGTGGGCTA CTTCCTCATC 300 GCAGCCGGCG TTGTGGTCTT TGCTCTTGGT TTCCTGGGCT GCTATGGTGC TAAGACTGAG 360 AGCAAGTGTG CCCTCGTGAC GTTCTTCTTC ATCCTCCTCC TCATCTTCAT TGCTGAGGTT 420 GCAGCTGCTG TGGTCGCCTT GGTGTACACC ACAATGGCTG AGCACTTCCT GACGTTGCTG 480 GTAGTGCCTG CCATCAAGAA AGATTATGGT TCCCAGGAAG ACTTCACTCA AGTGTGGAAC 540 ACCACCATGA AAGGGCTCAA GTGCTGTGGC TTCACCAACT ATACGGATTT TGAGGACTCA 600 CCCTACTTCA AAGAGAACAG TGCCTTTCCC CCATTCTGTT GCAATGACAA CGTCACCAAC 660 ACAGCCAATG AAACCTGCAC CAAGCAAAAG GCTCACGACC AAAAAGTAGA GGGTTGCTTC 720 AATCAGCTTT TGTATGACAT CCGAACTAAT GCAGTCACCG TGGGTGGTGT GGCAGCTGGA 780 ATTGGGGGCC TCGAGCTGGC TGCCATGAAT TGTGTCCATG TATCTGTACT GCAATCTACA 840 ATAAGTCCAC TTCTGCCTCT GCCACTACTG CTGCCACATG GGAACTGTGA AGAGGCACCC 900 TGGCAAGCAG CAGTGATTGG GGGAGGGGAC AGGATCTAAC AATGTCACTT GGGCCAGAAT 960 GGACCTGCCC TTTCTGCTCC AGACTTGGGG CTAGATAGGG ACCACTCCTT TTAGGCGATG 1020 CCTGACTTTC CTTCCATTGG TGGGTGGATG GGTGGGGGGC ATTCCAGAGC CTCTAAGGTA 1080 GCCAGTTCTG TTGCCCATTC CCCCAGTCTA TTAAACCCTT GATATGCCCC CTAGGCCTAG 1140 TGGTGATCCC AGTGCTCTAC TGGGGGATGA GAGAAAGGCA TTTTATAGCC TGGGCATAAG 1200 TGAAATCAGC AGAGCCTCTG GGTGGATGTG TAGAAGGCAC TTCAAAATGC ATAAACCTGT 1260 TACAATGTTA AAAAAAAAAA AAAAAAAA 1288 1236 base pairs nucleic acid single linear DNA (genomic) 5 AAAAAAAACA AGGTCCCCAC AGCAAAGAAA AGGAATAGGA TCAAGAGATA CGTGGCTGCT 60 GGCAGAGCAA GCATGAATTC GATGACTTCA GCAGTTCCGG TGGCCAATTC TGTGTTGGTG 120 GTGGCACCCC ACAATGGTTA TCCTGTGACC CCAGGAATTA TGTCTCACGT GCCCCTGTAT 180 CCAAACAGCC AGCCGCAAGT CCACCTAGTT CCTGGGAACC CACCTAGTTT GGTGTCGAAT 240 GTGAATGGGC AGCCTGTGCA GAAAGCTCTG AAAGAAGGCA AAACCTTGGG GGCCATCCAG 300 ATCATCATTG GCCTGGCTCA CATCGGCCTC GGCTCCATCA TGGCGACGGT TCTCGTAGGG 360 GAATACCTGT CTATTTCATT CTACGGAGGC TTTCCCTTCT GGGGAGGCTT GTGGTTTATC 420 ATTTCAGGAT CTCTCTCCGT GGCAGCAGAA AATCAGCCAT ATTCTTATTG CCTGCTGTCT 480 GGCAGTTTGG GCTTGAACAT CGTCAGTGCA ATCTGCTCTG CAGTTGGAGT CATACTCTTC 540 ATCACAGATC TAAGTATTCC CCACCCATAT GCCTACCCCG ACTATTATCC TTACGCCTGG 600 GGTGTGAACC CTGGAATGGC GATTTCTGGC GTGCTGCTGG TCTTCTGCCT CCTGGAGTTT 660 GGCATCGCAT GCGCATCTTC CCACTTTGGC TGCCAGTTGG TCTGCTGTCA ATCAAGCAAT 720 GTGAGTGTCA TCTATCCAAA CATCTATGCA GCAAACCCAG TGATCACCCC AGAACCGGTG 780 ACCTCACCAC CAAGTTATTC CAGTGAGATC CAAGCAAATA AGTAAGGCTA CAGATTCTGG 840 AAGCATCTTT CACTGGGACC AAAAGAAGTC CTCCTCCCTT TCTGGGCTTC CATAACCCAG 900 GTCGTTCCTG TTCTGACAGC TGAGGAAACG TCTCTCCCAC TGTTTGTACT CTCACCTTCA 960 TTCTTCAATT CAGTCTAGGA AACCATGCTG TTTCTCTATC AAGAAGAAGA CAGAGATTTT 1020 AAACAGATGT TAACCAAGAG GGACTCCCTA GGGCACATGC ATCAGCACAT ATGTGGGCAT 1080 CCAGCCTCTG GGGCCTTGGC ACACCCATTC GTGTGCTCTG CTGCATGTGA GCTTGTGGGT 1140 TAGAGGAACA AATATCTAGA CATTCAATCT TCACTCTTTC AATTGTGCAT TCATTTAATA 1200 AATAGATACT GAGCATTCAA AAAAAAAAAA AAAAAA 1236 1115 base pairs nucleic acid single linear DNA (genomic) 6 CACGAGCAGG GTCTCGGGCT AGTCATGGCG TCCCCGTCTC GGAGACTGCA GACTAAACCA 60 GTCATTACTT GTTTCAAGAG CGTTCTGCTA ATCTACACTT TTATTTTCTG GATCACTGGC 120 GTTATCCTTC TTGCAGTTGG CATTTGGGGC AAGGTGAGCC TGGAGAATTA CTTTTCTCTT 180 TTAAATGAGA AGGCCACCAA TGTCCCCTTC GTGCTCATTG CTACTGGTAC CGTCATTATT 240 CTTTTGGGCA CCTTTGGTTG TTTTGCTACC TGCCGAGCTT CTGCATGGAT GCTAAAACTG 300 TATGCAATGT TTCTGACTCT CGTTTTTTTG GTCGAACTGG TCGCTGCCAT CGTAGGATTT 360 GTTTTCAGAC ATGAGATTAA GAACAGCTTT AAGAATAATT ATGAGAAGGC TTTGAAGCAG 420 TATAACTCTA CAGGAGATTA TAGAAGCCAT GCAGTAGACA AGATCCAAAA TACGTTGCAT 480 TGTTGTGGTG TCACCGATTA TAGAGATTGG ACAGATACTA ATTATTACTC AGAAAAAGGA 540 TTTCCTAAGA GTTGCTGTAA ACTTGAAGAT TGTACTCCAC AGAGAGATGC AGACAAAGTA 600 AACAATGAAG GTTGTTTTAT AAAGGTGATG ACCATTATAG AGTCAGAAAT GGGAGTCGTT 660 GCAGGAATTT CCTTTGGAGT TGCTTGCTTC CAACTGATTG GAATCTTTCT CGCCTACTGC 720 CTCTCTCGTG CCATAACAAA TAACCAGTAT GAGATAGTGT AACCCAATGT ATCTGTGGGC 780 CTATTCCTCT CTACCTTTAA GGACATTTAG GGTCCCCCCT GTGAATTAGA AAGTTGCTTG 840 GCTGGAGAAC TGACAACACT ACTTACTGAT AGACCAAAAA ACTACACCAG TAGGTTGATT 900 CAATCAAGAT GTATGTAGAC CTAAAACTAC ACCAATAGGC TGATTCAATC AAGATCCGTG 960 CTCGCAGTGG GCTGATTCAA TCAAGATGTA TGTTTGCTAT GTTCTAAGTC CACCTTCTAT 1020 CCCATTCATG TTAGATCGTT GAAACCCTGT ATCCCTCTGA AACACTGGAA GAGCTAGTAA 1080 ATTGTAAATG AAGTAAAAAA AAAAAAAAAA AAAAA 1115 1662 base pairs nucleic acid single linear DNA (genomic) 7 CACGAGCATT GCCGCTCTCT CGGTGAGCGC AGCCCCGCTC TCCGGGCCGG GCCTTCGCGG 60 GCCACCGGCG CCATGGGCCA GTGCGGCATC ACCTCCTCCA AGACCGTGCT GGTCTTTCTC 120 AACCTCATCT TCTGGGGGGC AGCTGGCATT TTATGCTATG TGGGAGCCTA TGTCTTCATC 180 ACTTATGATG ACTATGACCA CTTCTTTGAA GATGTGTACA CGCTCATCCC TGCTGTAGTG 240 ATCATAGCTG TAGGAGCCCT GCTTTTCATC ATTGGGCTAA TTGGCTGCTG TGCCACAATC 300 CGGGAAAGTC GCTGTGGACT TGCCACGTTT GTCATCATCC TGCTCTTGGT TTTTGTCACA 360 GAAGTTGTTG TAGTGGTTTT GGGATATGTT TACAGAGCAA AGGTGGAAAA TGAGGTTGAT 420 CGCAGCATTC AGAAAGTGTA TAAGACCTAC AATGGAACCA ACCCTGATGC TGCTAGCCGG 480 GCTATTGATT ATGTACAGAG ACAGCTGCAT TGTTGTGGAA TTCACAACTA CTCAGACTGG 540 GAAAATACAG ATTGGTTCAA AGAAACCAAA AACCAGAGTG TCCCTCTTAG CTGCTGCAGA 600 GAGACTGCCA GCAATTGTAA TGGCAGCCTG GCCCACCCTT CCGACCTCTA TGCTGAGGGG 660 TGTGAGGCTC TAGTTGTGAA GAAGCTACAA GAAATCATGA TGCATGTGAT CTGGGCCGCA 720 CTGGCATTTG CAGCTATTCA GCTGCTGGGC ATGCTGTGTG CTTGCATCGT GTTGTGCAGA 780 AGGAGTAGAG ATCCTGCTTA CGAGCTCTTC ATCACTGGCG GAACCTATGC ATAGTTGACA 840 ATCTCAAGCC TGAGCTTTTT GGTCTTGTTC TGATTTGGAA GGTGAATTGA GCAGGTCTGC 900 TGCTGTTGGC CTCTGGAGTT CATTTAGTTA AAGCACATGT ACACTGGTGT TGGACAGAGC 960 AGCTTGGCTT TTCATGTGCC CACCTACTTA CCTACTACCT GCGACTTTCT TTTTCCTTGT 1020 TCTAGCTGAC TCTTCATGCC CCTAAGATTT TAAGTACGAT GGTGAACGTT CTAATTTCAG 1080 AACCAATTGC GAGTCATGTA GTGTGGTAGA ATTAAAGGAG GACACGAGCC TGCTTCTGTT 1140 ACCTCCAAGT GGTAACAGGA CTGATGCCGA AATGTCACCA GGTCCTTTCA GTCTTCACAG 1200 TGGAGAACTC TTGGCCAAAG GTTTTTGGGG GGAGGAGGAG GAAACCAGCT TTCTGGTTAA 1260 GGTTAACACC AGATGGTGCC CCTCATTGGT GTCCTTTTAA AAAATATTTA CTGTAGTCCA 1320 ATAAGATAGC AGCTGTACAA AATGACTAAA ATAGATTGTA GGATCATATG GCGTATATCT 1380 TGGTTCATCT TCAAAATCAG AGACTGAGCT TTGAAACTAG TGGTTTTTAA TCAAAGTTGG 1440 CTTTATAGGA GGAGTATAAT GTATGCACTA CTGTTTTAAA AGAATTAGTG TGAGTGTGTT 1500 TTTGTATGAA TGAGCCCATT CATGGTAAGT CTTAAGCTTG TTGGAAATAA TGTACCCATG 1560 TAGACTAGCA AAATAGTATG TAGATGTGAT CTCAGTTGTA AATAGAAAAA TCTAATTCAA 1620 TAAACTCTGT ATCAGCCCCC AACAAAAAAA AAAAAAAAAA AA 1662 1345 base pairs nucleic acid single linear DNA (genomic) 8 CACGAGCGCA GAGCTTGGGG CTTCCTTGGT CGCACCCACC ACCTGCCTGC CCACTGGTCA 60 GCCTTCAGGG ACCCTGAGCA CCGCCTGGTC TCTTTCCTGT GGCCAGCCCA GAACTGAAGC 120 GCTGCGGCAT GGCGCGCGCC TGCCTCCAGG CCGTCAAGTA CCTCATGTTC GCCTTCAACC 180 TGTTCTTCTG GCTGGGAGGC TGTGGCGTGC TGGGTGTCGG CATCTGGCTG GCCGCCACAC 240 AGGGGAGCTT CGCCACGCTG TCTTCTTCCT TCCCGTCCCT GTCGGCTGCC AACCTGCTCA 300 TCATCACCGG CGCCTTTGTC ATGGCCATCG GCTTCGTGGG CTGCCTGGGT GCCATCAAGG 360 AGAACAAGTG CCTCCTGCTC ACTTTCTTCC TGCTGCTGCT GCTGGTGTTC CTGCTGGAGG 420 CCACCATCGC CATCCTCTTC TTCGCCTACA CGGACAAGAT TGACAGGTAT GCCCAGCAAG 480 ACCTGAAGAA AGGCTTGCAC CTGTACGGCA CGCAGGGCAA CGTGGGCCTC ACCAACGCCT 540 GGAGCATCAT CCAGACCGAC TTCCGCTGCT GTGGCGTCTC CAACTACACT GACTGGTTCG 600 AGGTGTACAA CGCCACGCGG GTACCTGACT CCTGCTGCTT GGAGTTCAGT GAGAGCTGTG 660 GGCTGCACGC CCCCGGCACC TGGTGGAAGG CGCCGTGCTA CGAGACGGTG AAGGTGTGGC 720 TTCAGGAGAA CCTGCTGGCT GTGGGCATCT TTGGGCTGTG CACGGCGCTG GTGCAGATCC 780 TGGGCCTGAC CTTCGCCATG ACCATGTACT GCCAAGTGGT CAAGGCAGAC ACCTACTGCG 840 CGTAGGCCGC CCACCGCCGG CTTCTCTGCC AAAAGGACGC CCACGGGGAG ATGGCCGCAC 900 CCACAGCTGC TTTTCCCACC ACCAGCTTCG GTGTTCTGCC CCATGCTGGG AGGAGGGAGG 960 GAGGGACAGG TGCCTGGAGC CCCCGGAACC CTGTTTCTGG AAGGCCCTAG CTCAGGTGGC 1020 TTCAGGGCCT CCGGACCCCC CCTGGGAGGG GTGGCCACGT GCTGGCTGCG GAACCCAGGG 1080 CAGGGGTGGG AGGGGCCTCC AGCACTTTTT ATATTTACGT ATTCTCCAAA GCAGTGTTCA 1140 CACGGGAGCC AGCCTGTGGC CCCCAGCTTC CTGGAAAACA GGTTGGCGCT GGAGGAGCCG 1200 GGTCTTGGCA TCCTGGAGGT GGCCCCACTG GTCCTGGTGC TCCAGGCGGG GCCGTGGACC 1260 CCTCACCTAC ATTCCATAGT GGGCCCGTGG GGCTCCTGGT GCATCTTAAT AAAGTGTGAG 1320 CAGCAAAAAA AAAAAAAAAA AAAAA 1345 734 base pairs nucleic acid single linear DNA (genomic) 9 GCGCCGCCGG GCCGCAGCAT GGGGCGCTTC CGCGGGGGCC TGCGGTGCAT CAAGTACCTG 60 CTGCTTGGCT TCAACCTGCT CTTCTGGCTG GCTGGATCGG CCGTCATTGC TTTTGGACTA 120 TGGTTTCGGT TCGGAGGTGC CATAAAGGAG TTATCATCAG AGGACAAGTC CCCAGAGTAT 180 TTCTATGTGG GGCTGTATGT TCTGGTTGGA GCCGGGGCCC TGATGATGGC CGTGGGGTTC 240 TTCGGATGCT GCGGAGCCAT GCGGGAGTCG CAATGTGTGC TTGGATCATT TTTTACCTGC 300 CTCCTGGTGA TATTTGCTGC TGAAGTAACC ACTGGAGTAT TTGCTTTTAT AGGCAAGGGG 360 GTAGCTATCC GACATGTTCA GACCATGTAT GAAGAGGCTT ACAATGATTA CCTTAAAGAC 420 AGGGGAAAAG GCAATGGGAC ACTCATCACC TTCCACTCAA CATTTCAGTG CTGTGGAAAA 480 GAAAGCTCCG AACAGGTCCA ACCTACATGC CCAAAGGAGC TTCTAGGACA CAAGAATTGC 540 ATCGATGAAA TTGAGACCAT AATCAGTGTT AAGCTCCAGC TCATTGGAAT TGTCGGTATT 600 GGAATTGCAG GTCTGACGAT CTTTGGCATG ATATTCAGCA TGGTCCTCTG CTGTGCGATA 660 CGAAACTCAC GAGATGTGAT ATGAAGCTAC TTCTACATGA AAATTGCAAT CTAAAGCTTT 720 CATACCAAAT GTTC 734 577 base pairs nucleic acid single linear DNA (genomic) 10 AGTGTTTATG GGACTAAAAA ACTTTTAACA CCTTTTTAGG GGAAATATTT TGGTCCTATA 60 CAAAACATGT AAATATGCTT TATTACTTTC ATTTTCTGAC CCTGCTGTAA ACTACTGCAA 120 CCCTCACATC CCTCAAAGGG ACTTTTATGT CAAACTCTTC TGTTTCTCCA AATATAAGGA 180 AAAAAGACTA AAGCAAGAGA TCTGGCAGTT GAAAATTGTG GGAAAGAGAA TTTGTATGGG 240 CACTGTATCT ATGAAATACC TCATACTTAC GTTTACATGT TTTCCTAACT TTTTGTATTT 300 TTCTTGTATA GCCACCTAGA GAATTCTTCA TAGATTAAGA ACTACAGTTT TCACCACTTA 360 ACATAAGTAA AACAAAGTCC TTCATAATTT AACCATTAGC ATCTTTGGCC AAACCAAAAT 420 AAAGAAAAGC ATCTTCTCCT AGTTGTGTGT GGGCAACAGA AACAAGTTAA GGAAACAAAA 480 ATACTTATAT ATACACAGAA CAAAAATAAT GTTCTTTTTA TGCAAATCCC CTGTGAAAAT 540 AAAATTTTCA ATGTTTAAAA AAAAAAAAAA AAAAAAA 577 936 base pairs nucleic acid single linear DNA (genomic) 11 TTCGGCACGA GCTGCGGGCG GTGGGCGGCT GGGCGGCCCC GGGAGCCGCG CTCTCAGTCT 60 CTCTAGGCGC AGTCCCTTCG CCGCTTCCGG AGCCCCTGGC AGGGCCCAGA AGCCATGGCC 120 CACTATAAGA CTGAGCAGGA CGACTGGCTG ATCATCTACT TGAAGTATTT ACTCTTTGTC 180 TTCAACTTCT TCTTCTGGGT CGGGGGAGCA GCCGTCCTGG CTGTGGGCAT CTGGACCCTG 240 GTGGAGAAGA GTGGCTACCT CAGCGTCCTG GCCTCCAGCA CCTTTGCCGC CTCCGCCTAC 300 ATCCTCATCT TTGCGGGCGT ACTTGTCATG GTGACCGGCT TCCTGGGCTT CGGTGCCATC 360 CTCTGGGAGC GGAAGGGCTG CCTCTCCACG TATTTCTGCC TGTTGCTCGT CATCTTCCTG 420 GTTGAGCTGG TGGCGGGAGT CCTGGCCCAT GTGTATTACC AGAGGCTGAG TGATGAACTG 480 AAGCAGCACT TGAACCGGAC TCTGGCTGAG AACTACGGGC AGCCGGAGCA CGCAGATCAC 540 GCCTCAGTGG ACCGACTCCA GCAGGATTTC AAGTGCTGCG GAAGCAACAG CTCAGCCGAC 600 TGGCAGCACA GCACGTACAT CCTGTTGCGG GAGGCCGAGG GCCGCCAGGT GCCCGACAGC 660 TGCTGCAAGA CAGTGGTGGC GCGCTGCGGC CAGCGGGCCC ACCCCTCCAA CATCTATAAG 720 GTGGAGGGAG GCTGCCTCAC CAAGCTGGAG CAGTTCCTGG CCGACCACCT GCTGCTTATG 780 GGGGCAGTGG GCATCGGGGT GGCCTGCCTG CAGATCTGCG GGATGGTTCT CACCTGCTGC 840 TTGCACCAGA GGCTCCAGCG GCATTTTTAC TAATGGCAAC CACCTCCTCT TCCAACTGCC 900 CCTCAAGACA ACATGTGGCA CATGCCATCT GCAAGG 936 738 base pairs nucleic acid single linear DNA (genomic) 12 AGCTTACTTT CACTCACCGC CTGTCCTTCC TGACACCTCA CCATGTGTAC GGGAAAATGT 60 GCCCGCTGTG TGGGGCTCTC CCTCATTACC CTCTGCCTCG TCTGCATTGT GGCCAACGCC 120 CTCCTGCTGG TACCTAATGG GGAGACCTCC TGGACCAACA CCAACCATCT CAGCTTGCAA 180 GTCTGGCTCA TGGGCGGCTT CATTGGCGGG GGCCTAATGG TACTGTGTCC AGGGATTGCA 240 GCCGTTCGGG CAGGGGGCAA GGGCTGCTGT GGTGCTGGGT GCTGTGGAAA CCGCTGCAGG 300 ATGCTGCGCT CGGTCTTCTC CTCGGCGTTC GGGGTGCTTG GTGCCATCTA CTGCCTCTCG 360 GTGTCTGGAG CTGGGCTCCG AAATGGACCC AGATGCTTAA TGAACGGCGA GTGGGGCTAC 420 CACTTCGAAG ACACCGCGGG AGCTTACTTG CTCAACCGCA CTCTATGGGA TCGGTGCGAG 480 GCGCCCCCTC GCGTGGTCCC CTGGAATGTG ACGCTCTTCT CGCTGCTGGT GGCCGCCTCC 540 TGCCTGGAGA TAGTACTGTG TGGGATCCAG CTGGTGAACG CGACCATTGG TGTCTTCTGC 600 GGCGATTGCA GGAAAAAACA GGACACACCT CACTGAGGCT CCACTGACCG CCGGGTTACA 660 CCTGCTCCTT CCTGGACGCT CACTCCCTTG CTCGCTAGAA TAAACTGCTT TGCGCTCTCA 720 AAAAAAAAAA AAAAAAAC 738 1071 base pairs nucleic acid single linear DNA (genomic) 13 GGCACGAGAG ATTGTCGGCT GCGGGTATAT TCCAATTCCC CGTCTCCTCA TGAATATGAA 60 GTGAAGGGCT CTGACCCTGG AAGTGGTTCT AAGCAGGGCA AAATGGGGTC TCGGAAGTGT 120 GGAGGCTGCC TAAGTTGTTT GCTGATTCCG CTTGCACTTT GGAGTATAAT CGTGAACATA 180 TTATTGTATT TCCCGAATGG GCAAACTTCC TATGCATCCA GCAATAAACT CACCAACTAC 240 GTGTGGTATT TTGAAGGAAT CTGTTTCTCA GGCATCATGA TGCTTATAGT AACAACAGTT 300 CTTCTGGTAC TGGAGAATAA TAACAACTAT AAATGTTGCC AGAGTGAAAA CTGCAGCAAA 360 AAATATGTGA CACTGCTGTC AATTATCTTT TCTTCCCTCG GAATTGCTTT TTCTGGATAC 420 TGCCTGGTCA TCTCTGCCTT GGGTCTTGTC CAAGGGCCAT ATTGCCGCAC CCTTGATGGC 480 TGGGAGTATG CTTTTGAAGG CACTGCTGGA CGTTTCCTTA CAGATTCTAG CATATGGATT 540 CAGTGCCTGG AACCTGCACA TGTTGTGGAG TGGAACATCA TTTTATTTTC CATTCTCATA 600 ACCCTCAGTG GGCTTCAAGT GATCATCTGC CTCATCAGAG TAGTCATGCA ACTATCCAAG 660 ATACTGTGTG GAAGCTATTC AGTGATCTTC CAGCCTGGAA TCATTTGAAT AAGGACAAAA 720 TGTTTTCCAT TATCAAGACA TGGCCATCTA TCTAAATATT ATATCAACTG TGTTAGACTT 780 GAGGGCAATA TTGAAAATGA TGGTGCTTTC TGCATTTGGT GTTTATTTGT AAAAAATTTG 840 CAGTCCTCAC TGCACATGCA AGTATACCAC CCTTCCATTT AGTATGTTTT TTAAGTAATA 900 TGCATCAGAA ACTTCAGAAA TACTTCTGCC CTTTGATCAA ACAAATCCAT TTCCAAGAAT 960 CTGTACTAGG GAAGTAAATA AGAATATGAG AGAAACCTTT ATGCAATATG TATATTGCAA 1020 CATTATTTAA TATTCTGGAA AATTGGAAAC ACCCCAAAAT TCTAACTCAA A 1071 865 base pairs nucleic acid single linear DNA (genomic) 14 TTTGTGGAGG GCAGCAGAGA GTACCCAGCT GGACATCCTT TCCTGCTGAT GAGCCCCAGG 60 CTGGAGGTGC CCTGCTCACA TGCTCTTCCC CAGGGTCTCT CGCCTGGGCA GGTCATCATA 120 GTACGGGGAC TGGTCTTGCA AGAGCCGAAG CATTTTACTG TGAGCCTGAG GGACCAGGCT 180 GCCCATGCTC CTGTGACACT CAGGGCCTCC TTCGCAGACA GAACTCTGGC CTGGATCTCC 240 CGCTGGGGGC AGAAGAAACT GATCTCAGCC CCCTTCCTCT TTTACCCCCA GAGATTCTTT 300 GAGGTGCTGC TCCTGTTCCA GGAGGGAGGG CTGAAGCTGG CGCTCAATGG GCAGGGGCTG 360 GGGGCCACCA GCATGAACCA GCAGGCCCTG GAGCAGCTGC GGGAGCTCCG GATCAGTGGA 420 AGTGTCCAGC TCTACTGTGT CCACTCCTGA AGGATGGTTC CAGGAAATAC CGCAGAAAAC 480 AAGAGTCAGC CACTCCCCAG GGCCCCACTC TCCTCCCCTC ATTAAACCAT CCACCTGAAC 540 ACCAGCACAT CAGGGCCTGG TTCACCTCTG GGGTCACGAG ACTGAGTCTA CAGGAGCTTT 600 GGGCCTGAGG GAAGGCACAA GAGTGCAAAG GTTCCTCGAA CTCTGCACCT TCCTCCACCA 660 GGAGCCTGGG ATATGGCTCC ATCTGCCTTC AGGGCCTGGA CTGCACTCAC AGAGGCAAGT 720 GTTGTAGACT AACAAAGATA CTCCAAAATA CAATGGCTTA AAGAATGTGG TCATTTATTC 780 TTTATTATTT ATTTATTTGT GGTCAAATAA ATAAATAAGG TTATTTATTT AAAAAAAAAA 840 AAAAAAAAAA AAAAAAAAAA AAAAA 865 441 base pairs nucleic acid single linear DNA (genomic) 15 GCACGAGAGA CGACATCAGA GATGAGGACA GCATTGCTGC TCCTTGCAGC CCTGGCTGTG 60 GCTACAGGGC CAGCCCTTAC CCTGCGCTGC CACGTGTGCA CCAGCTCCAG CAACTGCAAG 120 CATTCTGTGG TCTGCCCGGC CAGCTCTCGC TTCTGCAAGA CCACGAACAC AGTGGAGCCT 180 CTGAGGGCTT CCCCGAAAGT CTGGGACCAG GTCCAGGTGG GCATGGAATG CTGATGACTT 240 GGAGCAGGCC CCACAGACCC CACAGAGGAT GAAGCCACCC CACAGAGGAT GCAGCCCCCA 300 GCTGCATGGA AGGTGGAGGA CAGAAGCCCT GTGGATCCCC GGATTTCACA CTCCTTCTGT 360 TTTGTTGCCG TTTATTTTTG TACTCAAATC TCTACATGGA GATAAATGAT TTAAACCAGT 420 AAAAAAAAAA AAAAAAAAAA A 441 1066 base pairs nucleic acid single linear DNA (genomic) 16 AGCGGGCCCG AACCCTCGTG TGAAGGGTGC AGTACCTAAG CCGGAGCGGG GTAGAGGCGG 60 GCCGGCACCC CCTTCTGACC TCCAGTGCCG CCGGCCTCAA GATCAGACAT GGCCCAGAAC 120 TTGAAGGACT TGGCGGGACG GCTGCCCGCC GGGCCCCGGG GCATGGGCAC GGCCCTGAAG 180 CTGTTGCTGG GGGCCGGCGC CGTGGCCTAC GGTGTGCGCG AATCTGTGTT CACCGTGGAA 240 GGCGGGCACA GAGCCATCTT CTTCAATCGG ATCGGTGGAG TGCAGCAGGA CACTATCCTG 300 GCCGAGGGCC TTCACTTCAG GATCCCTTGG TTCCAGTACC CCATTATCTA TGACATTCGG 360 GCCAGACCTC GAAAAATCTC CTCCCCTACA GGCTCCAAAG ACCTACAGAT GGTGAATATC 420 TCCCTGCGAG TGTTGTCTCG ACCCAATGCT CAGGAGCTTC CTAGCATGTA CCAGCGCCTA 480 GGGCTGGACT ACGAGGAACG AGTGTTGCCG TCCATTGTCA ACGAGGTGCT CAAGAGTGTG 540 GTGGCCAAGT TCAATGCCTC ACAGCTGATC ACCCAGCGGG CCCAGGTATC CCTGTTGATC 600 CGCCGGGAGC TGACAGAGAG GGCCAAGGAC TTCAGCCTCA TCCTGGATGA TGTGGCCATC 660 ACAGAGCTGA GCTTTAGCCG AGAGTACACA GCTGCTGTAG AAGCCAAACA AGTGGCCCAG 720 CAGGAGGCCC AGCGGGCCCA ATTCTTGGTA GAAAAAGCAA AGCAGGAACA GCGGCAGAAA 780 ATTGTGCAGG CCGAGGGTGA GGCCGAGGCT GCCAAGATGC TTGGAGAAGC ACTGAGCAAG 840 AACCCTGGCT ACATCAAACT TCGCAAGATT CGAGCAGCCC AGAATATCTC CAAGACGATC 900 GCCACATCAC AGAATCGTAT CTATCTCACA GCTGACAACC TTGTGCTGAA CCTACAGGAT 960 GAAAGTTTCA CCAGGGGAAG TGACAGCCTC ATCAAGGGTA AGAAATGAGC CTAGTCACCA 1020 AGAACTCCAC CCCCACAAGA AGTGGATCTG CTTCTCCAGT TTTTGA 1066 704 base pairs nucleic acid single linear DNA (genomic) 17 GGCACGAGAT GACATCACTA AGTGGCCGAT CTGCACAGAG CAGGCCAGGA GCAACCACAC 60 AGGCTTCCTG CACATGGACT GCGAGATCAA GGGCCGCCCC TGCTGCATCG GCACCAAGGG 120 CAGCTGTGAG ATCACCACCC GGGAATACTG TGAGTTCATG CACGGCTATT TCCATGAGGA 180 AGCAACACTC TGCTCCCAGG TGAGGCGAGG CAGGCCTGGA GTAGTGGAGG AGAGGACGCT 240 GGGCATGGCA GCCTGCTGGG GCCGGGGCTC ACGCACTCCC TCCCATGTCG GAGCCTCAGA 300 CTCAGGCTGC TTCTGGGGCG CTGAGCACCA TATGCCCATT CCCAGGTGCA CTGTTTTGGA 360 CAAGGTGTGT TGGGCTGCTG CCTTCCTCAA CCCTGAGGTC CCAGATCAGT TTTACAGGTC 420 TGGCTGTCTC TTTTCCTACA TGTTGGGTAA GAGGTCCTCA ATGCCCCCGA ACCCGACCCC 480 TGTGATGGAC ACCCAGGCGG ACCCCTGGGG AAAGGTTCCT GGGCCAGGGT ATGGTCGGTC 540 CAACCTGCCG AAGACTACTG CTCCTGAAGT GTCTGGATGA AGGCCGCTGC CTGGTGTGTC 600 CCTCCCCCAG TGTGGGTGCA CTGCCCTCGG TGTCTTGTGG GTCTTTTCAA ATGACATCCC 660 TGAAGGGGAC CTGGAGGAAG GTGGTCCGGC TGGCACCCTA TCGC 704 315 amino acids amino acid single linear protein 18 Met Leu Leu Leu Leu Leu Leu Pro Leu Leu Trp Gly Arg Glu Arg Val 1 5 10 15 Glu Gly Gln Lys Ser Asn Arg Lys Asp Tyr Ser Leu Thr Met Gln Ser 20 25 30 Ser Val Thr Val Gln Glu Gly Met Cys Val His Val Arg Cys Ser Phe 35 40 45 Ser Tyr Pro Val Asp Ser Gln Thr Asp Ser Asp Pro Val His Gly Tyr 50 55 60 Trp Phe Arg Ala Gly Asn Asp Ile Ser Trp Lys Ala Pro Val Ala Thr 65 70 75 80 Asn Asn Pro Ala Trp Ala Val Gln Glu Glu Thr Arg Asp Arg Phe His 85 90 95 Leu Leu Gly Asp Pro Gln Thr Lys Asn Cys Thr Leu Ser Ile Arg Asp 100 105 110 Ala Arg Met Ser Asp Ala Gly Arg Tyr Phe Phe Arg Met Glu Lys Gly 115 120 125 Asn Ile Lys Trp Asn Tyr Lys Tyr Asp Gln Leu Ser Val Asn Val Thr 130 135 140 Tyr Pro Pro Gln Asn Leu Thr Val Thr Val Phe Gln Gly Glu Gly Thr 145 150 155 160 Ala Ser Thr Ala Leu Gly Asn Ser Ser Ser Leu Ser Val Leu Glu Gly 165 170 175 Gln Ser Leu Arg Leu Val Cys Ala Val Asp Ser Asn Pro Pro Ala Arg 180 185 190 Leu Ser Trp Thr Trp Arg Ser Leu Thr Leu Tyr Pro Ser Gln Pro Ser 195 200 205 Asn Pro Leu Val Leu Glu Leu Gln Val His Leu Gly Asp Glu Gly Glu 210 215 220 Phe Thr Cys Arg Ala Gln Asn Ser Leu Gly Ser Gln His Val Ser Leu 225 230 235 240 Asn Leu Ser Leu Gln Gln Glu Tyr Thr Gly Lys Met Lys Pro Val Ser 245 250 255 Gly Val Leu Leu Gly Ala Val Gly Gly Thr Gly Ala Thr Ala Leu Val 260 265 270 Phe Leu Ser Phe Cys Val Ile Phe Ile Val Val Arg Ser Cys Arg Lys 275 280 285 Lys Ser Ala Arg Pro Ala Ala Asp Val Gly Asp Ile Gly Met Lys Asp 290 295 300 Ala Asn Thr Ile Gln Gly Leu Ser Leu Ser Gly 305 310 315 245 amino acids amino acid single linear protein 19 Met Ala Glu Ile His Thr Pro Tyr Ser Ser Leu Lys Lys Leu Leu Ser 1 5 10 15 Leu Leu Asn Gly Phe Val Ala Val Ser Gly Ile Ile Leu Val Gly Leu 20 25 30 Gly Ile Gly Gly Lys Cys Gly Gly Ala Ser Leu Thr Asn Val Leu Gly 35 40 45 Leu Ser Ser Ala Tyr Leu Leu His Val Gly Asn Leu Cys Leu Val Met 50 55 60 Gly Cys Ile Thr Val Leu Leu Gly Cys Ala Gly Trp Tyr Gly Ala Thr 65 70 75 80 Lys Glu Ser Arg Gly Thr Leu Leu Phe Cys Ile Leu Ser Met Val Ile 85 90 95 Val Leu Ile Met Glu Val Thr Ala Ala Thr Val Val Leu Leu Phe Phe 100 105 110 Pro Ile Val Gly Asp Val Ala Leu Glu His Thr Phe Val Thr Leu Arg 115 120 125 Lys Asn Tyr Arg Gly Tyr Asn Glu Pro Asp Asp Tyr Ser Thr Gln Trp 130 135 140 Asn Leu Val Met Glu Lys Leu Lys Cys Cys Gly Val Asn Asn Tyr Thr 145 150 155 160 Asp Phe Ser Gly Ser Ser Phe Glu Met Thr Thr Gly His Thr Tyr Pro 165 170 175 Arg Ser Cys Cys Lys Ser Ile Gly Ser Val Ser Cys Asp Gly Arg Asp 180 185 190 Val Ser Pro Asn Val Ile His Gln Lys Gly Cys Phe His Lys Leu Leu 195 200 205 Lys Ile Thr Lys Thr Gln Ser Phe Thr Leu Ser Gly Ser Ser Leu Gly 210 215 220 Ala Ala Val Ile Gln Arg Trp Gly Ser Arg Tyr Val Ala Gln Ala Gly 225 230 235 240 Leu Glu Leu Leu Ala 245 273 amino acids amino acid single linear protein 20 Met Gln Cys Phe Ser Phe Ile Lys Thr Met Met Ile Leu Phe Asn Leu 1 5 10 15 Leu Ile Phe Leu Cys Gly Ala Ala Leu Leu Ala Val Gly Ile Trp Val 20 25 30 Ser Ile Asp Gly Ala Ser Phe Leu Lys Ile Phe Gly Pro Leu Ser Ser 35 40 45 Ser Ala Met Gln Phe Val Asn Val Gly Tyr Phe Leu Ile Ala Ala Gly 50 55 60 Val Val Val Phe Ala Leu Gly Phe Leu Gly Cys Tyr Gly Ala Lys Thr 65 70 75 80 Glu Ser Lys Cys Ala Leu Val Thr Phe Phe Phe Ile Leu Leu Leu Ile 85 90 95 Phe Ile Ala Glu Val Ala Ala Ala Val Val Ala Leu Val Tyr Thr Thr 100 105 110 Met Ala Glu His Phe Leu Thr Leu Leu Val Val Pro Ala Ile Lys Lys 115 120 125 Asp Tyr Gly Ser Gln Glu Asp Phe Thr Gln Val Trp Asn Thr Thr Met 130 135 140 Lys Gly Leu Lys Cys Cys Gly Phe Thr Asn Tyr Thr Asp Phe Glu Asp 145 150 155 160 Ser Pro Tyr Phe Lys Glu Asn Ser Ala Phe Pro Pro Phe Cys Cys Asn 165 170 175 Asp Asn Val Thr Asn Thr Ala Asn Glu Thr Cys Thr Lys Gln Lys Ala 180 185 190 His Asp Gln Lys Val Glu Gly Cys Phe Asn Gln Leu Leu Tyr Asp Ile 195 200 205 Arg Thr Asn Ala Val Thr Val Gly Gly Val Ala Ala Gly Ile Gly Gly 210 215 220 Leu Glu Leu Ala Ala Met Asn Cys Val His Val Ser Val Leu Gln Ser 225 230 235 240 Thr Ile Ser Pro Leu Leu Pro Leu Pro Leu Leu Leu Pro His Gly Asn 245 250 255 Cys Glu Glu Ala Pro Trp Gln Ala Ala Val Ile Gly Gly Gly Asp Arg 260 265 270 Ile 250 amino acids amino acid single linear protein 21 Met Asn Ser Met Thr Ser Ala Val Pro Val Ala Asn Ser Val Leu Val 1 5 10 15 Val Ala Pro His Asn Gly Tyr Pro Val Thr Pro Gly Ile Met Ser His 20 25 30 Val Pro Leu Tyr Pro Asn Ser Gln Pro Gln Val His Leu Val Pro Gly 35 40 45 Asn Pro Pro Ser Leu Val Ser Asn Val Asn Gly Gln Pro Val Gln Lys 50 55 60 Ala Leu Lys Glu Gly Lys Thr Leu Gly Ala Ile Gln Ile Ile Ile Gly 65 70 75 80 Leu Ala His Ile Gly Leu Gly Ser Ile Met Ala Thr Val Leu Val Gly 85 90 95 Glu Tyr Leu Ser Ile Ser Phe Tyr Gly Gly Phe Pro Phe Trp Gly Gly 100 105 110 Leu Trp Phe Ile Ile Ser Gly Ser Leu Ser Val Ala Ala Glu Asn Gln 115 120 125 Pro Tyr Ser Tyr Cys Leu Leu Ser Gly Ser Leu Gly Leu Asn Ile Val 130 135 140 Ser Ala Ile Cys Ser Ala Val Gly Val Ile Leu Phe Ile Thr Asp Leu 145 150 155 160 Ser Ile Pro His Pro Tyr Ala Tyr Pro Asp Tyr Tyr Pro Tyr Ala Trp 165 170 175 Gly Val Asn Pro Gly Met Ala Ile Ser Gly Val Leu Leu Val Phe Cys 180 185 190 Leu Leu Glu Phe Gly Ile Ala Cys Ala Ser Ser His Phe Gly Cys Gln 195 200 205 Leu Val Cys Cys Gln Ser Ser Asn Val Ser Val Ile Tyr Pro Asn Ile 210 215 220 Tyr Ala Ala Asn Pro Val Ile Thr Pro Glu Pro Val Thr Ser Pro Pro 225 230 235 240 Ser Tyr Ser Ser Glu Ile Gln Ala Asn Lys 245 250 245 amino acids amino acid single linear protein 22 Met Ala Ser Pro Ser Arg Arg Leu Gln Thr Lys Pro Val Ile Thr Cys 1 5 10 15 Phe Lys Ser Val Leu Leu Ile Tyr Thr Phe Ile Phe Trp Ile Thr Gly 20 25 30 Val Ile Leu Leu Ala Val Gly Ile Trp Gly Lys Val Ser Leu Glu Asn 35 40 45 Tyr Phe Ser Leu Leu Asn Glu Lys Ala Thr Asn Val Pro Phe Val Leu 50 55 60 Ile Ala Thr Gly Thr Val Ile Ile Leu Leu Gly Thr Phe Gly Cys Phe 65 70 75 80 Ala Thr Cys Arg Ala Ser Ala Trp Met Leu Lys Leu Tyr Ala Met Phe 85 90 95 Leu Thr Leu Val Phe Leu Val Glu Leu Val Ala Ala Ile Val Gly Phe 100 105 110 Val Phe Arg His Glu Ile Lys Asn Ser Phe Lys Asn Asn Tyr Glu Lys 115 120 125 Ala Leu Lys Gln Tyr Asn Ser Thr Gly Asp Tyr Arg Ser His Ala Val 130 135 140 Asp Lys Ile Gln Asn Thr Leu His Cys Cys Gly Val Thr Asp Tyr Arg 145 150 155 160 Asp Trp Thr Asp Thr Asn Tyr Tyr Ser Glu Lys Gly Phe Pro Lys Ser 165 170 175 Cys Cys Lys Leu Glu Asp Cys Thr Pro Gln Arg Asp Ala Asp Lys Val 180 185 190 Asn Asn Glu Gly Cys Phe Ile Lys Val Met Thr Ile Ile Glu Ser Glu 195 200 205 Met Gly Val Val Ala Gly Ile Ser Phe Gly Val Ala Cys Phe Gln Leu 210 215 220 Ile Gly Ile Phe Leu Ala Tyr Cys Leu Ser Arg Ala Ile Thr Asn Asn 225 230 235 240 Gln Tyr Glu Ile Val 245 253 amino acids amino acid single linear protein 23 Met Gly Gln Cys Gly Ile Thr Ser Ser Lys Thr Val Leu Val Phe Leu 1 5 10 15 Asn Leu Ile Phe Trp Gly Ala Ala Gly Ile Leu Cys Tyr Val Gly Ala 20 25 30 Tyr Val Phe Ile Thr Tyr Asp Asp Tyr Asp His Phe Phe Glu Asp Val 35 40 45 Tyr Thr Leu Ile Pro Ala Val Val Ile Ile Ala Val Gly Ala Leu Leu 50 55 60 Phe Ile Ile Gly Leu Ile Gly Cys Cys Ala Thr Ile Arg Glu Ser Arg 65 70 75 80 Cys Gly Leu Ala Thr Phe Val Ile Ile Leu Leu Leu Val Phe Val Thr 85 90 95 Glu Val Val Val Val Val Leu Gly Tyr Val Tyr Arg Ala Lys Val Glu 100 105 110 Asn Glu Val Asp Arg Ser Ile Gln Lys Val Tyr Lys Thr Tyr Asn Gly 115 120 125 Thr Asn Pro Asp Ala Ala Ser Arg Ala Ile Asp Tyr Val Gln Arg Gln 130 135 140 Leu His Cys Cys Gly Ile His Asn Tyr Ser Asp Trp Glu Asn Thr Asp 145 150 155 160 Trp Phe Lys Glu Thr Lys Asn Gln Ser Val Pro Leu Ser Cys Cys Arg 165 170 175 Glu Thr Ala Ser Asn Cys Asn Gly Ser Leu Ala His Pro Ser Asp Leu 180 185 190 Tyr Ala Glu Gly Cys Glu Ala Leu Val Val Lys Lys Leu Gln Glu Ile 195 200 205 Met Met His Val Ile Trp Ala Ala Leu Ala Phe Ala Ala Ile Gln Leu 210 215 220 Leu Gly Met Leu Cys Ala Cys Ile Val Leu Cys Arg Arg Ser Arg Asp 225 230 235 240 Pro Ala Tyr Glu Leu Phe Ile Thr Gly Gly Thr Tyr Ala 245 250 238 amino acids amino acid single linear protein 24 Met Ala Arg Ala Cys Leu Gln Ala Val Lys Tyr Leu Met Phe Ala Phe 1 5 10 15 Asn Leu Phe Phe Trp Leu Gly Gly Cys Gly Val Leu Gly Val Gly Ile 20 25 30 Trp Leu Ala Ala Thr Gln Gly Ser Phe Ala Thr Leu Ser Ser Ser Phe 35 40 45 Pro Ser Leu Ser Ala Ala Asn Leu Leu Ile Ile Thr Gly Ala Phe Val 50 55 60 Met Ala Ile Gly Phe Val Gly Cys Leu Gly Ala Ile Lys Glu Asn Lys 65 70 75 80 Cys Leu Leu Leu Thr Phe Phe Leu Leu Leu Leu Leu Val Phe Leu Leu 85 90 95 Glu Ala Thr Ile Ala Ile Leu Phe Phe Ala Tyr Thr Asp Lys Ile Asp 100 105 110 Arg Tyr Ala Gln Gln Asp Leu Lys Lys Gly Leu His Leu Tyr Gly Thr 115 120 125 Gln Gly Asn Val Gly Leu Thr Asn Ala Trp Ser Ile Ile Gln Thr Asp 130 135 140 Phe Arg Cys Cys Gly Val Ser Asn Tyr Thr Asp Trp Phe Glu Val Tyr 145 150 155 160 Asn Ala Thr Arg Val Pro Asp Ser Cys Cys Leu Glu Phe Ser Glu Ser 165 170 175 Cys Gly Leu His Ala Pro Gly Thr Trp Trp Lys Ala Pro Cys Tyr Glu 180 185 190 Thr Val Lys Val Trp Leu Gln Glu Asn Leu Leu Ala Val Gly Ile Phe 195 200 205 Gly Leu Cys Thr Ala Leu Val Gln Ile Leu Gly Leu Thr Phe Ala Met 210 215 220 Thr Met Tyr Cys Gln Val Val Lys Ala Asp Thr Tyr Cys Ala 225 230 235 221 amino acids amino acid single linear protein 25 Met Gly Arg Phe Arg Gly Gly Leu Arg Cys Ile Lys Tyr Leu Leu Leu 1 5 10 15 Gly Phe Asn Leu Leu Phe Trp Leu Ala Gly Ser Ala Val Ile Ala Phe 20 25 30 Gly Leu Trp Phe Arg Phe Gly Gly Ala Ile Lys Glu Leu Ser Ser Glu 35 40 45 Asp Lys Ser Pro Glu Tyr Phe Tyr Val Gly Leu Tyr Val Leu Val Gly 50 55 60 Ala Gly Ala Leu Met Met Ala Val Gly Phe Phe Gly Cys Cys Gly Ala 65 70 75 80 Met Arg Glu Ser Gln Cys Val Leu Gly Ser Phe Phe Thr Cys Leu Leu 85 90 95 Val Ile Phe Ala Ala Glu Val Thr Thr Gly Val Phe Ala Phe Ile Gly 100 105 110 Lys Gly Val Ala Ile Arg His Val Gln Thr Met Tyr Glu Glu Ala Tyr 115 120 125 Asn Asp Tyr Leu Lys Asp Arg Gly Lys Gly Asn Gly Thr Leu Ile Thr 130 135 140 Phe His Ser Thr Phe Gln Cys Cys Gly Lys Glu Ser Ser Glu Gln Val 145 150 155 160 Gln Pro Thr Cys Pro Lys Glu Leu Leu Gly His Lys Asn Cys Ile Asp 165 170 175 Glu Ile Glu Thr Ile Ile Ser Val Lys Leu Gln Leu Ile Gly Ile Val 180 185 190 Gly Ile Gly Ile Ala Gly Leu Thr Ile Phe Gly Met Ile Phe Ser Met 195 200 205 Val Leu Cys Cys Ala Ile Arg Asn Ser Arg Asp Val Ile 210 215 220 252 amino acids amino acid single linear protein 26 Met Ala His Tyr Lys Thr Glu Gln Asp Asp Trp Leu Ile Ile Tyr Leu 1 5 10 15 Lys Tyr Leu Leu Phe Val Phe Asn Phe Phe Phe Trp Val Gly Gly Ala 20 25 30 Ala Val Leu Ala Val Gly Ile Trp Thr Leu Val Glu Lys Ser Gly Tyr 35 40 45 Leu Ser Val Leu Ala Ser Ser Thr Phe Ala Ala Ser Ala Tyr Ile Leu 50 55 60 Ile Phe Ala Gly Val Leu Val Met Val Thr Gly Phe Leu Gly Phe Gly 65 70 75 80 Ala Ile Leu Trp Glu Arg Lys Gly Cys Leu Ser Thr Tyr Phe Cys Leu 85 90 95 Leu Leu Val Ile Phe Leu Val Glu Leu Val Ala Gly Val Leu Ala His 100 105 110 Val Tyr Tyr Gln Arg Leu Ser Asp Glu Leu Lys Gln His Leu Asn Arg 115 120 125 Thr Leu Ala Glu Asn Tyr Gly Gln Pro Glu His Ala Asp His Ala Ser 130 135 140 Val Asp Arg Leu Gln Gln Asp Phe Lys Cys Cys Gly Ser Asn Ser Ser 145 150 155 160 Ala Asp Trp Gln His Ser Thr Tyr Ile Leu Leu Arg Glu Ala Glu Gly 165 170 175 Arg Gln Val Pro Asp Ser Cys Cys Lys Thr Val Val Ala Arg Cys Gly 180 185 190 Gln Arg Ala His Pro Ser Asn Ile Tyr Lys Val Glu Gly Gly Cys Leu 195 200 205 Thr Lys Leu Glu Gln Phe Leu Ala Asp His Leu Leu Leu Met Gly Ala 210 215 220 Val Gly Ile Gly Val Ala Cys Leu Gln Ile Cys Gly Met Val Leu Thr 225 230 235 240 Cys Cys Leu His Gln Arg Leu Gln Arg His Phe Tyr 245 250 197 amino acids amino acid single linear protein 27 Met Cys Thr Gly Lys Cys Ala Arg Cys Val Gly Leu Ser Leu Ile Thr 1 5 10 15 Leu Cys Leu Val Cys Ile Val Ala Asn Ala Leu Leu Leu Val Pro Asn 20 25 30 Gly Glu Thr Ser Trp Thr Asn Thr Asn His Leu Ser Leu Gln Val Trp 35 40 45 Leu Met Gly Gly Phe Ile Gly Gly Gly Leu Met Val Leu Cys Pro Gly 50 55 60 Ile Ala Ala Val Arg Ala Gly Gly Lys Gly Cys Cys Gly Ala Gly Cys 65 70 75 80 Cys Gly Asn Arg Cys Arg Met Leu Arg Ser Val Phe Ser Ser Ala Phe 85 90 95 Gly Val Leu Gly Ala Ile Tyr Cys Leu Ser Val Ser Gly Ala Gly Leu 100 105 110 Arg Asn Gly Pro Arg Cys Leu Met Asn Gly Glu Trp Gly Tyr His Phe 115 120 125 Glu Asp Thr Ala Gly Ala Tyr Leu Leu Asn Arg Thr Leu Trp Asp Arg 130 135 140 Cys Glu Ala Pro Pro Arg Val Val Pro Trp Asn Val Thr Leu Phe Ser 145 150 155 160 Leu Leu Val Ala Ala Ser Cys Leu Glu Ile Val Leu Cys Gly Ile Gln 165 170 175 Leu Val Asn Ala Thr Ile Gly Val Phe Cys Gly Asp Cys Arg Lys Lys 180 185 190 Gln Asp Thr Pro His 195 201 amino acids amino acid single linear protein 28 Met Gly Ser Arg Lys Cys Gly Gly Cys Leu Ser Cys Leu Leu Ile Pro 1 5 10 15 Leu Ala Leu Trp Ser Ile Ile Val Asn Ile Leu Leu Tyr Phe Pro Asn 20 25 30 Gly Gln Thr Ser Tyr Ala Ser Ser Asn Lys Leu Thr Asn Tyr Val Trp 35 40 45 Tyr Phe Glu Gly Ile Cys Phe Ser Gly Ile Met Met Leu Ile Val Thr 50 55 60 Thr Val Leu Leu Val Leu Glu Asn Asn Asn Asn Tyr Lys Cys Cys Gln 65 70 75 80 Ser Glu Asn Cys Ser Lys Lys Tyr Val Thr Leu Leu Ser Ile Ile Phe 85 90 95 Ser Ser Leu Gly Ile Ala Phe Ser Gly Tyr Cys Leu Val Ile Ser Ala 100 105 110 Leu Gly Leu Val Gln Gly Pro Tyr Cys Arg Thr Leu Asp Gly Trp Glu 115 120 125 Tyr Ala Phe Glu Gly Thr Ala Gly Arg Phe Leu Thr Asp Ser Ser Ile 130 135 140 Trp Ile Gln Cys Leu Glu Pro Ala His Val Val Glu Trp Asn Ile Ile 145 150 155 160 Leu Phe Ser Ile Leu Ile Thr Leu Ser Gly Leu Gln Val Ile Ile Cys 165 170 175 Leu Ile Arg Val Val Met Gln Leu Ser Lys Ile Leu Cys Gly Ser Tyr 180 185 190 Ser Val Ile Phe Gln Pro Gly Ile Ile 195 200 133 amino acids amino acid single linear protein 29 Met Ser Pro Arg Leu Glu Val Pro Cys Ser His Ala Leu Pro Gln Gly 1 5 10 15 Leu Ser Pro Gly Gln Val Ile Ile Val Arg Gly Leu Val Leu Gln Glu 20 25 30 Pro Lys His Phe Thr Val Ser Leu Arg Asp Gln Ala Ala His Ala Pro 35 40 45 Val Thr Leu Arg Ala Ser Phe Ala Asp Arg Thr Leu Ala Trp Ile Ser 50 55 60 Arg Trp Gly Gln Lys Lys Leu Ile Ser Ala Pro Phe Leu Phe Tyr Pro 65 70 75 80 Gln Arg Phe Phe Glu Val Leu Leu Leu Phe Gln Glu Gly Gly Leu Lys 85 90 95 Leu Ala Leu Asn Gly Gln Gly Leu Gly Ala Thr Ser Met Asn Gln Gln 100 105 110 Ala Leu Glu Gln Leu Arg Glu Leu Arg Ile Ser Gly Ser Val Gln Leu 115 120 125 Tyr Cys Val His Ser 130 70 amino acids amino acid single linear protein 30 Met Arg Thr Ala Leu Leu Leu Leu Ala Ala Leu Ala Val Ala Thr Gly 1 5 10 15 Pro Ala Leu Thr Leu Arg Cys His Val Cys Thr Ser Ser Ser Asn Cys 20 25 30 Lys His Ser Val Val Cys Pro Ala Ser Ser Arg Phe Cys Lys Thr Thr 35 40 45 Asn Thr Val Glu Pro Leu Arg Ala Ser Pro Lys Val Trp Asp Gln Val 50 55 60 Gln Val Gly Met Glu Cys 65 70 299 amino acids amino acid single linear protein 31 Met Ala Gln Asn Leu Lys Asp Leu Ala Gly Arg Leu Pro Ala Gly Pro 1 5 10 15 Arg Gly Met Gly Thr Ala Leu Lys Leu Leu Leu Gly Ala Gly Ala Val 20 25 30 Ala Tyr Gly Val Arg Glu Ser Val Phe Thr Val Glu Gly Gly His Arg 35 40 45 Ala Ile Phe Phe Asn Arg Ile Gly Gly Val Gln Gln Asp Thr Ile Leu 50 55 60 Ala Glu Gly Leu His Phe Arg Ile Pro Trp Phe Gln Tyr Pro Ile Ile 65 70 75 80 Tyr Asp Ile Arg Ala Arg Pro Arg Lys Ile Ser Ser Pro Thr Gly Ser 85 90 95 Lys Asp Leu Gln Met Val Asn Ile Ser Leu Arg Val Leu Ser Arg Pro 100 105 110 Asn Ala Gln Glu Leu Pro Ser Met Tyr Gln Arg Leu Gly Leu Asp Tyr 115 120 125 Glu Glu Arg Val Leu Pro Ser Ile Val Asn Glu Val Leu Lys Ser Val 130 135 140 Val Ala Lys Phe Asn Ala Ser Gln Leu Ile Thr Gln Arg Ala Gln Val 145 150 155 160 Ser Leu Leu Ile Arg Arg Glu Leu Thr Glu Arg Ala Lys Asp Phe Ser 165 170 175 Leu Ile Leu Asp Asp Val Ala Ile Thr Glu Leu Ser Phe Ser Arg Glu 180 185 190 Tyr Thr Ala Ala Val Glu Ala Lys Gln Val Ala Gln Gln Glu Ala Gln 195 200 205 Arg Ala Gln Phe Leu Val Glu Lys Ala Lys Gln Glu Gln Arg Gln Lys 210 215 220 Ile Val Gln Ala Glu Gly Glu Ala Glu Ala Ala Lys Met Leu Gly Glu 225 230 235 240 Ala Leu Ser Lys Asn Pro Gly Tyr Ile Lys Leu Arg Lys Ile Arg Ala 245 250 255 Ala Gln Asn Ile Ser Lys Thr Ile Ala Thr Ser Gln Asn Arg Ile Tyr 260 265 270 Leu Thr Ala Asp Asn Leu Val Leu Asn Leu Gln Asp Glu Ser Phe Thr 275 280 285 Arg Gly Ser Asp Ser Leu Ile Lys Gly Lys Lys 290 295 168 amino acids amino acid single linear protein 32 Met Asp Cys Glu Ile Lys Gly Arg Pro Cys Cys Ile Gly Thr Lys Gly 1 5 10 15 Ser Cys Glu Ile Thr Thr Arg Glu Tyr Cys Glu Phe Met His Gly Tyr 20 25 30 Phe His Glu Glu Ala Thr Leu Cys Ser Gln Val Arg Arg Gly Arg Pro 35 40 45 Gly Val Val Glu Glu Arg Thr Leu Gly Met Ala Ala Cys Trp Gly Arg 50 55 60 Gly Ser Arg Thr Pro Ser His Val Gly Ala Ser Asp Ser Gly Cys Phe 65 70 75 80 Trp Gly Ala Glu His His Met Pro Ile Pro Arg Cys Thr Val Leu Asp 85 90 95 Lys Val Cys Trp Ala Ala Ala Phe Leu Asn Pro Glu Val Pro Asp Gln 100 105 110 Phe Tyr Arg Ser Gly Cys Leu Phe Ser Tyr Met Leu Gly Lys Arg Ser 115 120 125 Ser Met Pro Pro Asn Pro Thr Pro Val Met Asp Thr Gln Ala Asp Pro 130 135 140 Trp Gly Lys Val Pro Gly Pro Gly Tyr Gly Arg Ser Asn Leu Pro Lys 145 150 155 160 Thr Thr Ala Pro Glu Val Ser Gly 165 551 amino acids amino acid single linear protein 33 Met Leu Pro Leu Leu Leu Leu Pro Leu Leu Trp Gly Gly Ser Leu Gln 1 5 10 15 Glu Lys Pro Val Tyr Glu Leu Gln Val Gln Lys Ser Val Thr Val Gln 20 25 30 Glu Gly Leu Cys Val Leu Val Pro Cys Ser Phe Ser Tyr Pro Trp Arg 35 40 45 Ser Trp Tyr Ser Ser Pro Pro Leu Tyr Val Tyr Trp Phe Arg Asp Gly 50 55 60 Glu Ile Pro Tyr Tyr Ala Glu Val Val Ala Thr Asn Asn Pro Asp Arg 65 70 75 80 Arg Val Lys Pro Glu Thr Gln Gly Arg Phe Arg Leu Leu Gly Asp Val 85 90 95 Gln Lys Lys Asn Cys Ser Leu Ser Ile Gly Asp Ala Arg Met Glu Asp 100 105 110 Thr Gly Ser Tyr Phe Phe Arg Val Glu Arg Gly Arg Asp Val Lys Tyr 115 120 125 Ser Tyr Gln Gln Asn Lys Leu Asn Leu Glu Val Thr Ala Leu Ile Glu 130 135 140 Lys Pro Asp Ile His Phe Leu Glu Pro Leu Glu Ser Gly Arg Pro Thr 145 150 155 160 Arg Leu Ser Cys Ser Leu Pro Gly Ser Cys Glu Ala Gly Pro Pro Leu 165 170 175 Thr Phe Ser Trp Thr Gly Asn Ala Leu Ser Pro Leu Asp Pro Glu Thr 180 185 190 Thr Arg Ser Ser Glu Leu Thr Leu Thr Pro Arg Pro Glu Asp His Gly 195 200 205 Thr Asn Leu Thr Cys Gln Met Lys Arg Gln Gly Ala Gln Val Thr Thr 210 215 220 Glu Arg Thr Val Gln Leu Asn Val Ser Tyr Ala Pro Gln Thr Ile Thr 225 230 235 240 Ile Phe Arg Asn Gly Ile Ala Leu Glu Ile Leu Gln Asn Thr Ser Tyr 245 250 255 Leu Pro Val Leu Glu Gly Gln Ala Leu Arg Leu Leu Cys Asp Ala Pro 260 265 270 Ser Asn Pro Pro Ala His Leu Ser Trp Phe Gln Gly Ser Pro Ala Leu 275 280 285 Asn Ala Thr Pro Ile Ser Asn Thr Gly Ile Leu Glu Leu Arg Arg Val 290 295 300 Arg Ser Ala Glu Glu Gly Gly Phe Thr Cys Arg Ala Gln His Pro Leu 305 310 315 320 Gly Phe Leu Gln Ile Phe Leu Asn Leu Ser Val Tyr Ser Leu Pro Gln 325 330 335 Leu Leu Gly Pro Ser Cys Ser Trp Glu Ala Glu Gly Leu His Cys Arg 340 345 350 Cys Ser Phe Arg Ala Arg Pro Ala Pro Ser Leu Cys Trp Arg Leu Glu 355 360 365 Glu Lys Pro Leu Glu Gly Asn Ser Ser Gln Gly Ser Phe Lys Val Asn 370 375 380 Ser Ser Ser Ala Gly Pro Trp Ala Asn Ser Ser Leu Ile Leu His Gly 385 390 395 400 Gly Leu Ser Ser Asp Leu Lys Val Ser Cys Lys Ala Trp Asn Ile Tyr 405 410 415 Gly Ser Gln Ser Gly Ser Val Leu Leu Leu Gln Gly Arg Ser Asn Leu 420 425 430 Gly Thr Gly Val Val Pro Ala Ala Leu Gly Gly Ala Gly Val Met Ala 435 440 445 Leu Leu Cys Ile Cys Leu Cys Leu Ile Phe Phe Leu Ile Val Lys Ala 450 455 460 Arg Arg Lys Gln Ala Ala Gly Arg Pro Glu Lys Met Asp Asp Glu Asp 465 470 475 480 Pro Ile Met Gly Thr Ile Thr Ser Gly Ser Arg Lys Lys Pro Trp Pro 485 490 495 Asp Ser Pro Gly Asp Gln Ala Ser Pro Pro Gly Asp Ala Pro Pro Leu 500 505 510 Glu Glu Gln Lys Glu Leu His Tyr Ala Ser Leu Ser Phe Ser Glu Met 515 520 525 Lys Ser Arg Glu Pro Lys Asp Gln Glu Ala Pro Ser Thr Thr Glu Tyr 530 535 540 Ser Glu Ile Lys Thr Ser Lys 545 550 219 amino acids amino acid single linear protein 34 Met Gly Met Ser Ser Leu Lys Leu Leu Lys Tyr Val Leu Phe Phe Phe 1 5 10 15 Asn Phe Leu Phe Trp Val Cys Gly Cys Cys Ile Leu Gly Phe Gly Ile 20 25 30 His Leu Leu Val Gln Asn Thr Tyr Gly Ile Leu Phe Arg Asn Leu Pro 35 40 45 Phe Leu Thr Leu Gly Asn Val Leu Val Ile Val Gly Ser Ile Ile Met 50 55 60 Val Val Ala Phe Leu Gly Cys Met Gly Ser Ile Lys Glu Asn Lys Cys 65 70 75 80 Leu Leu Met Ser Phe Phe Val Leu Leu Leu Leu Ile Leu Leu Ala Glu 85 90 95 Val Thr Leu Ala Ile Leu Leu Phe Val Tyr Glu Lys Lys Ile Asn Thr 100 105 110 Leu Val Ala Glu Gly Leu Asn Asp Ser Ile Gln His Tyr His Ser Asp 115 120 125 Asn Ser Thr Arg Met Ala Trp Asp Phe Ile Gln Ser Gln Leu Gln Cys 130 135 140 Cys Gly Val Asn Gly Ser Ser Asp Trp Ile Ser Gly Pro Pro Ser Ser 145 150 155 160 Cys Pro Ser Gly Ala Asp Val Gln Gly Cys Tyr Lys Lys Gly Gln Ala 165 170 175 Trp Phe His Ser Asn Phe Leu Tyr Ile Gly Ile Val Thr Ile Cys Val 180 185 190 Cys Val Ile Gln Val Leu Gly Met Ser Phe Ala Leu Thr Leu Asn Cys 195 200 205 Gln Ile Asp Lys Thr Ser Gln Ala Leu Gly Leu 210 215 253 amino acids amino acid single linear protein 35 Met Gly Glu Phe Asn Glu Lys Lys Thr Thr Cys Gly Thr Val Cys Leu 1 5 10 15 Lys Tyr Leu Leu Phe Thr Tyr Asn Cys Cys Phe Trp Leu Ala Gly Leu 20 25 30 Ala Val Met Ala Val Gly Ile Trp Thr Leu Ala Leu Lys Ser Asp Tyr 35 40 45 Ile Ser Leu Leu Ala Ser Gly Thr Tyr Leu Ala Thr Ala Tyr Ile Leu 50 55 60 Val Val Ala Gly Thr Val Val Met Val Thr Gly Val Leu Gly Cys Cys 65 70 75 80 Ala Thr Phe Lys Glu Arg Arg Asn Leu Leu Arg Leu Tyr Phe Ile Leu 85 90 95 Leu Leu Ile Ile Phe Leu Leu Glu Ile Ile Ala Gly Ile Leu Ala Tyr 100 105 110 Ala Tyr Tyr Gln Gln Leu Asn Thr Glu Leu Lys Glu Asn Leu Lys Asp 115 120 125 Thr Met Thr Lys Arg Tyr His Gln Pro Gly His Glu Ala Val Thr Ser 130 135 140 Ala Val Asp Gln Leu Gln Gln Glu Phe His Cys Cys Gly Ser Asn Asn 145 150 155 160 Ser Gln Asp Trp Arg Asp Ser Glu Trp Ile Arg Ser Gln Glu Ala Gly 165 170 175 Gly Arg Val Val Pro Asp Ser Cys Cys Lys Thr Val Val Ala Leu Cys 180 185 190 Gly Gln Arg Asp His Ala Ser Asn Ile Tyr Lys Val Glu Gly Gly Cys 195 200 205 Ile Thr Lys Leu Glu Thr Phe Ile Gln Glu His Leu Arg Val Ile Gly 210 215 220 Ala Val Gly Ile Gly Ile Ala Cys Val Gln Val Phe Gly Met Ile Phe 225 230 235 240 Thr Cys Cys Leu Tyr Arg Ser Leu Lys Leu Glu His Tyr 245 250 238 amino acids amino acid single linear DNA (genomic) 36 Met Ala Arg Ala Cys Leu Gln Ala Val Lys Tyr Leu Met Phe Ala Phe 1 5 10 15 Asn Leu Leu Phe Trp Leu Gly Gly Cys Gly Val Leu Gly Val Gly Ile 20 25 30 Trp Leu Ala Ala Thr Gln Gly Ser Phe Ala Thr Leu Ser Ser Ser Phe 35 40 45 Pro Ser Leu Ser Ala Ala Asn Leu Leu Ile Ile Thr Gly Ala Phe Val 50 55 60 Met Ala Ile Gly Phe Val Gly Cys Leu Gly Ala Ile Lys Glu Asn Lys 65 70 75 80 Cys Leu Leu Leu Thr Phe Phe Leu Leu Leu Leu Leu Val Phe Leu Leu 85 90 95 Glu Ala Thr Ile Ala Ile Leu Phe Phe Ala Tyr Thr Asp Lys Ile Asp 100 105 110 Arg Tyr Ala Gln Gln Asp Leu Lys Lys Gly Leu His Leu Tyr Gly Thr 115 120 125 Gln Gly Asn Val Gly Leu Thr Asn Ala Trp Ser Ile Ile Gln Thr Asp 130 135 140 Phe Arg Cys Cys Gly Val Ser Asn Tyr Thr Asp Trp Phe Glu Val Tyr 145 150 155 160 Asn Ala Thr Arg Val Pro Asp Ser Cys Cys Leu Glu Phe Ser Glu Ser 165 170 175 Cys Gly Leu His Ala Pro Gly Thr Trp Trp Lys Ala Pro Cys Tyr Glu 180 185 190 Thr Val Lys Val Trp Leu Gln Glu Asn Leu Leu Ala Val Gly Ile Phe 195 200 205 Gly Leu Cys Thr Ala Leu Val Gln Ile Leu Gly Leu Thr Phe Ala Met 210 215 220 Thr Met Tyr Cys Gln Val Val Lys Ala Asp Thr Tyr Cys Ala 225 230 235 244 amino acids amino acid single linear protein 37 Met Glu Thr Lys Pro Val Ile Thr Cys Leu Lys Thr Leu Leu Ile Ile 1 5 10 15 Tyr Ser Phe Val Phe Trp Ile Thr Gly Val Ile Leu Leu Ala Val Gly 20 25 30 Val Trp Gly Lys Leu Thr Leu Gly Thr Tyr Ile Ser Leu Ile Ala Glu 35 40 45 Asn Ser Thr Asn Ala Pro Tyr Val Leu Ile Gly Thr Gly Thr Thr Ile 50 55 60 Val Val Phe Gly Leu Phe Gly Cys Phe Ala Thr Cys Arg Gly Ser Pro 65 70 75 80 Trp Met Leu Lys Leu Tyr Ala Met Phe Leu Ser Leu Val Phe Leu Ala 85 90 95 Glu Leu Val Ala Gly Ile Ser Gly Phe Val Phe Arg His Glu Ile Lys 100 105 110 Asp Thr Phe Leu Arg Thr Tyr Thr Asp Ala Met Gln Thr Tyr Asn Gly 115 120 125 Asn Asp Glu Arg Ser Arg Ala Val Asp His Val Gln Arg Ser Leu Ser 130 135 140 Cys Cys Gly Val Gln Asn Tyr Thr Asn Trp Ser Thr Ser Pro Tyr Phe 145 150 155 160 Leu Glu His Gly Ile Pro Pro Ser Cys Cys Met Asn Glu Thr Asp Cys 165 170 175 Asn Pro Gln Asp Leu His Asn Leu Thr Val Ala Ala Thr Lys Val Asn 180 185 190 Gln Lys Gly Cys Tyr Asp Leu Val Thr Ser Phe Met Glu Thr Asn Met 195 200 205 Gly Ile Ile Ala Gly Val Ala Phe Gly Ile Ala Phe Ser Gln Leu Ile 210 215 220 Gly Met Leu Leu Ala Cys Cys Leu Ser Arg Phe Ile Thr Ala Asn Gln 225 230 235 240 Tyr Glu Met Val 297 amino acids amino acid single linear protein 38 Met Thr Thr Pro Arg Asn Ser Val Asn Gly Thr Phe Pro Ala Glu Pro 1 5 10 15 Met Lys Gly Pro Ile Ala Met Gln Ser Gly Pro Lys Pro Leu Phe Arg 20 25 30 Arg Met Ser Ser Leu Val Gly Pro Thr Gln Ser Phe Phe Met Arg Glu 35 40 45 Ser Lys Thr Leu Gly Ala Val Gln Ile Met Asn Gly Leu Phe His Ile 50 55 60 Ala Leu Gly Gly Leu Leu Met Ile Pro Ala Gly Ile Tyr Ala Pro Ile 65 70 75 80 Cys Val Thr Val Trp Tyr Pro Leu Trp Gly Gly Ile Met Tyr Ile Ile 85 90 95 Ser Gly Ser Leu Leu Ala Ala Thr Glu Lys Asn Ser Arg Lys Cys Leu 100 105 110 Val Lys Gly Lys Met Ile Met Asn Ser Leu Ser Leu Phe Ala Ala Ile 115 120 125 Ser Gly Met Ile Leu Ser Ile Met Asp Ile Leu Asn Ile Lys Ile Ser 130 135 140 His Phe Leu Lys Met Glu Ser Leu Asn Phe Ile Arg Ala His Thr Pro 145 150 155 160 Tyr Ile Asn Ile Tyr Asn Cys Glu Pro Ala Asn Pro Ser Glu Lys Asn 165 170 175 Ser Pro Ser Thr Gln Tyr Cys Tyr Ser Ile Gln Ser Leu Phe Leu Gly 180 185 190 Ile Leu Ser Val Met Leu Ile Phe Ala Phe Phe Gln Glu Leu Val Ile 195 200 205 Ala Gly Ile Val Glu Asn Glu Trp Lys Arg Thr Cys Ser Arg Pro Lys 210 215 220 Ser Asn Ile Val Leu Leu Ser Ala Glu Glu Lys Lys Glu Gln Thr Ile 225 230 235 240 Glu Ile Lys Glu Glu Val Val Gly Leu Thr Glu Thr Ser Ser Gln Pro 245 250 255 Lys Asn Glu Glu Asp Ile Glu Ile Ile Pro Ile Gln Glu Glu Glu Glu 260 265 270 Glu Glu Thr Glu Thr Asn Phe Pro Glu Pro Pro Gln Asp Gln Glu Ser 275 280 285 Ser Pro Ile Glu Asn Asp Ser Ser Pro 290 295 228 amino acids amino acid single linear protein 39 Met Pro Val Lys Gly Gly Thr Lys Cys Ile Lys Tyr Leu Leu Phe Gly 1 5 10 15 Phe Asn Phe Ile Phe Trp Leu Ala Gly Ile Ala Val Leu Ala Ile Gly 20 25 30 Leu Trp Leu Arg Phe Asp Ser Gln Thr Lys Ser Ile Phe Glu Gln Glu 35 40 45 Thr Asn Asn Asn Asn Ser Ser Phe Tyr Thr Gly Val Tyr Ile Leu Ile 50 55 60 Gly Ala Gly Ala Leu Met Met Leu Val Gly Phe Leu Gly Cys Cys Gly 65 70 75 80 Ala Val Gln Glu Ser Gln Cys Met Leu Gly Leu Phe Phe Gly Phe Leu 85 90 95 Leu Val Ile Phe Ala Ile Glu Ile Ala Ala Ala Ile Trp Gly Tyr Ser 100 105 110 His Lys Asp Glu Val Ile Lys Glu Val Gln Glu Phe Tyr Lys Asp Thr 115 120 125 Tyr Asn Lys Leu Lys Thr Lys Asp Glu Pro Gln Arg Glu Thr Leu Lys 130 135 140 Ala Ile His Tyr Ala Leu Asn Cys Cys Gly Leu Ala Gly Gly Val Glu 145 150 155 160 Gln Phe Ile Ser Asp Ile Cys Pro Lys Lys Asp Val Leu Glu Thr Phe 165 170 175 Thr Val Lys Ser Cys Pro Asp Ala Ile Lys Glu Val Phe Asp Asn Lys 180 185 190 Phe His Ile Ile Gly Ala Val Gly Ile Gly Ile Ala Val Val Met Ile 195 200 205 Phe Gly Met Ile Phe Ser Met Ile Leu Cys Cys Ala Ile Arg Arg Asn 210 215 220 Arg Glu Met Val 225 197 amino acids amino acid single linear protein 40 Met Cys Thr Gly Lys Cys Ala Arg Cys Val Gly Leu Ser Leu Ile Thr 1 5 10 15 Leu Cys Phe Val Cys Ile Val Ala Asn Ala Leu Leu Leu Val Pro Asn 20 25 30 Gly Glu Thr Ser Trp Thr Asn Thr Asn His Leu Ser Leu Gln Val Trp 35 40 45 Leu Met Gly Gly Phe Ile Gly Gly Gly Leu Met Val Leu Cys Pro Gly 50 55 60 Ile Ala Ala Val Arg Ala Gly Gly Lys Gly Cys Cys Gly Ala Gly Cys 65 70 75 80 Cys Gly Asn Arg Cys Arg Met Leu Arg Ser Val Phe Ser Ser Ala Phe 85 90 95 Gly Val Leu Gly Ala Ile Tyr Cys Leu Ser Val Ser Gly Ala Gly Leu 100 105 110 Arg Asn Gly Pro Arg Cys Leu Met Asn Gly Glu Trp Gly Tyr His Phe 115 120 125 Glu Asp Thr Ala Gly Ala Tyr Leu Leu Asn Arg Thr Leu Trp Asp Arg 130 135 140 Cys Glu Ala Pro Pro Arg Val Val Pro Trp Asn Val Thr Leu Phe Ser 145 150 155 160 Leu Leu Val Ala Ala Ser Cys Leu Glu Ile Val Leu Cys Gly Ile Gln 165 170 175 Leu Val Asn Ala Thr Ile Gly Val Phe Cys Gly Asp Cys Arg Lys Lys 180 185 190 Gln Asp Thr Pro His 195 202 amino acids amino acid single linear protein 41 Met Cys Tyr Gly Lys Cys Ala Arg Cys Ile Gly His Ser Leu Val Gly 1 5 10 15 Leu Ala Leu Leu Cys Ile Ala Ala Asn Ile Leu Leu Tyr Phe Pro Asn 20 25 30 Gly Glu Thr Lys Tyr Ala Ser Glu Asn His Leu Ser Arg Phe Val Trp 35 40 45 Phe Phe Ser Gly Ile Val Gly Gly Gly Leu Leu Met Leu Leu Pro Ala 50 55 60 Phe Val Phe Ile Gly Leu Glu Gln Asp Asp Cys Cys Gly Cys Cys Gly 65 70 75 80 His Glu Asn Cys Gly Lys Arg Cys Ala Met Leu Ser Ser Val Leu Ala 85 90 95 Ala Leu Ile Gly Ile Ala Gly Ser Gly Tyr Cys Val Ile Val Ala Ala 100 105 110 Leu Gly Leu Ala Glu Gly Pro Leu Cys Leu Asp Ser Leu Gly Gln Trp 115 120 125 Asn Tyr Thr Phe Ala Ser Thr Glu Gly Gln Tyr Leu Leu Asp Thr Ser 130 135 140 Thr Trp Ser Glu Cys Thr Glu Pro Lys His Ile Val Glu Trp Asn Val 145 150 155 160 Ser Leu Phe Ser Ile Leu Leu Ala Leu Gly Gly Ile Glu Phe Ile Leu 165 170 175 Cys Leu Ile Gln Val Ile Asn Gly Val Leu Gly Gly Ile Cys Gly Phe 180 185 190 Cys Cys Ser His Gln Gln Gln Tyr Asp Cys 195 200 145 amino acids amino acid single linear protein 42 Met Ser Ser Phe Ser Thr Gln Thr Pro Tyr Pro Asn Leu Ala Val Pro 1 5 10 15 Phe Phe Thr Ser Ile Pro Asn Gly Leu Tyr Pro Ser Lys Ser Ile Val 20 25 30 Ile Ser Gly Val Val Leu Ser Asp Ala Lys Arg Phe Gln Ile Asn Leu 35 40 45 Arg Cys Gly Gly Asp Ile Ala Phe His Leu Asn Pro Arg Phe Asp Glu 50 55 60 Asn Ala Val Val Arg Asn Thr Gln Ile Asn Asn Ser Trp Gly Pro Glu 65 70 75 80 Glu Arg Ser Leu Pro Gly Ser Met Pro Phe Ser Arg Gly Gln Arg Phe 85 90 95 Ser Val Trp Ile Leu Cys Glu Gly His Cys Phe Lys Val Ala Val Asp 100 105 110 Gly Gln His Ile Cys Glu Tyr Ser His Arg Leu Met Asn Leu Pro Asp 115 120 125 Ile Asn Thr Leu Glu Val Ala Gly Asp Ile Gln Leu Thr His Val Glu 130 135 140 Thr 145 318 amino acids amino acid single linear protein 43 Met Met Leu Ser Leu Asn Asn Leu Gln Asn Ile Ile Tyr Asn Pro Val 1 5 10 15 Ile Pro Phe Val Gly Thr Ile Pro Asp Gln Leu Asp Pro Gly Thr Leu 20 25 30 Ile Val Ile Arg Gly His Val Pro Ser Asp Ala Asp Arg Phe Gln Val 35 40 45 Asp Leu Gln Asn Gly Ser Ser Met Lys Pro Arg Ala Asp Val Ala Phe 50 55 60 His Phe Asn Pro Arg Phe Lys Arg Ala Gly Cys Ile Val Cys Asn Thr 65 70 75 80 Leu Ile Asn Glu Lys Trp Gly Arg Glu Glu Ile Thr Tyr Asp Thr Pro 85 90 95 Phe Gln Lys Glu Lys Lys Ser Phe Glu Ile Val Ile Met Val Leu Lys 100 105 110 Ala Lys Phe Gln Val Ala Val Asn Gly Lys His Thr Leu Leu Tyr Gly 115 120 125 His Arg Ile Gly Pro Glu Lys Ile Asp Thr Leu Gly Ile Tyr Gly Lys 130 135 140 Val Asn Ile His Ser Ile Gly Phe Ser Phe Ser Ser Asp Leu Gln Ser 145 150 155 160 Thr Gln Ala Ser Ser Leu Glu Leu Thr Glu Ile Ser Arg Glu Asn Val 165 170 175 Pro Lys Ser Gly Thr Pro Gln Leu Arg Leu Pro Phe Ala Ala Arg Leu 180 185 190 Asn Thr Pro Met Gly Pro Gly Arg Thr Val Val Val Lys Gly Glu Val 195 200 205 Asn Ala Asn Ala Lys Ser Phe Asn Val Asp Leu Leu Ala Gly Lys Ser 210 215 220 Lys Asp Ile Ala Leu His Leu Asn Pro Arg Leu Asn Ile Lys Ala Phe 225 230 235 240 Val Arg Asn Ser Phe Leu Gln Glu Ser Trp Gly Glu Glu Glu Arg Asn 245 250 255 Ile Thr Ser Phe Pro Phe Ser Pro Gly Met Tyr Phe Glu Met Ile Ile 260 265 270 Tyr Cys Asp Val Arg Glu Phe Lys Val Ala Val Asn Gly Val His Ser 275 280 285 Leu Glu Tyr Lys His Arg Phe Lys Glu Leu Ser Ser Ile Asp Thr Leu 290 295 300 Glu Ile Asn Gly Asp Ile His Leu Leu Glu Val Arg Ser Trp 305 310 315 128 amino acids amino acid single linear protein 44 Met Arg Thr Ala Leu Leu Leu Leu Ala Ala Leu Ala Val Ala Thr Gly 1 5 10 15 Pro Ala Leu Thr Leu Arg Cys His Val Cys Thr Ser Ser Ser Asn Cys 20 25 30 Lys His Ser Val Val Cys Pro Ala Ser Ser Arg Phe Cys Lys Thr Thr 35 40 45 Asn Thr Val Glu Pro Leu Arg Gly Asn Leu Val Lys Lys Asp Cys Ala 50 55 60 Glu Ser Cys Thr Pro Ser Tyr Thr Leu Gln Gly Gln Val Ser Ser Gly 65 70 75 80 Thr Ser Ser Thr Gln Cys Cys Gln Glu Asp Leu Cys Asn Glu Lys Leu 85 90 95 His Asn Ala Ala Pro Thr Arg Thr Ala Leu Ala His Ser Ala Leu Ser 100 105 110 Leu Gly Leu Ala Leu Ser Leu Leu Ala Val Ile Leu Ala Pro Ser Leu 115 120 125 299 amino acids amino acid single linear protein 45 Met Ala Gln Asn Leu Lys Asp Leu Ala Gly Arg Leu Pro Ala Gly Pro 1 5 10 15 Arg Gly Met Gly Thr Ala Leu Lys Leu Leu Leu Gly Ala Gly Ala Val 20 25 30 Ala Tyr Gly Val Arg Glu Ser Val Phe Thr Val Glu Gly Gly His Arg 35 40 45 Ala Ile Phe Phe Asn Arg Ile Gly Gly Val Gln Gln Asp Thr Ile Leu 50 55 60 Ala Glu Gly Leu His Phe Arg Ile Pro Trp Phe Gln Tyr Pro Ile Ile 65 70 75 80 Tyr Asp Ile Arg Ala Arg Pro Arg Lys Ile Ser Ser Pro Thr Gly Ser 85 90 95 Lys Asp Leu Gln Met Val Asn Ile Ser Leu Arg Val Leu Ser Arg Pro 100 105 110 Asn Ala Gln Glu Leu Pro Ser Met Tyr Gln Arg Leu Gly Leu Asp Tyr 115 120 125 Glu Glu Arg Val Leu Pro Ser Ile Val Asn Glu Val Leu Lys Ser Val 130 135 140 Val Ala Lys Phe Asn Ala Ser Gln Leu Ile Thr Gln Arg Ala Gln Val 145 150 155 160 Ser Leu Leu Ile Arg Arg Glu Leu Thr Glu Arg Ala Lys Asp Phe Ser 165 170 175 Leu Ile Leu Asp Asp Val Ala Ile Thr Glu Leu Ser Phe Ser Arg Glu 180 185 190 Tyr Thr Ala Ala Val Glu Ala Lys Gln Val Ala Gln Gln Glu Ala Gln 195 200 205 Arg Ala Gln Phe Leu Val Glu Lys Ala Lys Gln Glu Gln Arg Gln Lys 210 215 220 Ile Val Gln Ala Glu Gly Glu Ala Glu Ala Ala Lys Met Leu Gly Glu 225 230 235 240 Ala Leu Ser Lys Asn Pro Gly Tyr Ile Lys Leu Arg Lys Ile Arg Ala 245 250 255 Ala Gln Asn Ile Ser Lys Thr Ile Ala Thr Ser Gln Asn Arg Ile Tyr 260 265 270 Leu Thr Ala Asp Asn Leu Val Leu Asn Leu Gln Asp Glu Ser Phe Thr 275 280 285 Arg Gly Ser Asp Ser Leu Ile Lys Gly Lys Lys 290 295 80 amino acids amino acid single linear protein 46 Met Asp Cys Val Ile Thr Gly Arg Pro Cys Cys Ile Gly Thr Lys Gly 1 5 10 15 Arg Cys Glu Ile Thr Ser Arg Glu Tyr Cys Asp Phe Met Arg Gly Tyr 20 25 30 Phe His Glu Glu Ala Thr Leu Cys Ser Gln Val His Cys Met Asp Asp 35 40 45 Val Cys Gly Leu Leu Pro Phe Leu Asn Pro Glu Val Pro Asp Gln Phe 50 55 60 Tyr Arg Leu Trp Leu Ser Leu Phe Leu His Ala Gly Ile Leu His Cys 65 70 75 80 1497 base pairs nucleic acid single linear DNA (genomic) 47 TTTTTTTTTT TTTTTTTTTT CACGTTACAA TCTCACTATA TTCGGAATCT AAAGTAGTCA 60 TCCTTAGAGA AGTACAGAGG AGAATGGTGG GTACAGAGGC CAGGGCGGGG AGTGTGGACC 120 GATTGGATGG GGAAAGGGAG AGTTTGGTCA TCAGGCATGC ATTTTCAGTT AGACAAGAGG 180 AATAAGTTCT GATGTCTTGT TGCACAGCAT TGAGGGCTGC TAATTCTACT GGAATCAGCC 240 TCAGACTCCT TTGCTGGAGG GGTCGTGAAC CCTCAAACAA GCCCGAGCCT CTGCATTTTC 300 TTACTTGGGG ATCTTGATCT CTGAGTACTC ATTGTTGGTG GCTTCTTGAC CTGGATAGGT 360 CCTGAGGCTC CCCCTTATGA AAGCTGAGGG GTGCATACTG GGATCTCTCT TTCCTCCCCT 420 GAGGGAGTGG GCAGCCAGGC CATGGTGTCG GGGGTTATCA TCTGCCCAGG ACTCATCCAG 480 TTACCCTGAG AGGCTGAGCC CCTGAATGGT GTTTGCATCC TTCATGCCTA TGTCTCCCAC 540 GTCCGCTGCT GGTCTTGCCG ATTTCTTCCT GCAGGACCTC ACTACAATGA AGATGACACA 600 GAAGGAGAGG AAGACCAGGG CTGTGGCTCC AGTTCCCCCG ACCGCCCCCA GCAACACTCC 660 TGATACAGGC TTCATTTTGC CTGTGTACTC CTGTTGCAGG GAGAGGTTCA GGGAAACGTG 720 CTGGGAACCC AGAGAGTTCT GAGCTCGACA GGTGAATTCC CCTTCATCCC CCAGGTGCAC 780 TTGCAGCTCC AGTACCAGAG GGTTTGAGGG CTGTGAGGGG TACAGGGTCA GACTCCTCCA 840 GGTCCAGCTC AGCCTGGCAG GGGGATTGCT GTCAACAGCA CAGACCAAGC GCAGAGACTG 900 GCCCTCTAGG ACTGAAAGAG ATGAGCTGTT CCCCAGAGCT GTGGATGCTG TGCCTTCTCC 960 TTGGAAGACA GTCACAGTCA AGTTCTGAGG AGGGTATGTC ACGTTCACAG AGAGCTGGTC 1020 ATATTTATAA TTCCATTTTA TATTTCCTTT CTCCATACGA AAGAAGTATC TCCCCGCATC 1080 ACTCATTCTG GCATCTCTGA TGCTCAGGGT GCAATTTTTG GTCTGTGGGT CCCCAAGGAG 1140 GTGGAATCGG TCCCGAGTTT CCTCCTGCAC TGCCCAAGCT GGGTTGTTTG TGGCCACTGG 1200 AGCCTTCCAG CTTATATCAT TCCCTGCCCG GAACCAGTAG CCATGAACTG GGTCAGAGTC 1260 AGTCTGGCTG TCCACTGGGT AGGAGAAGGA GCAGCGCACA TGGACACACA TGCCCTCTTG 1320 CACGGTCACG GAACTCTGCA TCGTCAGCGA GTAATCCTTC CGGTTACTCT TCTGTCCTTC 1380 CACCCTCTCC CTCCCCCAGA GCAGGGGCAG CAGCAGCAGC AGCAGCATAT CTGGGGTTGG 1440 AGGTGCCAGG GCCGCGAGGG AACGTCTGTT CCTCAGGGTT CTTCTCTCAG GAACTGC 1497 1849 base pairs nucleic acid single linear DNA (genomic) 48 TTTTTTTTTA CAATCAAAAT GCACATTTAT TAAACTGTAC TGTGTGAGGG AATGTCTGAC 60 CAAAGAGCAT TCCCACAGGC ACTCGGGGCA CTGGCTGGAA AGCGCTCTCA GGTGTTCTTC 120 TCAGAACCGG AGAAGCTGCA CATCACTTGT ATTTGTAAAA TCCTTCTCCA GTCTTCTTGC 180 CGAACTTGTT CTCTGCTACC AGCTTATTTA AGGATGGGCT GGGCTGATGT AATGGGTTCT 240 CTGCATCCAT TTCATGCCAC CCATCCACGA TGAACTTCGT AGTATCCAGT CCGACATAAT 300 CTAGAAGCTC AAATGGGCCC ATGGGGTAAC CGGCTCCTAA TTTCATAGCA GTGTCAATGT 360 CTTCTTTGGA TGCGTCACCT TTTAATCAAA AGCAGAGATC CAGGATATCA ATCTGGGCCG 420 GCCATGCAAT TGCTCTGGCT GGGACTGTAG TGGGGGTGGT GGGAGTTCCA GAAACCTTTC 480 TCAGAAGCCC ACAGGGAAAG CCAGGAGGCC CTCGTTCATA CAGCCTGATT GCTTCCATGA 540 GGTATGGAAC CAGGAGGCGG TTCACAATAA ACCCAGGAGT GTCCTTGCAA GAAACAGGAT 600 GCTTTCCTAG GGTTTTGCTA AAGTCTACCA AAGATTCAAA TGTCTTCTGG CTGGTCATTG 660 GTGTTTTAAT GACCTCCACA AGTTTCATGA CAGGCACTGG GTTGAAGAAA TGGAGGCCAG 720 CGAATCGGTC TTGTCTGGTG GTGGCATTAG CTATGCTTGT AATCTGCAAG GAGGAAGTGT 780 TGCTGGCAAA GATTGTATGT CTTGGTGATG TGGCAGGTGG GGCTGCATGG AGATTCAGGG 840 ACAGCTCCTC TCAGGCAGAC CCTCAGGAAC CTTAAAAGGA TGCAGGAAGC CCAGCGTGGT 900 GGCTCACGCT GGTAAACCCA GCACTTTGGG AGGCCTAGGC GGGGGGATCG CTTTAGGCCA 960 GCAGTTCAAG ACCAGCCTGC GCAACATAGC GAGACCCCCA CCTCTGTATC ACTGCAGCTC 1020 CCAGAGAGCT CCCACTCAGG GTGAAGCTCT GAGTCTTGGT GATTTTTAGG AGTTTATGGA 1080 AACAGCCCTT CTGGTGGATG ACGTTTGGAG ACACATCGCG TCCGTCACAG GACACACTTC 1140 CGATGGATTT ACAGCAACTC CTGGGGTAGG TGTGGCCCGT TGTCATTTCG AAGGAAGAGC 1200 CAGAAAAATC TGTGTAGTTA TTCACCCCAC AGCACTTTAG CTTCTCCATG ACCAAGTTCC 1260 ACTGTGTAGA ATAGTCGTCT GGCTCGTTGT AACCTCTGTA ATTCTTCCTC AGGGTCACGA 1320 AGGTGTGTTC CAAGGCCACA TCTCCAACAA TTGGAAAGAA AAGAAGGACC ACTGTGGCAG 1380 CTGTAACTTC CATGATGAGG ACAATAACCA TTGACAGGAT GCAAAACAAG AGCGTGCCTC 1440 TGCTCTCTTT AGTCGCTCCA TACCACCCGG CACAGCCAAG CAGTACCGTG ATGCATCCCA 1500 TCACCAGGCA CAGGTTGCCA ACGTGAAGGA GGTATGCGGA GGACAGCCCG AGGACATTCG 1560 TCAGAGAGGC CCCTCCACAT TTACCACCAA TGCCCAGGCC AACTAGGATG ATGCCAGACA 1620 CAGCCACGAA GCCATTGAGT AAAGATAACA GTTTCTTCAA GGAAGAATAC GGAGTGTGGA 1680 TTTCAGCCAT GCTGAACAGA CTGGGGCACC CCGAACATTT AAGTTAACAT CTTCCTGAAC 1740 CTCTGGGCTA CTGTTTCCCA AGATGATAGG GATCTGAGGA AGGGGCGCCA ATGCTGACTT 1800 GCTCTGCCCC TCTGTGTCCT GGCTCCCTGA TGGTTGTCCA CTCGTGCCG 1849 741 base pairs nucleic acid single linear DNA (genomic) 49 GCTTTAGGCC AGCAGTTCAA GACCAGCCTG CGCAACATAG CGAGACCCCC ACCTCTGTAT 60 CACTGCAGCT CCCAGAGAGC TCCCACTCAG GGTGAAGCTC TGAGTCTTGG TGATTTTTAG 120 GAGTTTATGG AAACAGCCCT TCTGGTGGAT GACGTTTGGA GACACATCGC GTCCGTCACA 180 GGACACACTT CCGATGGATT TACAGCAACT CCTGGGGTAG GTGTGGCCCG TTGTCATTTC 240 GAAGGAAGAG CCAGAAAAAT CTGTGTAGTT ATTCACCCCA CAGCACTTTA GCTTCTCCAT 300 GACCAAGTTC CACTGTGTAG AATAGTCGTC TGGCTCGTTG TAACCTCTGT AATTCTTCCT 360 CAGGGTCACG AAGGTGTGTT CCAAGGCCAC ATCTCCAACA ATTGGAAAGA AAAGAAGGAC 420 CACTGTGGCA GCTGTAACTT CCATGATGAG GACAATAACC ATTGACAGGA TGCAAAACAA 480 GAGCGTGCCT CTGCTCTCTT TAGTCGCTCC ATACCACCCG GCACAGCCAA GCAGTACCGT 540 GATGCATCCC ATCACCAGGC ACAGGTTGCC AACGTGAAGG AGGTATGCGG AGGACAGCCC 600 GAGGACATTC GTCAGAGAGG CCCCTCCACA TTTACCACCA ATGCCCAGGC CAACTAGGAT 660 GATGCCAGAC ACAGCCACGA AGCCATTGAG TAAAGATAAC AGTTTCTTCA AGGAAGAATA 720 CGGAGTGTGG ATTTCAGCCA T 741 1288 base pairs nucleic acid single linear DNA (genomic) 50 TTTTTTTTTT TTTTTTTTTA ACATTGTAAC AGGTTTATGC ATTTTGAAGT GCCTTCTACA 60 CATCCACCCA GAGGCTCTGC TGATTTCACT TATGCCCAGG CTATAAAATG CCTTTCTCTC 120 ATCCCCCAGT AGAGCACTGG GATCACCACT AGGCCTAGGG GGCATATCAA GGGTTTAATA 180 GACTGGGGGA ATGGGCAACA GAACTGGCTA CCTTAGAGGC TCTGGAATGC CCCCCACCCA 240 TCCACCCACC AATGGAAGGA AAGTCAGGCA TCGCCTAAAA GGAGTGGTCC CTATCTAGCC 300 CCAAGTCTGG AGCAGAAAGG GCAGGTCCAT TCTGGCCCAA GTGACATTGT TAGATCCTGT 360 CCCCTCCCCC AATCACTGCT GCTTGCCAGG GTGCCTCTTC ACAGTTCCCA TGTGGCAGCA 420 GTAGTGGCAG AGGCAGAAGT GGACTTATTG TAGATTGCAG TACAGATACA TGGACACAAT 480 TCATGGCAGC CAGCTCGAGG CCCCCAATTC CAGCTGCCAC ACCACCCACG GTGACTGCAT 540 TAGTTCGGAT GTCATACAAA AGCTGATTGA AGCAACCCTC TACTTTTTGG TCGTGAGCCT 600 TTTGCTTGGT GCAGGTTTCA TTGGCTGTGT TGGTGACGTT GTCATTGCAA CAGAATGGGG 660 GAAAGGCACT GTTCTCTTTG AAGTAGGGTG AGTCCTCAAA ATCCGTATAG TTGGTGAAGC 720 CACAGCACTT GAGCCCTTTC ATGGTGGTGT TCCACACTTG AGTGAAGTCT TCCTGGGAAC 780 CATAATCTTT CTTGATGGCA GGCACTACCA GCAACGTCAG GAAGTGCTCA GCCATTGTGG 840 TGTACACCAA GGCGACCACA GCAGCTGCAA CCTCAGCAAT GAAGATGAGG AGGAGGATGA 900 AGAAGAACGT CACGAGGGCA CACTTGCTCT CAGTCTTAGC ACCATAGCAG CCCAGGAAAC 960 CAAGAGCAAA GACCACAACG CCGGCTGCGA TGAGGAAGTA GCCCACGTTG ACAAACTGCA 1020 TGGCACTGGA CGACAGTGGC CCGAAGATCT TCAGAAAGGA TGCCCCATCG ATTGACACCC 1080 AGATGCCCAC TGCCAACAGG GCTGCACCAC ACAGAAAGAT GAGCAAATTG AAGAGGATCA 1140 TCATGGTCTT AATGAAGCTG AAGCACTGCA TGGTGGCTCC TGTTCAGGGC TCTTGGCAGT 1200 GAGTTCTGAA AGAGGGAACT GCTGAGGCTC CACAAAGGAC AAAACAGCTC CCGGGTGTTG 1260 CCACTGAGTG GGCAGGCAGA GGGACGCC 1288 1236 base pairs nucleic acid single linear DNA (genomic) 51 TTTTTTTTTT TTTTTTTTGA ATGCTCAGTA TCTATTTATT AAATGAATGC ACAATTGAAA 60 GAGTGAAGAT TGAATGTCTA GATATTTGTT CCTCTAACCC ACAAGCTCAC ATGCAGCAGA 120 GCACACGAAT GGGTGTGCCA AGGCCCCAGA GGCTGGATGC CCACATATGT GCTGATGCAT 180 GTGCCCTAGG GAGTCCCTCT TGGTTAACAT CTGTTTAAAA TCTCTGTCTT CTTCTTGATA 240 GAGAAACAGC ATGGTTTCCT AGACTGAATT GAAGAATGAA GGTGAGAGTA CAAACAGTGG 300 GAGAGACGTT TCCTCAGCTG TCAGAACAGG AACGACCTGG GTTATGGAAG CCCAGAAAGG 360 GAGGAGGACT TCTTTTGGTC CCAGTGAAAG ATGCTTCCAG AATCTGTAGC CTTACTTATT 420 TGCTTGGATC TCACTGGAAT AACTTGGTGG TGAGGTCACC GGTTCTGGGG TGATCACTGG 480 GTTTGCTGCA TAGATGTTTG GATAGATGAC ACTCACATTG CTTGATTGAC AGCAGACCAA 540 CTGGCAGCCA AAGTGGGAAG ATGCGCATGC GATGCCAAAC TCCAGGAGGC AGAAGACCAG 600 CAGCACGCCA GAAATCGCCA TTCCAGGGTT CACACCCCAG GCGTAAGGAT AATAGTCGGG 660 GTAGGCATAT GGGTGGGGAA TACTTAGATC TGTGATGAAG AGTATGACTC CAACTGCAGA 720 GCAGATTGCA CTGACGATGT TCAAGCCCAA ACTGCCAGAC AGCAGGCAAT AAGAATATGG 780 CTGATTTTCT GCTGCCACGG AGAGAGATCC TGAAATGATA AACCACAAGC CTCCCCAGAA 840 GGGAAAGCCT CCGTAGAATG AAATAGACAG GTATTCCCCT ACGAGAACCG TCGCCATGAT 900 GGAGCCGAGG CCGATGTGAG CCAGGCCAAT GATGATCTGG ATGGCCCCCA AGGTTTTGCC 960 TTCTTTCAGA GCTTTCTGCA CAGGCTGCCC ATTCACATTC GACACCAAAC TAGGTGGGTT 1020 CCCAGGAACT AGGTGGACTT GCGGCTGGCT GTTTGGATAC AGGGGCACGT GAGACATAAT 1080 TCCTGGGGTC ACAGGATAAC CATTGTGGGG TGCCACCACC AACACAGAAT TGGCCACCGG 1140 AACTGCTGAA GTCATCGAAT TCATGCTTGC TCTGCCAGCA GCCACGTATC TCTTGATCCT 1200 ATTCCTTTTC TTTGCTGTGG GGACCTTGTT TTTTTT 1236 1115 base pairs nucleic acid single linear DNA (genomic) 52 TTTTTTTTTT TTTTTTTTTT TACTTCATTT ACAATTTACT AGCTCTTCCA GTGTTTCAGA 60 GGGATACAGG GTTTCAACGA TCTAACATGA ATGGGATAGA AGGTGGACTT AGAACATAGC 120 AAACATACAT CTTGATTGAA TCAGCCCACT GCGAGCACGG ATCTTGATTG AATCAGCCTA 180 TTGGTGTAGT TTTAGGTCTA CATACATCTT GATTGAATCA ACCTACTGGT GTAGTTTTTT 240 GGTCTATCAG TAAGTAGTGT TGTCAGTTCT CCAGCCAAGC AACTTTCTAA TTCACAGGGG 300 GGACCCTAAA TGTCCTTAAA GGTAGAGAGG AATAGGCCCA CAGATACATT GGGTTACACT 360 ATCTCATACT GGTTATTTGT TATGGCACGA GAGAGGCAGT AGGCGAGAAA GATTCCAATC 420 AGTTGGAAGC AAGCAACTCC AAAGGAAATT CCTGCAACGA CTCCCATTTC TGACTCTATA 480 ATGGTCATCA CCTTTATAAA ACAACCTTCA TTGTTTACTT TGTCTGCATC TCTCTGTGGA 540 GTACAATCTT CAAGTTTACA GCAACTCTTA GGAAATCCTT TTTCTGAGTA ATAATTAGTA 600 TCTGTCCAAT CTCTATAATC GGTGACACCA CAACAATGCA ACGTATTTTG GATCTTGTCT 660 ACTGCATGGC TTCTATAATC TCCTGTAGAG TTATACTGCT TCAAAGCCTT CTCATAATTA 720 TTCTTAAAGC TGTTCTTAAT CTCATGTCTG AAAACAAATC CTACGATGGC AGCGACCAGT 780 TCGACCAAAA AAACGAGAGT CAGAAACATT GCATACAGTT TTAGCATCCA TGCAGAAGCT 840 CGGCAGGTAG CAAAACAACC AAAGGTGCCC AAAAGAATAA TGACGGTACC AGTAGCAATG 900 AGCACGAAGG GGACATTGGT GGCCTTCTCA TTTAAAAGAG AAAAGTAATT CTCCAGGCTC 960 ACCTTGCCCC AAATGCCAAC TGCAAGAAGG ATAACGCCAG TGATCCAGAA AATAAAAGTG 1020 TAGATTAGCA GAACGCTCTT GAAACAAGTA ATGACTGGTT TAGTCTGCAG TCTCCGAGAC 1080 GGGGACGCCA TGACTAGCCC GAGACCCTGC TCGTG 1115 1662 base pairs nucleic acid single linear DNA (genomic) 53 TTTTTTTTTT TTTTTTTTTG TTGGGGGCTG ATACAGAGTT TATTGAATTA GATTTTTCTA 60 TTTACAACTG AGATCACATC TACATACTAT TTTGCTAGTC TACATGGGTA CATTATTTCC 120 AACAAGCTTA AGACTTACCA TGAATGGGCT CATTCATACA AAAACACACT CACACTAATT 180 CTTTTAAAAC AGTAGTGCAT ACATTATACT CCTCCTATAA AGCCAACTTT GATTAAAAAC 240 CACTAGTTTC AAAGCTCAGT CTCTGATTTT GAAGATGAAC CAAGATATAC GCCATATGAT 300 CCTACAATCT ATTTTAGTCA TTTTGTACAG CTGCTATCTT ATTGGACTAC AGTAAATATT 360 TTTTAAAAGG ACACCAATGA GGGGCACCAT CTGGTGTTAA CCTTAACCAG AAAGCTGGTT 420 TCCTCCTCCT CCCCCCAAAA ACCTTTGGCC AAGAGTTCTC CACTGTGAAG ACTGAAAGGA 480 CCTGGTGACA TTTCGGCATC AGTCCTGTTA CCACTTGGAG GTAACAGAAG CAGGCTCGTG 540 TCCTCCTTTA ATTCTACCAC ACTACATGAC TCGCAATTGG TTCTGAAATT AGAACGTTCA 600 CCATCGTACT TAAAATCTTA GGGGCATGAA GAGTCAGCTA GAACAAGGAA AAAGAAAGTC 660 GCAGGTAGTA GGTAAGTAGG TGGGCACATG AAAAGCCAAG CTGCTCTGTC CAACACCAGT 720 GTACATGTGC TTTAACTAAA TGAACTCCAG AGGCCAACAG CAGCAGACCT GCTCAATTCA 780 CCTTCCAAAT CAGAACAAGA CCAAAAAGCT CAGGCTTGAG ATTGTCAACT ATGCATAGGT 840 TCCGCCAGTG ATGAAGAGCT CGTAAGCAGG ATCTCTACTC CTTCTGCACA ACACGATGCA 900 AGCACACAGC ATGCCCAGCA GCTGAATAGC TGCAAATGCC AGTGCGGCCC AGATCACATG 960 CATCATGATT TCTTGTAGCT TCTTCACAAC TAGAGCCTCA CACCCCTCAG CATAGAGGTC 1020 GGAAGGGTGG GCCAGGCTGC CATTACAATT GCTGGCAGTC TCTCTGCAGC AGCTAAGAGG 1080 GACACTCTGG TTTTTGGTTT CTTTGAACCA ATCTGTATTT TCCCAGTCTG AGTAGTTGTG 1140 AATTCCACAA CAATGCAGCT GTCTCTGTAC ATAATCAATA GCCCGGCTAG CAGCATCAGG 1200 GTTGGTTCCA TTGTAGGTCT TATACACTTT CTGAATGCTG CGATCAACCT CATTTTCCAC 1260 CTTTGCTCTG TAAACATATC CCAAAACCAC TACAACAACT TCTGTGACAA AAACCAAGAG 1320 CAGGATGATG ACAAACGTGG CAAGTCCACA GCGACTTTCC CGGATTGTGG CACAGCAGCC 1380 AATTAGCCCA ATGATGAAAA GCAGGGCTCC TACAGCTATG ATCACTACAG CAGGGATGAG 1440 CGTGTACACA TCTTCAAAGA AGTGGTCATA GTCATCATAA GTGATGAAGA CATAGGCTCC 1500 CACATAGCAT AAAATGCCAG CTGCCCCCCA GAAGATGAGG TTGAGAAAGA CCAGCACGGT 1560 CTTGGAGGAG GTGATGCCGC ACTGGCCCAT GGCGCCGGTG GCCCGCGAAG GCCCGGCCCG 1620 GAGAGCGGGG CTGCGCTCAC CGAGAGAGCG GCAATGCTCG TG 1662 1345 base pairs nucleic acid single linear DNA (genomic) 54 TTTTTTTTTT TTTTTTTTTT TGCTGCTCAC ACTTTATTAA GATGCACCAG GAGCCCCACG 60 GGCCCACTAT GGAATGTAGG TGAGGGGTCC ACGGCCCCGC CTGGAGCACC AGGACCAGTG 120 GGGCCACCTC CAGGATGCCA AGACCCGGCT CCTCCAGCGC CAACCTGTTT TCCAGGAAGC 180 TGGGGGCCAC AGGCTGGCTC CCGTGTGAAC ACTGCTTTGG AGAATACGTA AATATAAAAA 240 GTGCTGGAGG CCCCTCCCAC CCCTGCCCTG GGTTCCGCAG CCAGCACGTG GCCACCCCTC 300 CCAGGGGGGG TCCGGAGGCC CTGAAGCCAC CTGAGCTAGG GCCTTCCAGA AACAGGGTTC 360 CGGGGGCTCC AGGCACCTGT CCCTCCCTCC CTCCTCCCAG CATGGGGCAG AACACCGAAG 420 CTGGTGGTGG GAAAAGCAGC TGTGGGTGCG GCCATCTCCC CGTGGGCGTC CTTTTGGCAG 480 AGAAGCCGGC GGTGGGCGGC CTACGCGCAG TAGGTGTCTG CCTTGACCAC TTGGCAGTAC 540 ATGGTCATGG CGAAGGTCAG GCCCAGGATC TGCACCAGCG CCGTGCACAG CCCAAAGATG 600 CCCACAGCCA GCAGGTTCTC CTGAAGCCAC ACCTTCACCG TCTCGTAGCA CGGCGCCTTC 660 CACCAGGTGC CGGGGGCGTG CAGCCCACAG CTCTCACTGA ACTCCAAGCA GCAGGAGTCA 720 GGTACCCGCG TGGCGTTGTA CACCTCGAAC CAGTCAGTGT AGTTGGAGAC GCCACAGCAG 780 CGGAAGTCGG TCTGGATGAT GCTCCAGGCG TTGGTGAGGC CCACGTTGCC CTGCGTGCCG 840 TACAGGTGCA AGCCTTTCTT CAGGTCTTGC TGGGCATACC TGTCAATCTT GTCCGTGTAG 900 GCGAAGAAGA GGATGGCGAT GGTGGCCTCC AGCAGGAACA CCAGCAGCAG CAGCAGGAAG 960 AAAGTGAGCA GGAGGCACTT GTTCTCCTTG ATGGCACCCA GGCAGCCCAC GAAGCCGATG 1020 GCCATGACAA AGGCGCCGGT GATGATGAGC AGGTTGGCAG CCGACAGGGA CGGGAAGGAA 1080 GAAGACAGCG TGGCGAAGCT CCCCTGTGTG GCGGCCAGCC AGATGCCGAC ACCCAGCACG 1140 CCACAGCCTC CCAGCCAGAA GAACAGGTTG AAGGCGAACA TGAGGTACTT GACGGCCTGG 1200 AGGCAGGCGC GCGCCATGCC GCAGCGCTTC AGTTCTGGGC TGGCCACAGG AAAGAGACCA 1260 GGCGGTGCTC AGGGTCCCTG AAGGCTGACC AGTGGGCAGG CAGGTGGTGG GTGCGACCAA 1320 GGAAGCCCCA AGCTCTGCGC TCGTG 1345 734 base pairs nucleic acid single linear DNA (genomic) 55 GAACATTTGG TATGAAAGCT TTAGATTGCA ATTTTCATGT AGAAGTAGCT TCATATCACA 60 TCTCGTGAGT TTCGTATCGC ACAGCAGAGG ACCATGCTGA ATATCATGCC AAAGATCGTC 120 AGACCTGCAA TTCCAATACC GACAATTCCA ATGAGCTGGA GCTTAACACT GATTATGGTC 180 TCAATTTCAT CGATGCAATT CTTGTGTCCT AGAAGCTCCT TTGGGCATGT AGGTTGGACC 240 TGTTCGGAGC TTTCTTTTCC ACAGCACTGA AATGTTGAGT GGAAGGTGAT GAGTGTCCCA 300 TTGCCTTTTC CCCTGTCTTT AAGGTAATCA TTGTAAGCCT CTTCATACAT GGTCTGAACA 360 TGTCGGATAG CTACCCCCTT GCCTATAAAA GCAAATACTC CAGTGGTTAC TTCAGCAGCA 420 AATATCACCA GGAGGCAGGT AAAAAATGAT CCAAGCACAC ATTGCGACTC CCGCATGGCT 480 CCGCAGCATC CGAAGAACCC CACGGCCATC ATCAGGGCCC CGGCTCCAAC CAGAACATAC 540 AGCCCCACAT AGAAATACTC TGGGGACTTG TCCTCTGATG ATAACTCCTT TATGGCACCT 600 CCGAACCGAA ACCATAGTCC AAAAGCAATG ACGGCCGATC CAGCCAGCCA GAAGAGCAGG 660 TTGAAGCCAA GCAGCAGGTA CTTGATGCAC CGCAGGCCCC CGCGGAAGCG CCCCATGCTG 720 CGGCCCGGCG GCGC 734 577 base pairs nucleic acid single linear DNA (genomic) 56 TTTTTTTTTT TTTTTTTTTT TAAACATTGA AAATTTTATT TTCACAGGGG ATTTGCATAA 60 AAAGAACATT ATTTTTGTTC TGTGTATATA TAAGTATTTT TGTTTCCTTA ACTTGTTTCT 120 GTTGCCCACA CACAACTAGG AGAAGATGCT TTTCTTTATT TTGGTTTGGC CAAAGATGCT 180 AATGGTTAAA TTATGAAGGA CTTTGTTTTA CTTATGTTAA GTGGTGAAAA CTGTAGTTCT 240 TAATCTATGA AGAATTCTCT AGGTGGCTAT ACAAGAAAAA TACAAAAAGT TAGGAAAACA 300 TGTAAACGTA AGTATGAGGT ATTTCATAGA TACAGTGCCC ATACAAATTC TCTTTCCCAC 360 AATTTTCAAC TGCCAGATCT CTTGCTTTAG TCTTTTTTCC TTATATTTGG AGAAACAGAA 420 GAGTTTGACA TAAAAGTCCC TTTGAGGGAT GTGAGGGTTG CAGTAGTTTA CAGCAGGGTC 480 AGAAAATGAA AGTAATAAAG CATATTTACA TGTTTTGTAT AGGACCAAAA TATTTCCCCT 540 AAAAAGGTGT TAAAAGTTTT TTAGTCCCAT AAACACT 577 936 base pairs nucleic acid single linear DNA (genomic) 57 CCTTGCAGAT GGCATGTGCC ACATGTTGTC TTGAGGGGCA GTTGGAAGAG GAGGTGGTTG 60 CCATTAGTAA AAATGCCGCT GGAGCCTCTG GTGCAAGCAG CAGGTGAGAA CCATCCCGCA 120 GATCTGCAGG CAGGCCACCC CGATGCCCAC TGCCCCCATA AGCAGCAGGT GGTCGGCCAG 180 GAACTGCTCC AGCTTGGTGA GGCAGCCTCC CTCCACCTTA TAGATGTTGG AGGGGTGGGC 240 CCGCTGGCCG CAGCGCGCCA CCACTGTCTT GCAGCAGCTG TCGGGCACCT GGCGGCCCTC 300 GGCCTCCCGC AACAGGATGT ACGTGCTGTG CTGCCAGTCG GCTGAGCTGT TGCTTCCGCA 360 GCACTTGAAA TCCTGCTGGA GTCGGTCCAC TGAGGCGTGA TCTGCGTGCT CCGGCTGCCC 420 GTAGTTCTCA GCCAGAGTCC GGTTCAAGTG CTGCTTCAGT TCATCACTCA GCCTCTGGTA 480 ATACACATGG GCCAGGACTC CCGCCACCAG CTCAACCAGG AAGATGACGA GCAACAGGCA 540 GAAATACGTG GAGAGGCAGC CCTTCCGCTC CCAGAGGATG GCACCGAAGC CCAGGAAGCC 600 GGTCACCATG ACAAGTACGC CCGCAAAGAT GAGGATGTAG GCGGAGGCGG CAAAGGTGCT 660 GGAGGCCAGG ACGCTGAGGT AGCCACTCTT CTCCACCAGG GTCCAGATGC CCACAGCCAG 720 GACGGCTGCT CCCCCGACCC AGAAGAAGAA GTTGAAGACA AAGAGTAAAT ACTTCAAGTA 780 GATGATCAGC CAGTCGTCCT GCTCAGTCTT ATAGTGGGCC ATGGCTTCTG GGCCCTGCCA 840 GGGGCTCCGG AAGCGGCGAA GGGACTGCGC CTAGAGAGAC TGAGAGCGCG GCTCCCGGGG 900 CCGCCCAGCC GCCCACCGCC CGCAGCTCGT GCCGAA 936 738 base pairs nucleic acid single linear DNA (genomic) 58 GTTTTTTTTT TTTTTTTTTG AGAGCGCAAA GCAGTTTATT CTAGCGAGCA AGGGAGTGAG 60 CGTCCAGGAA GGAGCAGGTG TAACCCGGCG GTCAGTGGAG CCTCAGTGAG GTGTGTCCTG 120 TTTTTTCCTG CAATCGCCGC AGAAGACACC AATGGTCGCG TTCACCAGCT GGATCCCACA 180 CAGTACTATC TCCAGGCAGG AGGCGGCCAC CAGCAGCGAG AAGAGCGTCA CATTCCAGGG 240 GACCACGCGA GGGGGCGCCT CGCACCGATC CCATAGAGTG CGGTTGAGCA AGTAAGCTCC 300 CGCGGTGTCT TCGAAGTGGT AGCCCCACTC GCCGTTCATT AAGCATCTGG GTCCATTTCG 360 GAGCCCAGCT CCAGACACCG AGAGGCAGTA GATGGCACCA AGCACCCCGA ACGCCGAGGA 420 GAAGACCGAG CGCAGCATCC TGCAGCGGTT TCCACAGCAC CCAGCACCAC AGCAGCCCTT 480 GCCCCCTGCC CGAACGGCTG CAATCCCTGG ACACAGTACC ATTAGGCCCC CGCCAATGAA 540 GCCGCCCATG AGCCAGACTT GCAAGCTGAG ATGGTTGGTG TTGGTCCAGG AGGTCTCCCC 600 ATTAGGTACC AGCAGGAGGG CGTTGGCCAC AATGCAGACG AGGCAGAGGG TAATGAGGGA 660 GAGCCCCACA CAGCGGGCAC ATTTTCCCGT ACACATGGTG AGGTGTCAGG AAGGACAGGC 720 GGTGAGTGAA AGTAAGCT 738 1071 base pairs nucleic acid single linear DNA (genomic) 59 TTTGAGTTAG AATTTTGGGG TGTTTCCAAT TTTCCAGAAT ATTAAATAAT GTTGCAATAT 60 ACATATTGCA TAAAGGTTTC TCTCATATTC TTATTTACTT CCCTAGTACA GATTCTTGGA 120 AATGGATTTG TTTGATCAAA GGGCAGAAGT ATTTCTGAAG TTTCTGATGC ATATTACTTA 180 AAAAACATAC TAAATGGAAG GGTGGTATAC TTGCATGTGC AGTGAGGACT GCAAATTTTT 240 TACAAATAAA CACCAAATGC AGAAAGCACC ATCATTTTCA ATATTGCCCT CAAGTCTAAC 300 ACAGTTGATA TAATATTTAG ATAGATGGCC ATGTCTTGAT AATGGAAAAC ATTTTGTCCT 360 TATTCAAATG ATTCCAGGCT GGAAGATCAC TGAATAGCTT CCACACAGTA TCTTGGATAG 420 TTGCATGACT ACTCTGATGA GGCAGATGAT CACTTGAAGC CCACTGAGGG TTATGAGAAT 480 GGAAAATAAA ATGATGTTCC ACTCCACAAC ATGTGCAGGT TCCAGGCACT GAATCCATAT 540 GCTAGAATCT GTAAGGAAAC GTCCAGCAGT GCCTTCAAAA GCATACTCCC AGCCATCAAG 600 GGTGCGGCAA TATGGCCCTT GGACAAGACC CAAGGCAGAG ATGACCAGGC AGTATCCAGA 660 AAAAGCAATT CCGAGGGAAG AAAAGATAAT TGACAGCAGT GTCACATATT TTTTGCTGCA 720 GTTTTCACTC TGGCAACATT TATAGTTGTT ATTATTCTCC AGTACCAGAA GAACTGTTGT 780 TACTATAAGC ATCATGATGC CTGAGAAACA GATTCCTTCA AAATACCACA CGTAGTTGGT 840 GAGTTTATTG CTGGATGCAT AGGAAGTTTG CCCATTCGGG AAATACAATA ATATGTTCAC 900 GATTATACTC CAAAGTGCAA GCGGAATCAG CAAACAACTT AGGCAGCCTC CACACTTCCG 960 AGACCCCATT TTGCCCTGCT TAGAACCACT TCCAGGGTCA GAGCCCTTCA CTTCATATTC 1020 ATGAGGAGAC GGGGAATTGG AATATACCCG CAGCCGACAA TCTCTCGTGC C 1071 865 base pairs nucleic acid single linear DNA (genomic) 60 TTTTTTTTTT TTTTTTTTTT TTTTTTTTTT TTTTTAAATA AATAACCTTA TTTATTTATT 60 TGACCACAAA TAAATAAATA ATAAAGAATA AATGACCACA TTCTTTAAGC CATTGTATTT 120 TGGAGTATCT TTGTTAGTCT ACAACACTTG CCTCTGTGAG TGCAGTCCAG GCCCTGAAGG 180 CAGATGGAGC CATATCCCAG GCTCCTGGTG GAGGAAGGTG CAGAGTTCGA GGAACCTTTG 240 CACTCTTGTG CCTTCCCTCA GGCCCAAAGC TCCTGTAGAC TCAGTCTCGT GACCCCAGAG 300 GTGAACCAGG CCCTGATGTG CTGGTGTTCA GGTGGATGGT TTAATGAGGG GAGGAGAGTG 360 GGGCCCTGGG GAGTGGCTGA CTCTTGTTTT CTGCGGTATT TCCTGGAACC ATCCTTCAGG 420 AGTGGACACA GTAGAGCTGG ACACTTCCAC TGATCCGGAG CTCCCGCAGC TGCTCCAGGG 480 CCTGCTGGTT CATGCTGGTG GCCCCCAGCC CCTGCCCATT GAGCGCCAGC TTCAGCCCTC 540 CCTCCTGGAA CAGGAGCAGC ACCTCAAAGA ATCTCTGGGG GTAAAAGAGG AAGGGGGCTG 600 AGATCAGTTT CTTCTGCCCC CAGCGGGAGA TCCAGGCCAG AGTTCTGTCT GCGAAGGAGG 660 CCCTGAGTGT CACAGGAGCA TGGGCAGCCT GGTCCCTCAG GCTCACAGTA AAATGCTTCG 720 GCTCTTGCAA GACCAGTCCC CGTACTATGA TGACCTGCCC AGGCGAGAGA CCCTGGGGAA 780 GAGCATGTGA GCAGGGCACC TCCAGCCTGG GGCTCATCAG CAGGAAAGGA TGTCCAGCTG 840 GGTACTCTCT GCTGCCCTCC ACAAA 865 441 base pairs nucleic acid single linear DNA (genomic) 61 TTTTTTTTTT TTTTTTTTTT TACTGGTTTA AATCATTTAT CTCCATGTAG AGATTTGAGT 60 ACAAAAATAA ACGGCAACAA AACAGAAGGA GTGTGAAATC CGGGGATCCA CAGGGCTTCT 120 GTCCTCCACC TTCCATGCAG CTGGGGGCTG CATCCTCTGT GGGGTGGCTT CATCCTCTGT 180 GGGGTCTGTG GGGCCTGCTC CAAGTCATCA GCATTCCATG CCCACCTGGA CCTGGTCCCA 240 GACTTTCGGG GAAGCCCTCA GAGGCTCCAC TGTGTTCGTG GTCTTGCAGA AGCGAGAGCT 300 GGCCGGGCAG ACCACAGAAT GCTTGCAGTT GCTGGAGCTG GTGCACACGT GGCAGCGCAG 360 GGTAAGGGCT GGCCCTGTAG CCACAGCCAG GGCTGCAAGG AGCAGCAATG CTGTCCTCAT 420 CTCTGATGTC GTCTCTCGTG C 441 1066 base pairs nucleic acid single linear DNA (genomic) 62 TCAAAAACTG GAGAAGCAGA TCCACTTCTT GTGGGGGTGG AGTTCTTGGT GACTAGGCTC 60 ATTTCTTACC CTTGATGAGG CTGTCACTTC CCCTGGTGAA ACTTTCATCC TGTAGGTTCA 120 GCACAAGGTT GTCAGCTGTG AGATAGATAC GATTCTGTGA TGTGGCGATC GTCTTGGAGA 180 TATTCTGGGC TGCTCGAATC TTGCGAAGTT TGATGTAGCC AGGGTTCTTG CTCAGTGCTT 240 CTCCAAGCAT CTTGGCAGCC TCGGCCTCAC CCTCGGCCTG CACAATTTTC TGCCGCTGTT 300 CCTGCTTTGC TTTTTCTACC AAGAATTGGG CCCGCTGGGC CTCCTGCTGG GCCACTTGTT 360 TGGCTTCTAC AGCAGCTGTG TACTCTCGGC TAAAGCTCAG CTCTGTGATG GCCACATCAT 420 CCAGGATGAG GCTGAAGTCC TTGGCCCTCT CTGTCAGCTC CCGGCGGATC AACAGGGATA 480 CCTGGGCCCG CTGGGTGATC AGCTGTGAGG CATTGAACTT GGCCACCACA CTCTTGAGCA 540 CCTCGTTGAC AATGGACGGC AACACTCGTT CCTCGTAGTC CAGCCCTAGG CGCTGGTACA 600 TGCTAGGAAG CTCCTGAGCA TTGGGTCGAG ACAACACTCG CAGGGAGATA TTCACCATCT 660 GTAGGTCTTT GGAGCCTGTA GGGGAGGAGA TTTTTCGAGG TCTGGCCCGA ATGTCATAGA 720 TAATGGGGTA CTGGAACCAA GGGATCCTGA AGTGAAGGCC CTCGGCCAGG ATAGTGTCCT 780 GCTGCACTCC ACCGATCCGA TTGAAGAAGA TGGCTCTGTG CCCGCCTTCC ACGGTGAACA 840 CAGATTCGCG CACACCGTAG GCCACGGCGC CGGCCCCCAG CAACAGCTTC AGGGCCGTGC 900 CCATGCCCCG GGGCCCGGCG GGCAGCCGTC CCGCCAAGTC CTTCAAGTTC TGGGCCATGT 960 CTGATCTTGA GGCCGGCGGC ACTGGAGGTC AGAAGGGGGT GCCGGCCCGC CTCTACCCCG 1020 CTCCGGCTTA GGTACTGCAC CCTTCACACG AGGGTTCGGG CCCGCT 1066 704 base pairs nucleic acid single linear DNA (genomic) 63 GCGATAGGGT GCCAGCCGGA CCACCTTCCT CCAGGTCCCC TTCAGGGATG TCATTTGAAA 60 AGACCCACAA GACACCGAGG GCAGTGCACC CACACTGGGG GAGGGACACA CCAGGCAGCG 120 GCCTTCATCC AGACACTTCA GGAGCAGTAG TCTTCGGCAG GTTGGACCGA CCATACCCTG 180 GCCCAGGAAC CTTTCCCCAG GGGTCCGCCT GGGTGTCCAT CACAGGGGTC GGGTTCGGGG 240 GCATTGAGGA CCTCTTACCC AACATGTAGG AAAAGAGACA GCCAGACCTG TAAAACTGAT 300 CTGGGACCTC AGGGTTGAGG AAGGCAGCAG CCCAACACAC CTTGTCCAAA ACAGTGCACC 360 TGGGAATGGG CATATGGTGC TCAGCGCCCC AGAAGCAGCC TGAGTCTGAG GCTCCGACAT 420 GGGAGGGAGT GCGTGAGCCC CGGCCCCAGC AGGCTGCCAT GCCCAGCGTC CTCTCCTCCA 480 CTACTCCAGG CCTGCCTCGC CTCACCTGGG AGCAGAGTGT TGCTTCCTCA TGGAAATAGC 540 CGTGCATGAA CTCACAGTAT TCCCGGGTGG TGATCTCACA GCTGCCCTTG GTGCCGATGC 600 AGCAGGGGCG GCCCTTGATC TCGCAGTCCA TGTGCAGGAA GCCTGTGTGG TTGCTCCTGG 660 CCTGCTCTGT GCAGATCGGC CACTTAGTGA TGTCATCTCG TGCC 704

Claims (21)

What is claimed is:
1. An isolated polynucleotide comprising a nucleotide sequence that has at least 80% identity over its entire length to a nucleotide sequence encoding the receptor polypeptide of SEQ ID NO: Y; or a nucleotide sequence complementary to said isolated polynucleotide.
2. The polynucleotide of claim 1 wherein said polynucleotide comprises the nucleotide sequence contained in SEQ ID NO: X encoding the receptor polypeptide of SEQ ID NO: Y.
3. The polynucleotide of claim 1 wherein said polynucleotide comprises a nucleotide sequence that is at least 80% identical to that of SEQ ID NO: X over its entire length.
4. The polynucleotide of claim 3 which is polynucleotide of SEQ ID NO: X.
5. The polynucleotide of claim 1 which is DNA or RNA.
6. A DNA or RNA molecule comprising an expression system, wherein said expression system is capable of producing a receptor polypeptide comprising an amino acid sequence, which has at least 80% identity with the polypeptide of SEQ ID NO: Y when said expression system is present in a compatible host cell.
7. A host cell comprising the expression system of claim 6.
8. A process for producing a receptor polypeptide comprising culturing a host of claim 7 under conditions sufficient for the production of said polypeptide and recovering the polypeptide from the culture.
9. A process for producing a cell which produces a receptor polypeptide thereof comprising transforming or transfecting a host cell with the expression system of claim 6 such that the host cell, under appropriate culture conditions, produces a receptor polypeptide.
10. A receptor polypeptide comprising an amino acid sequence which is at least 80% identical to the amino acid sequence of SEQ ID NO: Y over its entire length.
11. The polypeptide of claim 10 which comprises the amino acid sequence of SEQ ID NO: Y.
12. An antibody immunospecific for the receptor polypeptide of claim 10.
13. A method for the treatment of a subject in need of enhanced activity or expression of receptor polypeptide of claim 10 comprising:
(a) administering to the subject a therapeutically effective amount of an agonist to said receptor; and/or
(b) providing to the subject polynucleotide of claim 1 in a form so as to effect production of said receptor activity in vivo.
14. A method for the treatment of a subject having need to inhibit activity or expression of the receptor polypeptide of claim 10 comprising:
(a) administering to the subject a therapeutically effective amount of an antagonist to said receptor; and/or
(b) administering to the subject a nucleic acid molecule that inhibits the expression of the nucleotide sequence encoding said receptor; and/or
(c) administering to the subject a therapeutically effective amount of a polypeptide that competes with said receptor for its ligand.
15. A process for diagnosing a disease or a susceptibility to a disease in a subject related to expression or activity of the receptor polypeptide of claim 10 in a subject comprising:
(a) determining the presence or absence of a mutation in the nucleotide sequence encoding said receptor polypeptide in the genome of said subject; and/or
(b) analyzing for the presence or amount of the receptor polypeptide expression in a sample derived from said subject.
16. A method for identifying agonists to the receptor polypeptide of claim 10 comprising:
(a) contacting cells produced by claim 9 with a candidate compound; and
(b) determining whether the candidate compound effects a signal generated by activation of the receptor polypeptide.
17. An agonist identified by the method of claim 16.
18. The method for identifying antagonists to the receptor polypeptide of claim 10 comprising:
(a) contacting said cell produced by claim 9 with an agonist; and
(b) determining whether the signal generated by said agonist is diminished in the presence of a candidate compound.
19. An antagonist identified by the method of claim 18.
20. An isolated receptor polynucleotide comprising a nucleotide sequence selected from the group consisting of:
(a) a nucleotide sequence having at least 80% identity to a nucleotide sequence encoding the receptor polypeptide expressed by the cDNA insert deposited at the ATCC; and
(b) a nucleotide sequence complementary to the nucleotide sequence of (a).
21. A recombinant host cell produced by a method of claim 9 or a membrane thereof expressing a receptor polypeptide.
US10/156,136 1997-01-21 2002-05-29 Polynucleotides and polypeptides encoding receptors Abandoned US20030129696A1 (en)

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US10/156,136 US20030129696A1 (en) 1997-01-21 2002-05-29 Polynucleotides and polypeptides encoding receptors
US11/041,419 US20050176044A1 (en) 1997-01-21 2005-01-25 Polynucleotides and polypeptides encoding receptors
US11/832,019 US20080058247A1 (en) 1997-01-21 2007-08-01 Polynucleotides and Polypeptides Encoding Receptors
US12/431,986 US20090208969A1 (en) 1997-01-21 2009-04-29 Polynucleotides and Polypeptides Encoding Receptors
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US10/314,942 Expired - Fee Related US7098316B2 (en) 1997-01-21 2002-12-10 Human proteins
US11/041,419 Abandoned US20050176044A1 (en) 1997-01-21 2005-01-25 Polynucleotides and polypeptides encoding receptors
US11/459,845 Abandoned US20070004008A1 (en) 1997-01-21 2006-07-25 Human ccv polypeptides
US11/832,019 Abandoned US20080058247A1 (en) 1997-01-21 2007-08-01 Polynucleotides and Polypeptides Encoding Receptors
US12/431,986 Abandoned US20090208969A1 (en) 1997-01-21 2009-04-29 Polynucleotides and Polypeptides Encoding Receptors
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US11/459,845 Abandoned US20070004008A1 (en) 1997-01-21 2006-07-25 Human ccv polypeptides
US11/832,019 Abandoned US20080058247A1 (en) 1997-01-21 2007-08-01 Polynucleotides and Polypeptides Encoding Receptors
US12/431,986 Abandoned US20090208969A1 (en) 1997-01-21 2009-04-29 Polynucleotides and Polypeptides Encoding Receptors
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US7098316B2 (en) 2006-08-29
US6653445B1 (en) 2003-11-25
CA2278118A1 (en) 1998-07-23
US20080058247A1 (en) 2008-03-06
US20050176044A1 (en) 2005-08-11
WO1998031799A2 (en) 1998-07-23
WO1998031800A3 (en) 1998-11-26
US20090208969A1 (en) 2009-08-20
AU6030398A (en) 1998-08-07
US20070004008A1 (en) 2007-01-04
US20050119457A1 (en) 2005-06-02
AU5923398A (en) 1998-08-07
WO1998031800A2 (en) 1998-07-23
CA2278248A1 (en) 1998-07-23
EP1007663A2 (en) 2000-06-14
WO1998031799A3 (en) 1998-11-05
JP2001509029A (en) 2001-07-10

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