Modified small RNA viruses

Small RNA viruses and virus-like particles (VLPs) have altered or substituted Ig-like domains so as to modify host cell tropism. The invention also relates to the use of such small RNA viruses and VLPs in insecticidal and medicinal applications.

FIELD OF THE INVENTION
 This invention relates to small RNA viruses and virus-like particles (VLPs)
 having altered or substituted Ig-like domains so as to modify host cell
 tropism or, in other words, the specificity of host cell binding and
 infection. The invention also relates to the use of such small RNA viruses
 and VLPs in insecticidal and medicinal applications.
 BACKGROUND TO THE INVENTION
 Formally recognised small RNA viruses include members of Picornaviradae,
 the Nodaviradae and the Tetraviradae. However, there are many unrecognised
 insect viruses that also fall into this category. The Tetraviradae are a
 family of small isometric insect viruses with unenveloped, icosahedral
 capsids 35-41 nm in diameter and single-stranded positive-sense RNA
 (ss+RNA) genomes. They have not received wide attention from virologists.
 Their known host range is confirmed to only a few families of moths in a
 single insect order, the Lepidoptera (moths, butterflies), making them the
 only small RNA virus family restricted to insect hosts. While they appear
 to be effective at controlling several of their hosts that are important
 insect pests, they have been little used in this regard. The lack of a
 cell culture system or, until recently, a reliable means to obtain the
 virus from laboratory reared insects made it necessary to rely on
 sporadically available field-collected material of uncertain quality. Such
 was the difficulty that only recently did it emerge that there are
 actually two groups of tetraviruses, Nudaurelia .beta.-like viruses having
 a mono-partite genome of ca. 6 kb and Nudaurelia .omega.-like viruses
 having a bi-partite genome comprising ss RNAs of 5.3 and 2.5 kb. There are
 only two known Nudaurelia .omega.-like viruses. The complete genome of one
 member (Helicoverpa armigera stunt virus--HaSV) has been previously
 sequenced by the present inventors. The other member is Nudaurelia .omega.
 virus (N.omega.V) which has been partially sequenced.
 One of the most intriguing aspects of infections by tetraviruses is that
 they appear only to infect a single tissue type, which in the case of HaSV
 is the midgut. In a definitive experiment that highlights the specificity
 of HaSV, the present inventors showed that its midgut specificity
 prevailed even when virus was injected into the haemocoel of larvae,
 thereby exposing host non-midgut cell types not normally exposed to HaSV.
 The presence of virus was examined by using cloned cDNA probes on Northern
 blots of RNA extracted from midguts and from the rest of the carcasses
 from three groups of larvae, one injected with HaSV, one fed HaSV and
 uninfected controls. They observed a positive signal only in the midgut
 RNA of both groups of larvae treated with HaSV.
 Further evidence for specific binding of HaSV particles to a particular
 cell type comes from a rigorous examination of larvae of H. armigera
 infected with HaSV. The sensitive immuno-histochemistry technique of
 immuno-gold staining with silver enhancement was employed on a series of
 cross- and sagittal-sections of infected larvae. Sections in this series
 were also examined with electron microscopy. Staining appeared only in
 midgut cells despite close attention to tissues from the foregut, fat,
 body, salivary gland, and brain. Both types of differentiated cells of the
 midgut, the columnar and goblet cells, were found to be infected, as were
 the much smaller undifferentiated regenerative cells at the basal
 membrane. Although all these midgut cell types were found to be infected,
 analysis of virus binding to cells in sections of wax-embedded midgut
 showed that only goblet cells, and not columnar cells, were the primary
 target of HaSV binding.
 The two known .omega.-like viruses show a high degree of sequence identity.
 That is, the amino acid sequences of the coat proteins of the two
 .omega.-like viruses show an overall 67% identity (76% similarity). This
 comparison defined four domains in the coat (capsid) protein, with two
 regions of high homology (ca. 80% identity and containing extensive
 stretches of sequence reaching over 95% identity) (Hanzlik et al., 1995).
 A 49 residue amino-terminal domain shows lower homology, as does a 165
 residue sequence located towards the middle of the sequence and showing
 33% identity. Surprisingly, the high overall sequence identity is not
 reflected in a detectable serological relationship suggesting that the
 central domain of low sequence homology is exposed on the capsid surface
 as the sole immunogenic portion of the intact virion. As first suggested
 by Hanzlik et al. (1995), this region is responsible for the differing
 host specificities of the two viruses.
 The present inventors have now surprisingly realised that the central
 domain (corresponding to residues 287 to 416) of HaSV forms a structure
 belonging to the Immunoglobulin (Ig) superfamily. Other protein domains
 whose structures show an Ig-like fold include the variable (V) and
 constant (C) domains found on antibodies (e.g. the Fab fragment of IgGs),
 the HLA surface antigens of the MHC complex and cell adhesion proteins and
 receptors (e.g. the CD4 receptor recognised by HIV gp 120). Mediation of
 cell adhesion to other cells or the extracellular matrix by these proteins
 is central to development, differentiation, the immune response and tissue
 structure and healing. Many of these proteins are also used as receptors
 by viruses (Lentz (1990).
 Recent studies based on cell adhesion assays and analysis of artificial
 lipid bilayers attached to plates have elucidated the basis of cell
 adhesion promoted by binding of surface proteins. These studies are
 exemplified by work on the binding between the MHC class II and CD4
 proteins, which mediate adhesion of antigen presenting cells (APCs) and
 CD4.sup.+ T cells in the immune response. Soluble (monomeric) CD4 (sCD4)
 fails to inhibit the MHC class II-specific proliferative response of
 T-cell clones (Hussey et al., 1988) or the binding of MHC class II.sup.+ B
 cells to CD4-transfected COS-7 cells in cell adhesion assays, even at a
 concentration of 100 .mu.M (Sakihama et al., 1995a). This implies that the
 affinity of the monomeric sCD4 for the MHC class II proteins is &gt;10.sup.-4
 M. It has now been shown that oligomerization of CD4 molecules on the
 surface of CD4.sup.+ cells is required for stable binding to MHC class II
 proteins, by increasing the avidity of the interaction between these cell
 adhesion protein molecules (Sakihama et al., 1995 a,b). This
 oligomerization follows an initial interaction between 1 or 2 CD4
 molecules and MHC class II dimers. Characterization of chimaeric CD4
 molecules has shown that the membrane proximal domains 3 and/or 4 appear
 to be involved in oligomerization.
 The present inventors have now recognised that the lack of sequence
 similarity between the Ig-like domain of HaSV and the corresponding domain
 of N.omega.V may allow tetravirus particles to be used as icosahedral
 platforms capable of carrying altered Ig-like domains or substituted
 tertiary structures and thereby show modified host cell binding
 specificities.
 The Ig-like domain forms a prominent protrusion which interacts with either
 quasi 3-fold or icosahedral 3-fold related subunits on the surface of the
 tetravirus capsid. The icosahedral particles therefore present a defined
 oligomeric form of the Ig-like domain which is likely to allow stable
 binding of the complete capsid to the cell-surface receptor, analogous to
 the binding between CD4 and MHC class II oligomers. Support for this
 notion comes from the findings of Weber and Karjalainen (1993), who
 reported that a soluble, pentameric immunofusion construct of mouse CD4
 and human C.mu. could inhibit the interaction between polymer-bound mouse
 sCD4 and B cells, whereas a soluble monomeric immunofusion construct of
 mouse CD4 and mouse C.kappa. could not.
 DISCLOSURE OF THE INVENTION
 Thus, in a first aspect, the present invention provides an isolated small
 RNA virus of a kind which includes an Ig-like domain within the wild-type
 coat protein(s), wherein said Ig-like domain has been altered or
 substituted so as to modify host cell tropism.
 By "Ig-like domain" we refer to a distinct structural domain having a core
 structure with seven to nine antiparallel .beta.-strands forming a
 "barrel-like" shape however, since hydrogen bonds do not extend around the
 barrel, there is, in effect, two distinct .beta.-pleated sheets and
 physically the fold is a .beta.-sandwich (Bork et al. 1994). Some Ig-like
 domains within this definition (such as the tetravirus Ig-like domain),
 may also have additional .beta.-strands outside of the core structure.
 By "host cell tropism" we refer to the capacity of viruses (and virus-like
 particles (VLPs) as described below) to bind, enter and commence infection
 in specific populations of cells within an organism.
 Preferably, the Ig-like domain is altered such that the virus selectively
 binds and infects a predetermined cell type which is other than the virus'
 normal host cell type(s). Such "targeting" enables, for example, the
 utilisation of the small RNA virus' insecticidal properties in the control
 of pest insects outside of the normal host species range. Small RNA
 viruses according to the invention thereby offer significant potential as
 insecticidal agents.
 Whilst the invention is particularly described in relation to Tetraviradae,
 it is anticipated that Ig-like domains are also located in other small RNA
 viruses. Accordingly, the small RNA virus of the first aspect is selected
 from members of Picornaviradae, the Nodaviradae and the Tetraviradae.
 Preferably, the small RNA virus is a member of the Tetraviradae family
 such as a Nudaurelia .beta.-like virus (particularly N.beta.V). More
 preferably, the small RNA virus is a member of the genus of Nudaurelia
 .omega.-like viruses. Most preferably, the small RNA virus is selected
 from Helicoverpa armigera stunt virus (HaSV) and Nudaurelia .omega. virus
 (N.omega.V).
 The Ig-like domain of the HaSV wild-type coat protein (p71) is located at
 residues 281 to 414 of the amino acid sequence shown at FIG. 1. The
 Ig-like domain of the N.beta.V wild-type coat protein is located within
 residues 285 to 433 of the 634 amino acid sequence shown at FIG. 2. The
 Ig-like domain of the N.omega.V wild-type coat protein is located at
 residues 280 to 413 of the sequence reported by Agrawal and Johnson, 1995.
 Alterations or substitutions of the Ig-like domain may be achieved by
 replacing the wild-type coat protein gene(s) with a chimaeric gene(s)
 including nucleotide sequences encoding all or a functional portion(s) of
 Ig-like domains derived from other proteins such as those mentioned above.
 Functional portion(s) in this context refers to portion(s) of Ig-like
 domains which still permit the small RNA virus to specifically bind and
 infect one or more cell types.
 For targeting the small RNA virus to cell types of pest insects outside of
 the normal host species range, the chimaeric gene(s) may include
 nucleotide sequences encoding all or a functional portion(s) of the
 variable (V) or constant (C) domains of antibodies specific to gut cell
 types belonging to the target pest insect. Alternatively, the chimaeric
 gene(s) may include nucleotide sequences encoding all or a functional
 portion(s) of Ig-like domains derived from proteins involved in cell
 adhesion or monoclonal antibodies specific for cell surface epitopes.
 Whilst it is preferred to alter or substitute the Ig-like domain using
 nucleotide sequences encoding Ig-like domains or functional portion(s)
 thereof derived from other proteins, it is to be understood that the
 invention contemplates alteration and substitution of the Ig-like domain
 using nucleotide sequences encoding non-Ig-like tertiary structures so as
 to achieve favourable modification of host cell tropism. For example, the
 Ig-like domain may be altered by inclusion of, or substituted with, a
 peptide loop (e.g. such as those present on the coat protein of
 nodaviruses), small protein or lectin.
 Suitable alterations of the Ig-like domain might also be achieved with
 techniques such as site-directed mutagenesis of the wild-type coat protein
 gene(s).
 In a second aspect, the present invention provides a method for controlling
 the proliferation of a pest insect, comprising applying to an area
 infected with said pest insect a small RNA virus according to the first
 aspect, optionally in admixture with an agriculturally acceptable carrier.
 The coat proteins from both N.omega.V and HaSV have the ability to form
 virus like particles (VLPs) when expressed in a baculovirus expression
 system. The findings of the present inventors therefore offer the
 possibility of producing VLPs for use as specific delivery agents of, for
 example, nucleic acid molecules. These VLPs may therefore be useful as
 insecticidal agents or for use as a means of specific gene delivery for,
 for example, gene therapy. The production of VLPs from small RNA viruses
 is discussed in International Patent Application No. PCT/AU93/00411, the
 entire disclosure of which is to be regarded as incorporated herein by
 reference.
 The HaSV VLPs have properties highly similar to those of HaSV virions.
 These include resistance to proteolytic degradation, buoyancy in CsCl
 solutions, morphology and dimensions, ability to protect encapsidated RNA
 from degradation, and affinity to the H. armigera gut cell receptor for
 HaSV. The latter property was demonstrated by the observation that VLPs
 bound in an identical manner to receptors on H. armigera gut cells in wax
 cross sections of larvae. This indicates that VLPs will be able to enter
 the cells and express RNAs within them.
 Thus, in a third aspect, the present invention provides a virus-like
 particle (VLP) prepared from expression of a coat protein gene(s) derived
 from a small RNA virus of a kind which includes an Ig-like domain within
 the wild-type coat protein(s), said gene(s) having been altered such that
 the Ig-like domain of the expressed coat protein is altered or substituted
 so as to modify host cell tropism.
 Preferably, the VLP is prepared from expression of a coat protein gene(s)
 which has been altered such that the Ig-like domain of the expressed coat
 protein is altered or substituted such that the VLP selectively binds and
 infects a predetermined cell type(s) which is other than a host cell
 type(s) which the VLP, absent the alteration or substitution of the
 Ig-like domain of its coat protein(s), would bind and infect.
 Preferably, the coat protein gene(s) is derived from a member of
 Picornaviradae, the Nodaviradae and the Tetraviradae. However, preferably,
 the gene(s) is derived from a member of the Tetraviradae family such as
 Nudaurelia .beta.-like virus (particularly N.beta.V). More preferably, the
 gene(s) is derived from a member of the genus of Nudaurelia .omega.-like
 viruses. Most preferably, the gene(s) is derived from Helicoverpa armigera
 stunt virus (HaSV) or Nudaurelia .omega. virus (N.omega.V).
 The coat protein gene(s) used to express the VLP may be produced by
 replacing the wild-type coat protein gene(s) with a chimaeric gene(s) as
 described above in regard to the first aspect.
 VLPs according to the third aspect of the present invention offer
 significant potential for specifically delivering nucleic acid molecules
 to a predetermined cell type(s). For use as insecticidal agents, the
 nucleic acid may, for example, encode a toxin such as ricin, neurotoxins,
 gelonin and diptheria toxins. In medicinal applications, the nucleic acid
 molecules may, for example, encode a cytotoxin (e.g. for cancer treatment)
 or other peptide, polypeptide or protein as required (e.g. for gene
 therapy).
 Although the inventors have observed, on occasion, that VLPs from the HaSV
 coat protein will encapsidate low molecular weight RNA having no virus
 sequences, it is probably necessary that encapsidation (and replication)
 signal sequences on the virus RNA be utilised, if the VLPs of the third
 aspect are to be useful for delivering desired genes to target cells. That
 is, it is probably necessary that encapsidation (and replication) signals
 be utilised to allow production of VLPs which specifically encapsidate and
 deliver expressible RNA of exogenous origin, thereby enabling the delivery
 of desirable activities to target cells. This may be in the form of an
 mRNA to produce a functional protein when translated in the target cell or
 in the form of retroviral or retrotransposon RNA which will be
 incorporated into the target cell genome from which the product will
 eventually be expressed.
 The possibility of altering or substituting the Ig-like domain of small RNA
 virus coat proteins also offers the development of VLPs carrying antigenic
 tertiary structures. Such VLPs would offer considerable promise as
 vaccination agents.
 Thus, in a fourth aspect, the present invention provides a vaccine
 comprising a virus-like particle (VLP) prepared from expression of a coat
 protein gene(s) derived from a small RNA virus of a kind which includes an
 Ig-like domain within the wild-type coat protein(s), said gene(s) having
 been altered such that the Ig-like domain of the expressed coat protein is
 altered or substituted so that the VLP presents a surface located antigen
 to elicit an immune response in a host organism.
 The antigen may be all or an antigenic portion of a protein from, for
 example, a virus (e.g. HIV, HCV, CMV) or bacteria (e.g. Mycobacteria,
 Streptococcus, Haemophilias).
 From studies conducted on tetravirus coat proteins and VLPs, the present
 inventors have identified a unique group of six properties or
 characteristics which enable the production of the specific RNA delivery
 VLPs contemplated by the present invention. These characteristics may be
 summarised as:
 1. The ability of tetravirus coat proteins when expressed from exogenous
 expression systems to readily produce VLPs.
 2. The ability of tetravirus VLPs to readily encapsidate exogenous mRNAs
 including viral encapsidation signal sequences and encoding peptides,
 polypeptides and proteins of differing activities.
 3. The ability of tetravirus VLPs to be able to deliver exogenous mRNAs in
 such a manner that translation of encoded peptides, polypeptides or
 proteins occurs specifically in the cells to which the VLPs bind and
 infect.
 4. The provision within the tetravirus coat proteins of a distinct region
 that forms an Ig-like domain responsible for host cell tropism.
 5. The possibility of modifying or substituting the Ig-like domain on
 tetravirus coat proteins with other Ig-like domains and structures of
 exogenous origin.
 6. The possibility of producing tetravirus VLPs exhibiting low reactivity
 to the vertebrate immune system.
 These characteristics and the feasibility of producing specific RNA
 delivery VLPs is described in greater detail below with reference to the
 following, non-limiting examples and accompanying figures.

EXAMPLE 1
 VLP production from exogenous expression systems:
 The tetravirus coat proteins easily produce VLPs after being expressed by
 exogenous expression systems, and importantly, they assemble into
 RNA-containing VLPs under in vitro conditions. In vitro assembly
 facilitates inexpensive, large scale production of VLPs carrying mRNAs
 encoding a variety of desired peptides, polypeptides or proteins and
 including cytotoxins which would be expected to hamper in vivo production
 due to their toxicities towards the host. In vitro production of VLPs may
 also be of importance in medicinal applications, since it should be
 possible to readily meet the stringent requirements for elimination of
 contaminating organisms/factors.
 In vivo production of tetravirus VLPs in eukaryotic expression systems such
 as baculoviruses, yeast and plant cells is described in the abovementioned
 International Patent Specification No. PCT/AU/93/00411, and Hanzlik and
 Gordon, 1997. Briefly, the production of tetravirus VLPs in these systems
 involves the expression of the coat protein precursor gene (e.g. for HaSV;
 p71 of RNA2) with a strong promoter, then purifying the VLPs as for HaSV
 virions or by the procedure of Agrawal and Johnson (1995). To produce
 tetravirus VLPs under in vitro conditions, a procedure described by
 Yusibov et al. (1996) may be used after expression of the coat protein
 precursor in a prokaryotic host such as E. coli.
 EXAMPLE 2
 Production of HaSV VLPs encapsidating exogenous RNA:
 The VLPs produced from tetravirus coat proteins readily incorporate
 exogenous mRNAs having certain viral encapsidation signal sequences. Such
 mRNAs may encode a variety of desired peptides, polypeptides and proteins.
 This can be demonstrated by the following experiment which places the
 nonviral gene, E. coli .beta.-glucuronidase (GUS) within HaSV VLPs.
 HaSV VLPs having translatable GUS mRNA within them can be made by
 coinfecting Sf9 cells with two recombinant baculoviruses. Using the
 commercially available baculovirus vector, pFastBac of the Bac-to-Bac
 Expression System (Gibco-BRL). Baculovirus 1 was constructed by placing
 the p71 coat protein open reading frame (ORF) (see FIG. 1) behind the
 polyhedrin promoter. When Baculovirus 1 infects Sf9 cells by itself, VLPs
 are formed which selectively encapsidates the transcribed mRNAs of the
 coat protein ORF. This indicates that an encapsidation signal sequence is
 within the coat protein ORF. This information was used to construct
 Baculovirus 2 which produced an encapsidatable RNA that expressed GUS
 activity.
 Baculovirus 2 or pFBGUSp71 virus was constructed by placing the GUS ORF
 (.beta.-glucuronidase, Jefferson et al., 1986) between the coat protein
 ORF and the polyhedrin promoter so that the initiating AUG codon would
 start translation of the GUS ORF instead of the coat protein ORF. Thus,
 when transcription occurs during the baculovirus infection, mRNA is
 produced that is expressed as GUS. This mRNA also possesses the
 encapsidation signal sequences possessed by the HaSV p71 coat protein ORF
 placed behind the GUS ORF. Consequently, when Baculoviruses 1 and 2 infect
 the same cell, VLPs made from Baculovirus 1 selectively encapsidate RNAs
 with the coat protein ORF only as well as those RNAs with the GUS ORF
 followed by the coat protein ORF.
 Encapsidation of the GUS mRNA is confirmed by Northern blotting of RNA
 extracted from purified VLPs produced from Sf9 cells coinfected with both
 baculoviruses. To purify the VLPs, Sf9 cells are infected with the two
 viruses and after four days the cells are lysed with freeze/thaw and
 vortexing in Tris buffer (50 mM Tris pH 7.4) with 0.2% Nonidet P40
 detergent. After clarification at 10,000.times.g for 10 minutes, the
 supernatant of homogenate is pelleted through a 10% sucrose cushion at
 100,000.times.g for three hours. The pellet, resuspended by an overnight
 incubation, is directly layered onto a centrifuge tube having equal
 volumes of 30% and 60% CsCl in Tris buffer which is then spun at
 200,000.times.g for 12 hours. The opalescent band is then pelleted at
 100,000.times.g for three hours then resuspended in Tris buffer. When the
 extracted RNA is probed with a radioactively labelled GUS only probe, the
 RNA from the VLPs hybridises strongly to a 4.6 kb band, which is the size
 of the expected mRNA transcribed from the pFBGUSp71 virus. These GUS RNA
 containing VLPs also bind to H. armigera midgut cells in a manner highly
 similar to HaSV virions. This is seen when the particles are incubated
 with wax cross-sections of H. armigera midguts and immunologically
 detected according to the procedure of Bravo et al. (1992).
 Alternative constructions of Baculovirus 2 could have included all of the
 HaSV RNA2 (FIG. 1) placed behind the GUS ORF, or the GUS ORF placed within
 RNA2 with the initiating AUG codon located at the site of the initiating
 AUG codon of either the p17 or p71 ORFs.
 VLPs containing almost any mRNA can be made in vitro by first transcribing
 capped RNA in vitro with T7 polymerase then assembling the transcripts
 with purified coat proteins as described by Yusibov (1996).
 EXAMPLE 3
 Delivery of exogenous RNA encapsidated in HaSV VLPs:
 Tetravirus VLPs are able to deliver encapsidated mRNAs for translation
 specifically in cells to which they bind and infect. This phenomenon has
 been observed by feeding GUS mRNA containing VLPs made in accordance with
 Example 2 from HaSV p71, to neonate larvae of H. armigera.
 A 10% sucrose solution with 100 .mu.g/ml (mRNA) concentration of GUS VLPs
 were fed to neonate larvae with the droplet feeding method (Hughes and
 Wood, 1981) and then sacrificed after three hours at room temperature.
 Eleven (11) GUS VLP-fed larvae were collected and separately homogenized
 in GUS extraction buffer Jefferson et al., 1986) with 1 mM X-Gluc (50 mM
 NaHPO.sub.4, pH 7.0, 5 mM dithiothreitol, 1 mM Na.sub.2 EDTA, 0.1% triton
 X-100). A distinct blue colour indicating the presence of GUS, developed
 overnight in the extract, whilst a similar extract obtained from control
 larvae (11) fed VLPs without GUS mRNA, remained colourless. The result was
 confirmed by excising the midguts of the neonate larvae fed GUS mRNA
 containing VLPs and placing them into X-Gluc assay buffer (2 mM X-Gluc, 50
 mM NaHPO.sub.4, pH 7.0, 0.1% triton X-100). After incubation overnight, a
 blue spot occurred directly behind the stromadeal valve indicating GUS
 activity. The controls failed to show any blue colour.
 EXAMPLE 4
 Substituting the Ig-like domain of HaSV and N.omega.V VLPs:
 Tetravirus coat proteins have a distinct region in the amino acid sequence
 that forms a domain on the surface of the VLP which is responsible for
 host cell tropism. X-ray crystallography studies indicate that this domain
 has a immunoglobulin-like (Ig-like) tertiary structure (Munshi et al.,
 1996). The importance of the Ig-like domain in host cell tropism is made
 evident by the following experimentation which show that the HaSV Ig-like
 domain binds highly specifically to a factor in the midgut goblet cell
 cavity.
 H. armigera midguts were excised and embedded in wax then sectioned by
 standard procedures. HaSV virions and GUS VLPs produced according to
 Example 2 were then incubated with the sections for 30 min, washed and
 then histochemically tested for the presence of HaSV virions or VLPs
 according to method of Bravo et al. (1992). The results obtained showed
 that specific binding of HaSV VLPs occurs only to the goblet cell factor.
 No binding occurs on other tissues or cultured cells. In addition, no
 binding of HaSV VLPs occurs to other lepidopteran midguts such as
 Nudaurelia cyntheria capensis or Galleria melonella.
 Experimentation also showed that the binding is saturable. This was
 observed by a double label experiment using HaSV virions and GUS VLPs
 labeled with photo-biotin (Bresatec) in accordance with the supplier's
 instructions, and detected with avidin reagents according to standard
 procedures. Biotin labelled particles incubated with midgut wax sections
 were only detected in the absence of a 30 min preincubation with
 unlabelled HaSV VLPs.
 In further experimentation involving the wax section binding assay
 described above, it was shown that the HaSV Ig-like domain is responsible
 for binding activity. This was achieved by producing hybrid Nudaurelia
 .omega. virus (N.omega.V) VLPs having the Ig-like domain of HaSV, thereby
 conferring to the N.omega.V VLPs the identical, specific binding activity
 to H. armigera midgut goblet cells as that of HaSV virions and VLPs.
 Furthermore, the hybrid particles were able to deliver GUS mRNA having the
 N.omega.V RNA2 sequence (Agrawal and Johnson, 1992) on the transcript 3'
 to the GUS ORF. This was also shown in a complementary experiment where
 HaSV hybrid particles with the Ig-like domain of N.omega.V showed specific
 binding to Nudaurelia midguts not shown by HaSV VLPs.
 The N.omega.V hybrid particles with the HaSV Ig-like domains were made by
 placing the N.omega.V coat protein ORF (Agrawal and Johnson, 1995) into
 the baculovirus expression vector, pFastBac (Gibco-BRL) to generate
 pFBWCAP and performing the seamless cloning procedure described by Padgett
 and Sorge (1996). Primer Omega1 (ATGACTCTTCTCTGTGTGGTGGCGATCGGAGTAAG) (SEQ
 ID NO:7) and primer Omega2 (AGTACTCTTCAACTACCGCTGCTTCTAATCGCAG) (SEQ ID
 NO:8) were used to produce a 6.4 kb PCR fragment from pFBWCAP and having
 the vector containing the N-terminal and C-terminal regions of the coat
 protein ORF prior to and after the Ig-like domain (from residues M1-Q274
 and T415-stop 445). Similarly, a 428 bp fragment having residues Q277-T420
 of the HaSV coat protein was produced by PCR with Pfu polymerase from
 Primers StuntIgN (AGTACTCTTCGCAGTACGACGTCAGCGAGGCCGAC) (SEQ ID NO:9) and
 primerStuntIgC, (ATGACTCTTCGAGTCTCTAAGAGCGTGTTCCTAAA) (SEQ ID NO:10). Both
 fragments were digested with Eam 1104 I and ligated to form plasmid
 pFBWIg. This plasmid was then used to produce a recombinant baculovirus
 according to the supplier (Gibco-BRL) of the Bac-to-Bac baculovirus
 expression system. The resulting hybrid VLPs were prepared from Sf9 cells
 infected with the recombinant baculovirus by the procedure used to prepare
 HaSV VLPs in Example 2.
 EXAMPLE 5
 Modification of the Ig-like domain of HaSV VLPs:
 The tetravirus Ig-like domain can be substituted for other structures
 without interfering with particle formation.
 (i) Substitution with loop structures.
 The purpose of this experiment was to show that the region encoding the
 Ig-like domain of tetravirus coat proteins could be exchanged for a
 minimum loop structure without affecting particle formation and RNA
 encapsidation. Such loops could be used to modify the host cell tropism of
 VLPs.
 The HaSV p71 coat protein ORF was modified by removing the Ig-like domain
 between residues Q276-T416 and inserting a linker of five SGSGS residues
 (SEQ ID NO:11). This was done by the method of Imai et al. (1991) with the
 primers HR2noIgL (CTGCGGTAGGCTAGTCGGGGT) (SEQ ID NO:12) and HR2Loop
 (AGTGGAAGTGGCACTACTCGACCCTCCTCTCGTAGG), the latter having an anchor
 sequence encoding the SGSGS linker (SEQ ID NO:13). The PCR with kinased
 primers was performed on the plasmid pFBp71 which contained the p71 ORF
 and the ends of the resulting 6.8 kb fragment were ligated and transformed
 into E. coli and screened. The resulting plasmid pFBHloop was used to
 produce a recombinant baculovirus with the Bac-to-Bac system (Gibco-BRL).
 Particles were purified as for HaSV virions and showed the expected
 dimensions and morphology of 32-34 nM diameter and a smoother appearance
 than unmodified VLPs. The particles with modified p71 also encapsidated
 RNA as seen by the presence of RNA on a formaldehyde RNA gel after RNA
 extraction from the particles.
 The Hloop construct can also be made by inserting an SGSGS (SEQ ID NO:11)
 loop domain at alternative sites of the tetravirus coat protein. For
 example, an SGSGS (SEQ ID NO:11) loop can be placed with a similar
 procedure to the above HR2loop, between G281 and E414. Or alternatively as
 an addition on one of the loops of the endogenous Ig-like domain itself;
 for example D353 and E358.
 That loop structures are likely to give tetravirus VLPs predetermined host
 cell tropisms is evident in the comparison of the crystal structures of
 nodavirus and tetravirus coat proteins (Munshi et al., 1996). That is, at
 the analogous region of the Ig-like domain of the tetravirus coat protein,
 nodavirus coat protein have a pentapeptide loop with varying sequences
 (Dasgupta and Sgro, 1989). Hence replacement of the tetravirus Ig-like
 domain with the pentapeptide loop, ATTFA (SEQ ID NO:14), of the flock
 house virus (Wery et al., 1994) will likely give the resulting VLPs a
 binding and entry affinity to Drosophila cells similar to FHV. Another
 means of modifying the host cell tropism of tetravirus VLPs is to place
 the tripeptide sequence, RGD, in an accessible place on the coat protein.
 This will likely give the resulting VLPs binding affinity for RGD
 receptors of the integrin family of proteins located on many human cells
 (Pierschbacher and Ruoslahti, 1984). This can either be done with the
 nodavirus-like loop structure or by replacing an existing tripeptide
 sequence with RGD on one of the loops present on the endogenous tetravirus
 Ig-like domain.
 Loop structures with binding affinities to cells with particular cell
 surface epitopes should be readily obtained with stochastic methods. One
 such method would be based on the pSKAN procedure (MoBiTec) which provides
 a 6-8 residue loop having desired binding affinities with a phagemid
 display system (Rottgen and Collins, 1995). A second method would be based
 on the use of the tetravirus coat protein itself to form VLPs with
 variable loop regions which are then selected for desired binding
 affinities. Recovery of VLPs with a desired affinity produced from this
 second method is facilitated by the fact that the VLPs will encapsidate
 the mRNA encoding the desirable loop region. A reiterative process will
 enrich for the VLPs with the desired affinity. This may be achieved by a
 process similar to the pSKAN procedure but suitably modified to account
 for the non-replicating nature of VLPs.
 In detail, an altered loop version of the HaSV p71, pFBHLoop, may be used
 to place a hypervariable region, derived from a loop primer, in the loop
 region. The primer HR2noIgL (CTGCGGTAGGCTAGTCGGGGT) (SEQ ID NO:13) can
 then be used in conjunction with HR2LoopVar
 (NNNNNNNNNNNNNNNCTCGACCCTCCTCTCGTAGG) (SEQ ID NO:15), to PCR a 6.8 kb
 fragment from pFBp71 which is then ligated to itself to produce a series
 of plasmids with p71 having different loop regions behind the polyhedrin
 promoter. These plasmids may then be used to produce pools of colonies
 with recombinant baculoviruses produced with the Bac-to-Bac system.
 Recombinant baculoviruses would then be prepared from the pools and used
 to transfect Sf9 cells. After 6 days, the Sf9 cells would be lysed with
 freeze-thaw and sonication (0.1% Triton X-100 in Tris buffer pH 8.0) and
 the particles allowed to mature by incubation a 4.degree. C. for 1 week.
 The lysate can then be incubated with the desired ligand or surface
 epitope protein bound to magnetic beads according to the manufacturer
 (Dynal). The bound particles will be washed extensively but gently and
 directly extracted for RNA without elution. The RNA can then be used to
 perform RT-PCR with primers HR236F5 (AGAAGAAACCAACGGCGT) (SEQ ID NO:16)
 and HR2R2140 (AGGACGTTGCCTCCGACTTC) (SEQ ID NO:17) to produce a 1.7 kb
 fragment which can be digested with EcoRI and NotI enzymes then ligated to
 the larger fragment of pFBp71 resulting from digestion of the same two
 enzymes and having the rest of the HaSV p71 ORF. The resulting plasmid is
 then used to commence a reiterative second round of recombinant
 baculovirus production/transfection/particle binding/RT-PCR/plasmid
 preparation.
 At least three rounds of recombinant baculovirus
 production/transfection/particle binding/RT-PCR/plasmid preparation would
 be required to arrive at particles with loops having affinity to the
 desired surface epitope.
 (ii) Substitution with small proteins.
 The purpose of this experiment was to demonstrate that small proteins with
 less than 30 kDa molecular weight can be inserted into the Ig-like domain
 of tetravirus coat proteins so that when VLPs are made the small protein
 is displayed on the outside of the particles. This can either be used to
 modify host cell tropism or to produce vaccines to the protein. For
 example, it was demonstrated that the 27 kDa green fluorescent protein
 (GFP) (Prasher et al., 1992) could be displayed on the outside of the
 N.omega.V VLP. This was achieved by a procedure similar to that described
 in Example 4 to insert the HaSV Ig-like domain into the N.omega.V coat
 protein. The procedure utilised the primers WGFPN
 (AGTACTCTTCGCAGAGTATGAGTAAAGGAGAAGAACTT) (SEQ ID NO:18) and WGFPC
 (ATGACTCTTCGAGTACTGCCACTTCCACTTTTGTATAGTTCATCCATG CC) (SEQ ID NO:19) to
 perform PCR on gfp10 cDNA (Prasher et al., 1992) to produce a 750 bp
 fragment which, when digested with Eam 1104I, had complementary ends to
 the Eam 1104I digested 6.4 kb PCR fragment produced with .omega.1 and
 .omega.2 from pFBWCAP. When ligated together into pFBWGFP, a hybrid
 N.omega.V coat protein was formed having the primary structure: (N.omega.V
 M1-Q280)-(GFP)-(linker peptide SGSGS)-(N.omega.V T415-stop 445). This
 plasmid was used to produce a recombinant baculovirus according to the
 Bac-to-Bac system.
 The hybrid protein was expressed in a manner similar to pFBWCAP and
 fluorescing cells were evident when irradiated with UV light. Particles
 were evident inside cells when examined with transmission electron
 microscopy (TEM), although they proved to be unstable when purified.
 However, when a particle was formed with a combination of proteins
 produced from pFBW loop virus and pFBWGFP virus at a ratio of 3:1, a
 stable VLP was formed which was able to be purified. Virus pFBW loop is
 the analogous N.omega.V VLP version of Hloop having the loop structure and
 made by the same procedure and inserting the residues, SGSGS (SEQ ID
 NO:11) in place of the N.omega.V Ig-like domain. The particle had a larger
 diameter, 45 nm, and the morphology showed larger protrusions on the
 outside of the purified particles. The particles were shown to encapsidate
 RNA.
 The successful demonstration of hybrid tetravirus/GFP particles showed that
 proteins of less than 30 kDa could be displayed on the outside of the
 tetravirus particle. If such proteins possess binding affinities for cell
 surface proteins, then the tropism of the VLPs could be predetermined.
 Immunoglobulin domains or lectins are excellent examples of such proteins
 which could be inserted into the region specified as the Ig-like domain of
 tetravirus coat proteins. However, certain modifications may be necessary
 to the proteins before their insertion to the tetravirus coat protein ORF.
 This is because of the need for the N-terminus and C-terminus to be
 adjacent in the tertiary structure of the protein as this conformation is
 evident in the tertiary structure of the tetravirus Ig-like domain. It is
 this conformation which makes the Ig-like domain exchange for other
 proteins possible without extensive reconstruction that would be
 detrimental to the conformation of the tetravirus coat protein. Examples
 of proteins to be modified to make the N- and C-termini adjacent are the
 V- and C-type domains of the Immunoglobulin superfamily and Ig-like
 domains from antibodies where the N-termini are separated from the
 C-termini by nearly the length of the protein (Bork et al., 1994, Williams
 and Barclay, 1988). Examination of the three dimensional structure of
 candidate proteins for insertion into tetravirus coat proteins will show
 if modifications are necessary. An example of how to modify proteins with
 Ig-like domains for insertion into tetravirus coat proteins is provided
 below.
 (iii) Substitution with exogenous Ig-like domains.
 The use of protein members of the Immunoglobulin superfamily is
 particularly desirable for determining tropisms for tetravirus VLPs as
 many of these proteins are known to be involved in cell surface
 recognition (Williams and Barclay, 1988), and in binding events such as
 those between antibodies and their respective antigens (Rees et al.,
 1994). This makes it likely that the presence of such proteins on the
 exterior surface of the tetravirus VLPs will cause the VLPs to bind to the
 same cells that are normally bound by the proteins.
 However, most such Ig-like proteins have their N- and C-termini at the
 opposite ends of the three dimensional structure of the protein and thus
 modification of the Ig-like protein is necessary before insertion into the
 tetravirus coat protein as discussed in the previous section. Modification
 may be achieved by adding a 15-20 residue peptide linker which connects
 the last tetravirus coat protein residue before the commencement of the
 tetravirus Ig-like domain to the N-terminus of the nominated Ig-like
 domain to be inserted into the region of the tetravirus Ig-like domain. In
 such a manner the N-terminus, which would normally be at the non-proximal
 end of the Ig-like domain, is connected to the surface of the tetravirus
 capsid. The C-terminus of the nominated Ig-like domain is then connected
 to the residue terminating the tetravirus Ig-like domain by a shorter 3-5
 residue peptide linker. Lengths of the linkers need to be empirically
 determined for optimal conformation of the Ig-like domain on the surface
 of the VLP. Composition of the peptide linkers may be alternating Ser-Gly
 residues for the required length as described by Bird et al. (1988).
 Alternative linker compositions may be more optimal in some cases such as
 (Gly 4Ser) 4 (Somia et al., 1995). For example, the construction of one
 such hybrid tetravirus coat protein employing the N.omega.V coat protein
 would be (N.omega.V M1-Q280)-(linker peptide [SerGly]8)-(N-term-V-type Ig
 domain-C-term)-(linker peptide SerGlySer)-(N.omega.V T415-stop 445).
 An example of how a V-type Ig may be placed into the tetravirus coat
 protein so as to modify the tropism of the VLP to human cells having the
 low density lipoprotein receptor is based on the work of Somia et al.
 (1995). A 400 bp fragment containing the gamma Ig region of the C7
 hybridoma is produced with PCR from pBS(Gly 4Ser) 4 Somia et al. (1995)
 with the primer GlySer (GGCGGTGGCGGATCGGGCGGT) (SEQ ID NO:20) and GammaC
 GCCTTTAATTAATGAGGAGAC) (SEQ ID NO:21) and blunt end cloned to the 6.8 kb
 PCR fragment from pFBp71 with the primers HR2noIgL (CTGCGGTAGGCTAGTCGGGGT)
 (SEQ ID NO:12) and HR2LoopIg (AGTGGCACTACTCGACCCTCCTCTCGTAGG) (SEQ ID
 NO:22), the latter having an anchor sequence encoding a SGS linker. The
 resulting plasmid produces a protein having the primary structure (HaSV
 p71 M1-Q276)-(Gly 4Ser) 4-(gamma V-type Ig domain)-(SerGlySer)-(HaSV p71
 T421-N446) when used to produce a recombinant baculovirus with the
 Bac-to-Bac system. Stable VLPs encapsidating RNA and capable of binding to
 QT6 cells, should be produced when this protein is expressed (Somia et
 al., 1995). Suitable Ig-like domains with binding specificities for
 desired cell types can also be derived stochastically with phage display
 techniques (Clackson et al., 1991).
 EXAMPLE 6
 Production of HaSV VLPs with low reactivity to the vertebrate immune
 system:
 VLPs produced from tetravirus coat proteins can be made to have a low
 reactivity to the vertebrate immune system.
 The human immune system is one of the largest obstacles to therapeutics
 based on particles containing nucleic acids. This limits their use to only
 a few occasions before an immune reaction neutralises the particles before
 they enter cells. However, hybrid tetravirus VLPs may have a means to
 counter this phenomenon by being "invisible" to the immune system.
 Experiments described below show that &gt;98% of the VLPs immunogenicity to
 the rabbit and mouse immune systems resides in the tetravirus Ig-like
 domain and that the VLP's contiguous surface (ie. the surface created by
 loop-type constructs of the tetravirus coat protein) displays little, if
 any, immunogenicity in the presence of an Ig-like feature on the surface.
 This suggests that the placement of an Ig-like domain from a human source
 will not induce the human immune system conditioned to the presence of
 such proteins (i.e. similar to a blood transfusion with different human
 antibodies with human Ig-like domains).
 To determine the region of the tetravirus coat protein responsible for
 immunogenicity of the particle, the following experiment was conducted.
 Plasmid pT7T2p69 was constructed as outlined by Hanzlik et al. (1995) for
 plasmid pT7T2p71. However, instead of expressing HaSV p71 in bacteria as
 for pT7T2p71, the plasmid pT7T2p69 expressed a fusion of a part of HaSV
 p17 (Hanzlik et al., 1995) and the p71 coat protein by virtue of a
 frame-shift mutation after nucleotide C569 where an additional C was
 inserted. Thus fusion protein produced incorporated M1-P96 of p17 and
 N70-N646 of p71. The region encoding the Ig-like domain of p71 was deleted
 using the method of Imai et al. (1991) using pFBp71 and the primers
 HR2noIgR and HR2noIgL (see above for sequences). This removed residues
 Q280-T415 from the resulting protein expressed by the recombinant
 baculovirus produced from the plasmid with the Bac-to-Bac system. When
 Western blotted on two different membranes and separately probed with
 anti-p17 or anti-p71 antisera (Hanzlik et al., 1995) and detected using
 alkaline phosphatase induced luminescence on film, the signal from the
 deleted protein probed with anti-p71 was less than 2% than that of the
 non-deleted protein. Normalisation of the anti-p17 signal which accounted
 for differing amounts of antigen on the membrane was achieved with the
 signal from p17 which was unaffected by the deletion. The phenomenon of
 the Ig-like domain accounting for &gt;98% of the immunogenicity was true for
 two different rabbit and three different mouse polyclonal antiseras. This
 observation is supported by that of Hanzlik et al. (1995) who noted that
 the anti-seras against N.omega.V and HaSV did not cross react despite &gt;80%
 identity in areas of the coat protein other than the Ig-like domain which
 had &lt;35% identity.
 It will be appreciated by persons skilled in the art that numerous
 variations and/or modifications may be made to the invention as shown in
 the specific embodiments without departing from the spirit or scope of the
 invention as broadly described. The present embodiments are, therefore, to
 be considered in all respects as illustrative and not restrictive.
 References
 Agrawal, D. K. and Johnson, J. E. (1992). Virology 190, 89-97
 Agrawal, D. K. and Johnson, J. E. (1995). Virology 207, 89-97.
 Bird, R. E. and Walker, B. W. (1988) TibTech 9, 132-137.
 Bork, P., Holm, L., and Sander, C. (1994) J. Mol. Biol. 242, 309-320
 Bravo, A., Hendrick, K. Jansens, S. and Peferaen, M. (1992). J. of Invert.
 Pathol. 60, 247-253.
 Clackson, T., Hoogenboom, H. R., Griffiths, A. D. and Winter, G. (1991)
 Nature 352, 624-628
 Dasgupta, R. and Sgro, J-Y. (1989) Nuc. Acids Res. 17, 7525-7526.
 Hanzlik and Gordon, (1997) Advances in Virus Research (in press)
 Hanzlik, T. N., Dorrian, S. J., Gordon, K. H. J. and Christian, P. D.
 (1993). J. Gen. Virol. 74, 1105-1110.
 Hanzlik, T. N., Dorrian, S. J., Johnson, K. N., Brooks, E. M. and Gordon,
 K. H. J. (1995). J. Gen. Virol. 76, 799-811.
 Hughes, P. R. and Wood, H. A. (1981) J. Invert. Pathol. 37, 154-159.
 Hussey, R. E., Richardson, N. E., Kowalski, M., Brown, N. R., Chang, H.-C.,
 Siliciano, R. F., Dorfman, T., Walker, B., Sodroski, J. & Reinherz, E. L.
 (1988). Nature 331, 78-81.
 Imai, Y., Matsushima, Y. Sugimura, T., and Terada, M. (1991) Nuc. Acids
 Res. 19, 2785.
 Jefferson, R. A., Burgess, S. M. and Hirsh, D. (1986) Proc. Natl. Acad. Sci
 USA 86, 8447-8451.
 Lentz (1990) J. Gen. Virol. 71, 751-766.
 Munshi, S., Liljas, L., Cavarelli, J., Bomu, W., McKinney, B., Reddy, V.
 and Johnson, J. E. (1996). J. Mol. Biol. 261, 1-10.
 Padgett, K. A. and Sorge, J. A. (1996) Gene 168, 31-35.
 Prasher, D. C., Eckenrode, V. K. Ward, W. W., Prendergast, F. G. and
 Cormier, M. J. (1992) Gene 141, 229-233
 Pierschbacher, M. D. and Ruoslahti, E. (1984) Nature 309, 30-33.
 Rees, A. R., Staunton, D., Webster, D. M., Searle, S. J., Henry, A. H.,
 Pedersen, J. T. (1994) TibTech 12, 199-206.
 Rottgen, P., and Collins, J. (1995) Gene 164, 243-250.
 Sakihama, T., Smolyar, A. & Reinherz, E. L. (1995a). Proc. Natl. Acad. Sci.
 USA 92, 6444-6448.
 Sakihama, T., Smolyar, A. & Reinherz, E. L. (1995b). Immunology Today 16,
 581-587.
 Somia, N. V., Zoppe, M., Verma, I. M. (1995) Proc. Natl. Acad. Sci. USA 92,
 7570-7574
 Weber, S. & Karjalainen, K. (1993). Int. Immunol. 5, 695-698.
 Williams, A. F. and Barclay, A. N. (1988) Ann. Rev. Immunol. 6,381-405
 Yusibov, V. Kumar, A. North, A. Johnson, J. E. and Loesch-Fries, S. (1996)
 J. Gen Virol. 77, 567-573.
 SEQUENCE LISTING
 (1) GENERAL INFORMATION:
 (iii) NUMBER OF SEQUENCES: 22
 (2) INFORMATION FOR SEQ ID NO: 1:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 2478 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: double
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: cDNA
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1
 GTTTTTCTTT CTTTACCAAG TGTGGTAAAA TTTAAACAAA GAAGAAAACC AGGACCGTAA 60
 CCCGGCCCTT ACACACCTCG AGTCCGTGAC CACCGGATTA TACGTCGCCC ACCACACGGC 120
 GCCTTTTCCG ACCACTCTCG AGAGTCGTTG GGAGTTTCGT CCGTGACCAC CCGGTTGGCA 180
 GTCGACAGAC GCTTCCGGAC CACTAGAACC TCCTCGAGCG ACGCACACAC AGCACACACA 240
 CCGCCTTAGC TGCACCTACG GCAGCGTTGA TAGCGCGGAT TTATGAGCGA GCACACCATC 300
 GCCCACTCCA TCACATTACC ACCCGGTTAC ACCCTTGCCC TAATACCCCC TGAACCTGAA 360
 GCAGGATGGG AGATGCTGGA GTGGCGTCAC AGCGACCTCA CAACCGTCGC GGAACCCGTA 420
 ACGTTCGGGT CAGCGCCAAC ACCGTCACCG TCAATGGTAG AAGAAACCAA CGGCGTCGGA 480
 CCGGAAGGCA AGTTTCTCCC CCTGACAATT TCACCGCTGC TGCACAAGAC CTCGCGCAAA 540
 GCCTTGACGC CAACACCGTC ACTTTCCCCG CTAACATCTC TAGCATGCCC GAATTCCGGA 600
 ATTGGGCCAA GGGAAAGATC GACCTCGACT CCGATTCCAT CGGCTGGTAC TTCAAGTACC 660
 TTGACCCAGC GGGTGCTACA GAGTCTGCGC GCGCCGTCGG CGAGTACTCG AAGATCCCTG 720
 ACGGCCTCGT CAAGTTCTCC GTCGACGCAG AGATAAGAGA GATCTATAAC GAGGAGTGCC 780
 CCGTCGTCAC TGACGTGTCC GTCCCCCTCG ACGGCCGCCA GTGGAGCCTC TCGATTTTCT 840
 CCTTTCCGAT GTTCAGAACC GCCTACGTCG CCGTAGCGAA CGTCGAGAAC AAGGAGATGT 900
 CGCTCGACGT TGTCAACGAC CTCATCGAGT GGCTCAACAA TCTCGCCGAC TGGCGTTATG 960
 TCGTTGACTC TGAACAGTGG ATTAACTTCA CCAATGACAC CACGTACTAC GTCCGCATCC 1020
 GCGTTCTACG TCCAACCTAC GACGTTCCAG ACCCCACAGA GGGCCTTGTT CGCACAGTCT 1080
 CAGACTACCG CCTCACTTAT AAGGCGATAA CATGTGAAGC CAACATGCCA ACACTCGTCG 1140
 ACCAAGGCTT TTGGATCGGC GGCCAGTACG CTCTCACCCC GACTAGCCTA CCGCAGTACG 1200
 ACGTCAGCGA GGCCTACGCT CTGCACACTT TGACCTTCGC CAGACCATCC AGCGCCGCTG 1260
 CACTCGCGTT TGTGTGGGCA GGTTTGCCAC AGGGTGGCAC TGCGCCTGCA GGCACTCCAG 1320
 CCTGGGAGCA GGCATCCTCG GGTGGCTACC TCACCTGGCG CCACAACGGT ACTACTTTCC 1380
 CAGCTGGCTC CGTTAGCTAC GTTCTCCCTG AGGGTTTCGC CCTTGAGCGC TACGACCCGA 1440
 ACGACGGCTC TTGGACCGAC TTCGCTTCCG CAGGAGACAC CGTCACTTTC CGGCAGGTCG 1500
 CCGTCGACGA GGTCGTTGTG ACCAACAACC CCGCCGGCGG CGGCAGCGCC CCCACCTTCA 1560
 CCGTGAGAGT GCCCCCTTCA AACGCTTACA CCAACACCGT GTTTAGGAAC ACGCTCTTAG 1620
 AGACTCGACC CTCCTCTCGT AGGCTCGAAC TCCCTATGCC ACCTGCTGAC TTTGGACAGA 1680
 CGGTCGCCAA CAACCCGAAG ATCGAGCAGT CGCTTCTTAA AGAAACACTT GGCTGCTATT 1740
 TGGTCCACTC CAAAATGCGA AACCCCGTTT TCCAGCTCAC GCCAGCCAGC TCCTTTGGCG 1800
 CCGTTTCCTT CAACAATCCG GGTTATGAGC GCACACGCGA CCTCCCGGAC TACACTGGCA 1860
 TCCGTGACTC ATTCGACCAG AACATGTCCA CCGCTGTGGC CCACTTCCGC TCACTCTCCC 1920
 ACTCCTGCAG TATCGTCACT AAGACCTACC AGGGTTGGGA AGGCGTCACG AACGTCAACA 1980
 CGCCTTTCGG CCAATTCGCG CACGCGGGCC TCCTCAAGAA TGAGGAGATC CTCTGCCTCG 2040
 CCGACGACCT GGCCACCCGT CTCACAGGTG TCTACCCCGC CACTGACAAC TTCGCGGCCG 2100
 CCGTTTCTGC CTTCGCCGCG AACATGCTGT CCTCCGTGCT GAAGTCGGAG GCAACGTCCT 2160
 CCATCATCAA GTCCGTTGGC GAGACTGCCG TCGGCGCGGC TCAGTCCGGC CTCGCGAAGC 2220
 TACCCGGACT GCTAATGAGT GTACCAGGGA AGATTGCCGC GCGTGTCCGC GCGCGCCGAG 2280
 CGCGCCGCCG CGCCGCTCGT GCCAATTAGT TTGCTCGCTC CTGTTTCGCC GTTTCGTAAA 2340
 ACGGCGTGGT CCCGCACATT ACGCGTACCC TAAAGACTCT GGTGAGTCCC CGTCGTTACA 2400
 CGACGGGTCT GCCGCGGTTC GATTCCATTC CCAAGCGGCA AGAAGGACGT AGTTAGCTCT 2460
 GCGTCCCTCG GGATACCA 2478
 (2) INFORMATION FOR SEQ ID NO: 2:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 157 amino acids
 (B) TYPE: amino acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: protein
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2
 Met Ser Glu His Thr Ile Ala His Ser Ile Thr Leu Pro Pro Gly Tyr
 1 5 10 15
 Thr Leu Ala Leu Ile Pro Pro Glu Pro Glu Ala Gly Trp Glu Met Leu
 20 25 30
 Glu Trp Arg His Ser Asp Leu Thr Thr Val Ala Glu Pro Val Thr Phe
 35 40 45
 Gly Ser Ala Pro Thr Pro Ser Pro Ser Met Val Glu Glu Thr Asn Gly
 50 55 60
 Val Gly Pro Glu Gly Lys Phe Leu Pro Leu Thr Ile Ser Pro Leu Leu
 65 70 75 80
 His Lys Thr Ser Arg Lys Ala Leu Thr Pro Thr Pro Ser Leu Ser Pro
 85 90 95
 Leu Thr Ser Leu Ala Cys Pro Asn Ser Gly Ile Gly Pro Arg Glu Arg
 100 105 110
 Ser Thr Ser Thr Pro Ile Pro Ser Ala Gly Thr Ser Ser Thr Leu Thr
 115 120 125
 Gln Arg Val Leu Gln Ser Leu Arg Ala Pro Ser Ala Ser Thr Arg Arg
 130 135 140
 Ser Leu Thr Ala Ser Ser Ser Ser Pro Ser Thr Gln Arg
 145 150 155
 (2) INFORMATION FOR SEQ ID NO: 3:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 647 amino acids
 (B) TYPE: amino acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: protein
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3
 Met Gly Asp Ala Gly Val Ala Ser Gln Arg Pro His Asn Arg Arg Gly
 1 5 10 15
 Thr Arg Asn Val Arg Val Ser Ala Asn Thr Val Thr Val Asn Gly Arg
 20 25 30
 Arg Asn Gln Arg Arg Arg Thr Gly Arg Gln Val Ser Pro Pro Asp Asn
 35 40 45
 Phe Thr Ala Ala Ala Gln Asp Leu Ala Gln Ser Leu Asp Ala Asn Thr
 50 55 60
 Val Thr Phe Pro Ala Asn Ile Ser Ser Met Pro Glu Phe Arg Asn Trp
 65 70 75 80
 Ala Lys Gly Lys Ile Asp Leu Asp Ser Asp Ser Ile Gly Trp Tyr Phe
 85 90 95
 Lys Tyr Leu Asp Pro Ala Gly Ala Thr Glu Ser Ala Arg Ala Val Gly
 100 105 110
 Glu Tyr Ser Lys Ile Pro Asp Gly Leu Val Lys Phe Ser Val Asp Ala
 115 120 125
 Glu Ile Arg Glu Ile Tyr Asn Glu Glu Cys Pro Val Val Thr Asp Val
 130 135 140
 Ser Val Pro Leu Asp Gly Arg Gln Trp Ser Leu Ser Ile Phe Ser Phe
 145 150 155 160
 Pro Met Phe Arg Thr Ala Tyr Val Ala Val Ala Asn Val Glu Asn Lys
 165 170 175
 Glu Met Ser Leu Asp Val Val Asn Asp Leu Ile Glu Trp Leu Asn Asn
 180 185 190
 Leu Ala Asp Trp Arg Tyr Val Val Asp Ser Glu Gln Trp Ile Asn Phe
 195 200 205
 Thr Asn Asp Thr Thr Tyr Tyr Val Arg Ile Arg Val Leu Arg Pro Thr
 210 215 220
 Tyr Asp Val Pro Asp Pro Thr Glu Gly Leu Val Arg Thr Val Ser Asp
 225 230 235 240
 Tyr Arg Leu Thr Tyr Lys Ala Ile Thr Cys Glu Ala Asn Met Pro Thr
 245 250 255
 Leu Val Asp Gln Gly Phe Trp Ile Gly Gly Gln Tyr Ala Leu Thr Pro
 260 265 270
 Thr Ser Leu Pro Gln Tyr Asp Val Ser Glu Ala Tyr Ala Leu His Thr
 275 280 285
 Leu Thr Phe Ala Arg Pro Ser Ser Ala Ala Ala Leu Ala Phe Val Trp
 290 295 300
 Ala Gly Leu Pro Gln Gly Gly Thr Ala Pro Ala Gly Thr Pro Ala Trp
 305 310 315 320
 Glu Gln Ala Ser Ser Gly Gly Tyr Leu Thr Trp Arg His Asn Gly Thr
 325 330 335
 Thr Phe Pro Ala Gly Ser Val Ser Tyr Val Leu Pro Glu Gly Phe Ala
 340 345 350
 Leu Glu Arg Tyr Asp Pro Asn Asp Gly Ser Trp Thr Asp Phe Ala Ser
 355 360 365
 Ala Gly Asp Thr Val Thr Phe Arg Gln Val Ala Val Asp Glu Val Val
 370 375 380
 Val Thr Asn Asn Pro Ala Gly Gly Gly Ser Ala Pro Thr Phe Thr Val
 385 390 395 400
 Arg Val Pro Pro Ser Asn Ala Tyr Thr Asn Thr Val Phe Arg Asn Thr
 405 410 415
 Leu Leu Glu Thr Arg Pro Ser Ser Arg Arg Leu Glu Leu Pro Met Pro
 420 425 430
 Pro Ala Asp Phe Gly Gln Thr Val Ala Asn Asn Pro Lys Ile Glu Gln
 435 440 445
 Ser Leu Leu Lys Glu Thr Leu Gly Cys Tyr Leu Val His Ser Lys Met
 450 455 460
 Arg Asn Pro Val Phe Gln Leu Thr Pro Ala Ser Ser Phe Gly Ala Val
 465 470 475 480
 Ser Phe Asn Asn Pro Gly Tyr Glu Arg Thr Arg Asp Leu Pro Asp Tyr
 485 490 495
 Thr Gly Ile Arg Asp Ser Phe Asp Gln Asn Met Ser Thr Ala Val Ala
 500 505 510
 His Phe Arg Ser Leu Ser His Ser Cys Ser Ile Val Thr Lys Thr Tyr
 515 520 525
 Gln Gly Trp Glu Gly Val Thr Asn Val Asn Thr Pro Phe Gly Gln Phe
 530 535 540
 Ala His Ala Gly Leu Leu Lys Asn Glu Glu Ile Leu Cys Leu Ala Asp
 545 550 555 560
 Asp Leu Ala Thr Arg Leu Thr Gly Val Tyr Pro Ala Thr Asp Asn Phe
 565 570 575
 Ala Ala Ala Val Ser Ala Phe Ala Ala Asn Met Leu Ser Ser Val Leu
 580 585 590
 Lys Ser Glu Ala Thr Ser Ser Ile Ile Lys Ser Val Gly Glu Thr Ala
 595 600 605
 Val Gly Ala Ala Gln Ser Gly Leu Ala Lys Leu Pro Gly Leu Leu Met
 610 615 620
 Ser Val Pro Gly Lys Ile Ala Ala Arg Val Arg Ala Arg Arg Ala Arg
 625 630 635 640
 Arg Arg Ala Ala Arg Ala Asn
 645
 (2) INFORMATION FOR SEQ ID NO: 4:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 6534 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: double
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: cDNA
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4
 CCTTGATATC GCTTGTGTTA GGCACAAGTG ATGGAAGACG CAAGCAAGCA GCTCCGCGTC 60
 CTGGATGCCC AGGAGCGCGC GAAGGCCGCC TTCCAACTCG ACTTCATAGC CTCTGTCGAG 120
 ACTTTGGAAG ACGCTCAGGA GAAGTACGAG GGCATGATGT TTCGCAGTGG CACGAAACTG 180
 CCATCAACCC ATATTAAGTT GGCAATCGAT CTGAGAGTTG CGGAGAAAGA TCTACGCCGG 240
 CACGTTAAGA ATGTACCGAC AGTGCTGGAA ATTGGACCCA GTGTTGAGAG CGTGCGTTAC 300
 GCTGTGCAGA CTCGAGACAA GGAGAGAGTC CATGGCTGCA CCTTCTCCGA CGCGCGTGAT 360
 AACCTCCGCC ACAATAAGAT CGGTTATGAA GCCCATTACG ACAGAAAGAT TGGACCTGAC 420
 GCCGCCCTTC TGGCCGCTGG TATCCCAACT GACACCTTCT GTGTCGACGG CTTCTCCAAT 480
 GCGAGTACCA ATCCCCCCTC GCCATTGCCT GCCACTCACT TTACCCCGAT GGGGAAAGTA 540
 ATAGTATTAT GGACGTGGCT AAAGGCATGG CTCTCCACGG CACCCACGTG ATATATGCGT 600
 GGATGCATCT GCCCGTGGAA CTGCTAACGC TCACCGATGC AGACAATATT TTTGAAGGGT 660
 TGACCCAGCG GGTGCTACAG AGTCTGCGCG CGCCGTCGGC GAGTACTCGA AGATCCCTGT 720
 TCTCCGGTTA TAACGATTTT GGTTCGGCCT ATGTGCACGA TGCCCACCAT TGGGCTGGTT 780
 GGCTTAAGCA TCGGGGAGTA GACACCCCGT ATGGCTTCTC CATATTGATC GACATACAAC 840
 AGAGGTTCGG TATGCACACG AAATTAAAGA TCACCCGTGG GCACAGCAGT GGCAGTATCA 900
 CCACCGTGTT CCCGTTGTCG AAATTGGGCT TGATCTGGGT GCCGAACATA GTCAAAATAA 960
 TGTACCCTAA AGCCAAACAC GAGCCGGAGT ACATCGTCAC GGATAAGAAG AAGTATGAAG 1020
 GCGTTTGCGT GTACGTCGGA ACGAGGGTGC AAAGTTCCGG CAAGTCTATT ACGCTCGCTG 1080
 AGATTGTTCA ATACATCCGA ACAAGATTAA CACGCATCAT TCTGAATGGC ACTGTCCACG 1140
 AGAAAACGTG GACCATAGCA GAGCAAGACA TTGAGCGACT TGCCGTTAGC ATTATGTTCC 1200
 GCAAGAATGT GGAACGCGCT GTGTCTGAAA AGGCACTGAT GAGAGCGCAG AAGAAGTGCA 1260
 AGAGCGCTGA AAAACAAGCG CTGCTGCCAG TTTGGATGCG GAGGATCGCC AATTGGTTCC 1320
 AAGACAAATT TCAAATCGAC GAGGAGGTCG TACGCAAGCG CTACCTTGAG TGTCTCAAGG 1380
 CGCAACCCTG GATCCACGCC GATAAAGTGG TGAACTGCGA GACCAAGCGC TATAACCCTA 1440
 CTGTCGCCGA GGTGGGTCCT AAGAATCATT TGCTCGCCAC TACCGGATTG CGCGAGCTCC 1500
 AAAGGGAAAT ACCCAGTGCT AACGAACCGC AAGATAGAGG AGCCAAGGCA TGGCACTCCG 1560
 CTCACGCCGA TCTCGACATT TACGCCGAGG GACTCCGACT CGACTCCGCT AAAGAGGCAA 1620
 GACTCGACCC TCCTCTCGTA GGCTCGAACT CCCTATGCCA CCTGCTGACT TTGGACAGAA 1680
 CCAAGTGCGA GGGGTGCAAC AACATTGAAA TCGAGTACTG GACCGGACCC CCCGGTTCCG 1740
 GGAAATCCAG GGCCGCTAAG CCGAGATTTG CAGATTTGCA GGGGGGCGTG TTGTACTGCG 1800
 CCCCTACGCG CACGCTGCGC GACGCCCTCG ACGAAAGCGT CGTGCACCCT TCCCGTGTTT 1860
 GCACTTACCA CAACGCACTG CATGTCGCTG CCAAAGAGTC TGGCAATAGG CCTTTTGACG 1920
 TTATCGTCAT CGATGAAGCG GAGACGACGC CGGCTTGCTA CGTAGGTACG ATGCATCATG 1980
 CATCGCCTAG TAGTAGGATC GTCTGTCTGG GCGATCCGCA CCAGATCGGT TACATCGACT 2040
 TTTCGGATCG AAAAGACGAT TTGAAACCTT TCAGTATCAT AGCAGCCGAA TGTCGCACTC 2100
 GTAGGTTTAA CACCACTTAT AGGTGCCCAC AAGACGTTTT AAACTTGCCC ATATTCAAAA 2160
 CTCTATACCC GGACGCGATA TCGTTCAGCA AACAATTGAC TAGCATCCGT TACCTCACAC 2220
 GGGCAAGATC AGTTACCCGA ACACGCCACG CTCAGACCCT GACGCAGGAC CAAAAGCCAC 2280
 ATTCGGAACC GCCAGTGACC GCGCATGAGC CGCAGGCACG ACGTACGGAC GTTATAGTGC 2340
 ATTACGCCGG CACTTTACCC GAAAGGGCAC TGTTAGAGAA GGTGCGGCAT ATAAACGTCG 2400
 CGTTGACTCG GCACACAAAC GCCCTATATA TCAGGGACGA AAGTGAAAAA GGAGAGTTGG 2460
 TACCTTCATT AATGACACCG CCAAGCTGGA GCACTTATCG GTGCACCCCC GTTGACAAGC 2520
 AAATGGTACC GGATCCGGTT GCAGTGGAGC GAGAGAACGG ATCGTCTGGT CCGTGTGACT 2580
 CCCACCATAT CGGCGCGATT ACTATATTGC AAGAGCTCGG CAAATTAACG GATACGAAAG 2640
 GCGTACGAGT ATTTGAATCC GAAGCCGTCC CAACCGCTCA CCGGCGCGTA GTGCTTGACG 2700
 GCAACCTCGA TTCAGGGCCC GATCGTTACC CGATGTATCA GTTCACTAAC CTCCGCGGGA 2760
 CCAAATACAC GAATATCAAG GACAACCAAC AAGCGTTGCA TACGCTCGTC GGCCGGTATG 2820
 CACGCAAGAT AAACAGCTCG AGCCGAGAGA CGCCGAGTTT GACGTTAAGA GAATCACAGC 2880
 CAGCTCAAGA ATGGATTCCT TTTAGACACG CAGAGCCCGA GCAAGTCGAC AGTTGCTTTG 2940
 CGACGCCATG CAAAAGATGC GAACGCGGCC ATGGCGTCGA TGACATCGAG GACTTCTGGT 3000
 CGAACGAAGG CCAAAGAATT TCTTACCACC TTAAGGGCCA GCAAAAAGTC ATGGACCCCA 3060
 CCAAACTGAA ACTTGGACAA GGTATCTCCG CGCATGAAAA ATGCGCTAAC ATTGCCTCAG 3120
 CGCGTGGGTG AGGATTATCC AAGATCAGAT GAGCACGTCA GAGAAGTTCA TCTTCGCGAA 3180
 TGGGCAGTCA GACCGCGATA CCATGTCTAT CATTGAGGCA CGCCTGCAGG AGAAGGCGCG 3240
 GGAATTCAAA TCTATAGATA TCAAGGAGTT CGATACGGTA CATAACTGGG TCAGTATTCT 3300
 TGTCTTCTCG TGGCGTTGCG ACCGTGGGTG CCCAGAGCAC CTTATCGAGT ATTTCGAGAA 3360
 ACGCTCGAAA AGCCGGACGC TCTCAAGCCG CATAGGAAGC GTCGACGTTA GCTTCATGCT 3420
 CGATTCTGGC GCTGTCTGGA CCATTGCCAG AAACACCTTA TTTGCCTCGG GTCTTATGCT 3480
 CGCCCTTTTC GTCGGCGTCG ATTTCATCGC GGCGAAAGGC GATGATGTCT TCCTCGCAGG 3540
 GAATAATTTG TACTTGGACG CAGAACGGCT TCGCATGGGA TCTTACTTAG CCGCAAACAA 3600
 CTTGAAGATC GAGAAGACGG CGGTCGTGAG CTTTATAGGG TTTATCGTTT CCCAAGCCGC 3660
 CGTCACAGCT GATGTCGTGC GTCTAGCCAC CCGGACTTAC GGTCGAAGTT ATAAAAACGT 3720
 GATGATCTAG CGAGTATAAG ATAGCTATCG CTGACCACTG CAGTTGTTTA GATCACCGAG 3780
 AACTCGTCTC ATGACCGCGA TCAACTGCGC CACCCTTTAC GGCACCTCGA AAGGTGCATC 3840
 AATTATCTGA TGGACGCGTT GGACGATTCG GACACACTAA AATGAGCGAC CTACACTTGG 3900
 ATCCCGGTTT TGTCATGCGG GTCACCCCCA TGAAGGTGGA CGAGCGGGTT TATTCCGGAC 3960
 AAGATGGATG CCAACGTGCA GATAAGACCC GCGAGAAACA ACCCGAACCC AGGGCAACCA 4020
 GGGCCGCGCA AACAACAACA ACAACGTCGA CGCAGGAGGC GGGGTCTAAA ACTTCCCCCC 4080
 GTAGTCGCAC CGATTACCAG CCCGCCAGAT GGCCGAACCC CGAACCACGC GAACACCCGG 4140
 GTCAACCGCG GTCGGACACG CGTGAGGGGG CTAAGGCAAG CGATGATGGA GAGTCCCATG 4200
 GCAGCGACAT CAAGGCATGG ATTCACGACT ATCTAGACCC GGACGGAGAA TACAAGACGA 4260
 GCCTGGACGA CGGGAAAATT CCCGACGGCG CGATACCTCA GTCAACATGC GGTCAATTTC 4320
 GAGGGACCGT GGGCGCCAGA TACCCGGGAC TGAATTCTAC GACGCTACCG CTGGATGGCG 4380
 GGACCTGGCC TCTACTAGTG ATGCATCTCC CGTTCTTCAG GCATCCGTTG TTGTTCATCA 4440
 CCACCACCAG CAACACGGAA GTCGAAGTGA CGAACGCCGA TCTGGATGCG TTCGCGAACG 4500
 ATTGGAACAA CAGGACGGAC TGGACCGAAG CGACGTACCC AAGTTGGGCG CAAGTCGGGA 4560
 ACGTGTTTTA CATGGTCGTC CCGACCGAAG CGCTGACGGA CGTACCACCC CCGACTCAAC 4620
 TGGGTGTATC AGGGTTACTC GAGAGTTACC GTCTGACATC GAGCGGCGTC ACAGCGTACT 4680
 TCAACGCACC CACTCTCGTG AATCAGGGAG TGGCGGTGAT CGCGCAGTTC CAACCGGACA 4740
 AAGAACACCA GAAGGAGAAC CCGGACATAG TAGCCGGGAC CACCCAAACG GGCGGAACGT 4800
 TACAGCTCGG CGGTTCAGGG CCGAACTACA CATTGACGAT GACGATCGGG GACCAGGTCG 4860
 AGTTCGGGGG CGCAGCAATC CCGCTACCCA CGGTGTCGAT GGGGCCGATG CCGGAGTCGG 4920
 GGCAGCTGGT GTTCCAGACT GCGAACCTGA CATTCGACGT CGGAAACACA ATCACCATCA 4980
 CGACCACGCT GCCACCAGGG TCGGTGACGG GAATGTGGCA ATTCACAGCC AGCAACGGGA 5040
 CGGACACCGT GACCGTGGAC GCGGGAGCGA CTGTACGCGT TCGGAGCGAA TTTGGACGCC 5100
 TCGGAACTGA ATCTGCAGGA CATCAACTCA ATCAAGATTC CACCAACGAC ATGAACCCAA 5160
 ATGATGCAGG CAACGCCAAG ACCATTCAGT TCCAACTAAC GAAACGAGGG CATTATATGC 5220
 CTGAGGCGTC AATCCGTGTT CGAAATGACA ATGCGACGTC TTATGGACCG GTCGATGAAG 5280
 ACACCGAGGA CAACTGTGGT AGATTACACC GGGCAATTGG TGCACTCCAA GGATACCATC 5340
 GACAGCAACT TCGCGATAGG TTGCCGTCGA TGACCGGTAT GTCTACATCA ACCGTACCCT 5400
 ACTTGCAAGG TGTTCCGACG CTTCGAAGCG ATACCGGCGG AGGGGAGCCT TGGGGCCCCT 5460
 TCGCTAGTGC GACACCTCCG AAGGACGACG TGGCGCTAAC AGTGGCTCGA ACTTGGACCG 5520
 ATCTGCACCC ATTCGCATAC CCGGAACGAT ACAACGGATT CGGGGCCCTA TTCGCGATGG 5580
 TGGCCAAGAC CATAGCCCAG ATACCTCGCT ATGTGCGATC AGCAGCCGGA GTGGCGAATG 5640
 CGGTGACGGA CTGCATAGAG AGCGCGACCG AGAGTGTAGC CTCGAATTCC ACCTCGGAGA 5700
 GGCGGCAACG AAGAGCGAGA CGTGTTGGCG GAATCGCTCG AGGAGCCCGC AATCTTGTGG 5760
 GCCGCATAGG GAACCTTAGC TTGTAGGTTC ATTGCGACAT GGGATGTTCT TCAGTCAGCA 5820
 GCTCTTCGGT TTCATCTCCA CTGACGACCC TCTGCACGTA TTTTCCCATC ATCGTGGTGC 5880
 TGATCATCAT TTGCGGTCTG GTTTGGCTCG CTTCCTATTG TTTTCATGGC AGATCAACTC 5940
 GACCCAATCG AAATCTTCAT CGAATTCCTC GGATTTCGAA AGATTTCCGG AGCCATTCGC 6000
 TGCTTCCAGT GTAAGCAAGT CTTGGGACCT GCAGGACCCG TGGATTCCCA CCTCACTGAT 6060
 TGTCAGTGGA AGGCCGCGGT GTTAAATCTT ATTAACAATC AGCTTTACGA CGTCGATATC 6120
 GATGAGACGA ATCCGTTTCT TTACGGACCT CACCGCGACT GAGATGTGGA AGACCACATT 6180
 GTTCCTTCAC ACATGCCCAG AGTGCGGTTA TTCCACCAGG GACACAGAAA CTACGAGATC 6240
 GTGTCCCCGA GATTGCCAAG ACGGCAATCT TATGCACGCA TCTTCGGTCG GCTATATTTG 6300
 TCACAAATGC CGGTTAGAAG CAAACACATT TTACCACGGT TTATGCTCTC AGTGTCGCGA 6360
 CCGTGATAAT AAAAAACGAC GCTGAAGAGA GGACTCACAA CTACCTCGAT CTCGTTTATC 6420
 GGACGAGTGA TACAATTGAC CCAGGGTCAT CCTGCAAAAC ACGCAGGTTT CCGATAGTGG 6480
 TGCAAATCCA CCCGCCAGTC GTCGGTGGTC CCTTGCGGGA CCTATACGGT ACCA 6534
 (2) INFORMATION FOR SEQ ID NO: 5:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 1233 amino acids
 (B) TYPE: amino acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: protein
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5
 Met Glu Asp Ala Ser Lys Gln Leu Arg Val Leu Asp Ala Gln Glu Arg
 1 5 10 15
 Ala Lys Ala Ala Phe Gln Leu Asp Phe Ile Ala Ser Val Glu Thr Leu
 20 25 30
 Glu Asp Ala Gln Glu Lys Tyr Glu Gly Met Met Phe Arg Ser Gly Thr
 35 40 45
 Lys Leu Pro Ser Thr His Ile Lys Leu Ala Ile Asp Leu Arg Val Ala
 50 55 60
 Glu Lys Asp Leu Arg Arg His Val Lys Asn Val Pro Thr Val Leu Glu
 65 70 75 80
 Ile Gly Pro Ser Val Glu Ser Val Arg Tyr Ala Val Gln Thr Arg Asp
 85 90 95
 Lys Glu Arg Val His Gly Cys Thr Phe Ser Asp Ala Arg Asp Asn Leu
 100 105 110
 Arg His Asn Lys Ile Gly Tyr Glu Ala His Tyr Asp Arg Lys Ile Gly
 115 120 125
 Pro Asp Ala Ala Leu Leu Ala Ala Gly Ile Pro Thr Asp Thr Phe Cys
 130 135 140
 Val Asp Gly Phe Ser Asn Cys Glu Tyr Gln Ser Pro Leu Ala Ile Ala
 145 150 155 160
 Cys His Ser Leu Tyr Pro Asp Gly Glu Ser Asn Ser Ile Met Asp Val
 165 170 175
 Ala Lys Gly Met Ala Leu His Gly Thr His Val Ile Tyr Ala Trp Met
 180 185 190
 His Leu Pro Val Glu Leu Leu Thr Leu Thr Asp Ala Asp Asn Ile Phe
 195 200 205
 Glu Gly Tyr Ser Ile Arg Phe Glu Glu Thr Gly Ala Leu Pro Cys Thr
 210 215 220
 Lys Arg Arg Lys Ala Ile Phe Ser Gly Tyr Asn Asp Phe Gly Ser Ala
 225 230 235 240
 Tyr Val His Asp Ala His His Trp Ala Gly Trp Leu Lys His Arg Gly
 245 250 255
 Val Asp Thr Pro Tyr Gly Phe Ser Ile Leu Ile Asp Ile Gln Gln Arg
 260 265 270
 Phe Gly Met His Thr Lys Leu Lys Ile Thr Arg Gly His Ser Ser Gly
 275 280 285
 Ser Ile Thr Thr Val Phe Pro Leu Ser Lys Leu Gly Leu Ile Trp Val
 290 295 300
 Pro Asn Ile Val Lys Ile Met Tyr Pro Lys Ala Lys His Glu Pro Glu
 305 310 315 320
 Tyr Ile Val Thr Asp Lys Lys Lys Tyr Glu Gly Val Cys Val Tyr Val
 325 330 335
 Gly Thr Arg Val Gln Ser Ser Gly Lys Ser Ile Thr Leu Ala Glu Ile
 340 345 350
 Val Gln Tyr Ile Arg Thr Arg Leu Thr Arg Ile Ile Leu Asn Gly Thr
 355 360 365
 Val His Glu Lys Thr Trp Thr Ile Ala Glu Gln Asp Ile Glu Arg Leu
 370 375 380
 Ala Val Ser Ile Met Phe Arg Lys Asn Val Glu Arg Ala Val Ser Glu
 385 390 395 400
 Lys Ala Leu Met Arg Ala Gln Lys Lys Cys Lys Ser Ala Glu Lys Gln
 405 410 415
 Ala Leu Leu Pro Val Trp Met Arg Arg Ile Ala Asn Trp Phe Gln Asp
 420 425 430
 Lys Phe Gln Ile Asp Glu Glu Val Val Arg Lys Arg Tyr Leu Glu Cys
 435 440 445
 Leu Lys Ala Gln Pro Trp Ile His Ala Asp Lys Val Val Asn Cys Glu
 450 455 460
 Thr Lys Arg Tyr Asn Pro Thr Val Ala Glu Val Gly Pro Lys Asn His
 465 470 475 480
 Leu Leu Ala Thr Thr Gly Leu Arg Glu Leu Gln Arg Glu Ile Pro Ser
 485 490 495
 Ala Asn Glu Pro Gln Asp Arg Gly Ala Lys Ala Trp His Ser Ala His
 500 505 510
 Ala Asp Leu Asp Ile Tyr Ala Glu Gly Leu Arg Leu Asp Ser Ala Lys
 515 520 525
 Glu Ala Ala Ala Gly Lys Gln Ser Leu Ala Ile Thr Leu Gln Gln Ala
 530 535 540
 Phe Gln Val Leu Gly Lys Thr Lys Cys Glu Gly Cys Asn Asn Ile Glu
 545 550 555 560
 Ile Glu Tyr Trp Thr Gly Pro Pro Gly Ser Gly Lys Ser Arg Ala Ala
 565 570 575
 Lys Pro Arg Phe Ala Asp Leu Gln Gly Gly Val Leu Tyr Cys Ala Pro
 580 585 590
 Thr Arg Thr Leu Arg Asp Ala Leu Asp Glu Ser Val Val His Pro Ser
 595 600 605
 Arg Val Cys Thr Tyr His Asn Ala Leu His Val Ala Ala Lys Glu Ser
 610 615 620
 Gly Asn Arg Pro Phe Asp Val Ile Val Ile Asp Glu Ala Glu Thr Thr
 625 630 635 640
 Pro Ala Cys Tyr Val Gly Thr Met His His Ala Ser Pro Ser Ser Arg
 645 650 655
 Ile Val Cys Leu Gly Asp Pro His Gln Ile Gly Tyr Ile Asp Phe Ser
 660 665 670
 Asp Arg Lys Asp Asp Leu Lys Pro Phe Ser Ile Ile Ala Ala Glu Cys
 675 680 685
 Arg Thr Arg Arg Phe Asn Thr Thr Tyr Arg Cys Pro Gln Asp Val Leu
 690 695 700
 Asn Leu Pro Ile Phe Lys Thr Leu Tyr Pro Asp Ala Ile Ser Phe Ser
 705 710 715 720
 Lys Gln Leu Thr Ser Ile Arg Tyr Leu Thr Arg Ala Arg Ser Val Thr
 725 730 735
 Arg Thr Arg His Ala Gln Thr Leu Thr Gln Asp Gln Lys Pro His Ser
 740 745 750
 Glu Pro Pro Val Thr Ala His Glu Pro Gln Ala Arg Arg Thr Asp Val
 755 760 765
 Ile Val His Tyr Ala Gly Thr Leu Pro Glu Arg Ala Leu Leu Glu Lys
 770 775 780
 Val Arg His Ile Asn Val Ala Leu Thr Arg His Thr Asn Ala Leu Tyr
 785 790 795 800
 Ile Arg Asp Glu Ser Glu Lys Gly Glu Leu Val Pro Ser Leu Met Thr
 805 810 815
 Pro Pro Ser Trp Ser Thr Tyr Arg Cys Thr Pro Val Asp Lys Gln Met
 820 825 830
 Val Pro Asp Pro Val Ala Val Glu Arg Glu Asn Gly Ser Ser Gly Pro
 835 840 845
 Cys Asp Ser His His Ile Gly Ala Ile Thr Ile Leu Gln Glu Leu Gly
 850 855 860
 Lys Leu Thr Asp Thr Lys Gly Val Arg Val Phe Glu Ser Glu Ala Val
 865 870 875 880
 Pro Thr Ala His Arg Arg Val Val Leu Asp Gly Asn Leu Asp Ser Gly
 885 890 895
 Pro Asp Arg Tyr Pro Met Tyr Gln Phe Thr Asn Leu Arg Gly Thr Lys
 900 905 910
 Tyr Thr Asn Ile Lys Asp Asn Gln Gln Ala Leu His Thr Leu Val Gly
 915 920 925
 Arg Tyr Ala Arg Lys Ile Asn Ser Ser Ser Arg Glu Thr Pro Ser Leu
 930 935 940
 Thr Leu Arg Glu Ser Gln Pro Ala Gln Glu Trp Ile Pro Phe Arg His
 945 950 955 960
 Ala Glu Pro Glu Gln Val Asp Ser Cys Phe Ala Thr Pro Cys Lys Arg
 965 970 975
 Cys Glu Arg Gly His Gly Val Asp Asp Ile Glu Asp Phe Trp Ser Asn
 980 985 990
 Glu Gly Gln Arg Ile Ser Tyr His Leu Lys Gly Gln Gln Lys Val Met
 995 1000 1005
 Asp Pro Thr Lys Leu Lys Leu Gly Gln Gly Ile Ser Ala His Glu Lys
 1010 1015 1020
 Cys Ala Asn Ile Ala Leu Ser Ala Trp Val Arg Ile Ile Gln Asp Gln
 1025 1030 1035 1040
 Met Ser Thr Ser Glu Lys Phe Ile Phe Ala Asn Gly Gln Ser Asp Arg
 1045 1050 1055
 Asp Thr Met Ser Ile Ile Glu Ala Arg Leu Gln Glu Lys Ala Arg Glu
 1060 1065 1070
 Phe Lys Ser Ile Asp Ile Lys Glu Phe Asp Thr Val His Asn Trp Val
 1075 1080 1085
 Ser Ile Leu Val Phe Ser Trp Arg Cys Asp Arg Gly Cys Pro Glu His
 1090 1095 1100
 Leu Ile Glu Tyr Phe Glu Lys Arg Ser Lys Ser Arg Thr Leu Ser Ser
 1105 1110 1115 1120
 Arg Ile Gly Ser Val Asp Val Ser Phe Met Leu Asp Ser Gly Ala Val
 1125 1130 1135
 Trp Thr Ile Ala Arg Asn Thr Leu Phe Ala Ser Gly Leu Met Leu Ala
 1140 1145 1150
 Leu Phe Val Gly Val Asp Phe Ile Ala Ala Lys Gly Asp Asp Val Phe
 1155 1160 1165
 Leu Ala Gly Asn Asn Leu Tyr Leu Asp Ala Glu Arg Leu Arg Met Gly
 1170 1175 1180
 Ser Tyr Leu Ala Ala Asn Asn Leu Lys Ile Glu Lys Thr Ala Val Val
 1185 1190 1195 1200
 Ser Phe Ile Gly Phe Ile Val Ser Gln Ala Ala Val Thr Ala Asp Val
 1205 1210 1215
 Val Arg Leu Ala Thr Arg Thr Tyr Gly Arg Ser Tyr Lys Asn Val Met
 1220 1225 1230
 Ile
 (2) INFORMATION FOR SEQ ID NO: 6:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 634 amino acids
 (B) TYPE: amino acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: protein
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6
 Met Ser Asp Leu His Leu Asp Pro Gly Phe Val Met Arg Val Thr Pro
 1 5 10 15
 Met Lys Val Asp Glu Arg Val Tyr Ser Gly Gln Asp Gly Cys Gln Arg
 20 25 30
 Ala Asp Lys Thr Arg Glu Lys Gln Pro Glu Pro Arg Ala Thr Arg Ala
 35 40 45
 Ala Gln Thr Thr Thr Thr Thr Ser Thr Gln Glu Ala Gly Ser Lys Thr
 50 55 60
 Ser Pro Arg Ser Arg Thr Asp Tyr Gln Pro Ala Arg Trp Pro Asn Pro
 65 70 75 80
 Glu Pro Arg Glu His Pro Gly Gln Pro Arg Ser Asp Thr Arg Glu Gly
 85 90 95
 Ala Lys Ala Ser Asp Asp Gly Glu Ser His Gly Ser Asp Ile Lys Ala
 100 105 110
 Trp Ile His Asp Tyr Leu Asp Pro Asp Gly Glu Tyr Lys Thr Ser Leu
 115 120 125
 Asp Asp Gly Lys Ile Pro Asp Gly Ala Ile Pro Gln Ser Thr Cys Gly
 130 135 140
 Gln Phe Arg Gly Thr Val Gly Ala Arg Tyr Pro Gly Leu Asn Ser Thr
 145 150 155 160
 Thr Leu Pro Leu Asp Gly Gly Thr Trp Pro Leu Leu Val Met His Leu
 165 170 175
 Pro Phe Phe Arg His Pro Leu Leu Phe Ile Thr Thr Thr Ser Asn Thr
 180 185 190
 Glu Val Glu Val Thr Asn Ala Asp Leu Asp Ala Phe Ala Asn Asp Trp
 195 200 205
 Asn Asn Arg Thr Asp Trp Thr Glu Ala Thr Tyr Pro Ser Trp Ala Gln
 210 215 220
 Val Gly Asn Val Phe Tyr Met Val Val Pro Thr Glu Ala Leu Thr Asp
 225 230 235 240
 Val Pro Pro Pro Thr Gln Leu Gly Val Ser Gly Leu Leu Glu Ser Tyr
 245 250 255
 Arg Leu Thr Ser Ser Gly Val Thr Ala Tyr Phe Asn Ala Pro Thr Leu
 260 265 270
 Val Asn Gln Gly Val Ala Val Ile Ala Gln Phe Gln Pro Asp Lys Glu
 275 280 285
 His Gln Lys Glu Asn Pro Asp Ile Val Ala Gly Thr Thr Gln Thr Gly
 290 295 300
 Gly Thr Leu Gln Leu Gly Gly Ser Gly Pro Asn Tyr Thr Leu Thr Met
 305 310 315 320
 Thr Ile Gly Asp Gln Val Glu Phe Gly Gly Ala Ala Ile Pro Leu Pro
 325 330 335
 Thr Val Ser Met Gly Pro Met Pro Glu Ser Gly Gln Leu Val Phe Gln
 340 345 350
 Thr Ala Asn Leu Thr Phe Asp Val Gly Asn Thr Ile Thr Ile Thr Thr
 355 360 365
 Thr Leu Pro Pro Gly Ser Val Thr Gly Met Trp Gln Phe Thr Ala Ser
 370 375 380
 Asn Gly Thr Asp Thr Val Thr Val Asp Ala Gly Ala Thr Val Arg Val
 385 390 395 400
 Arg Ser Glu Phe Gly Arg Leu Gly Thr Glu Ser Ala Gly His Gln Leu
 405 410 415
 Asn Gln Asp Ser Thr Asn Asp Met Asn Pro Asn Asp Ala Gly Asn Ala
 420 425 430
 Lys Thr Ile Gln Phe Gln Leu Thr Lys Arg Gly His Tyr Met Pro Glu
 435 440 445
 Ala Ser Ile Arg Val Arg Asn Asp Asn Ala Thr Ser Tyr Gly Pro Val
 450 455 460
 Asp Glu Asp Thr Glu Asp Asn Cys Gly Arg Leu His Arg Ala Ile Gly
 465 470 475 480
 Ala Leu Gln Gly Tyr His Arg Gln Gln Leu Arg Asp Arg Leu Pro Ser
 485 490 495
 Met Thr Gly Met Ser Thr Ser Thr Val Pro Tyr Leu Gln Gly Val Pro
 500 505 510
 Thr Leu Arg Ser Asp Thr Gly Gly Gly Glu Pro Trp Gly Pro Phe Ala
 515 520 525
 Ser Ala Thr Pro Pro Lys Asp Asp Val Ala Leu Thr Val Ala Arg Thr
 530 535 540
 Trp Thr Asp Leu His Pro Phe Ala Tyr Pro Glu Arg Tyr Asn Gly Phe
 545 550 555 560
 Gly Ala Leu Phe Ala Met Val Ala Lys Thr Ile Ala Gln Ile Pro Arg
 565 570 575
 Tyr Val Arg Ser Ala Ala Gly Val Ala Asn Ala Val Thr Asp Cys Ile
 580 585 590
 Glu Ser Ala Thr Glu Ser Val Ala Ser Asn Ser Thr Ser Glu Arg Arg
 595 600 605
 Gln Arg Arg Ala Arg Arg Val Gly Gly Ile Ala Arg Gly Ala Arg Asn
 610 615 620
 Leu Val Gly Arg Ile Gly Asn Leu Ser Leu
 625 630
 (2) INFORMATION FOR SEQ ID NO: 7:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 35 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: DNA (genomic)
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:7
 ATGACTCTTC TCTGTGTGGT GGCGATCGGA GTAAG 35
 (2) INFORMATION FOR SEQ ID NO: 8:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 34 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: DNA (genomic)
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:8
 AGTACTCTTC AACTACCGCT GCTTCTAATC GCAG 34
 (2) INFORMATION FOR SEQ ID NO: 9:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 35 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: DNA (genomic)
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:9
 AGTACTCTTC GCAGTACGAC GTCAGCGAGG CCGAC 35
 (2) INFORMATION FOR SEQ ID NO: 10:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 35 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: DNA (genomic)
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:10
 ATGACTCTTC GAGTCTCTAA GAGCGTGTTC CTAAA 35
 (2) INFORMATION FOR SEQ ID NO: 11:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 5 amino acids
 (B) TYPE: amino acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: peptide
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:11
 Ser Gly Ser Gly Ser
 1 5
 (2) INFORMATION FOR SEQ ID NO: 12:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 21 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: DNA (genomic)
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:12
 CTGCGGTAGG CTAGTCGGGG T 21
 (2) INFORMATION FOR SEQ ID NO: 13:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 36 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: DNA (genomic)
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:13
 AGTGGAAGTG GCACTACTCG ACCCTCCTCT CGTAGG 36
 (2) INFORMATION FOR SEQ ID NO: 14:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 5 amino acids
 (B) TYPE: amino acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: peptide
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:14
 Ala Thr Thr Phe Ala
 1 5
 (2) INFORMATION FOR SEQ ID NO: 15:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 21 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: DNA (genomic)
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:15
 ACTCGACCCT CCTCTCGTAG G 21
 (2) INFORMATION FOR SEQ ID NO: 16:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 18 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: DNA (genomic)
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:16
 AGAAGAAACC AACGGCGT 18
 (2) INFORMATION FOR SEQ ID NO: 17:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 20 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: DNA (genomic)
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:17
 AGGACGTTGC CTCCGACTTC 20
 (2) INFORMATION FOR SEQ ID NO: 18:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 38 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: DNA (genomic)
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:18
 AGTACTCTTC GCAGAGTATG AGTAAAGGAG AAGAACTT 38
 (2) INFORMATION FOR SEQ ID NO: 19:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 50 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: DNA (genomic)
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:19
 ATGACTCTTC GAGTACTGCC ACTTCCACTT TTGTATAGTT CATCCATGCC 50
 (2) INFORMATION FOR SEQ ID NO: 20:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 21 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: DNA (genomic)
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:20
 GGCGGTGGCG GATCGGGCGG T 21
 (2) INFORMATION FOR SEQ ID NO: 21:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 21 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: DNA (genomic)
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:21
 GCCTTTAATT AATGAGGAGA C 21
 (2) INFORMATION FOR SEQ ID NO: 22:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 30 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: DNA (genomic)
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:22
 AGTGGCACTA CTCGACCCTC CTCTCGTAGG 30