CA2268036A1 - Compounds and methods for diagnosis of tuberculosis - Google Patents

Abstract

Compounds and methods for diagnosing tuberculosis are disclosed. The compounds provided include polypeptides that contain at least one antigenic portion of one or more M. tuberculosis proteins, and DNA sequences encoding such polypeptides. Diagnostic kits containing such polypeptides or DNA sequences and a suitable detection reagent may be used for the detection of M.
tuberculosis infection in patients and biological samples. Antibodies directed against such polypeptides are also provided.

Description

wo gyms rc~rms~nszi4 COMPOUNDS AND METHODS FOR DIAGNOSIS OF TUBERCULOSIS
' TECHNICAL FIELD
The present invention relates generally to the detection of Mycobacterium tuberculosis infection. The invention is more particularly related to polypeptides comprising a Mycobacterium tuberculosis antigen, or a portion or other variant thereof, and the use of such polypeptides for the serodiagnosis of Mycobacterium tuberculosis infection.
BACKGROUND OF THE INVENTION
Tuberculosis is a chronic, infectious disease, that is generally caused by infection with Mycobacterium tuberculosis. It is a major disease in developing countries, as well as an increasing problem in developed areas of the world, with about 8 million new cases and 3 million deaths each year. Although the infection may be asymptomatic for a considerable period of time, the disease is most commonly manifested as an acute inflammation of the lungs, resulting in fever and a nonproductive cough. If left untreated, serious complications and death typically result.
Although tuberculosis can generally be controlled using extended antibiotic therapy, such treatment is not sufficient to prevent the spread of the disease. Infected individuals may be asymptomatic, but contagious, for some time. In addition, although compliance with the treatment regimen is critical, patient behavior is difficult to monitor.
Some patients do not complete the course of treatment, which can lead to ineffective treatment and the development of drug resistance.
Inhibiting the spread of tuberculosis will require effective vaccination and accurate, early diagnosis of the disease. Currently, vaccination with live bacteria is the most efficient method for inducing protective immunity. The most common Mycobacterium for this purpose is Bacillus Calmette-Guerin (BCG), an avirulent strain of Mycobacterium bovis.
However, the safety and efficacy of BCG is a source of controversy and some countries, such as the United States, do not vaccinate the general public. Diagnosis is commonly achieved using a skin test, which involves intradermal exposure to tuberculin PPD
(protein-purified derivative). Antigen-specific T cell responses result in measurable incubation at the injection site by 48-72 hours after injection, which indicates exposure to Mycobacterial antigens.
Sensitivity and specificity have, however, been a problem with this test, and individuals vaccinated with BCG cannot be distinguished from infected individuals.
While macrophages have been shown to act as the principal effectors of M. tuberculosis immunity, T cells are the predominant inducers of such immunity. The essential role of T cells in protection against M. tuberculosis infection is illustrated by the frequent occurrence of M. tuberculosis in AIDS patients, due to the depletion of CD4 T cells associated with human immunodeficiency virus (HIV) infection. Mycobacterium-reactive CD4 T cells have been shown to be potent producers of gamma-interferon (IFN-y), which, in turn, has been shown to trigger the anti-mycobacterial effects of macrophages in mice. While the role of IFN-y in humans is less clear, studies have shown that 1,25-dihydroxy-vitamin D3, either alone or in combination with IFN-y or tumor necrosis factor-alpha, activates human macrophages to inhibit M. tuberculosis infection. Furthermore, it is known that IFN-y stimulates human macrophages to make 1,25-dihydroxy-vitamin D3. Similarly, IL-12 has been shown to play a role in stimulating resistance to M. tuberculosis infection. For a review of the immunology of M. tuberculosis infection see Chan and Kaufmann, in Tuberculosis:
Pathogenesis, Protection and Control, Bloom (ed.), ASM Press, Washington, DC, 1994.
Accordingly, there is a need in the art for improved diagnostic methods for detecting tuberculosis. The present invention fulfills this need and further provides other related advantages.
SUMMARY OF THE INVENTION
Briefly stated, the present invention provides compositions and methods for diagnosing tuberculosis. In one aspect, polypeptides are provided comprising an antigenic portion of a soluble M. tuberculosis antigen, or a variant of such an antigen that differs only in conservative substitutions and/or modifications. In one embodiment of this aspect, the soluble antigen has one of the following N-terminal sequences:
(a) Asp-Pro-Val-Asp-Ala-Val-Ile-Asn-Thr-Thr-Cys-Asn-Tyr-Gly-Gln- , Val-Val-Ala-Ala-Leu (SEQ ID NO: 115);

WO 98/16645 PCT/US97/1$214 (b) Ala-Val-Glu-Ser-Gly-Met-Leu-Ala-Leu-Gly-Thr-Pro-Ala-Pro-Ser (SEQ ID NO: 116);
(c) Ala-Ala-Met-Lys-Pro-Arg-Thr-Gly-Asp-Gly-Pro-Leu-Glu-Ala-Ala-Lys-Glu-Gly-Arg (SEQ ID NO: 117);
(d) Tyr-Tyr-Trp-Cys-Pro-Gly-Gln-Pro-Phe-Asp-Pro-Ala-Trp-Gly-Pro (SEQ ID NO: 118);
(e) Asp-Ile-Gly-Ser-Glu-Ser-Thr-Glu-Asp-Gln-Gln-Xaa-Ala-Val (SEQ ID
NO: 119);
(fj Ala-Glu-Glu-Ser-Ile-Ser-Thr-Xaa-Glu-Xaa-Ile-Val-Pro (SEQ ID
NO: 120);
(g) Asp-Pro-Glu-Pro-Ala-Pro-Pro-Val-Pro-Thr-Thr-Ala-Ala-Ser-Pro-Pro-Ser (SEQ ID NO: 121 );
(h) Ala-Pro-Lys-Thr-Tyr-Xaa-Glu-Glu-Leu-Lys-Gly-Thr-Asp-Thr-Gly (SEQ ID NO: 122);
(i) Asp-Pro-Ala-Ser-Ala-Pro-Asp-Val-Pro-Thr-Ala-Ala-Gln-Leu-Thr-Ser-Leu-Leu-Asn-Ser-Leu-Ala-Asp-Pro-Asn-Val-Ser-Phe-Ala-Asn (SEQ
ID NO: 123);
(j) Xaa-Asp-Ser-Glu-Lys-Ser-Ala-Thr-Ile-Lys-Val-Thr-Asp-Ala-Ser;
(SEQ ID NO: 129) (k) Ala-Gly-Asp-Thr-Xaa-Ile-Tyr-Ile-Val-Gly-Asn-Leu-Thr-Ala-Asp;
(SEQ ID NO: 130) or (I) Ala-Pro-Glu-Ser-Gly-Ala-Gly-Leu-Gly-Gly-Thr-Val-Gln-Ala-Gly;
(SEQ ID NO: 131) wherein Xaa may be any amino acid.
In a related aspect, polypeptides are provided comprising an immunogenic portion of an M. tuberculosis antigen, or a variant of such an antigen that differs only in conservative substitutions and/or modifications, the antigen having one of the following N-terminal sequences:

(m) Xaa-Tyr-Ile-Ala-Tyr-Xaa-Thr-Thr-Ala-Gly-Ile-Val-Pro-Gly-Lys-Ile-Asn-Val-His-Leu-Val; (SEQ ID NO: 132) or (n) Asp-Pro-Pro-Asp-Pro-His-Gln-Xaa-Asp-Met-Thr-Lys-Gly-Tyr-Tyr-Pro-Gly-Gly-Arg-Arg-Xaa-Phe; (SEQ ID NO: 124) wherein Xaa may be any amino acid.
In another embodiment, the soluble M. tuberculosis antigen comprises an amino acid sequence encoded by a DNA sequence selected from the group consisting of the sequences recited in SEQ ID NOS: 1, 2, 4-10, 13-25, 52, 94 and 96, the complements of said sequences, and DNA sequences that hybridize to a sequence recited in SEQ ID
NOS: 1, 2, 4-10, 13-25, 52, 94 and 96 or a complement thereof under moderately stringent conditions.
In a related aspect, the polypeptides comprise an antigenic portion of a M. tuberculosis antigen, or a variant of such an antigen that differs only in conservative substitutions and/or modifications, wherein the antigen comprises an amino acid sequence encoded by a DNA sequence selected from the group consisting of the sequences recited in SEQ ID NOS: 26-51, 133, 134, 158-178 and 196, the complements of said sequences, and DNA sequences that hybridize to a sequence recited in SEQ ID NOS: 26-51, 133, 134, 158-178 and 196 or a complement thereof under moderately stringent conditions.
In related aspects, DNA sequences encoding the above polypeptides, recombinant expression vectors comprising these DNA sequences and host cells transformed or transfected with such expression vectors are also provided.
In another aspect, the present invention provides fusion proteins comprising a first and a second inventive polypeptide or, alternatively, an inventive polypeptide and a known M. tuberculosis antigen.
In further aspects of the subject invention, methods and diagnostic kits are provided for detecting tuberculosis in a patient. The methods comprise: (a) contacting a biological sample with at least one of the above polypeptides; and (b) detecting in the sample the presence of antibodies that bind to the polypeptide or polypeptides, thereby detecting M. tuberculosis infection in the biological sample. Suitable biological samples include whole blood, sputum, serum, plasma, saliva, cerebrospinal fluid and urine. The diagnostic kits comprise one or more of the above polypeptides in combination with a detection reagent.

The present invention also provides methods for detecting M. tuberculosis infection comprising: (a) obtaining a biological sample from a patient; (b) contacting the " sample with at least one oligonucleotide primer in a polymerase chain reaction, the oligonucleotide primer being specific for a DNA sequence encoding the above polypeptides;
5 and (c) detecting in the sample a DNA sequence that amplifies in the presence of the first and second oligonucleotide primers. In one embodiment, the oligonucleotide primer comprises at least about 10 contiguous nucleotides of such a DNA sequence.
In a further aspect, the present invention provides a method for detecting M. tuberculosis infection in a patient comprising: (a) obtaining a biological sample from the patient; (b) contacting the sample with an oligonucleotide probe specific for a DNA sequence encoding the above polypeptides; and (c) detecting in the sample a DNA
sequence that hybridizes to the oligonucleotide probe. In one embodiment, the oligonucleotide probe comprises at least about 15 contiguous nucleotides of such a DNA sequence.
In yet another aspect, the present invention provides antibodies, both polyclonal and monoclonal, that bind to the polypeptides described above, as well as methods for their use in the detection of M. tuberculosis infection.
These and other aspects of the present invention will become apparent upon reference to the following detailed description and attached drawings. All references disclosed herein are hereby incorporated by reference in their entirety as if each was incorporated individually.
BRIEF DESCRIPTION OF THE DRAWINGS AND SEQUENCE IDENTIFIERS
Figure 1 A and B illustrate the stimulation of proliferation and interferon-y production in T cells derived from a first and a second M. tuberculosis-immune donor, respectively, by the 14 Kd, 20 Kd and 26 Kd antigens described in Example 1.
Figures 2A-D illustrate the reactivity of antisera raised against secretory M.
tuberculosis proteins, the known M. tuberculosis antigen 85b and the inventive antigens Tb38-1 and TbH-9, respectively, with M. tuberculosis lysate (lane 2), M.
tuberculosis secretory proteins (lane 3), recombinant Tb38-1 (lane 4), recombinant TbH-9 (lane 5) and - 30 recombinant 85b (lane 5).

Figure 3A illustrates the stimulation of proliferation in a TbH-9-specific T
cell clone by secretory M. tuberculosis proteins, recombinant TbH-9 and a control antigen, TbRal 1.
Figure 3B illustrates the stimulation of interferon-y production in a TbH-9-specific T cell clone by secretory M. tuberculosis proteins, PPD and recombinant TbH-9.
Figure 4 illustrates the reactivity of two representative polypeptides with sera from M. tuberculosis-infected and uninfected individuals, as compared to the reactivity of bacterial lysate.
Figure 5 shows the reactivity of four representative polypeptides with sera from M. tuberculosis-infected and uninfected individuals, as compared to the reactivity of the 38 kD antigen.
Figure 6 shows the reactivity of recombinant 38 kD and TbRal 1 antigens with sera from M. tuberculosis patients, PPD positive donors and normal donors.
Figure 7 shows the reactivity of the antigen TbRa2A with 38 kD negative sera.
Figure 8 shows the reactivity of the antigen of SEQ ID NO: 60 with sera from M. tuberculosis patients and normal donors.
Figure 9 illustrates the reactivity of the recombinant antigen TbH-29 (SEQ ID
NO: 137) with sera from M. tuberculosis patients, PPD positive donors and normal donors as determined by indirect ELISA.
Figure 10 illustrates the reactivity of the recombinant antigen TbH-33 (SEQ
ID NO: 140) with sera from M. tuberculosis patients and from normal donors, and with a pool of sera from M. tuberculosis patients, as determined both by direct and indirect ELISA
Figure 11 illustrates the reactivity of increasing concentrations of the recombinant antigen TbH-33 (SEQ ID NO: 140) with sera from M. tuberculosis patients and from normal donors as determined by ELISA.
SEQ. ID NO. 1 is the DNA sequence of TbRal .
SEQ. ID NO. 2 is the DNA sequence of TbRalO.
SEQ. ID NO. 3 is the DNA sequence of TbRal 1.
SEQ. ID NO. 4 is the DNA sequence of TbRal2. -WO 98I1b645 PCT/US97/18214 SEQ. ID NO. 5 is the DNA sequence of TbRal3.
SEQ. ID NO. 6 is the DNA sequence of TbRal6.
' SEQ. ID NO. 7 is the DNA sequence of TbRa17.
SEQ. ID NO. 8 is the DNA sequence of TbRal8.
SEQ. ID NO. 9 is the DNA sequence of TbRal9.
SEQ. ID NO. 10 is the DNA sequence of TbRa24.
SEQ. ID NO. 11 is the DNA sequence of TbRa26.
SEQ. ID NO. 12 is the DNA sequence of TbRa28.
SEQ. ID NO. 13 is the DNA sequence of TbRa29.
SEQ. ID NO. 14 is the DNA sequence of TbRa2A.
SEQ. ID NO. 15 is the DNA sequence of TbRa3.
SEQ. ID NO. 16 is the DNA sequence of TbRa32.
SEQ. ID NO. 17 is the DNA sequence of TbRa35.
SEQ. ID NO. 18 is the DNA sequence of TbRa36.
SEQ. ID NO. 19 is the DNA sequence of TbRa4.
SEQ. ID NO. 20 is the DNA sequence of TbRa9.
SEQ. ID NO. 21 is the DNA sequence of TbRaB.
SEQ. ID NO. 22 is the DNA sequence of TbRaC.
SEQ. ID NO. 23 is the DNA sequence of TbRaD.
SEQ. ID NO. 24 is the DNA sequence of YYWCPG.
SEQ. ID NO. 25 is the DNA sequence of AAMK.
SEQ. ID NO. 26 is the DNA sequence of TbL-23.
SEQ. ID NO. 27 is the DNA sequence of TbL-24.
SEQ. ID NO. 28 is the DNA sequence of TbL-25.
SEQ. ID NO. 29 is the DNA sequence of TbL-28.
SEQ. ID NO. 30 is the DNA sequence of TbL-29.
SEQ. ID NO. 31 is the DNA sequence of TbH-5.
SEQ. ID NO. 32 is the DNA sequence of TbH-8.
SEQ. ID NO. 33 is the DNA sequence of TbH-9.
SEQ. ID NO. 34 is the DNA sequence of TbM-1.

SEQ. ID NO. 35 is the DNA sequence of TbM-3.
SEQ. ID NO. 36 is the DNA sequence of TbM-6.
SEQ. ID NO. 37 is the DNA sequence of TbM-7. ' SEQ. ID NO. 38 is the DNA sequence of TbM-9.
SEQ. ID NO. 39 is the DNA sequence of TbM-12.
SEQ. ID NO. 40 is the DNA sequence of TbM-13.
SEQ. ID NO. 41 is the DNA sequence of TbM-14.
SEQ. ID NO. 42 is the DNA sequence of TbM-15.
SEQ. ID NO. 43 is the DNA sequence of TbH-4.
SEQ. ID NO. 44 is the DNA sequence of TbH-4-FWD.
SEQ. ID NO. 45 is the DNA sequence of TbH-12.
SEQ. ID NO. 46 is the DNA sequence of Tb38-1.
SEQ. ID NO. 47 is the DNA sequence of Tb38-4.
SEQ. ID NO. 48 is the DNA sequence of TbL-17.
SEQ. ID NO. 49 is the DNA sequence of TbL-20.
SEQ. ID NO. 50 is the DNA sequence of TbL-21.
SEQ. ID NO. 51 is the DNA sequence of TbH-16.
SEQ. ID NO. 52 is the DNA sequence of DPEP.
SEQ. ID NO. 53 is the deduced amino acid sequence of DPEP.
SEQ. ID NO. 54 is the protein sequence of DPV N-terminal Antigen.
SEQ. ID NO. 55 is the protein sequence of AVGS N-terminal Antigen.
SEQ. ID NO. 56 is the protein sequence of AAMK N-terminal Antigen.
SEQ. ID NO. 57 is the protein sequence of YYWC N-terminal Antigen.
SEQ. ID NO. 58 is the protein sequence of DIGS N-terminal Antigen.
SEQ. ID NO. 59 is the protein sequence of AEES N-terminal Antigen.
SEQ. ID NO. 60 is the protein sequence of DPEP N-terminal Antigen.
SEQ. ID NO. 61 is the protein sequence of APKT N-terminal Antigen.
SEQ. ID NO. 62 is the protein sequence of DPAS N-terminal Antigen.
SEQ. ID NO. 63 is the deduced amino acid sequence of TbM-1 Peptide.
SEQ. ID NO. 64 is the deduced amino acid sequence of TbRal . -SEQ. ID NO. 65 is the deduced amino acid sequence of TbRalO.
SEQ. ID NO. 66 is the deduced amino acid sequence of TbRal 1.
SEQ. ID NO. 67 is the deduced amino acid sequence of TbRal2.
SEQ. ID NO. 68 is the deduced amino acid sequence of TbRal3.
SEQ. ID NO. 69 is the deduced amino acid sequence of TbRal6.
SEQ. ID NO. 70 is the deduced amino acid sequence of TbRal7.
SEQ. ID NO. 71 is the deduced amino acid sequence of TbRal 8.
SEQ. ID NO. 72 is the deduced amino acid sequence of TbRal9.
SEQ. ID NO. 73 is the deduced amino acid sequence of TbRa24.
SEQ. ID NO. 74 is the deduced amino acid sequence of TbRa26.
SEQ. ID NO. 75 is the deduced amino acid sequence of TbRa28.
SEQ. ID NO. 76 is the deduced amino acid sequence of TbRa29.
SEQ. ID NO. 77 is the deduced amino acid sequence of TbRa2A.
SEQ. ID NO. 78 is the deduced amino acid sequence of TbRa3.
SEQ. ID NO. 79 is the deduced amino acid sequence of TbRa32.
SEQ. ID NO. 80 is the deduced amino acid sequence of TbRa35.
SEQ. ID NO. 81 is the deduced amino acid sequence of TbRa36.
SEQ. ID NO. 82 is the deduced amino acid sequence of TbRa4.
SEQ. ID NO. 83 is the deduced amino acid sequence of TbRa9.
SEQ. ID NO. 84 is the deduced amino acid sequence of TbRaB.
SEQ. ID NO. 85 is the deduced amino acid sequence of TbRaC.
SEQ. ID NO. 86 is the deduced amino acid sequence of TbRaD.
SEQ. ID NO. 87 is the deduced amino acid sequence of YYWCPG.
SEQ. ID NO. 88 is the deduced amino acid sequence of TbAAMK.
SEQ. ID NO. 89 is the deduced amino acid sequence of Tb38-1.
SEQ. ID NO. 90 is the deduced amino acid sequence of TbH-4.
SEQ. ID NO. 91 is the deduced amino acid sequence of TbH-8.
SEQ. ID NO. 92 is the deduced amino acid sequence of TbH-9.
SEQ. ID NO. 93 is the deduced amino acid sequence of TbH-12.
- 30 SEQ. ID NO. 94 is the DNA sequence of DPAS.

SEQ. ID NO. 95 is the deduced amino acid sequence of DPAS.
SEQ. ID NO. 96 is the DNA sequence of DPV.
SEQ. ID NO. 97 is the deduced amino acid sequence of DPV.
SEQ. ID NO. 98 is the DNA sequence of ESAT-6.
5 SEQ. ID NO. 99 is the deduced amino acid sequence of ESAT-6.
SEQ. ID NO. 100 is the DNA sequence of TbH-8-2.
SEQ. ID NO. 101 is the DNA sequence of TbH-9FL.
SEQ. ID NO. 102 is the deduced amino acid sequence of TbH-9FL.
SEQ. ID NO. 103 is the DNA sequence of TbH-9-1.

10 SEQ. ID NO. 104 is the deduced amino acid sequence of TbH-9-1.
SEQ. ID NO. 105 is the DNA sequence of TbH-9-4.
SEQ. ID NO. 106 is the deduced amino acid sequence of TbH-9-4.
SEQ. ID NO. 107 is the DNA sequence of Tb38-1F2 IN.
SEQ. ID NO. 108 is the DNA sequence of Tb38-1F2 RP.
SEQ. ID NO. 109 is the deduced amino acid sequence of Tb37-FL.
SEQ. ID NO. 110 is the deduced amino acid sequence of Tb38-IN.
SEQ. ID NO. 111 is the DNA sequence of Tb38-1F3.
SEQ. ID NO. 112 is the deduced amino acid sequence of Tb38-1F3.
SEQ. ID NO. 113 is the DNA sequence of Tb38-1F5.
SEQ. ID NO. 114 is the DNA sequence of Tb38-1F6.
SEQ. ID NO. 115 is the deduced N-terminal amino acid sequence of DPV.
SEQ. ID NO. 116 is the deduced N-terminal amino acid sequence of AVGS.
SEQ. ID NO. 117 is the deduced N-terminal amino acid sequence of AAMK.
SEQ. ID NO. 118 is the deduced N-terminal amino acid sequence of YYWC.
SEQ. ID NO. 119 is the deduced N-terminal amino acid sequence of DIGS.
SEQ. ID NO. 120 is the deduced N-terminal amino acid sequence of AAES.
SEQ. ID NO. 121 is the deduced N-terminal amino acid sequence of DPEP.
SEQ. ID NO. 122 is the deduced N-terminal amino acid sequence of APKT.
SEQ. ID NO. 123 is the deduced N-terminal amino acid sequence of DPAS.
SEQ. ID NO. 124 is the protein sequence of DPPD N-terminal Antigen. _ SEQ ID NO. 125-128 are the protein sequences of four DPPD cyanogen bromide fragments.
SEQ ID NO. 129 is the N-terminal protein sequence of XDS antigen.
SEQ ID NO. 130 is the N-terminal protein sequence of AGD antigen.
SEQ ID NO. 131 is the N-terminal protein sequence of APE antigen.
SEQ ID NO. 132 is the N-terminal protein sequence of XYI antigen.
SEQ ID NO. 133 is the DNA sequence of TbH-29.
SEQ ID NO. 134 is the DNA sequence of TbH-30.
SEQ ID NO. 135 is the DNA sequence of TbH-32.
SEQ ID NO. 136 is the DNA sequence of TbH-33.
SEQ ID NO. 137 is the predicted amino acid sequence of TbH-29.
SEQ ID NO. 138 is the predicted amino acid sequence of TbH-30.
SEQ ID NO. 139 is the predicted amino acid sequence of TbH-32.
SEQ ID NO. 140 is the predicted amino acid sequence of TbH-33.
SEQ ID NO: 141-146 are PCR primers used in the preparation of a fusion protein containing TbRa3, 38 kD and Tb38-1.
SEQ ID NO: 147 is the DNA sequence of the fusion protein containing TbRa3, 38 kD
and Tb38-1.
SEQ ID NO: 148 is the amino acid sequence of the fusion protein containing TbRa3, 38 kD and Tb38-1.
SEQ ID NO: 149 is the DNA sequence of the M. tuberculosis antigen 38 kD.
SEQ ID NO: 150 is the amino acid sequence of the M. tuberculosis antigen 38 kD.
SEQ ID NO: 1 S 1 is the DNA sequence of XP 14.
SEQ ID NO: 152 is the DNA sequence of XP24.
SEQ ID NO: 153 is the DNA sequence of XP31.
SEQ ID NO: 154 is the 5' DNA sequence of XP32.
SEQ ID NO: 155 is the 3' DNA sequence of XP32.
SEQ ID NO: 156 is the predicted amino acid sequence of XP14.
SEQ ID NO: 157 is the predicted amino acid sequence encoded by the reverse complement of XP 14.

SEQ ID NO: 158 is the DNA sequence of XP27.
SEQ ID NO: 159 is the DNA sequence of XP36.
SEQ ID NO: 160 is the 5' DNA sequence of XP4. ' SEQ ID NO: 161 is the 5' DNA sequence of XPS.
SEQ ID NO: 162 is the 5' DNA sequence of XP 17.
SEQ ID NO: 163 is the 5' DNA sequence of XP30.
SEQ ID NO: 164 is the 5' DNA sequence of XP2.

SEQ ID NO: 165 is the 3' DNA sequence of XP2.

SEQ ID NO: 166 is the 5' DNA sequence of XP3.

SEQ ID NO: 167 is the 3' DNA sequence of XP3.

SEQ ID NO: 168 is the 5' DNA sequence of XP6.
SEQ ID NO: 169 is the 3' DNA sequence of XP6.
SEQ ID NO: 170 is the S' DNA sequence of XP 18:
SEQ ID NO: 171 is the 3' DNA sequence of XP18.
SEQ ID NO: 172 is the 5' DNA sequence of XP19.
SEQ ID NO: 173 is the 3' DNA sequence of XP 19.
SEQ ID NO: 174 is the 5' DNA sequence of XP22.
SEQ ID NO: 175 is the 3' DNA sequence of XP22.
SEQ ID NO: 176 is the 5' DNA sequence of XP25.
SEQ ID NO: 177 is the 3' DNA sequence of XP25.
SEQ ID NO: 178 is the full-length DNA sequence of TbH4-XP 1.
SEQ ID NO: 179 is the predicted amino acid sequence of TbH4-XP1.
SEQ ID NO: 180 is the predicted amino acid sequence encoded by the reverse complement of TbH4-XP 1.
SEQ ID NO: 181 is a first predicted amino acid sequence encoded by XP36.
SEQ ID NO: 182 is a second predicted amino acid sequence encoded by XP36.
SEQ ID NO: 183 is the predicted amino acid sequence encoded by the reverse complement of XP36.
SEQ ID NO: 184 is the DNA sequence of RDIF2.
SEQ ID NO: 185 is the DNA sequence of RDIFS. -SEQ ID NO: 186 is the DNA sequence of RDIFB.
SEQ ID NO: 187 is the DNA sequence of RDIF 10.
SEQ ID NO: 188 is the DNA sequence of RDIF 11.
SEQ ID NO: 189 is the predicted amino acid sequence of RDIF2.

S SEQ ID NO: 190 is the predicted amino acid sequence of RDIFS.

SEQ iD NO: 191 is the predicted amino acid sequence of RDIFB.

SEQ ID NO: 192 is the predicted amino acid sequence of RDIF
10.

SEQ ID NO: 193 is the predicted amino acid sequence of RDIF
11.

SEQ ID NO: 194 is the 5' DNA sequence of RDIF 12.

SEQ ID NO: 195 is the 3' DNA sequence of RDIF12.

SEQ ID NO: 196 is the DNA sequence of RDIF7.

SEQ ID NO: 197 is the predicted amino acid sequence of RDIF7.

SEQ ID NO: 198 is the DNA sequence of DIF2-1.

SEQ ID NO: 199 is the predicted amino acid sequence of DIF2-1.

SEQ ID NO: 200-207 are PCR primers used in the preparation of a fusion protein containing TbRa3, 38 kD, Tb38-l and DPEP (hereinafter referred to as TbF-2).

SEQ ID NO: 208 is the DNA sequence of the fusion protein TbF-2.

SEQ ID NO: 209 is the amino acid sequence of the fusion protein TbF-2.

DETAILED DESCRIPTION OF THE INVENTION
As noted above, the present invention is generally directed to compositions and methods for diagnosing tuberculosis. The compositions of the subject invention include polypeptides that comprise at least one antigenic portion of a M. tuberculosis antigen, or a variant of such an antigen that differs only in conservative substitutions and/or modifications.
Polypeptides within the scope of the present invention include, but are not limited to, soluble M. tuberculosis antigens. A "soluble M. tuberculosis antigen" is a protein of M. tuberculosis origin that is present in M. tuberculosis culture filtrate. As used herein, the term "polypeptide" encompasses amino acid chains of any length, including full length proteins (i.e., antigens), wherein the amino acid residues are linked by covalent peptide bonds. Thus, wo 9sn6sas rc~rrt~s9~nsma a polypeptide comprising an antigenic portion of one of the above antigens may consist entirely of the antigenic portion, or may contain additional sequences. The additional sequences may be derived from the native M. tuberculosis antigen or may be heterologous, and such sequences may (but need not) be antigenic.
An "antigenic portion" of an antigen (which may or may not be soluble) is a portion that is capable of reacting with sera obtained from an M. tuberculosis-infected individual (i.e., generates an absorbance reading with sera from infected individuals that is at least three standard deviations above the absorbance obtained with sera from uninfected individuals, in a representative ELISA assay described herein). An "M.
tuberculosis-infected individual" is a human who has been infected with M. tuberculoses (e.g., has an intradermal skin test response to PPD that is at least 0.5 cm in diameter). Infected individuals may display symptoms of tuberculosis or may be free of disease symptoms.
Polypeptides comprising at least an antigenic portion of one or more M. tuberculosis antigens as described herein may generally be used, alone or in combination, to detect tuberculosis in a patient.
The compositions and methods of this invention also encompass variants of the above polypeptides. A "variant," as used herein, is a polypeptide that differs from the native antigen only in conservative substitutions and/or modifications, such that the antigenic properties of the polypeptide are retained. Such variants may generally be identified by modifying one of the above polypeptide sequences, and evaluating the antigenic properties of the modified polypeptide using, for example, the representative procedures described herein:
A "conservative substitution" is one in which an amino acid is substituted for another amino acid that has similar properties, such that one skilled in the art of peptide chemistry would expect the secondary structure and hydropathic nature of the polypeptide to be substantially unchanged. In general, the following groups of amino acids represent conservative changes: (1) ala, pro, gly, glu, asp, gln, asn, ser, thr; (2) cys, ser, tyr, thr; (3) val, ile, leu, met, ala, phe; (4) lys, arg, his; and {5) phe, tyr, trp, his.
Variants may also (or alternatively) be modified by, for example, the deletion or addition of amino acids that have minimal influence on the antigenic properties, secondary structure and hydropathic nature of the polypeptide. For example, a polypeptide may be conjugated to a signal (or leader) sequence at the N-terminal end of the protein which co- _ WO 98/16645 PCTlUS97/18214 translationally or post-translationally directs transfer of the protein. The polypeptide may also be conjugated to a linker or other sequence for ease of synthesis, purification or " identification of the polypeptide (e.g., poly-His), or to enhance binding of the polypeptide to a solid support. For example, a polypeptide may be conjugated to an immunoglobulin Fc 5 region.
In a related aspect, combination polypeptides are disclosed. A "combination polypeptide" is a polypeptide comprising at least one of the above antigenic portions and one or more additional antigenic M. tuberculosis sequences, which are joined via a peptide linkage into a single amino acid chain. The sequences may be joined directly (i.e., with no 10 intervening amino acids) or may be joined by way of a linker sequence (e.g., Gly-Cys-Gly) that does not significantly diminish the antigenic properties of the component polypeptides.
In general, M. tuberculosis antigens, and DNA sequences encoding such antigens, may be prepared using any of a variety of procedures. For example, soluble antigens may be isolated from M. tuberculosis culture filtrate by procedures known to those 15 of ordinary skill in the art, including anion-exchange and reverse phase chromatography.
Purified antigens may then be evaluated for a desired property, such as the ability to react with sera obtained from an M. tuberculosis-infected individual. Such screens may be performed using the representative methods described herein. Antigens may then be partially sequenced using, for example, traditional Edman chemistry. See Edman and Berg, Eur. J.
Biochem. 80:116-132, 1967.
Antigens may also be produced recombinantly using a DNA sequence that encodes the antigen, which has been inserted into an expression vector and expressed in an appropriate host. DNA molecules encoding soluble antigens may be isolated by screening an appropriate M. tuberculosis expression library with anti-sera (e.g., rabbit) raised specifically against soluble M. tuberculosis antigens. DNA sequences encoding antigens that may or may not be soluble may be identified by screening an appropriate M. tuberculosis genomic or cDNA expression library with sera obtained from patients infected with M.
tuberculosis.
Y
Such screens may generally be performed using techniques well known in the art, such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratories, Cold Spring Harbor, NY, 1989.

DNA sequences encoding soluble antigens may also be obtained by screening an appropriate M. tuberculosis cDNA or genomic DNA library for DNA sequences that hybridize to degenerate oligonucleotides derived from partial amino acid sequences of isolated soluble antigens. Degenerate oligonucleotide sequences for use in such a screen may be designed and synthesized, and the screen may be performed, as described (for example) in Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratories, Cold Spring Harbor, NY (and references cited therein).
Polymerase chain reaction (PCR) may also be employed, using the above oligonucleotides in methods well known in the art, to isolate a nucleic acid probe from a cDNA or genomic library. The library screen may then be performed using the isolated probe.
Regardless of the method of preparation, the antigens described herein are "antigenic." More specifically, the antigens have the ability to react with sera obtained from an M. tuberculosis-infected individual. Reactivity may be evaluated using, for example, the representative ELISA assays described herein, where an absorbance reading with sera from infected individuals that is at least three standard deviations above the absorbance obtained with sera from uninfected individuals is considered positive.
Antigenic portions of M. tuberculosis antigens may be prepared and identified using well known techniques, such as those summarized in Paul, Fundamental Immunology, 3d ed., Raven Press, 1993, pp. 243-247 and references cited therein. Such techniques include screening polypeptide portions of the native antigen for antigenic properties.
The representative ELISAs described herein may generally be employed in these screens. An antigenic portion of a polypeptide is a portion that, within such representative assays, generates a signal in such assays that is substantially similar to that generated by the full length antigen. In other words, an antigenic portion of a M. tuberculosis antigen generates at least about 20%, and preferably about 100%, of the signal induced by the full length antigen in a model ELISA as described herein.
Portions and other variants of M. tuberculosis antigens may be generated by synthetic or recombinant means. Synthetic polypeptides having fewer than about 100 amino acids, and generally fewer than about 50 amino acids, may be generated using techniques well known in the art. For example, such polypeptides may be synthesized using any of the _ commercially available solid-phase techniques, such as the Mernfield solid-phase synthesis method, where amino acids are sequentially added to a growing amino acid chain. See ' Merrifield, J. Am. Chem. Soc. 85:2149-2146, 1963. Equipment for automated synthesis of polypeptides is commercially available from suppliers such as Applied BioSystems, Inc., Foster City, CA, and may be operated according to the manufacturer's instructions. Variants of a native antigen may generally be prepared using standard mutagenesis techniques, such as oligonucleotide-directed site-specific mutagenesis. Sections of the DNA
sequence may also be removed using standard techniques to permit preparation of truncated polypeptides.
Recombinant polypeptides containing portions and/or variants of a native antigen may be readily prepared from a DNA sequence encoding the polypeptide using a variety of techniques well known to those of ordinary skill in the art. For example, supernatants from suitable host/vector systems which secrete recombinant protein into culture media may be first concentrated using a commercially available filter.
Following concentration, the concentrate may be applied to a suitable purification matrix such as an affinity matrix or an ion exchange resin. Finally, one or more reverse phase HPLC steps can be employed to further purify a recombinant protein.
Any of a variety of expression vectors known to those of ordinary skill in the art may be employed to express recombinant polypeptides as described herein.
Expression may be achieved in any appropriate host cell that has been transformed or transfected with an expression vector containing a DNA molecule that encodes a recombinant polypeptide.
Suitable host cells include prokaryotes, yeast and higher eukaryotic cells.
Preferably, the host cells employed are E. coli, yeast or a mammalian cell line, such as COS or CHO. The DNA
sequences expressed in this manner may encode naturally occurring antigens, portions of naturally occurnng antigens, or other variants thereof.
In general, regardless of the method of preparation, the polypeptides disclosed herein are prepared in substantially pure form. Preferably, the polypeptides are at least about 80% pure, more preferably at least about 90% pure and most preferably at least about 99%
pure. For use in the methods described herein, however, such substantially pure polypeptides may be combined.

In certain specific embodiments, the subject invention discloses polypeptides comprising at least an antigenic portion of a soluble M. tuberculosis antigen (or a variant of such an antigen), where the antigen has one of the following N-terminal sequences:
(a) Asp-Pro-Val-Asp-Ala-Val-Ile-Asn-Thr-Thr-Cys-Asn-Tyr-Gly-Gln-Val-Val-Ala-Ala-Leu (SEQ ID NO: 115);
(b) Ala-Val-Glu-Ser-Gly-Met-Leu-Ala-Leu-Gly-Thr-Pro-Ala-Pro-Ser (SEQ ID NO: 116);
(c) Ala-Ala-Met-Lys-Pro-Arg-Thr-Gly-Asp-Gly-Pro-Leu-Glu-Ala-Ala-Lys-Glu-Gly-Arg (SEQ ID NO: 117);
(d) Tyr-Tyr-Trp-Cys-Pro-Gly-Gln-Pro-Phe-Asp-Pro-Ala-Trp-Gly-Pro (SEQ ID NO: 118);
(e) Asp-Ile-Gly-Ser-Glu-Ser-Thr-Glu-Asp-Gln-Gln-Xaa-Ala-Val (SEQ ID
NO: 119);
(fj Ala-Glu-Glu-Ser-Ile-Ser-Thr-Xaa-Glu-Xaa-Ile-Val-Pro (SEQ ID
NO: 120);
(g) Asp-Pro-Glu-Pro-Ala-Pro-Pro-Val-Pro-Thr-Thr-Ala-Ala-Ser-Pro-Pro-Ser (SEQ ID NO: 121);
(h) Ala-Pro-Lys-Thr-Tyr-Xaa-Glu-Glu-Leu-Lys-Gly-Thr-Asp-Thr-Gly (SEQ ID NO: 122);
(i) Asp-Pro-Ala-Ser-Ala-Pro-Asp-Val-Pro-Thr-Ala-Ala-Gln-Gln-Thr-Ser-Leu-Leu-Asn-Ser-Leu-Ala-Asp-Pro-Asn-Val-Ser-Phe-Ala-Asn (SEQ
ID NO: 123);
(j) Xaa-Asp-Ser-Glu-Lys-Ser-Ala-Thr-Ile-Lys-Val-Thr-Asp-Ala-Ser;
(SEQ ID NO: 129) (k) Ala-Gly-Asp-Thr-Xaa-Ile-Tyr-Ile-Val-Gly-Asn-Leu-Thr-Ala-Asp;
(SEQ ID NO: 130) or (1) Ala-Pro-Glu-Ser-Gly-Ala-Gly-Leu-Gly-Gly-Thr-Val-Gln-Ala-Gly;
(SEQ ID NO: 131) wherein Xaa may be any amino acid, preferably a cysteine residue. A DNA
sequence encoding the antigen identified as (g) above is provided in SEQ ID NO: 52, the deduced amino acid sequence of which is provided in SEQ ID NO: 53. A DNA sequence encoding the antigen identified as (a) above is provided in SEQ ID NO: 96; its deduced amino acid ' sequence is provided in SEQ ID NO: 97. A DNA sequence corresponding to antigen (d) above is provided in SEQ ID NO: 24, a DNA sequence corresponding to antigen (c) is provided in SEQ ID NO: 25 and a DNA sequence corresponding to antigen (I) is disclosed in SEQ ID NO: 94 and its deduced amino acid sequence is provided in SEQ ID NO:
95.
In a further specific embodiment, the subject invention discloses polypeptides comprising at least an immunogenic portion of an M. tuberculosis antigen having one of the following N-terminal sequences, or a variant thereof that differs only in conservative substitutions and/or modifications:
(m) Xaa-Tyr-Ile-Ala-Tyr-Xaa-Thr-Thr-Ala-Gly-Ile-Val-Pro-Gly-Lys-Ile-Asn-Val-His-Leu-Val; (SEQ ID NO: 132) or (n) Asp-Pro-Pro-Asp-Pro-His-Gln-Xaa-Asp-Met-Thr-Lys-Gly-Tyr-Tyr-Pro-Gly-Gly-Arg-Arg-Xaa-Phe; (SEQ ID NO: 124) wherein Xaa may be any amino acid, preferably a cysteine residue.
In other specific embodiments, the subject invention discloses polypeptides comprising at least an antigenic portion of a soluble M. tuberculosis antigen (or a variant of such an antigen) that comprises one or more of the amino acid sequences encoded by (a) the DNA sequences of SEQ ID NOS: 1, 2, 4-10, 13-25, 52, 94 and 96, (b) the complements of such DNA sequences, or {c) DNA sequences substantially homologous to a sequence in (a) or (b).
In further specific embodiments, the subject invention discloses polypeptides comprising at least an antigenic portion of a M. tuberculosis antigen (or a variant of such an antigen), which may or may not be soluble, that comprises one or more of the amino acid sequences encoded by (a) the DNA sequences of SEQ ID NOS: 26-51, 133, 134, 158-178 and 196, (b) the complements of such DNA sequences or (c) DNA sequences substantially homologous to a sequence in (a) or (b).
In the specific embodiments discussed above, the M. tuberculosis antigens include variants that are encoded DNA sequences which are substantially homologous to one WO 98/16645 PCT/I1S9~/182I4 or more of DNA sequences specifically recited herein. "Substantial homology,"
as used herein, refers to DNA sequences that are capable of hybridizing under moderately stringent conditions. Suitable moderately stringent conditions include prewashing in a solution of SX
SSC, 0.5% SDS, 1.0 mM EDTA (pH 8.0); hybridizing at 50°C-65°C, SX SSC, overnight or, S in the event of cross-species homology, at 45°C with O.SX SSC;
followed by washing twice at 65°C for 20 minutes with each of 2X, O.SX and 0.2X SSC containing O.I% SDS). Such hybridizing DNA sequences are also within the scope of this invention, as are nucleotide sequences that, due to code degeneracy, encode an immunogenic polypeptide that is encoded by a hybridizing DNA sequence.
10 In a related aspect, the present invention provides fusion proteins comprising a f rst and a second inventive polypeptide or, alternatively, a polypeptide of the present invention and a known M. tuberculosis antigen, such as the 38 kD antigen described above or ESAT-6 (SEQ ID NOS: 98 and 99), together with variants of such fusion proteins. The fusion proteins of the present invention may also include a linker peptide between the first 1 S and second polypeptides.
A DNA sequence encoding a fusion protein of the present invention is constructed using known recombinant DNA techniques to assemble separate DNA
sequences encoding the first and second polypeptides into an appropriate expression vector. The 3' end of a DNA sequence encoding the first polypeptide is ligated, with or without a peptide linker, 20 to the 5' end of a DNA sequence encoding the second polypeptide so that the reading frames of the sequences are in phase to permit mRNA translation of the two DNA
sequences into a single fusion protein that retains the biological activity of both the first and the second polypeptides.
A peptide linker sequence may be employed to separate the first and the second polypeptides by a distance sufficient to ensure that each polypeptide folds into its secondary and tertiary structures. Such a peptide linker sequence is incorporated into the fusion protein using standard techniques well known in the art. Suitable peptide linker sequences may be chosen based on the following factors: (1) their ability to adopt a flexible extended conformation; (2) their inability to adopt a secondary structure that could interact with functional epitopes on the first and second polypeptides; and (3) the lack of hydrophobic , or charged residues that might react with the polypeptide functional epitopes.
Preferred peptide linker sequences contain Gly, Asn and Ser residues. Other near neutral amino acids, ' such as Thr and Ala may also be used in the linker sequence. Amino acid sequences which may be usefully employed as linkers include those disclosed in Maratea et al., Gene 40:39-46, 1985; Murphy et al., Proc. Natl. Acad. Sci. USA 83:8258-8562, 1986; U.S.
Patent No. 4,935,233 and U.S. Patent No. 4,751,180. The linker sequence may be from 1 to about 50 amino acids in length. Peptide linker sequences are not required when the first and second polypeptides have non-essential N-terminal amino acid regions that can be used to separate the functional domains and prevent steric hindrance.
In another aspect, the present invention provides methods for using the polypeptides described above to diagnose tuberculosis. In this aspect, methods are provided for detecting M. tuberculosis infection in a biological sample, using one or more of the above polypeptides, alone or in combination. In embodiments in which multiple polypeptides are employed, polypeptides other than those specifically described herein, such as the 38 kD
antigen described in Andersen and Hansen, Infect. Immun. 57:2481-2488, 1989, may be included. As used herein, a "biological sample" is any antibody-containing sample obtained from a patient. Preferably, the sample is whole blood, sputum, serum, plasma, saliva, cerebrospinal fluid or urine. More preferably, the sample is a blood, serum or plasma sample obtained from a patient or a blood supply. The polypeptide(s) are used in an assay, as described below, to determine the presence or absence of antibodies to the polypeptide(s) in the sample, relative to a predetermined cut-off value. The presence of such antibodies indicates previous sensitization to mycobacterial antigens which may be indicative of tuberculosis.
In embodiments in which more than one polypeptide is employed, the polypeptides used are preferably complementary (i.e., one component polypeptide will tend to detect infection in samples where the infection would not be detected by another component polypeptide). Complementary polypeptides may generally be identified by using each polypeptide individually to evaluate serum samples obtained from a series of patients known to be infected with M. tuberculosis. After determining which samples test positive (as described below) with each polypeptide, combinations of two or more polypeptides may be formulated that are capable of detecting infection in most, or all, of the samples tested. Such polypeptides are complementary. For example, approximately 25-30% of sera from tuberculosis-infected individuals are negative for antibodies to any single protein, such as the 38 kD antigen mentioned above. Complementary polypeptides may, therefore, be used in S combination with the 38 kD antigen to improve sensitivity of a diagnostic test.
There are a variety of assay formats known to those of ordinary skill in the art for using one or more polypeptides to detect antibodies in a sample. See, e.g., Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, 1988, which is incorporated herein by reference. In a preferred embodiment, the assay involves the use of polypeptide immobilized on a solid support to bind to and remove the antibody from the sample. The bound antibody may then be detected using a detection reagent that contains a reporter group. Suitable detection reagents include antibodies that bind to the antibody/polypeptide complex and free polypeptide labeled with a reporter group (e.g., in a semi-competitive assay). Alternatively, a competitive assay may be utilized, in which an antibody that binds to the polypeptide is labeled with a reporter group and allowed to bind to the immobilized antigen after incubation of the antigen with the sample. The extent to which components of the sample inhibit the binding of the labeled antibody to the polypeptide is indicative of the reactivity of the sample with the immobilized polypeptide.
The solid support may be any solid material known to those of ordinary skill in the art to which the antigen may be attached. For example, the solid support may be a test well in a microtiter plate or a nitrocellulose or other suitable membrane.
Alternatively, the support may be a bead or disc, such as glass, fiberglass, latex or a plastic material such as polystyrene or polyvinylchloride. The support may also be a magnetic particle or a fiber optic sensor, such as those disclosed, for example, in U.S. Patent No.
5,359,681.
The polypeptides may be bound to the solid support using a variety of techniques known to those of ordinary skill in the art, which are amply described in the patent and scientific literature. In the context of the present invention, the term "bound" refers to both noncovalent association, such as adsorption, and covalent attachment (which may be a direct linkage between the antigen and functional groups on the support or may be a linkage by way of a cross-linking agent). Binding by adsorption to a well in a microtiter plate or to a _ membrane is preferred. In such cases, adsorption may be achieved by contacting the polypeptide, in a suitable buffer, with the solid support for a suitable amount of time. The - contact time varies with temperature, but is typically between about 1 hour and 1 day. In general, contacting a well of a plastic microtiter plate (such as polystyrene or polyvinylchloride) with an amount of polypeptide ranging from about 10 ng to about 1 pg, and preferably about 100 ng, is sufficient to bind an adequate amount of antigen.
Covalent attachment of polypeptide to a solid support may generally be achieved by first reacting the support with a bifunctional reagent that will react with both the support and a functional group, such as a hydroxyl or amino group, on the polypeptide. For example, the polypeptide may be bound to supports having an appropriate polymer coating using benzoquinone or by condensation of an aldehyde group on the support with an amine and an active hydrogen on the polypeptide (see, e.g., Pierce Immunotechnology Catalog and Handbook, 1991, at A12-A13).
In certain embodiments, the assay is an enzyme linked immunosorbent assay (ELISA). This assay may be performed by first contacting a polypeptide antigen that has been immobilized on a solid support, commonly the well of a microtiter plate, with the sample, such that antibodies to the polypeptide within the sample are allowed to bind to the immobilized polypeptide. Unbound sample is then removed from the immobilized polypeptide and a detection reagent capable of binding to the immobilized antibody-polypeptide complex is added. The amount of detection reagent that remains bound to the solid support is then determined using a method appropriate for the specific detection reagent.
More specifically, once the polypeptide is immobilized on the support as described above, the remaining protein binding sites on the support are typically blocked.
Any suitable blocking agent known to those of ordinary skill in the art, such as bovine serum albumin or Tween 20TM (Sigma Chemical Co., St. Louis, MO) may be employed. The immobilized polypeptide is then incubated with the sample, and antibody is allowed to bind to the antigen. The sample may be diluted with a suitable diluent, such as phosphate-buffered saline (PBS) prior to incubation. In general, an appropriate contact time (i.e., incubation time) is that period of time that is sufficient to detect the presence of antibody within a M. tuberculosis-infected sample. Preferably, the contact time is sufficient to achieve a level of binding that is at least 95% of that achieved at equilibrium between bound and unbound antibody. Those of ordinary skill in the art will recognize that the time necessary to achieve equilibrium may be readily determined by assaying the level of binding that occurs over a period of time. At room temperature, an incubation time of about 30 minutes is generally sufficient.
Unbound sample may then be removed by washing the solid support with an appropriate buffer, such as PBS containing 0.1% Tween 20TM. Detection reagent may then be added to the solid support. An appropriate detection reagent is any compound that binds to the immobilized antibody-polypeptide complex and that can be detected by any of a variety of means known to those in the art. Preferably, the detection reagent contains a binding agent (such as, for example, Protein A, Protein G, immunoglobulin, lectin or free antigen) conjugated to a reporter group. Preferred reporter groups include enzymes (such as horseradish peroxidase), substrates, cofactors, inhibitors, dyes, radionuclides, luminescent groups, fluorescent groups and biotin. The conjugation of binding agent to reporter group may be achieved using standard methods known to those of ordinary skill in the art.
Common binding agents may also be purchased conjugated to a variety of reporter groups from many commercial sources (e.g., Zymed Laboratories, San Francisco, CA, and Pierce, Rockford, IL).
The detection reagent is then incubated with the immobilized antibody-polypeptide complex for an amount of time sufficient to detect the bound antibody. An appropriate amount of time may generally be determined from the manufacturer's instructions or by assaying the level of binding that occurs over a period of time. Unbound detection reagent is then removed and bound detection reagent is detected using the reporter group.
The method employed for detecting the reporter group depends upon the nature of the reporter group. For radioactive groups, scintillation counting or autoradiographic methods are generally appropriate. Spectroscopic methods may be used to detect dyes, luminescent groups and fluorescent groups. Biotin may be detected using avidin, coupled to a different reporter group (commonly a radioactive or fluorescent group or an enzyme).
Enzyme reporter groups may generally be detected by the addition of substrate (generally for a specific period of time), followed by spectroscopic or other analysis of the reaction products. , WO 98/16645 PCT/US9?/1$214 To determine the presence or absence of anti-M. tuberculosis antibodies in the sample, the signal detected from the reporter group that remains bound to the solid support is ' generally compared to a signal that corresponds to a predetermined cut-off value. In one preferred embodiment, the cut-off value is the average mean signal obtained when the 5 immobilized antigen is incubated with samples from an uninfected patient. In general, a sample generating a signal that is three standard deviations above the predetermined cut-off value is considered positive for tuberculosis. In an alternate preferred embodiment, the cut off value is determined using a Receiver Operator Curve, according to the method of Sackett et al., Clinical Epidemiology: A Basic Science for Clinical Medicine, Little Brown and Co., 10 1985, pp. 106-107. Briefly, in this embodiment, the cut-off value may be determined from a plot of pairs of true positive rates (i.e., sensitivity) and false positive rates (100%-specificity) that correspond to each possible cut-off value for the diagnostic test result.
The cut-off value on the plot that is the closest to the upper left-hand corner (i.e., the value that encloses the largest area) is the most accurate cut-off value, and a sample generating a signal that is higher 15 than the cut-off value determined by this method may be considered positive. Alternatively, the cut-off value may be shifted to the left along the plot, to minimize the false positive rate, or to the right, to minimize the false negative rate. In general, a sample generating a signal that is higher than the cut-off value determined by this method is considered positive for tuberculosis.
20 In a related embodiment, the assay is performed in a rapid flow-through or strip test format, wherein the antigen is immobilized on a membrane, such as nitrocellulose.
In the flow-through test, antibodies within the sample bind to the immobilized polypeptide as the sample passes through the membrane. A detection reagent (e.g., protein A-colloidal gold) then binds to the antibody-polypeptide complex as the solution containing the detection 25 reagent flows through the membrane. The detection of bound detection reagent may then be performed as described above. In the strip test format, one end of the membrane to which polypeptide is bound is immersed in a solution containing the sample. The sample migrates along the membrane through a region containing detection reagent and to the area of immobilized polypeptide. Concentration of detection reagent at the polypeptide indicates the presence of anti-M. tuberculosis antibodies in the sample. Typically, the concentration of detection reagent at that site generates a pattern, such as a line, that can be read visually. The absence of such a pattern indicates a negative result. In general, the amount of polypeptide immobilized on the membrane is selected to generate a visually discernible pattern when the biological sample contains a level of antibodies that would be sufficient to generate a positive signal in an ELISA, as discussed above. Preferably, the amount of polypeptide immobilized on the membrane ranges from about 25 ng to about 1 p.g, and more preferably from about 50 ng to about 500 ng. Such tests can typically be performed with a very small amount (e.g., one drop) of patient serum or blood.
Of course, numerous other assay protocols exist that are suitable for use with the polypeptides of the present invention. The above descriptions are intended to be exemplary only.
In yet another aspect, the present invention provides antibodies to the inventive polypeptides. Antibodies may be prepared by any of a variety of techniques known to those of ordinary skill in the art. See, e.g., Harlow and Lane, Antibodies:
A Laboratory Manual, Cold Spring Harbor Laboratory, 1988. In one such technique, an immunogen comprising the antigenic polypeptide is initially injected into any of a wide variety of mammals (e.g., mice, rats, rabbits, sheep and goats). In this step, the polypeptides of this invention may serve as the immunogen without modification. Alternatively, particularly for relatively short polypeptides, a superior immune response may be elicited if the polypeptide is joined to a carrier protein, such as bovine serum albumin or keyhole limpet hemocyanin.
The immunogen is injected into the animal host, preferably according to a predetermined schedule incorporating one or more booster immunizations, and the animals are bled periodically. Polyclonal antibodies specific for the polypeptide may then be purified from such antisera by, for example, affinity chromatography using the polypeptide coupled to a suitable solid support.
Monoclonal antibodies specific for the antigenic poiypeptide of interest may be prepared, for example, using the technique of Kohler and Milstein, Eur. J.
Immunol.
6:511-519, 1976, and improvements thereto. Briefly, these methods involve the preparation of immortal cell lines capable of producing antibodies having the desired specificity (i.e., reactivity with the polypeptide of interest): Such cell lines may be produced, for example, , wo Xmas rc-r~s9~nszia from spleen cells obtained from an animal immunized as described above. The spleen cells are then immortalized by, for example, fusion with a myeloma cell fusion partner, preferably one that is syngeneic with the immunized animal. A variety of fusion techniques may be employed. For example, the spleen cells and myeloma cells may be combined with a nonionic detergent for a few minutes and then plated at low density on a selective medium that supports the growth of hybrid cells, but not myeloma cells. A preferred selection technique uses HAT (hypoxanthine, aminopterin, thymidine) selection. After a sufficient time, usually about 1 to 2 weeks, colonies of hybrids are observed. Single colonies are selected and tested for binding activity against the polypeptide. Hybridomas having high reactivity and specificity are preferred.
Monoclonal antibodies may be isolated from the supernatants of growing hybridoma colonies. In addition, various techniques may be employed to enhance the yield, such as injection of the hybridoma cell line into the peritoneal cavity of a suitable vertebrate host, such as a mouse. Monoclonal antibodies may then be harvested from the ascites fluid or the blood. Contaminants may be removed from the antibodies by conventional techniques, such as chromatography, gel filtration, precipitation, and extraction. The polypeptides of this invention may be used in the purification process in, for example, an affinity chromatography step.
Antibodies may be used in diagnostic tests to detect the presence of M. tuberculosis antigens using assays similar to those detailed above and other techniques well known to those of skill in the art, thereby providing a method for detecting M. tuberculosis infection in a patient.
Diagnostic reagents of the present invention may also comprise DNA
sequences encoding one or more of the above polypeptides, or one or more portions thereof.
For example, at least two oligonucleotide primers may ~be employed in a polymerase chain reaction (PCR) based assay to amplify M. tuberculosis-specific cDNA derived from a biological sample, wherein at least one of the oligonucleotide primers is specific for a DNA
molecule encoding a polypeptide of the present invention. The presence of the amplified cDNA is then detected using techniques well known in the art, such as gel electrophoresis.
Similarly, oligonucleotide probes specific for a DNA molecule encoding a polypeptide of the present invention may be used in a hybridization assay to detect the presence of an inventive polypeptide in a biological sample.
As used herein, the term "oligonucleotide primer/probe specific for a DNA ' molecule" means an oligonucleotide sequence that has at least about 80%, preferably at least S about 90% and more preferably at least about 95%, identity to the DNA
molecule in question.
Oligonucleotide primers and/or probes which may be usefully employed in the inventive diagnostic methods preferably have at least about 10-40 nucleotides. In a preferred embodiment, the oligonucleotide primers comprise at least about 10 contiguous nucleotides of a DNA molecule encoding one of the polypeptides disclosed herein.
Preferably, oligonucleotide probes for use in the inventive diagnostic methods comprise at least about 15 contiguous oligonucleotides of a DNA molecule encoding one of the polypeptides disclosed herein. Techniques for both PCR based assays and hybridization assays are well known in the art (see, for example, Mullis et al. Ibid; Ehrlich, Ibid). Primers or probes may thus be used to detect M. tuberculosis-specific sequences in biological samples. DNA
probes or primers comprising oligonucleotide sequences described above may be used alone, in combination with each other, or with previously identified sequences, such as the 38 kD
antigen discussed above.
The following Examples are offered by way of illustration and not by way of limitation.
EXAMPLES

PURIFICATION AND CHARACTERIZATION OF POLYPEPTIDES
FROM M. TUBERCULOSIS CULTURE FILTRATE
This example illustrates the preparation of M. tuberculosis soluble polypeptides from culture filtrate. Unless otherwise noted, all percentages in the following example are weight per volume.

wo Xmas rc~rn~rs9~nszia M. tuberculosis (either H37Ra, ATCC No. 25177, or H37Rv, ATCC
No. 25618) was cultured in sterile GAS media at 37°C for fourteen days.
The media was then vacuum filtered (leaving the bulk of the cells) through a 0.45 p filter into a sterile 2.5 L
bottle. The media was then filtered through a 0.2 p. filter into a sterile 4 L
bottle. NaN3 was then added to the culture filtrate to a concentration of 0.04%. The bottles were then placed in a 4°C cold room.
The culture filtrate was concentrated by placing the filtrate in a 12 L
reservoir that had been autoclaved and feeding the filtrate into a 400 ml Amicon stir cell which had been rinsed with ethanol and contained a 10,000 kDa MWCO membrane. The pressure was maintained at 60 psi using nitrogen gas. This procedure reduced the 12 L
volume to approximately 50 ml.
The culture filtrate was then dialyzed into 0.1 % ammonium bicarbonate using a 8,000 kDa MWCO cellulose ester membrane, with two changes of ammonium bicarbonate solution. Protein concentration was then determined by a commercially available BCA assay (Pierce, Rockford, IL).
The dialyzed culture filtrate was then lyophilized, and the polypeptides resuspended in distilled water. The polypeptides were then dialyzed against 0.01 mM 1,3 bis[tris(hydroxymethyl)-methylamino)propane, pH 7.5 (Bis-Tris propane buffer), the initial conditions for anion exchange chromatography. Fractionation was performed using gel profusion chromatography on a POROS 146 II Q/M anion exchange column 4.6 mm x 100 mm (Perseptive BioSystems, Framingham, MA) equilibrated in 0.01 mM Bis-Tris propane buffer pH 7.5. Polypeptides were eluted with a linear 0-0.5 M NaCI
gradient in the above buffer system. The column eluent was monitored at a wavelength of 220 nm.
The pools of polypeptides eluting from the ion exchange column were dialyzed against distilled water and lyophilized. The resulting material was dissolved in 0.1%
trifluoroacetic acid (TFA) pH 1.9 in water, and the polypeptides were purified on a Delta-Pak C18 column (Waters, Milford, MA) 300 Angstrom pore size, 5 micron particle size (3.9 x 150 mm). The polypeptides were eluted from the column with a linear gradient from 0-60%
dilution buffer (0.1% TFA in acetonitrile). The flow rate was 0.75 ml/minute and the HPLC
eluent was monitored at 214 nm. Fractions containing the eluted polypeptides were collected to maximize the purity of the individual samples. Approximately 200 purified polypeptides were obtained.
The purified polypeptides were then screened for the ability to induce T-cell ' proliferation in PBMC preparations. The PBMCs from donors known to be PPD skin test 5 positive and whose T cells were shown to proliferate in response to PPD and crude soluble proteins from MTB were cultured in medium comprising RPMI 1640 supplemented with 10% pooled human serum and SO p,g/ml gentamicin. Purified polypeptides were added in duplicate at concentrations of 0.5 to 10 ~,g/mL. After six days of culture in 96-well round-bottom plates in a volume of 200 ~1, 50 ~,l of medium was removed from each well for 10 determination of iFN-y levels, as described below. The plates were then pulsed with 1 ~,Ci/well of tritiated thymidine for a further 18 hours, harvested and tritium uptake determined using a gas scintillation counter. Fractions that resulted in proliferation in both replicates three fold greater than the proliferation observed in cells cultured in medium alone were considered positive.
15 IFN-y was measured using an enzyme-linked immunosorbent assay (ELISA).
ELISA plates were coated with a mouse monoclonal antibody directed to human IFN-y (Chemicon) in PBS for four hours at room temperature. Wells were then blocked with PBS
containing 5% (W/V) non-fat dried milk for 1 hour at room temperature. The plates were then washed six times in PBS/0.2% TWEEN-20 and samples diluted 1:2 in culture medium 20 in the ELISA plates were incubated overnight at room temperature. The plates were again washed and a polyclonal rabbit anti-human IFN-y serum diluted 1:3000 in PBS/10% normal goat serum was added to each well. The plates were then incubated for two hours at room temperature, washed and horseradish peroxidase-coupled anti-rabbit IgG
(Jackson Labs.) was added at a 1:2000 dilution in PBS/5% non-fat dried milk. After a further two hour incubation 25 at room temperature, the plates were washed and TMB substrate added. The reaction was stopped after 20 min with 1 N sulfuric acid. Optical density was determined at 450 nm using 570 nm as a reference wavelength. Fractions that resulted in both replicates giving an OD
two fold greater than the mean OD from cells cultured in medium alone, plus 3 standard deviations, were considered positive.

For sequencing, the polypeptides were individually dried onto BiobreneT"' (Perkin Elmer/Applied BioSystems Division, Foster City, CA) treated glass fiber - filters. The filters with polypeptide were loaded onto a Perkin Elmer/Applied BioSystems Division Procise 492 protein sequencer. The polypeptides were sequenced from the amino ' S terminal and using traditional Edman chemistry. The amino acid sequence was determined for each polypeptide by comparing the retention time of the PTH amino acid derivative to the appropriate PTH derivative standards.
Using the procedure described above, antigens having the following N-terminal sequences were isolated:
(a) Asp-Pro-Val-Asp-Ala-Val-Ile-Asn-Thr-Thr-Xaa-Asn-Tyr-Gly-Gln Val-Val-Ala-Ala-Leu (SEQ ID NO: 54);
(b) Ala-Val-Glu-Ser-Gly-Met-Leu-Ala-Leu-Gly-Thr-Pro-Ala-Pro-Ser (SEQ ID NO: 55);
(c) Ala-Ala-Met-Lys-Pro-Arg-Thr-Gly-Asp-Gly-Pro-Leu-Glu-Ala-Ala-Lys-Glu-Gly-Arg (SEQ ID NO: 56);
(d) Tyr-Tyr-Trp-Cys-Pro-Gly-Gln-Pro-Phe-Asp-Pro-Ala-Trp-Gly-Pro (SEQ ID NO: 57);
(e) Asp-Ile-Gly-Ser-Glu-Ser-Thr-Glu-Asp-Gln-Gln-Xaa-Ala-Val (SEQ ID
NO: 58);
(f) Ala-Glu-Glu-Ser-Ile-Ser-Thr-Xaa-Glu-Xaa-Ile-Val-Pro (SEQ ID
NO: 59);
(g) Asp-Pro-Glu-Pro-Ala-Pro-Pro-Val-Pro-Thr-Ala-Ala-Ala-Ala-Pro-Pro-Ala (SEQ ID NO: 60); and (h) Ala-Pro-Lys-Thr-Tyr-Xaa-Glu-Glu-Leu-Lys-Gly-Thr-Asp-Thr-Gly (SEQ ID NO: 61);
wherein Xaa may be any amino acid.
An additional antigen was isolated employing a rnicrobore HPLC purification step in addition to the procedure described above. Specifically, 20 p,l of a fraction comprising a mixture of antigens from the chromatographic purification step previously described, was purified on an Aquapore C18 column (Perkin Elmer/Applied Biosystems Division, Foster City, CA) with a 7 micron pore size, column size 1 mm x 100 mm, in a Perkin Elmer/Applied Biosystems Division Model 172 HPLC. Fractions were eluted from the column with a linear gradient of 1%/minute of acetonitrile (containing O.OS% TFA) in water (O.OS%
TFA) at a flow rate of 80 p,l/minute. The eluent was monitored at 2S0 nm. The original fraction was S separated into 4 major peaks plus other smaller components and a polypeptide was obtained which was shown to have a molecular weight of 12.OS4 Kd (by mass spectrometry) and the following N-terminal sequence:
(i) Asp-Pro-Ala-Ser-Ala-Pro-Asp-Val-Pro-Thr-Ala-Ala-Gln-Gln-Thr-Ser-Leu-Leu-Asn-Asn-Leu-Ala-Asp-Pro-Asp-Val-Ser-Phe-Ala-Asp (SEQ
ID NO: 62).
This polypeptide was shown to induce proliferation and IFN-y production in PBMC
preparations using the assays described above.
Additional soluble antigens were isolated from M. tuberculosis culture filtrate as follows. M. tuberculosis culture filtrate was prepared as described above.
Following 1 S dialysis against Bis-Tris propane buffer, at pH S.S, fractionation was performed using anion exchange chromatography on a Poros QE column 4.6 x 100 mm (Perseptive Biosystems) equilibrated in Bis-Tris propane buffer pH S.S. Polypeptides were eluted with a linear 0-1.S
M NaCI gradient in the above buffer system at a flow rate of 10 ml/min. The column eluent was monitored at a wavelength of 214 nm.
The fractions eluting from the ion exchange column were pooled and subjected to reverse phase chromatography using a Poros R2 column 4.6 x 100 mm (Perseptive Biosystems). Polypeptides were eluted from the column with a linear gradient from 0-100% acetonitrile (0.1 % TFA) at a flow rate of S ml/min. The eluent was monitored at 214 nm.
Fractions containing the eluted polypeptides were lyophilized and resuspended in 80 ~1 of aqueous 0.1% TFA and further subjected to reverse phase chromatography on a Vydac C4 column 4.6 x 1 SO mm (Western Analytical, Temecula, CA) with a linear gradient of 0-100% acetonitrile (0.1% TFA) at a flow rate of 2 ml/min. Fluent was monitored at 214 nm.

The fraction with biological activity was separated into one major peak plus other smaller components. Western blot of this peak onto PVDF membrane revealed three - major bands of molecular weights 14 Kd, 20 Kd and 26 Kd. These polypeptides were determined to have the following N-terminal sequences, respectively:
' S (j) Xaa-Asp-Ser-Glu-Lys-Ser-Ala-Thr-Ile-Lys-Val-Thr-Asp-Ala-Ser;
(SEQ ID NO: 129) (k) Ala-Gly-Asp-Thr-Xaa-Ile-Tyr-Ile-Val-Gly-Asn-Leu-Thr-Ala-Asp;
(SEQ ID NO: 130) and {l) Ala-Pro-Glu-Ser-Gly-Ala-Gly-Leu-Gly-Gly-Thr-Val-Gln-Ala-Gly;
(SEQ ID NO: 131 ), wherein Xaa may be any amino acid.
Using the assays described above, these polypeptides were shown to induce proliferation and IFN-y production in PBMC preparations. Figs. 1 A and B show the results of such assays using PBMC preparations from a first and a second donor, respectively.
DNA sequences that encode the antigens designated as (a), (c), (d) and (g) above were obtained by screening a M. tuberculosis genomic library using 32P
end labeled degenerate oligonucleotides corresponding to the N-terminal sequence and containing M. tuberculosis codon bias. The screen performed using a probe ~rresponding to antigen (a) above identified a clone having the sequence provided in SEQ ID NO: 96. The polypeptide encoded by SEQ ID NO: 96 is provided in SEQ ID NO: 97. The screen performed using a probe corresponding to antigen (g) above identified a clone having the sequence provided in SEQ ID NO: 52. The polypeptide encoded by SEQ ID NO: 52 is provided in SEQ ID
NO: 53. The screen performed using a probe corresponding to antigen {d) above identified a clone having the sequence provided in SEQ ID NO: 24, and the screen performed with a probe corresponding to antigen (c) identified a clone having the sequence provided in SEQ ID
NO: 25.
The above amino acid sequences were compared to known amino acid sequences in the gene bank using the DNA STAR system. The database searched contains some 173,000 proteins and is a combination of the Swiss, PIR databases along with translated protein sequences (Version 87). No significant homologies to the amino acid sequences for antigens (a)-(h) and (1) were detected.

The amino acid sequence for antigen (i) was found to be homologous to a sequence from M. leprae. The full length M. leprae sequence was amplified from genomic DNA using the sequence obtained from GENBANK. This sequence was then used to screen ' an M. tuberculosis library and a full length copy of the M. tuberculosis homologue was obtained (SEQ ID NO: 94).
The amino acid sequence for antigen (j) was found to be homologous to a known M. tuberculosis protein translated from a DNA sequence. To the best of the inventors' knowledge, this protein has not been previously shown to possess T-cell stimulatory activity. The amino acid sequence for antigen (k) was found to be related to a sequence from M. leprae.
In the proliferation and IFN-y assays described above, using three PPD
positive donors, the results for representative antigens provided above are presented in Table 1:

RESULTS OF PBMC PROLIFERATION AND IFN-y ASSAYS
Sequence Proliferation IFN-y (a) +

(c) +++ +++

(d) ++ ++

(g) +++ +++

(h) +++ +++

In Table 1, responses that gave a stimulation index (SI) of between 2 and 4 (compared to cells cultured in medium alone) were scored as +, as SI of 4-8 or 2-4 at a concentration of 1 ~g or less was scored as ++ and an SI of greater than 8 was scored as +++.
The antigen of sequence (i) was found to have a high SI (+++) for one donor and lower SI
(++ ~d +) for the two other donors in both proliferation and IFN-y assays.
These results indicate that these antigens are capable of inducing proliferation and/or interferon-y production.

S USE OF PATIENT SERA TO ISOLATE M. TUBERCULOSIS ANTIGENS
This example illustrates the isolation of antigens from M. tuberculosis lysate by screening with serum from M. tuberculosis-infected individuals.
Dessicated M. tuberculosis H37Ra (Difco Laboratories) was added to a 2%
10 NP40 solution, and alternately homogenized and sonicated three times. The resulting suspension was centrifuged at 13,000 rpm in microfuge tubes and the supernatant put through a 0.2 micron syringe filter. The filtrate was bound to Macro Prep DEAE beads (BioRad, Hercules, CA). The beads were extensively washed with 20 mM Tris pH 7.5 and bound proteins eluted with 1 M NaCI. The NaCI elute was dialyzed overnight against 10 mM Tris, 15 pH 7.5. Dialyzed solution was treated with DNase and RNase at 0.05 mg/ml for 30 min. at room temperature and then with a-D=mannosidase, 0.5 U/mg at pH 4.5 for 3-4 hours at room temperature. After returning to pH 7.5, the material was fractionated via FPLC
over a Bio Scale-Q-20 column (BioRad). Fractions were combined into nine pools, concentrated in a Centriprep 10 (Amicon, Beverley, MA) and screened by Western blot for serological activity 20 using a serum pool from M. tuberculosis-infected patients which was not immunoreactive with other antigens of the present invention.
The most reactive fraction was run in SDS-PAGE and transferred to PVDF. A
band at approximately 85 Kd was cut out yielding the sequence:
(m) Xaa-Tyr-Ile-Ala-Tyr-Xaa-Thr-Thr-Ala-Gly-Ile-Val-Pro-Gly-Lys-Ile-25 Asn-Val-His-Leu-Val; (SEQ ID NO: 132), wherein Xaa may be any amino acid.
Comparison of this sequence with those in the gene bank as described above, revealed no significant homologies to known sequences.
A DNA sequence that encodes the antigen designated as (m) above was 30 obtained by screening a genomic M. tuberculosis Erdman strain library using labeled degenerate oligonucleotides corresponding to the N-terminal sequence of SEQ ID
N0:137. A
clone was identified having the DNA sequence provided in SEQ ID NO: 198. This sequence was found to encode the amino acid sequence provided in SEQ ID NO: 199.
Comparison of these sequences with those in the genebank revealed some similarity to sequences previously identified in M. tuberculosis and M. bovis.

PREPARATION OF DNA SEQUENCES ENCODING M TUBERCULOSIS ANTIGENS
This example illustrates the preparation of DNA sequences encoding M. tuberculosis antigens by screening a M. tuberculosis expression library with sera obtained from patients infected with M. tuberculosis, or with anti-sera raised against M. tuberculosis antigens.
1 S A. PREPARATION OF M. TUBERCULOSIS SOLUBLE ANTIGENS USING RABBIT ANTI-SERA
RAISED AGAINST M. TUBERCULOSIS SUPERNATANT
Genomic DNA was isolated from the M. tuberculosis strain H37Ra. The DNA
was randomly sheared and used to construct an expression library using the Lambda ZAP
expression system (Stratagene, La Jolla, CA). Rabbit anti-sera was generated against secretory proteins of the M. tuberculosis strains H37Ra, H37Rv and Erdman by immunizing a rabbit with concentrated supernatant of the M. tuberculosis cultures.
Specifically, the rabbit was first immunized subcutaneously with 200 p,g of protein antigen in a total volume of 2 ml containing 100 p,g muramyl dipeptide (Calbiochem, La Jolla, CA) and 1 ml of incomplete Freund's adjuvant. Four weeks later the rabbit was boosted subcutaneously with 100 ~,g antigen in incomplete Freund's adjuvant. Finally, the rabbit was immunized intravenously , four weeks later with 50 ~.g protein antigen. The anti-sera were used to screen the expression library as described in Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratories, Cold Spring Harbor, NY, 1989. Bacteriophage plaques expressing immunoreactive antigens were purified. Phagemid from the plaques was rescued and the nucleotide sequences of the M. tuberculosis clones deduced.

Thirty two clones were purified. Of these, 25 represent sequences that have not been previously identified in M. tuberculosis. Proteins were induced by IPTG and ' purified by gel elution, as described in Skeiky et al., J. Exp. Med.
181:1527-1537, 1995.
Representative partial sequences of DNA molecules identified in this screen are provided in ' 5 SEQ ID NOS: 1-25. The corresponding predicted amino acid sequences are shown in SEQ
ID NOS: 64-88.
On comparison of these sequences with known sequences in the gene bank using the databases described above, it was found that the clones referred to hereinafter as TbRA2A, TbRAl6, TbRAl8, and TbRA29 (SEQ ID NOS: 77, 69, 71, 76) show some homology to sequences previously identified in Mycobacterium leprae but not in M. tuberculosis. TbRAI l, TbRA26, TbRA28 and TbDPEP (SEQ ID NOS: 66, 74, 75, 53) have been previously identified in M. tuberculosis. No significant homologies were found to TbRA 1, TbRA3, TbRA4, TbRA9, TbRA 10, TbRA 13, TbRA 17, TbRA 19, TbRA29, TbRA32, TbRA36 and the overlapping clones TbRA35 and TbRAl2 (SEQ ID NOS: 64, 78, 82, 83, 65, 68, 76, 72, 76, 79, 81, 80, 67, respectively). The clone TbRa24 is overlapping with clone TbRa29.
B. USE OF SERA FROM PATIENTS HAVING PULMONARY OR PLEURAL TUBERCULOSIS TO
IDENTIFY DNA SEQUENCES ENCODING M. TUBERCULOSIS ANTIGENS
The genomic DNA library described above, and an additional H37Rv library, were screened using pools of sera obtained from patients with active tuberculosis. To prepare the H37Rv library, M. tuberculosis strain H37Rv genomic DNA was isolated, subjected to partial Sau3A digestion and used to construct an expression library using the Lambda Zap expression system (Stratagene, La Jolla, Ca). Three different pools of sera, each containing sera obtained from three individuals with active pulmonary or pleural disease, were used in the expression screening. The pools were designated TbL, TbM and TbH, referring to relative reactivity with H37Ra lysate (i.e., TbL = low reactivity, TbM =
medium reactivity Y. and TbH = high reactivity) in both ELISA and immunoblot format. A fourth pool of sera from seven patients with active pulmonary tuberculosis was also employed. All of the sera lacked increased reactivity with the recombinant 38 kD M. tuberculosis H37Ra phosphate-binding protein.
All pools were pre-adsorbed with E. coli lysate and used to screen the H37Ra and H37Rv expression libraries, as described in Sambrook et al., Molecular Cloning: A
Laboratory Manual, Cold Spring Harbor Laboratories, Cold Spring Harbor, NY, 1989.
Bacteriophage plaques expressing immunoreactive antigens were purified.
Phagemid from the plaques was rescued and the nucleotide sequences of the M. tuberculosis clones deduced.
Thirty two clones were purified. Of these, 31 represented sequences that had not been previously identified in human M. tuberculosis. Representative sequences of the DNA molecules identified are provided in SEQ ID NOS:: 26-51 and 100. Of these, TbH-8-2 (SEQ. ID NO. 100) is a partial clone of TbH-8, and TbH-4 (SEQ. ID NO. 43) and TbH-4-FWD (SEQ. ID NO. 44) are non-contiguous sequences from the same clone. Amino acid sequences for the antigens hereinafter identified as Tb38-1, TbH-4, TbH-8, TbH-9, and TbH-12 are shown in SEQ ID NOS.: 89-93. Comparison of these sequences with known sequences in the gene bank using the databases identified above revealed no significant homologies to TbH-4, TbH-8, TbH-9 and TbM-3, although weak homologies were found to TbH-9. TbH-12 was found to be homologous to a 34 kD antigenic protein previously identified in M. paratuberculosis (Acc. No. 528515). Tb38-1 was found to be located 34 base pairs upstream of the open reading frame for the antigen ESAT-6 previously identified in M. bovis (Acc. No. U34848) and in M. tuberculosis (Sorensen et al., Infec.
Immun.
63:1710-1717, 1995).
Probes derived from Tb38-1 and TbH-9, both isolated from an H37Ra library, were used to identify clones in an H37Rv library. Tb38-1 hybridized to Tb38-1F2, Tb38-1F3, Tb38-1F5 and Tb38-1F6 (SEQ. ID NOS: 107, 108, 111, 113, and 114). (SEQ ID
NOS:
107 and 108 are non-contiguous sequences from clone Tb38-IF2.) Two open reading frames were deduced in Tb38-IF2; one corresponds to Tb37FL (SEQ. ID. NO. 109), the second, a partial sequence, may be the homologue of Tb38-1 and is called Tb38-IN (SEQ.
ID NO. 110).
The deduced amino acid sequence of Tb38-1F3 is presented in SEQ. ID. NO. 112.
A TbH-9 probe identified three clones in the H37Rv library: TbH-9-FL (SEQ. ID NO. 1 O1 ), which may be the homologue of TbH-9 (R37Ra), TbH-9-1 (SEQ. ID NO. 103), and TbH-8-2 (SEQ.

wo ms~as rcr~s9~nszi4 ID NO. 105) is a partial clone of TbH-8. The deduced amino acid sequences for these three clones are presented in SEQ ID NOS: 102, 104 and 106.
Further screening of the M. tuberculosis genomic DNA library, as described above, resulted in the recovery of ten additional reactive clones, representing seven different genes. One of these genes was identified as the 38 Kd antigen discussed above, one was determined to be identical to the l4Kd alpha crystallin heat shock protein previously shown to be present in M. tuberculosis, and a third was determined to be identical to the antigen TbH-8 described above. The determined DNA sequences for the remaining five clones (hereinafter referred to as TbH-29, TbH-30, TbH-32 and TbH-33) are provided in SEQ ID
NO: 133-136, respectively, with the corresponding predicted amino acid sequences being provided in SEQ ID NO: 137-140, respectively. The DNA and amino acid sequences for these antigens were compared with those in the gene bank as described above.
No homologies were found to the 5' end of TbH-29 (which contains the reactive open reading frame), although the 3' end of TbH-29 was found to be identical to the M.
tuberculosis cosmid Y227. TbH-32 and TbH-33 were found to be identical to the previously identified M. tuberculosis insertion element IS6110 and to the M. tuberculosis cosmid Y50, respectively. No significant homologies to TbH-30 were found.
Positive phagemid from this additional screening were used to infect E. coli XL-1 Blue MRF', as described in Sambrook et al., supra. Induction of recombinant protein was accomplished by the addition of IPTG. Induced and uninduced lysates were run in duplicate on SDS-PAGE and transferred to nitrocellulose filters. Filters were reacted with human M. tuberculosis sera (1:200 dilution) reactive with TbH and a rabbit sera (1:200 or 1:250 dilution) reactive with the N-terminal 4 Kd portion of lacZ. Sera incubations were performed for 2 hours at room temperature. Bound antibody was detected by addition of'ZSI-labeled Protein A and subsequent exposure to film for variable times ranging from 16 hours to 11 days. The results of the immunoblots are summarized in Table 2.

Human M. tb Anti-lacZ

Antisen Sera Sera TbH-29 45 Kd 45 Kd TbH-30 No reactivity 29 Kd TbH-32 12 Kd 12 Kd TbH-33 16 Kd 16 Kd Positive reaction of the recombinant human M. tuberculosis antigens with both the human M. tuberculosis sera and anti-lacZ sera indicate that reactivity of the human M.
tuberculosis sera is directed towards the fusion protein. Antigens reactive with the anti.-lacZ
sera but not with the human M. tuberculosis sera may be the result of the human M.
tuberculosis sera recognizing conformational epitopes, or the antigen-antibody binding kinetics may be such that the 2 hour sera exposure in the immunoblot is not sufficient.
Studies were undertaken to determine whether the antigens TbH-9 and Tb38-1 represent cellular proteins or are secreted into M. tuberculosis culture media. In the first study, rabbit sera were raised against A) secretory proteins of M.
tuberculosis, B) the known secretory recombinant M. tuberculosis antigen 85b, C) recombinant Tb38-l and D) recombinant TbH-9, using protocols substantially as described in Example 3A.
Total M.
tuberculosis lysate, concentrated supernatant of M. tuberculosis cultures and the recombinant antigens 85b, TbH-9 and Tb38-1 were resolved on denaturing gels, immobilized on nitrocellulose membranes and duplicate blots were probed using the rabbit sera described above.
The results of this analysis using control sera (panel I) and antisera (panel II) ' against secretory proteins, recombinant 85b, recombinant Tb38-1 and recombinant TbH-9 are shown in Figures 2A-D, respectively, wherein the lane designations are as follows: 1 ) molecular weight protein standards; 2) 5 p,g of M. tuberculosis lysate; 3) 5 p,g secretory proteins; 4) SO ng recombinant Tb38-1; 5) 50 ng recombinant TbH-9; and 6) 50 ng recombinant 85b. The recombinant antigens were engineered with six terminal histidine residues and would therefore be expected to migrate with a mobility approximately 1 kD
larger that the native protein. In Figure 2D, recombinant TbH-9 is lacking approximately 10 kD of the full-length 42 kD antigen, hence the significant difference in the size of the immunoreactive native TbH-9 antigen in the lysate lane (indicated by an arrow). These results demonstrate that Tb38-1 and TbH-9 are intracellular antigens and are not actively secreted by M. tuberculosis.
The finding that TbH-9 is an intracellular antigen was confirmed by determining the reactivity of TbH-9-specific human T cell clones to recombinant TbH-9, secretory M. tuberculosis proteins and PPD. A TbH-9-specific T cell clone (designated 131 TbH-9) was generated from PBMC of a healthy PPD-positive donor. The proliferadve response of 131 TbH-9 to secretory proteins, recombinant TbH-9 and a control M.
tuberculosis antigen, TbRa11, was determined by measuring uptake of tritiated thymidine, as described in Example 1. As shown in Figure 3A, the clone I3ITbH-9 responds specifically to TbH-9, showing that TbH-9 is not a significant component of M. tuberculosis secretory proteins. Figure 3B shows the production of IFN-y by a second TbH-9-specific T
cell clone (designated PPD 800-10) prepared from PBMC from a healthy PPD-positive donor, following stimulation of the T cell clone with secretory proteins, PPD or recombinant TbH-9.
These results further confirm that TbH-9 is not secreted by M. tuberculosis.
C. USE OF SERA FROM PATIENTS HAVING EXTRAPULMONARY TUBERCULOSIS TO IDENTIFY
DNA SEQUENCES ENCODING M. TUBERCULOSIS ANTIGENS
Genomic DNA was isolated from M. tuberculosis Erdman strain, randomly sheared and used to construct an expression library employing the Lambda ZAP
expression system (Stratagene, La Jolla, CA). The resulting library was screened using pools of sera ' obtained from individuals with extrapulmonary tuberculosis, as described above in Example 3B, with the secondary antibody being goat anti-human IgG + A + M (H+L) conjugated with alkaline phosphatase.
- Eighteen clones were purified. Of these, 4 clones (hereinafter referred to as XP14, XP24, XP31 and XP32) were found to bear some similarity to known sequences. The determined DNA sequences for XP14, XP24 and XP31 are provided in SEQ ID NOS:

153, respectively, with the S' and 3' DNA sequences for XP32 being provided in SEQ ID
NOS: 154 and 155, respectively. The predicted amino acid sequence for XP14 is provided in SEQ ID NO: 156. The reverse complement of XP14 was found to encode the amino acid ' sequence provided in SEQ ID NO: 157.
Comparison of the sequences for the remaining 14 clones (hereinafter referred -to as XP 1-XP6, XP 17-XP 19, XP22, XP25, XP27, XP30 and XP36) with those in the genebank as described above, revealed no homologies with the exception of the 3' ends of XP2 and XP6 which were found to bear some homology to known M. tuberculosis cosmids.
The DNA sequences for XP27 and XP36 are shown in SEQ ID NOS: 158 and 159, respectively, with the 5' sequences for XP4, XPS, XP17 and XP30 being shown in SEQ ID
NOS: 160-163, respectively, and the S' and 3' sequences for XP2, XP3, XP6, XP18, XP19, XP22 and XP25 being shown in SEQ ID NOS: 164 and 165; 166 and 167; 168 and 169; 170 and 171; 172 and 173; 174 and 175; and 176 and 177, respectively. XP 1 was found to overlap with the DNA sequences for TbH4, disclosed above. The full-length DNA
sequence for TbH4-XPI is provided in SEQ ID NO: 178. This DNA sequence was found to contain an open reading frame encoding the amino acid sequence shown in SEQ ID NO: 179.
The reverse complement of TbH4-XP 1 was found to contain an open reading frame encoding the amino acid sequence shown in SEQ ID NO: 180. The DNA sequence for XP36 was found to contain two open reading frames encoding the amino acid sequence shown in SEQ
ID NOS:
181 and 182, with the reverse complement containing an open reading frame encoding the amino acid sequence shown in SEQ ID NO: 183.
Recombinant XP1 protein was prepared as described above in Example 3B, with a metal ion affinity chromatography column being employed for purification.
Recombinant XP 1 was found to stimulate cell proliferation and IFN-y production in T cells isolated from an M. tuberculosis-immune donors.
D. PREPARATION OF M. TUBERCULOSIS SOLUBLE ANTIGENS USING RABBIT ANTI-SERA
RAISED AGAINST M. TUBERCULOSIS FRACTIONATED PROTEINS
M. tuberculosis lysate was prepared as described above in Example 2. The resulting material was fractionated by HPLC and the fractions screened by Western blot for -WO 98/16645 PCT/tTS97t18214 serological activity with a serum pool from M. tuberculosis-infected patients which showed little or no immunoreactivity with other antigens of the present invention.
Rabbit anti-sera - was generated against the most reactive fraction using the method described in Example 3A .
The anti-sera was used to screen an M. tuberculosis Erdman strain genomic DNA
expression ' S library prepared as described above. Bacteriophage plaques expressing immunoreactive antigens were purified. Phagemid from the plaques was rescued and the nucleotide sequences of the M. tuberculosis clones determined.
Ten different clones were purified. Of these, one was found to be TbRa35, described above, and one was found to be the previously identified M.
tuberculosis antigen, HSP60. Of the remaining eight clones, six (hereinafter referred to as RDIF2, RDIFS, RDIFB, RDIF 10, RDIF 11 and RDIF 12) were found to bear some similarity to previously identified M. tuberculosis sequences. The determined DNA sequences for RDIF2, RDIFS, RDIFB, RDIF10 and RDIF11 are provided in SEQ ID NOS: 184-188, respectively, with the corresponding predicted amino acid sequences being provided in SEQ ID NOS: 189-193, respectively. The 5' and 3' DNA sequences for RDIF12 are provided in SEQ ID
NOS: 194 and 195, respectively. No significant homologies were found to the antigen RDIF-7. The determined DNA and predicted amino acid sequences for RDIF7 are provided in SEQ ID
NOS: 196 and 197, respectively. One additional clone, referred to as RDIF6 was isolated, however, this was found to be identical to RDIFS.
Recombinant RDIF6, RDIFB, RDIF 10 and RDIF 11 were prepared as described above. These antigens were found to stimulate cell proliferation and IFN-y production in T cells isolated from M. tuberculosis-immune donors.

PURIFICATION AIVD CHARACTERIZATION OF A POLYPEPTIDE FROM TUBERCULIN PURIFIED
PROTEIN DERIVATIVE
An M. tuberculosis polypeptide was isolated from tuberculin purified protein derivative (PPD) as follows.

PPD was prepared as published with some modification (Seibert, F. et al., Tuberculin purified protein derivative. Preparation and analyses of a large quantity for standard. The American Review of Tuberculosis 44:9-25, 1941). M. tuberculosis Rv strain was grown for 6 weeks in synthetic medium in roller bottles at 37°C.
Bottles containing the bacterial growth were then heated to 100°C in water vapor for 3 hours.
Cultures were sterile ' filtered using a 0.22 p, filter and the liquid phase was concentrated 20 times using a 3 kD cut-off membrane. Proteins were precipitated once with 50% ammonium sulfate solution and eight times with 25% ammonium sulfate solution. The resulting proteins (PPD) were fractionated by reverse phase liquid chromatography (RP-HPLC) using a C 18 column (7.8 x 300 mM; Waters, Milford, MA) in a Biocad HPLC system (Perceptive Biosystems, Framingham, MA). Fractions were eluted from the column with a linear gradient from 0-100% buffer (0.1 % TFA in acetonitrile). The flow rate was 10 ml/minute and eluent was monitored at 214 nm and 280 nm.
Six fractions were collected, dried, suspended in PBS and tested individually in M. tuberculosis-infected guinea pigs for induction of delayed type hypersensitivity (DTH) reaction. One fraction was found to induce a strong DTH reaction and was subsequently fractionated further by RP-HPLC on a microbore Vydac C18 column (Cat. No.
218TP5115) in a Perkin Elmer/Applied Biosystems Division Model 172 HPLC. Fractions were eluted with a linear gradient from S-100% buffer (0.05% TFA in acetonitrile) with a flow rate of 80 p.l/minute. Eluent was monitored at 215 nm. Eight fractions were collected and tested for induction of DTH in M. tuberculosis-infected guinea pigs. One fraction was found to induce strong DTH of about 16 mm induration. The other fractions did not induce detectable DTH.
The positive fraction was submitted to SDS-PAGE gel electrophoresis and found to contain a single protein band of approximately 12 kD molecular weight.
This polypeptide, herein after referred to as DPPD, was sequenced from the amino terminal using a Perkin Elmer/Applied Biosystems Division Procise 492 protein sequencer as described above and found to have the N-terminal sequence shown in SEQ ID
NO:: 124. Comparison of this sequence with known sequences in the gene bank as described above revealed no known homologies. Four cyanogen bromide fragments of DPPD
were isolated and found to have the sequences shown in SEQ ID NOS: 125-128.

wo mr~sas rc~r~smnma SYNTHESIS OF SYNTHETIC POLYPEPTIDES
' S Polypeptides may be synthesized on a Millipore 9050 peptide synthesizer using FMOC chemistry with HPTU (O-Benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate) activation. A Gly-Cys-Gly sequence may be attached to the amino terminus of the peptide to provide a method of conjugation or labeling of the peptide.
Cleavage of the peptides from the solid support may be carried out using the following 10 cleavage mixture: trifluoroacetic acid:ethanedithiolahioanisole:water:phenol (40:1:2:2:3).
After cleaving for 2 hours, the peptides may be precipitated in cold methyl-t-butyl-ether. The peptide pellets may then be dissolved in water containing 0.1 %
trifluoroacetic acid (TFA) and lyophilized prior to purification by C18 reverse phase HPLC. A gradient of 0-60%
acetonitrile (containing 0.1 % TFA) in water (containing 0.1 % TFA) may be used to elute the 15 peptides. Following lyophilization of the pure fractions, the peptides may be characterized using electrospray mass spectrometry and by amino acid analysis.
This procedure was used to synthesize a TbM-1 peptide that contains one and a half repeats of a TbM-1 sequence. The TbM-1 peptide has the sequence GCGDRSGGNLDQIRLRRDRSGGNL (SEQ ID NO: 63).

USE OF REPRESENTATIVE ANTIGENS FOR SERODIAGNOSIS OF TUBERCULOSIS
This Example illustrates the diagnostic properties of several representative antigens.
Assays were performed in 96-well plates were coated with 200 ng antigen diluted to 50 p,L in carbonate coating buffer, pH 9.6. The wells were coated overnight at 4°C
(or 2 hours at 37°C). The plate contents were then removed and the wells were blocked for 2 hours with 200 p,L of PBS/1% BSA. After the blocking step, the wells were washed five WO 98/16645 PGT/US9~/18214 times with PBS/0.1 % Tween 20T"". 50 p,L sera, diluted 1:100 in PBS/0. I %
Tween 20T""l0.1 BSA, was then added to each well and incubated for 30 minutes at room temperature. The plates were then washed again five times with PBS/0.1% Tween 20T"".
The enzyme conjugate (horseradish peroxidase - Protein A, Zymed, San Francisco, CA) was then diluted 1:10,000 in PBS/0.1% Tween 20T""/0.1% BSA, and 50 p,L of the diluted conjugate was added to each well and incubated for 30 minutes at room temperature. Following incubation, the wells were washed five times with PBS/0.1 % Tween 20T"". 100 p,L of tetramethylbenzidine peroxidase (TMB) substrate (Kirkegaard and Perry Laboratories, Gaithersburg, MD) was added, undiluted, and incubated for about 15 minutes.
The reaction was stopped with the addition of 100 p.L of 1 N HzS04 to each well, and the plates were read at 450 nm.
Figure 4 shows the ELISA reactivity of two recombinant antigens isolated using method A in Example 3 (TbRa3 and TbRa9) with sera from M. tuberculosis positive and negative patients. The reactivity of these antigens is compared to that of bacterial lysate isolated from M. tuberculosis strain H37Ra (Difco, Detroit, MI). In both cases, the recombinant antigens differentiated positive from negative sera. Based on cut-off values obtained from receiver-operator curves, TbRa3 detected 56 out of 87 positive sera, and TbRa9 detected 111 out of 165 positive sera.
Figure 5 illustrates the ELISA reactivity of representative antigens isolated using method B of Example 3. The reactivity of the recombinant antigens TbH4, TbH 12, Tb38-1 and the peptide TbM-1 (as described in Example 4) is compared to that of the 38 kD
antigen described by Andersen and Hansen, Infect. Immun. 57:2481-2488, 1989.
Again, all of the polypeptides tested differentiated positive from negative sera. Based on cut-off values obtained from receiver-operator curves, TbH4 detected 67 out of 126 positive sera, TbH 12 detected 50 out of 125 positive sera, 38-1 detected 61 out of 101 positive sera and the TbM-1 peptide detected 25 out of 30 positive sera.
The reactivity of four antigens (TbRa3, TbRa9, TbH4 and TbHl2) with sera from a group of M. tuberculosis infected patients with differing reactivity in the acid fast stain of sputum (Smithwick and David, Tubercle 52:226, 1971 ) was also examined, and compared to the reactivity of M. tuberculosis lysate and the 38 kD antigen. The results are presented in Table 3, below:

REACTIVITY OF ANTIGENS WITH SERA FROM M. TUBERCULOSIS PATIENTS
Acid ELISA
Fast Values Patient Sputum Lysate 381cD
TbRa9 TbHl2 TbH4 TbRa3 Tb01 B93I-2 ++++ 1.853 0.634 0.998 1.022 1.030 1.314 TbO1B93I-19 ++++ 2.657 2.322 0.608 0.837 1.857 2.335 TbO1B93I-8 +++ 2.703 0.527 0.492 0.281 0.501 2.002 TbO1B93I-10 +++ 1.665 1.301 0.685 0.216 0.448 0.458 TbO1B93I-11 +++ 2.817 0.697 0.509 0.301 0.173 2.608 TbO1B93I-15 +++ 1.28 0.283 0.808 0.218 1.537 0.811 TbO1B93I-16 +++ 2.908 >3 0.899 0.441 0.593 1.080 TbO1B93I-25 +++ 0.395 0.131 0.335 0.211 0.107 0.948 TbO1B93I-87 +++ 2.653 2.432 2.282 0.977 1.221 0.857 TbO1B93I-89 +++ 1.912 2.370 2.436 0.876 0.520 0.952 TbO1B94I-108 +++ 1.639 0.341 0.797 0.368 0.654 0.798 Tb01 B94I-201+++ 1.721 0.419 0.661 0.137 0.064 0.692 TbO1B93I-88 ++ 1.939 1.269 2.519 1.381 0.214 0.530 TbO1B93I-92 ++ 2.355 2.329 2.78 0.685 0.997 2.527 TbO1B94I-109 ++ 0.993 0.620 0.574 0.441 0.5 2.558 TbO1B94I-210 ++ 2.777 >3 0.393 0.367 1.004 1.315 TbO1B94I-224 ++ 2.913 0.476 0.251 1.297 1.990 0.256 Acid ELISA
Fast Values Patient Sputum Lysate 38kD
TbRa9 TbHl2 TbH4 TbRa3 TbO1B93I-9 + 2.649 0.278 0.210 0.140 0.181 1.586 TbO1B93I-14 + >3 1.538 0.282 0.291 0.549 2.880 Tb01 B93I-21 + 2.645 0.739 2.499 0.783 0.536 1.770 Tb01 B93I-22 + 0.714 0.451 2.082 0.285 0.269 1.159 TbO1B93I-31 + 0.956 0.490 1.019 0.812 0.176 1.293 TbO1B93I-32 2.261 0.786 0.668 0.273 0.535 0.405 TbOlB93I-52 - 0.658 0.114 0.434 0.330 0.273 1.140 TbO1B93I-99 - 2.118 0.584 1.62 0.119 0.977 0.729 TbO1B94I-130 1.349 0.224 0.86 0.282 0.383 2.146 Tb01 B94I-131 0.685 0.324 1.173 0.059 0.118 1.431 AT4-0070 Normal 0.072 0.043 0.092 0.071 0.040 0.039 AT4-0105 Normal 0.397 0.121 0.118 0.103 0.078 0.390 3/15/94-1 Normal 0.227 0.064 0.098 0.026 0.001 0.228 4/15/93-2 Normal 0.114 0.240 0.071 0.034 0.041 0.264 5/26/94-4 Normal 0.089 0.259 0.096 0.046 0.008 0.053 5/26/94-3 Normal 0.139 0.093 0.085 0.019 0.067 0.01 Based on cut-off values obtained from receiver-operator curves, TbRa3 detected 23 out of 27 positive sera, TbRa9 detected 22 out of 27, TbH4 detected 18 out of 27 and TbH 12 detected 15 out of 27. If used in combination, these four antigens would have a theoretical sensitivity of 27 out of 27, indicating that these antigens should complement each other in the serological detection of M. tuberculosis infection. In addition, several of the recombinant antigens detected positive sera that were not detected using the 38 kD antigen, indicating that these antigens may be complementary to the 38 kD antigen. ' The reactivity of the recombinant antigen TbRall with sera from M. tuberculosis patients shown to be negative for the 38 kD antigen, as well as with sera from - PPD positive and normal donors, was determined by ELISA as described above.
The results are shown in Figure 6 which indicates that TbRal 1, while being negative with sera from PPD
positive and normal donors, detected sera that were negative with the 38 kD
antigen. Of the thirteen 38 kD negative sera tested, nine were positive with TbRal l, indicating that this antigen may be reacting with a sub-group of 38 kD antigen negative sera. In contrast, in a group of 38 kD positive sera where TbRal 1 was reactive, the mean OD 450 for TbRal l was lower than that for the 38 kD antigen. The data indicate an inverse relationship between the presence of TbRal 1 activity and 38 kD positivity.
The antigen TbRa2A was tested in an indirect ELISA using initially 50 ~,1 of serum at 1:100 dilution for 30 minutes at room temperature followed by washing in PBS
Tween and incubating for 30 minutes with biotinylated Protein A (Zymed, San Francisco, CA) at a 1:10,000 dilution. Following washing, 50 p,l of streptavidin-horseradish peroxidase (Zymed) at 1:10,000 dilution was added and the mixture incubated for 30 minutes. After washing, the assay was developed with TMB substrate as described above. The reactivity of TbRa2A with sera from M. tuberculosis patients and normal donors in shown in Table 4. The mean value for reactivity of TbRa2A with sera from M. tuberculosis patients was 0.444 with a standard deviation of 0.309. The mean for reactivity with sera from normal donors was 0.109 with a standard deviation of 0.029. Testing of 38 kD negative sera (Figure 7) also indicated that the TbRa2A antigen was capable of detecting sera in this category.

REACTIVITY OF TBRA2A WITH SERA FROM M. TUBERCULOSIS PATIENTS AND FROM NORMAL
DotJORs Serum ID Status OD 450 Tb85 TB 0.680 Tb86 TB 0.450 Tb87 TB 0.263 Tb88 TB 0.275 - ~ Tb89 TB 0.403 Tb91 TB 0.393 Tb92 TB 0.401 Tb93 TB 0.232 Tb94 TB 0.333 Tb95 TB 0.435 Tb96 TB 0.284 Tb97 TB 0.320 Tb99 TB 0.328 Tb 100 TB 0.817 Tb 1 O TB 0.607 l Tb 102 TB 0.191 Tb 103 TB 0.228 Tb107 TB 0.324 TbI09 TB 1.572 Tb112 TB 0.338 DL4-0176 Normal 0.036 AT4-0043 Normal 0.126 AT4-0044 Normal 0.130 AT4-0052 Normal 0.135 AT4-0053 Normal 0.133 AT4-0062 Normal 0.128 AT4-0070 Normal 0.088 AT4-0091 Normal 0.108 AT4-0100 Normal 0.106 AT4-0105 Normal 0.108 AT4-0109 Normal 0.105 The reactivity of the recombinant antigen (g) (SEQ ID NO: 60) with sera from M. tuberculosis patients and normal donors was determined by ELISA as described above.
Figure 8 shows the results of the titration of antigen (g) with four M.
tuberculosis positive 5 sera that were all reactive with the 38 kD antigen and with four donor sera.
All four positive sera were reactive with antigen (g).
The reactivity of the recombinant antigen TbH-29 (SEQ ID NO: I37) with sera from M. tuberculosis patients, PPD positive donors and normal donors was determined by indirect ELISA as described above. The results are shown in Figure 9. TbH-29 detected 10 30 out of 60 M. tuberculosis sera, 2 out of 8 PPD positive sera and 2 out of 27 normal sera.
Figure 10 shows the results of ELISA tests (both direct and indirect) of the antigen TbH-33 (SEQ ID NO: 140) with sera from M. tuberculosis patients and from normal donors and with a pool of sera from M. tuberculosis patients. The mean OD 450 was demonstrated to be higher with sera from M. tuberculosis patients than from normal donors, with the mean OD 450 being significantly higher in the indirect ELISA than in the direct ELISA. Figure 11 is a titration curve for the reactivity of recombinant TbH-33 with sera S from M. tuberculosis patients and from normal donors showing an increase in OD 450 with increasing concentration of antigen.
The reactivity of the recombinant antigens RDIF6, RDIF8 and RDIF10 (SEQ
ID NOS: 184-187, respectively) with sera from M. tuberculosis patients and normal donors was determined by ELISA as described above. RDIF6 detected & out of 32 M.
tuberculosis sera and 0 out of 15 normal sera; RDIF8 detected 14 out of 32 M. tuberculosis sera and 0 out of 15 normal sera; and RDIF 10 detected 4 out of 27 M. tuberculosis sera and 1 out of 15 normal sera. In addition, RDIF10 was found to detect 0 out of 5 sera from PPD-positive donors.

PREPARATION AND CHARACTERIZATION OF M. TUBERCULOSIS FUSION PROTEINS
A fusion protein containing TbRa3, the 38 kD antigen and Tb38-1 was prepared as follows.
Each of the DNA constructs TbRa3, 38 kD and Tb38-1 were modified by PCR
in order to facilitate their fusion and the subsequent expression of the fusion protein TbRa3-38 kD-Tb38-1. TbRa3, 38 kD and Tb38-1 DNA was used to perform PCR using the primers PDM-64 and PDM-65 (SEQ ID NO: 141 and 142), PDM-57 and PDM-58 (SEQ ID NO: 143 and 144), and PDM-69 and PDM-60 (SEQ ID NO: 145-146), respectively. In each case, the DNA amplification was performed using 10 p,l 1 OX Pfu buffer, 2 ~l 10 mM
dNTPs, 2 ~l each of the PCR primers at 10 ~.M concentration, 81.5 ~,1 water, 1.5 ~.l Pfu DNA
polymerase (Stratagene, La Jolla, CA) and 1 ~,l DNA at either 70 ng/~tl {for TbRa3) or 50 ng/~,l (for 38 kD and Tb38-1). For TbRa3, denaturation at 94°C was performed for 2 min, followed by 40 cycles of 96°C for 15 sec and 72°C for 1 min, and lastly by 72°C for 4 min. For 38 kD, denaturation at 96°C was performed for 2 min, followed by 40 cycles of 96°C for 30 sec, 68°C for 15 sec and 72°C for 3 min, and finally by 72°C
for 4 min. For Tb38-1 denaturation at 94°C for 2 min was followed by 10 cycles of 96°C for 15 sec, 68°C for 15 sec and 72°C for 1.5 min, 30 cycles of 96°C for 15 sec, 64°C for 15 sec and 72°C for 1.5, and finally by 72°C ' for 4 min.
The TbRa3 PCR fragment was digested with NdeI and EcoRI and cloned directly into pT7~L2 IL 1 vector using NdeI and EcoRI sites. The 38 kD PCR
fragment was digested with Sse8387I, treated with T4 DNA polymerase to make blunt ends and then digested with EcoRI for direct cloning into the pT7~L2Ra3-I vector which was digested with StuI and EcoRI. The 38-1 PCR fragment was digested with Eco47III and EcoRI and directly subcloned into pT7~L2Ra3/38kD-17 digested with the same enzymes. The whole fusion was then transferred to pET28b using NdeI and EcoRI sites. The fusion construct was confirmed by DNA sequencing.
The expression construct was transformed to BLR pLys S E. coli (Novagen, Madison, WI) and grown overnight in LB broth with kanamycin (30 ~g/ml) and chloramphenicol (34 ~,g/ml). This culture (12 ml) was used to inoculate 500 ml 2XYT with the same antibiotics and the culture was induced with IPTG at an OD560 of 0.44 to a final concentration of 1.2 mM. Four hours post-induction, the bacteria were harvested and sonicated in 20 mM Tris (8.0), 100 mM NaCI, 0.1 % DOC, 20 p,g/ml Leupeptin, 20 mM
PMSF followed by centrifugation at 26,000 X g. The resulting pellet was resuspended in 8 M
urea, 20 mM Tris (8.0), 100 mM NaCI and bound to Pro-bond nickel resin (Invitrogen, Carlsbad, CA). The column was washed several times with the above buffer then eluted with an imidazole gradient (50 mM, 100 mM, 500 mM imidazole was added to 8 M urea, 20 mM
Tris (8.0), 100 mM NaCI). The eluates containing the protein of interest were then dialzyed against 10 mM Tris (8.0).
The DNA and amino acid sequences for the resulting fusion protein (hereinafter referred to as TbRa3-38 kD-Tb38-1) are provided in SEQ ID NO: 147 and 148, respectively.
A fusion protein containing the two antigens TbH-9 and Tb38-1 (hereinafter referred to as TbH9-Tb38-1) without a hinge sequence, was prepared using a similar procedure to that described above. The DNA sequence for the TbH9-Tb38-1 fusion protein is provided in SEQ ID NO: 151.
' A fusion protein containing TbRa3, the antigen 38kD, Tb38-1 and DPEP was prepared as follows.
Each of the DNA constructs TbRa3, 38 kD and Tb38-1 were modified by PCR
and cloned into vectors essentially as described above, with the primers PDM-69 (SEQ ID
N0:145 and PDM-83 (SEQ ID NO: 200) being used for amplification of the Tb38-lA
fragment. Tb38-lA differs from Tb38-1 by a DraI site at the 3' end of the coding region that keeps the final amino acid intact while creating a blunt restriction site that is in frame. The TbRa3/38kD/Tb38-lA fusion was then transferred to pET28b using NdeI and EcoRl sites.
DPEP DNA was used to perform PCR using the primers PDM-84 and PDM-85 (SEQ ID NO: 201 and 202, respectively) and 1 ~1 DNA at 50 ng/p,l.
Denaturation at 94 °C
was performed for 2 min, followed by 10 cycles of 96 °C for 15 sec, 68 °C for 15 sec and 72 °C for 1.5 min; 30 cycles of 96 °C for 15 sec, 64 °C for 15 sec and 72 °C for 1.5 min; and finally by 72 °C for 4 min. The DPEP PCR fragment was digested with EcoRI and Eco72I
and clones directly into the pET28Ra3/38kD/38-lA construct which was digested with DraI
and EcoRI. The fusion construct was confirmed to be correct by DNA sequencing.
Recombinant protein was prepared as described above. The DNA and amino acid sequences for the resulting fusion protein (hereinafter referred to as TbF-2) are provided in SEQ ID NO:
203 and 204, respectively.

USE OF M. TUBERCULOSIS FUSION PROTEINS FOR
SERODIAGNOSIS OF TUBERCULOSIS
The effectiveness of the fusion protein TbRa3-38 kD-Tb38-1, prepared as described above, in the serodiagnosis of tuberculosis infection was examined by ELISA.
The ELISA protocol was as described above in Example 6, with the fusion protein being coated at 200 ng/well. A panel of sera was chosen from a group of tuberculosis patients previously shown, either by ELISA or by western blot analysis, to react with each of the three antigens individually or in combination. Such a panel enabled the dissection of the serological reactivity of the fusion protein to determine if all three epitopes functioned with the fusion protein. As shown in Table 5, all four sera that reacted with TbRa3 only were ' detectable with the fusion protein. Three sera that reacted only with Tb38-1 were also detectable, as were two sear that reacted with 38 kD alone. The remaining 15 sera were all positive with the fusion protein based on a cut-off in the assay of mean negatives +3 standard deviations. This data demonstrates the functional activity of all three epitopes in the fusion protein.

REACTIVITY OF TRI-PEPTIDE FUSION PROTEIN WITH SERA FROM M. TUBERCULOSIS
PATIENTS
Serum ID Status ELISA Fusion Fusion and/or recombinantRecombinant Western OD 450 Status Blot Reactivity with Individual proteins 38kd Tb38-1 TbRa3 O 1 B 93I-40TB - - + 0.413 +

O1B93I-41 TB - + + 0.392 +

O1B93I-29 TB + _ + 2.217 +

O1B93I-109TB + t + 0.522 +

O1B93I-132TB + + + 0.937 +

5004 TB ~ + + 1.098 +

15004 TB + + + 2.077 +

39004 TB + + + 1.675 +

68004 TB + + + 2.388 +

99004 TB - + t 0.607 +

107004 TB - + ~ 0.667 +

92004 TB + ~ ~ 1.070 +

97004 TB + - t 1.152 + , 118004 TB + - ~ 2.694 +

173004 TB + + + 3.258 +

175004 TB + - + 2.514 +

274004 TB - - + 3.220 + ' 276004 TB - + - 2.991 +

282004 TB + - - 0.824 +

289004 TB - - + 0.848 +

308004 TB - + - 3.338 +

- 314004 TB - + - 1.362 +

317004 TB + - - 0.763 +

312004 TB - - + 1.079 +

D 176 PPD - - - 0.145 -D 162 PPD - - - 0.073 -D161 PPD - - - 0.097 -D27 PPD - - - 0.082 -A6-124 NORMAL - - - 0.053 -A6-125 NORMAL - - - 0.087 -A6-126 NORMAL - - - 0.346 +

A6-127 NORMAL - - - 0.064 -A6-128 NORMAL - - - 0.034 -A6-129 NORMAL - - - 0.037 -A6-130 NORMAL - - - 0.057 -A6-131 NORMAL - - - 0.054 -A6-132 NORMAL - - 0.022 -A6-133 NORMAL - - 0.147 -A6-134 NORMAL - - - 0.101 -A6-135 NORMAL - - 0.066 -A6-136 NORMAL - - 0.054 -A6-137 NORMAL - - - 0.065 -A6-138 NORMAL - - - 0.041 -A6-139 NORMAL - - - 0.103 -A6-140 NORMAL - - - 0.212 -A6-141 NORMAL - - - 0.056 -A6-142 NORMAL - - - 0.051 -The reactivity of the fusion protein TbF-2 with sera from M. tuberculosis-infected patients was examined by ELISA using the protocol described above.
The results of . these studies (Table 6) demonstrate that all four antigens function independently in the fusion 5 protein.

Serum Status TbF StatusTbF-2 StatusELISA
ID OD450 OD450 Reactivity 38 TbRa3 Tb38-1DPEP
kD

B931-40 TB 0.57 + 0.321 + _ + _ +

B931-41 TB 0.601 + 0.396 + + + + _ B931-109TB 0.494 + 0.404 + + + +_ _ B931-132TB 1.502 + 1.292 + + + + t 5004 TB 1.806 + 1.666 + + _ 15004 TB 2.862 + 2.468 + + + + -39004 TB 2.443 + 1.722 + + + + _ 68004 TB 2.871 + 2.575 + + + + _ 99004 TB 0.691 + 0.971 + _ + _ 107004 TB 0.875 + 0.732 + + _ 92004 TB 1.632 + 1.394 + + f _ 97004 TB 1.491 + 1.979 + + _ +

118004 TB 3.182 + 3.045 + + f _ _ 173004 TB 3.644 + 3.578 + + + + _ 175004 TB 3.332 + 2.916 + + + - _ 274004 TB 3.696 + 3.716 + + - +

276004 TB 3.243 + 2.56 + - _ + _ 282004 TB 1.249 + 1.234 + + _ _ _ 289004 TB 1.373 + 1,17 + _ + _ _ 308004 TB 3.708 + 3.355 + _ + _ 314004 TB 1.663 + 1.399 + - - + _ 317004 TB 1.163 + 0.92 + + _ _ _ 312004 TB 1.709 + 1.453 + - + _ _ 380004 TB 0.238 - 0.461 + _ +

451004 TB 0.18 - 0.2 - - - +_ 478004 TB 0.188 - 0.469 + - _ +_ 410004 TB 0.384 + 2.392 + _ _ +

411004 TB 0.306 + 0.874 + + _ +

421004 TB 0.357 + 1.456 + + +

528004 TB 0.047 0.196 - - +

A6-87 Normal 0.094 0.063 - _ _ A6-88 Normal 0.214 - 0.19 - - _ _ A6-89 Normal 0.248 - 0.125 - - _ _ A6-90 Normal 0.179 - 0.206 - - - _ A6-91 Normal 0.135 - 0.151 - - - _ _ A6-92 Normal 0.064 - 0.097 - - - _ A6-93 Normal 0.072 - 0.098 - - - _ A6-94 Normal 0.072 - 0.064 - - _ A6-95 Normal 0.125 - 0.159 - - - _ A6-96 Normal 0.121 0.12 - - _ _ Cut-off ~ 0.284 0.266 ~ ~

One of skill in the art will appreciate that the order of the individual antigens within the fusion protein may be changed and that comparable activity would be expected - provided each of the epitopes is still functionally available. In addition, truncated forms of the proteins containing active epitopes may be used in the construction of fusion proteins.
S
From the foregoing, it will be appreciated that, although specific embodiments of the invention have been described herein for the purpose of illustration, various modifications may be made without deviating from the spirit and scope of the invention.

SEQUENCE LISTING
(1) GENERAL INFORMATION:
(i) APPLICANT:
(A) NAME: Corixa Corporation (B) STREET: 1124 Columbia Street (C) CITY: Seattle (D) STATE: Washington (E) COUNTRY: USA
(F) POSTAL CODE (ZIP): 98104 (G) TELEPHONE: (206) 754-5711 (H) TELEFAX: (206) 754-5715 (I) TELEX:
(ii) TITLE OF INVENTION: Compounds and Methods for Diagnosis of Tuberculosis (iii) NUMBER OF SEQUENCES: 209 (iv) CORRESPONDENCE ADDRESS:
(A) ADDRESSEE: Osler, Hoskin & l3arcourt (B) STREET: 50 O'Connor Street (C) CITY: Ottawa (D) STATE: Ontario (E) COUNTRY: Canada (F) ZIP: K1P 6L2 (v) COMPUTER READABLE FORM:
(A) MEDIUM TYPE: Floppy disk (B) COMPUTER: IBM PC compatible (C) OPERATING SYSTEM: PC-DOS/MS-DOS
(D) SOFTWARE: PatentIn Release #1.0, Version #1.30 (vi) CURRENT APPLICATION DATA:
(A) APPLICATION NUMBER: 2,268,036 (B) FILING DATE: 7-OCT-1997 (C) CLASSIFICATION:
(vii) PRIOR APPLICATION DATA:
(A) APPLICATION NUMBER: US 08/729,622 (B) FILING DATE: 11-OCT-1996 (vii) PRIOR APPLICATION DATA:
(A) APPLICATION NUMBER: US 08/818,111 (B) FILING DATE: 13-MAR-1997 (viii) ATTORNEY/AGENT INFORMATION:
(A) NAME: Aitken, David W.
(B) REFERENCE/DOCKET NUMBER: 13590 (2) INFORMATION FOR SEQ ID N0:1:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 766 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1:

GTNTGCGCAGGGNCGCACGCACCGCCCGGTGCAAGCCG'TCCTCGAGATAGGTGGTGNCTC 720 (2) INFORMATION
FOR
SEQ
ID N0:2:

(i) S EQUENCE RACTERISTICS:
CHA

(A) LENGTH:752 base pairs (B) TYPE: ucleic n acid (C) STRANDEDNESS:
single (D) TOPOLOGY: linear (xi) TION:
SEQUENCE SEQ ID
DESCRIP N0:2:

GTGGAAGGGCTCCCGCCGGGCTCGGCGTTGCTGGTAGTC;AAACGAGGCCC CAACGCCGGG180 TTTCTCGACGACGTGACCGTGAGCCGTCGCCATGCTGAF,TTCCGGTTGGA AAACAACGAA300 (2) INFORMATION FOR SEQ ID N0:3:

(i) SEQUENCE
CHARACTERISTICS:

(A) LENGTH:813 base airs p (B) TYPE: ucleic n acid (C) STRANDEDNESS: le sing (D) TOPOLOGY: linear (xi) SEQUENCE
DESCRIPTION:
SEQ
ID N0:3:

CATATGCATCACCATCACCATCACACTTCTAACCGCCC.AGCGCGTCGGGG GCGTCGAGCA60 CCACGCGACACCGGGCCCGATCGATCTGCTAGCTTGAG'TCTGGTCAGGCA TCGTCGTCAG120 ATGCTGGTCACGGCTGTCGTTTTGCTCTGTTGTTCGGG'rGTGGCCACGGC CGCGCCCAAG300 ACCTACTGCGAGGAGTTGAAAGGCACCGATACCGGCCA(JGCGTGCCAGAT TCAAATGTCC360 GACCCGGCCTACAACATCAACATCAGCCTGCCCAGTTA(:TACCCCGACCA GAAGTCGCTG420 CGTGGTACGCAGGCCGTGGTGCTCAMGGTCTACCACAA<:GCCGGCGGCAC GCACCCAACG600 ACCACGTACAAGGCCTTCGATTGGGACCAGGCCTATCGC:AAGCCAATCAC CTATGACACG660 CTGTGGCAGGCTGACACCGATCCGCTGCCAGTCGTCTTC:CCCATTGTTGC AAGGTGAACT720 GAGCAACGCAGACCGGGACAACWGGTATCGATAGCCGCC:NAATGCCGGCT TGGAACCCNG780 (2) INFORMATION
FOR
SEQ
ID N0:4:

(i) S EQUENCE CHARACTERISTICS:

(A) LENGTH: 447 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE
DESCRIPTION:
SEQ
ID N0:4:

(2) INFORMATION
FOR
SEQ
ID N0:5:

(i) SEQUENCE
CHARACTERISTICS:

(A) LENGTH: 604 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE
DESCRIPTION:
SEQ
ID N0:5:

NGTNGNGGNTATCAGGATGT TCTTCGNCGA AANCTGAT(~NCGAGGAACAG GGTGTNCCCG420 NAAAAGGGTGGANCAGNNNN AANTNGNGGN CCNAANAAPdCNNNANNGNNG NNAGNTNGNT540 NNNTNTTNNCANNNNNNNTG NNGNNGNNCN NNNCAANCPdNNTNNNNGNAA NNGGNTTNTT600 (2) INFORMATION
FOR
SEQ
ID N0:6:

(i) S EQUENCE CHARACTERISTICS:

(A) LENGTH: 633 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS:
single (D) TOPOLOGY: linear (xi) SEQUENCE
DESCRIPTION:
SEQ
ID N0:6:

(2) INFORMATION
FOR SEQ
ID N0:7:

(i) S EQUENCE S:
CHARACTERISTIC

(A) LENGTH:1362 basepairs (B) TYPE:ucleic n acid (C) STRANDEDNESS: le sing (D) TOPOLOGY: linear (xi) S EQUENCE CRIPTION:
DES SEQ ID
N0:7:

CGACGACGACGGCGCCGGAGAGCGGGCGCGAACGGCGA'rCGACGCGGCCCTGGCCAGAGT 60 CCGCCGGCACCGTTCGGCCCGGATGTCGCCGCCGAATAC;CTGGGCACCGCGGTGCAATTC 540 CGCGCCCAACAGCTCATGCGCCGCGCCGGTGGACTGGTCiTTCGCCCGCAAGGTGCGCGCG 660 GCATGGGCAACACCGTCCGAGCCCATAGCAACCGCGTTC;GCCGCGCTCAGCCACCACCTG 780 GACACCGCGCCGCACCTGCCGCCACCGACTCGTCAGGTCiGTCAGGCGGGTCGTGGGGTCG 840 GTGACCGACGACGACGTCGCCGCGGCCCGATCCCTGCTC'GACACCGATGCGGCGCTGGTT 1020 (2) INFORMATION FOR SEQ ID N0:8:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 1458 base pairs (B) TYPE:
nucleic acid (C) STRANDEDNESS:
single (D) TOPOLOGY: linear (xi) S EQUENCE CRIPTION:EQ ID
DES S N0:8:

CGAGGCGGTGGGCCGAGCGGTTCGCCACGCTATTACGC.AACCTGGAATTCCTGCCGAATT420 CGATTGAGGATTCGCTGCAATCGATCTTTGCGACGCTGcJGACAGGCCGCCGAGCTGCAGC540 CGGGTGTGGTCTCCATGGGCGGTCGCCGGCGTGGCGCC'.CGTATGGCTGTGCTTGATGTGT720 ATTTCAACCTATCGGTTGGTGTGACCGACGCGTTCCTGC;GGGCCGTCGAACGCAACGGCC840 ACACGATCAATAGGGCAAACCCGGTGCCGGGGAGAGGCC;GCATCGAGGCGACCAACCCGT1020 GCGGGGAGGTCCCACTGCTGCCTTACGAGTCATGTAATC;TCGGCTCGATCAACCTCGCCC1080 TGCGGTTCCTTGATGACGTCATCGATGTCAGCCGCTACC',CCTTCCCCGAACTGGGTGAGG1200 (2) INFORMATION FOR SEQ ID N0:9:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 862 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE
DESCRIPTION:
SEQ ID
N0:9:

CCGCCTACGTTTACTCGCTGGACAACAAGCGGTTGTGG'rCCAACCTGGACTGCGCGCCCT 540 (2) INFORMATION
FOR SEQ
ID N0:10:

(i) SEQUENCE
CHARACTERISTICS:

(A) LENGTH: 622 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE :
DESCRIPTION:
SEQ ID
N0:1.0 GACACCCCGGGCGCCAAGAT CGTCGAAGTA GTGGCCGGT'GGTGCTGCCGC GAACGCTGGA120 (2) INFORMATION
FOR SEQ
ID N0:11:

(i) S EQUENCE RACTERISTICS:
CHA

(A) LENGTH:1200 basepairs (B) TYPE:ucleic n acid (C) STRANDEDNESS: le sing (D) TOPOLOGY: linear (xi) S EQUENCE EQ ID :
DESCRIPTION: NO:11 S

AAGGAGCTCCACTCCAGCGGCTCGACCGCACAAGAAAA'rGCCATGGAGCA GTTCGTCTAT180 CTTGACGGACCCACTACCGCCAAGATTTTCAACGGCAC(:ATCACCGTGTG GAATGATCCA480 GGGGCGTGGGGCAAAGGCGCCAGCGAAACGTTCAGCGGC~GGCGTCGGCGT CGGCGCCAGC660 GGGAACAACGGAACGTCGGCCCTACTGCAGACGACCGAC:GGGTCGATCAC CTACAACGAG720 GGACAAGGCAACGACCTGGTATTGGACACGTCGTCGTTC:TACAGACCCAC CCAGCCTGGC900 TCTTACCCGATCGTGCTGGCGACCTATGAGATCGTCTGC:TCGAAATACCC GGATGCGACG960 (2) INFORMATION FOR SEQ ID N0:12:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 1155 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:12:

GGTTGCTCCAAGCGGTGGCCGCCGACGGCCGCATCCAC;ACCACGTTCAACCAGACGATCG 240 TCATCGAGGCGTTCAACACCGGGGAGGACCTGTATTCG'rTCGTCGCGTCCCGGGTGTTCG 480 GCGCCGTAGTCGAGCGGGCCCGCAAGGACGGCTACACC'.PCGACGGTGCTGGGCCGTCGCC 720 GCTACCTGCCCGAGCTGGACAGCAGCAACCGTCAAGTG(:GGGAGGCCGCCGAGCGGGCGG 780 GCTGGGACGCGGCGGCGCACTGAGTGCCGAGCGTGCATC;TGGGGCGGGAATTCGGCGATT 1080 (2) INFORMATION
FOR SEQ
ID N0:13:

(i) SEQUENCE
CHARACTERISTICS:

(A) LENGTH: 1771 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE
DESCRIPTION:
SEQ ID
N0:13:

TCGGGCCTCGGGTTGGCGAT CGTCAAACAG GTGGTGCTC;AACCACGGCGG ATTGCTGCGC120 CGGGTTCAAC CGGGCACCCGCCGGCCCCAGCGGCGGCC~~AGTGGCTGCCA GCGCGGCGCC780 AAGCATCCCC GCAGCAAACATGCCGCCGGGGTCGGTCG:~ACAGGTGGCGG CCAAGGTGGT840 ACCCTTCACG GTGGTGGGGGCTGACCCCACCAGTGATA'.PCGCCGTCGTCC GTGTTCAGGG1080 CGTCTCCGGG CTCACCCCGATCTCCCTGGGTTCCTCCTC:GGACCTGAGGG TCGGTCAGCC1140 GGTGCTGGCG ATCGGGTCGCCGCTCGGTTTGGAGGGCA(:CGTGACCACGG GGATCGTCAG1200 CGCCATTCAG ACCGACGCCGCGATCAACCCCGGTAACTC:CGGGGGCGCGC TGGTGAACAT1320 GAACGCTCAA CTCGTCGGAGTCAACTCGGCCATTGCCAC;GCTGGGCGCGG ACTCAGCCGA1380 TGCGCAGAGC GGCTCGATCGGTCTCGGTTTTGCGATTCC;AGTCGACCAGG CCAAGCGCAT1440 CGCCGACGAG TTGATCAGCACCGGCAAGGCGTCACATGC;CTCCCTGGGTG TGCAGGTGAC1500 CGCGGACGCG TTGGTTGCCGCCGTGCGGTCCAAAGCGCC'GGGCGCCACGG TGGCGCTAAC1680 CTTTCAGGAT CCCTCGGGCGGTAGCCGCACAGTGCAAGT'CACCCTCGGCA AGGCGGAGCA1740 (2) INFORMATION Q ID N0:14:
FOR SE

(i) SEQUENCE CHARACTERISTICS :

(A) LENGTH: 1058 baseairs p (B) TYPE: nu cleic acid (C) STRANDED NESS: e singl (D) TOPOLOGY : linear (xi) SEQUENCE DESCRIPTION: Q ID N0:14:
SE

CTCTAGAACT AGTGGATCCC

GTTGTCGAAC

CGGAATGGCG CGAGTGAGG:~1 CCGGCGACGGCGAGCGCCGGAATGGCGCGAGTGAGGAG'GCGGGCAGTCATGCCCAGCGTG 240 TCACGCAGTCGAAATGGAACGAACCCGTCAACGTCGAC'.CAGGCCGAAGTTGCGTCGACGC 1020 (2) INFORMATION
FOR SEQ
ID N0:15:

(i) SEQUENCE
CHARACTERISTICS:

(A) LENGTH: 542 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE
DESCRIPTION:
SEQ ID
N0:1.5:

GGCGGCGGAGGCGGTCCAGC GGGCGCGGGA TAGCGTCGP,TGACATCCGCG TCGCTCGGGT120 AGTGTCGTTCAAGATGAGGC CGGCGCAACC GCGCTAGCA.CGGGCCGGCGA GCAAGACGCA240 (2) INFORMATION FOR SEQ ID N0:16:

(i) SEQUENCE
CHARACTERISTICS:

(A) LENGTH:913 base pairs (B) TYPE: ucleic n acid (C) STRANDEDNESS:
single (D) TOPOLOGY: linear (xi) SEQUENCE :
DESCRIPTION:
SEQ ID
N0:16 CCGAACAGCCAMGCACCGTTGCCGCCAGCCCCGCCGCCcJTTAACGGCGCT GCCGGGCGCC360 CCGGGCGCCGGAGNGCGTGCCCGCCGGCGCCGCCAACGC:CCAAAAGCCCG GGGTTGCCAC660 CGGCCCCGCCGGACCCACCGGTCCCGCCGATCCCCCCG7.'TGCCGCCGGTG CCGCCGCCAT720 TGGTGCTGCTGAAGCCGTTAGCGCCGGTTCCGCSGGTTC;CGGCGGTGGCG CCNTGGCCGC780 CGGCCCCGCCGTTGCCGTACAGCCACCCCCCGGTGGCGC;CGTTGCCGCCA TTGCCGCCAT840 TGCCGCCGTTGCCGCCATTGCCGCCGTTCCCGCCGCCAC;CGCCGGNTTGG CCGCCGGCGC900 (2) INFORMATION
FOR SEQ
ID N0:17:

(i) S EQUENCE CHARACTERISTICS:

(A) LENGTH: 1872 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE
DESCRIPTION:
SEQ ID
N0:17:

GACCAACAACCACGTGATCG CGGGCGCCAC CGACATCAA'PGCGTTCAGCG TCGGCTCCGG420 CCAAATCCGATCGGGTGGGGGGTCACCCACCGTTCATA'rCGGGCCTACCGCCTTCCTCGG900 CTTGGGTGTTGTCGACAACAACGGCAACGGCGCACGAG'PCCAACGCGTGGTCGGAAGCGC960 TCCGGCGGCAAGTCTCGGCATCTCCACCGGCGACGTGA'CCACCGCGGTCGACGGCGCTCC1020 CTCGGTGAACTGGCAAACCAAGTCGGGCGGCACGCGTA(:AGGGAACGTGACATTGGCCGA1140 CAGCCGTGATTGCCGCGTGAGCCCCCGAGTTCCGTCTCC:CGTGCGCGTGGCATTGTGGAA1260 GCAATGAACGAGGCAGAACACAGCGTTGAGCACCCTCCC:GTGCAGGGCAGTTACGTCGAA1320 GGCGGTGTGGTCGAGCATCCGGATGCCAAGGACTTCGGC:AGCGCCGCCGCCCTGCCCGCC1380 GCCAGCGCGGACGGTTCCGNCGATCTGCGTGGACTCATC:GATCGCCTCGACTACCTGCAG1500 GGTTACGACATTCGCGACTTCTACAAGGTGCTGCCCGAP.TTCGGCACCGTCGACGATTTC1620 (2) INFORMATION FOR
SEQ ID
N0:18:

(i) SE QUENCE :
CHARACTERISTICS

(A) LENGTH: 1482 baseairs p ( B) TYPE:
nucleic acid ( C) STRANDEDNESS:
single ( D) TOPOLOGY: linear (xi) SEQUENCE
DESCRIPTION:
SEQ ID
N0:1'B:

ACCTGATGCC
GAGGAACAGG
GTGTTCCCG'P
GAGCCCGACG
GCGTCCGACC

TTTCGACCAC CAAAATCACCGGGACCATCCCCGCGAGC'rCTGTCAAGATGCTTGATCCTG480 GACCGGGCGG TTGGTGGTTATTCTTCGGTGGTTCCGGC'.PGGTGGGACGCGGCCGAGGTCG780 AGCGGATAGC GGCCAAACCGGGTGAGTTCGGCGTAGATC~CGCCCGGCGTGGTGAGCCTCG1080 GCGAACCGTG CTACCCATTCGGCGGCGGTGGCGAACAGC:ACCCGATGACCGGCCTGACAC1140 CACGACGTTA TCGCGGGCGGTGATGAAATCCAGGGTGCC:CAGATGTGCGATGGTGTCGCG1260 TTTGAGGCCA CGAGCATGCTCAAAGTCGAACTCTTCCAP.,CGACTTCCGAACCGGGAAGCG1320 (2) INFORMATION Q ID N0:19:
FOR SE

(i) SEQUENCE CHARACTERISTICS :

(A) LENGTH: 876 base irs pa (B) TYPE: nucleic acid (C) STRANDEDNESS: e singl (D) TOPOLOGY : linear (xi) SEQUENCE DESCRIPTION:
SEQ ID N0:19:

ATAGCTTCTG GGCCGCGGCC CTCGAGGGTT

GGCGCACCAC CCTGACCGG'r AACACGCCGA

ACGCCACCAA CCCGGCGGTG
GTTGCCTACG ACCCGGCCTT

ATCGGCTACA

GCAACGCACCAACAAGGNGCAGATCCTGGCCTCCGGGG'rAGCGATGCCCGCGGCGCTGCG 420 CGCGGTGTCGGACTGGATGCGCGCGGTCCCCGAGCAGA'.CCCGACCGTGGGTGCCGGGCAC 660 TCGACGGGTGAATATCGACCCATTCGGTGCCGGTCGTGC~GCCGCCCGCCCAGTTACCCGG 840 (2) INFORMATION
FOR SEQ
ID N0:20:

(i) S EQUENCE S:
CHARACTERISTIC

(A) LENGTH:1021 basepairs (B) TYPE:
nucleic acid (C) STRANDEDNESS: le sing (D) TOPOLOGY:
linear (xi) S EQUENCE :
DESCRIPTION:
SEQ ID
N0:2'0 ATCCCCCCGGGCTGCAGGAATTCGGCACGAGAGACAAAP.TTCCACGCGTT AATGCAGGAA60 CAGATTCATAACGAATTCACAGCGGCACAACAATATGTC'GCGATCGCGGT TTATTTCGAC120 TCCAGCCAGGCCTTGGTGCGGCCGGGGTGGTGAGTACC~~TCCAGGCCAC CCCGACCTCC660 GCGGTTGGCCCGACCGCCGTGGCCGCACTGCTGGTCAGG'PATCGGGGGGT CTTGGCGAGC840 T

(2) INFORMATION FOR SEQ ID N0:21:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 321 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:21:
CGTGCCGACG AACGGAAGAA CACAACCATG AAGATGGTcJA AATCGATCGC CGCAGGTCTG 60 (2) INFORMATION
FOR
SEQ
ID N0:22:

(i) S EQUENCE CHARACTERISTICS:

(A) LENGTH: 373 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) EQUENCE DESCRIPTION: SEQ
S ID N0:2:2:

ACGCGATGACCCCGATCGGC CGCGGGCAGC GCCAGCTGA.TCATCGGGGAC CGCAAGACCG240 (2) INFORMATION FOR SEQ ID N0:23:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 352 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE
DESCRIPTION:
SEQ ID
N0:23:

TCTTGACGGCCTGGTACGGGTTGGCCGATTTAGCCGAG.ATCAAGGCGGGCGAATCGGTGC 180 TTGACGACGANCCATATCGGNGATTCCCNCACATNCGA;~GTTCCGANGGAGA 352 (2) INFORMATION FOR SEQ ID N0:24:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 726 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID :
NO::?4 GCGGTTCGCG GCGCTCATGG GTCACAGCGA GTAATCAGC:AAGTTCTCTGG TATATCGCAC120 CTAGCGTCCA GTTGCTTGCC AGATCGCTTT CGTACCGTC:ATCGCATGTAC CGGTTCGCGT180 CTTTCGACCC CGCATGGGGG CCCAACTGGG ATCCCTACF~CCTGCCATGAC GACTTCCACC360 GCGACAC~CGA CGGCCCCGAC CACAGCCGCG ACCCATCCTC GAAGGTCCCG420 ACTACCCCGG

(2) INFORMATION FOR SEQ ID N0:25:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 580 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID
N0:2.5:

CGCGACGACG ACGAACGTCG GGCCCACCAC CGCCTATGCc.;TTGATGCAGG CGACCGGGAT60 TGACACCCGA CGAAGCCGCCGCACTGGGTG ACGAACTC.~1AAGGCGTTACT AGCTAAGACC480 (2) INFORMATION
FOR SEQ ID N0:26:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 160 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS:
single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION:
SEQ ID N0:26:

AACGGAGGCG CCGGGGGTTTTGGCGGGGCC GGGGCGGTC;GGCGGCAACGG CGGGGCCGGC60 GGTGTCACGG GTACGTCGGCCAGCACACCG GGTGGATCC;G 160 (2) INFORMATION FOR SEQ ID N0:27:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 272 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:27:

(2) INFORMATION FOR SEQ ID N0:28:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 317 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY:
linear (xi) SEQUENCE
DESCRIPTION:
SEQ
ID N0:28:

(2) INFORMATION FOR SEQ ID N0:29:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 182 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:'<?9:
GATCGTGGAG CTGTCGATGA ACAGCGTTGC CGGACGCGC:G GCGGCCAGCA CGTCGGTGTA 60 CGCTTCGGGC GCGCTACGAA ACACCGCGAC ACCGTGCGC:G GCGGCGCCGG ACGCCGCCGT 180 (2) INFORMATION FOR SEQ ID N0:30:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 308 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:30:

(2) INFORMATION FOR SEQ ID N0:31:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 267 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY:
linear (xi) SEQUENCE
DESCRIPTION:
SEQ ID
N0:31:

(2) INFORMATION
FOR SEQ
ID N0:32:

(i) S EQUENCE RACTERISTICS:
CHA

(A) LENGTH:1539 basepairs (B) TYPE: ucleic n acid (C) STRANDEDNESS: le sing (D) TOPOLOGY: linear (xi) S EQUENCE EQ ID :
DESCRIPTION: N0:32 S

CTCGTGCCGAAAGAATGTGAGGGGACACGATGAGCAATC;ACACCTACCGA GTGATCGAGA60 TCGTCGGGACCTCGCCCGACGGCGTCGACGCGGCAATCC;AGGGCGGTCTG GCCCGAGCTG120 AACCTTCAAGCGCGGCCGATAACTGAGGTGCATCATTAF,GCGACTTTTCC AGAACATCCT300 GCGGATGGCGTTGCCGCTCACCGGCTATCTGAACAGCGA.GGGACGCTACG CCGGCTTCGA540 (2) INFORMATION
FOR SEQ
ID N0:33:

(i) SEQUENCE RACTERISTICS:
CHA

(A) LENGTH:851 base pairs (B) TYPE:ucleic n acid (C) STRANDEDNESS:
single (D) TOPOLOGY: linear (xi) SEQUENCE :
DESCRIPTION:
SEQ ID
N0::33 CCGGGTTGCTGCGGCGGCCTACGAGACGGCGTATGGGC'~GACGGTGCCCC CGCCGGTGAT120 CGCCGAGAACCGTGCTGAACTGATGATTCTGATAGCGA(:CAACCTCTTGG GGCAAAACAC180 GATGTTTGGCTACGCCGCGGCGACGGCGACGGCGACGGC:GACGTTGCTGC CGTTCGAGGA300 CTCCGACACCGCCGCGGCGAACCAGTTGATGAACAATG7.'GCCCCAGGCGC TGAAACAGTT420 GACCAACTCGGGTGTGTCGATGACCAACACCTTGAGCTC',GATGTTGAAGG GCTTTGCTCC600 (2) INFORMATION FOR SEQ ID N0:34:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 254 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:34:

(2) INFORMATION
FOR SEQ
ID N0:35:

(i) S EQUENCE RACTERISTICS:
CHA

(A) LENGTH:1227 basepairs (B) TYPE:ucleic n acid (C) STRANDEDNESS: le sing (D) TOPOLOGY: linear (xi) S EQUENCE EQ ID :
DESCRIPTION: N0::35 S

GATCCTGACCGAAGCGGCCGCCGCCAAGGCGAAGTCGC'CGTTGGACCAGG AGGGACGGGA60 CGATCTGGCGCTGCGGATCGCGGTTCAGCCGGGGGGGT(sCGCTGGATTGC GCTATAACCT120 TTTCTTCGACGACCGGACGCTGGATGGTGACCAAACCG(:GGAGTTCGGTG GTGTCAGGTT180 GATCGTGGACCGGATGAGCGCGCCGTATGTGGAAGGCGC:GTCGATCGATT TCGTCGACAC240 TATTGAGAAGCAAGGTTCACCATCGACAATCCCAACGCC;ACCGGCTCCTG CGCGTGCGGG300 CCAAGACCTGACCGCGCTGGAAAAGCAACTGAGCGATGC;CTTGCACCTGA CCGCGTGGCG420 CGCTGCTCAGCTTGGCCAAGGCCTGATCGGAGCGCTTGT'CGCGCACGCCG TCGTGGATAC600 CCTGAATCGCGGTTTTGGCCGGTCCCTCCGAGAATGTGC'CTGCCGTGTTG GCTCCGTTGG720 (2) INFORMATION FOR SEQ ID N0:36:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 181 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:36:

GGACCGGCGC TAACGGTGGT GCCGGCGGCA ACGCCTGG'TT GTTCGGGGCC GGCGGGTCCG 120 (2) INFORMATION FOR SEQ ID N0:37:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 290 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:37:

GCGACGGCGTCTTTGCCGGTGCCGGCGGCCAGGGCGGCC;TCGGTGGGCAGGGCGGCAATG 120 (2) INFORMATION FOR SEQ ID N0:38:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 34 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:38:

(2) INFORMATION FOR SEQ ID N0:39:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 155 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:39:

(2) INFORMATION FOR SEQ ID N0:40:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 53 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:~40:

(2) INFORMATION FOR SEQ ID N0:41:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 132 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:~Il:
GATCCACCGC GGGTGCAGAC GGTGCCCGCG GCGCCACCC:C GACCAGCGGC GGCAACGGCG 60 (2) INFORMATION FOR SEQ ID N0:42:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 132 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:42:

(2) INFORMATION FOR SEQ ID N0:43:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 702 base pairs (By TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:43:

(2) INFORMATION FOR SEQ ID N0:44:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 298 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi} SEQUENCE DESCRIPTION: SEQ ID N0:44:

GGCGGCGGGG TGCCGTCGGC GCCGTTGGGA TCCGCGATC',G GGGGCGCCGA ATCGGTGCGG 120 CCCGCTGGCG CTGGTGACAT TGCCGGCTTA GGCCAGGGP,A GGGCCGGCGG CGGCGCCGCG 180 (2) INFORMATION FOR SEQ ID N0:45:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 1058 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi} SEQUENCE DESCRIPTION: SEQ ID N0:45:

TGAACATCGC GGTGGCAGTG CTCGGTCTGG CTGCGTACT'r CGCCAGCTTC GGCCCAATGT 240 (2) INFORMATION FOR SEQ ID N0:46:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 327 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:46:

AATACTCGAG GGCCGACGAG GAGCAGCAGC AGGCGCTGT'C CTCGCAAATG GGCTTCTGAC 300 (2) INFORMATION FOR SEQ ID N0:47:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 170 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:47:
CGGTCGCGAT GATGGCGTTG TCGAACGTGA CCGATTCTG'T ACCGCCGTCG TTGAGATCAA 60 (2) INFORMATION FOR SEQ ID N0:48:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 127 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:48:

(2) INFORMATION FOR SEQ ID N0:49:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 81 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:49:
CGGCGGCAAG GGCGGCACCG CCGGCAACGG GAGCGGCGC;G GCCGGCGGCA ACGGCGGCAA 60 (2) INFORMATION FOR SEQ ID N0:50:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 149 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:50:

(2) INFORMATION FOR SEQ ID N0:51:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 355 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:51:

(2) INFORMATION
FOR
SEQ
ID N0:52:

(i) S EQUENCE S:
CHARACTERISTIC

(A) LENGTH:999 base airs p (B) TYPE:
nucleic acid (C) STRANDEDNESS: le ;
sing (D) TOPOLOGY:
linear (xi) EQUENCE :
S DESCRIPTION:
SEQ ID
NO:.'>2 ATGCATCACCATCACCATCACATGCATCAGGTGGACCCC:AACTTGACACG TCGCAAGGGA60 CGATTGGCGGCACTGGCTATCGCGGCGATGGCCAGCGCC:AGCCTGGTGAC CGTTGCGGTG120 GCCGCCGCCAACACGCCGAATGCCCAGCCGGGCGATCCC;AACGCAGCACC TCCGCCGGCC300 GACCCGAACGCACCGCCGCCACCTGTCATTGCCCCAAAC;GCACCCCAACC TGTCCGGATC360 GACAACCCGGTTGGAGGATTCAGCTTCGCGCTGCCTGCT'GGCTGGGTGGA GTCTGACGCC420 CCGACGACACCGACACCGCAGCGGACCTTACCGGCCTGA ggg (2) INFORMATION FOR SEQ ID N0:53:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 332 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:53:
Met His His His His His His Met His Gln Val Asp Pro Asn Leu Thr Arg Arg Lys Gly Arg Leu Ala Ala Leu ,~11a Ile Ala Ala Met Ala Ser Ala Ser Leu Val Thr Val Ala Val Pro Ala Thr Ala Asn Ala Asp Pro Glu Pro Ala Pro Pro Val Pro Thr Thr i~la Ala Ser Pro Pro Ser Thr Ala Ala Ala Pro Pro Ala Pro Ala Thr 1?ro Val Ala Pro Pro Pro Pro Ala Ala Ala Asn Thr Pro Asn Ala Gln F?ro Gly Asp Pro Asn Ala Ala Pro Pro Pro Ala Asp Pro Asn Ala Pro F?ro Pro Pro Val Ile Ala Pro Asn Ala Pro Gln Pro Val Arg Ile Asp Asn Pro Val Gly Gly Phe Ser Phe Ala Leu Pro Ala Gly Trp Val Glu Ser Asp Ala Ala His Phe Asp Tyr Gly Ser Ala Leu Leu Ser Lys Thr Thr Gly Asp Pro Pro Phe Pro Gly Gln Pro Pro Pro Val Ala Asn Asp T'hr Arg Ile Val Leu Gly Arg Leu Asp Gln Lys Leu Tyr Ala Ser Ala Glu Ala Thr Asp Ser Lys Ala Ala Ala Arg Leu Gly Ser Asp Met Gly Glu Phe Tyr Met Pro Tyr Pro Gly Thr Arg Ile Asn Gln Glu Thr Val Ser Leu Asp Ala Asn Gly Val Ser Gly Ser Ala Ser Tyr Tyr Glu Val Lys Phe Ser Asp Pro Ser Lys Pro Asn Gly Gln Ile Trp Thr Gly Val Ile Gly Ser Pro Ala Ala Asn Ala Pro Asp Ala Gly Pro Pro Gln Arg Trp Phe Val Val Trp Leu Gly Thr Ala Asn Asn Pro Val Asp Lys Gly A.la Ala Lys Ala Leu Ala Glu Ser Ile Arg Pro Leu Val Ala Pro Pro P:ro Ala Pro Ala Pro Ala Pro Ala Glu Pro Ala Pro Ala Pro Ala Pro Ala Gly Glu Val Ala Pro Thr Pro Thr Thr Pro Thr Pro Gln Arg Thr Leu Pro Ala (2) INFORMATION FOR SEQ ID N0:59:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 20 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:54:
Asp Pro Val Asp Ala Val Ile Asn Thr 'Phr Xaa Asn Tyr Gly Gln Val 1 5 :LO 15 Val Ala Ala Leu (2) INFORMATION FOR SEQ ID N0:55:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 15 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:55:
Ala Val Glu Ser Gly Met Leu Ala Leu Gly Thr Pro Ala Pro Ser (2) INFORMATION FOR SEQ ID N0:56:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 19 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:56:
Ala Ala Met Lys Pro Arg Thr Gly Asp Gly Pro Leu Glu Ala Ala Lys Glu Gly Arg (2) INFORMATION FOR SEQ ID N0:57:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 15 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:5'7:
Tyr Tyr Trp Cys Pro Gly Gln Pro Phe Aap Pro Ala Trp Gly Pro (2) INFORMATION FOR SEQ ID N0:58:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 14 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:58:
Asp Ile Gly Ser Glu Ser Thr Glu Asp Gln Gln Xaa Ala Val (2) INFORMATION FOR SEQ ID N0:59:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 13 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:.'i9:
Ala Glu Glu Ser Ile Ser Thr Xaa Glu Xaa Ile Val Pro (2) INFORMATION FOR SEQ ID N0:60:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 17 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:E~O:
Asp Pro Glu Pro Ala Pro Pro Val Pro Thr Ala Ala Ala Ala Pro Pro Ala (2) INFORMATION FOR SEQ ID N0:61:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 15 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:61:
Ala Pro Lys Thr Tyr Xaa Glu Glu Leu Lys Gly Thr Asp Thr Gly (2) INFORMATION FOR SEQ ID N0:62:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 30 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:62:
Asp Pro Ala Ser Ala Pro Asp Val Pro Thr Ala Ala Gln Gln Thr Ser Leu Leu Asn Asn Leu Ala Asp Pro Asp Val Ser Phe Ala Asp (2) INFORMATION FOR SEQ ID N0:63:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 29 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:i53:
Gly Cys Gly Asp Arg Ser Gly Gly Asn Leu Asp Gln Ile Arg Leu Arg Arg Asp Arg Ser Gly Gly Asn Leu (2) INFORMATION FOR SEQ ID N0:64:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 187 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:64:
Thr Gly Ser Leu Asn Gln Thr His Asn Arg Arg Ala Asn Glu Arg Lys Asn Thr Thr Met Lys Met Val Lys Ser Ile Ala Ala Gly Leu Thr Ala Ala Ala Ala Ile Gly Ala Ala Ala Ala Gly Val Thr Ser Ile Met Ala Gly Gly Pro Val Val Tyr Gln Met Gln Pro Val Val Phe Gly Ala Pro Leu Pro Leu Asp Pro Ala Ser Ala Pro Asp Val Pro Thr Ala Ala Gln 65 70 75 gp Leu Thr Ser Leu Leu Asn Ser Leu Ala Asp Pro Asn Val Ser Phe Ala Asn Lys Gly Ser Leu Val Glu Gly Gly Ile Gly Gly Thr Glu Ala Arg Ile Ala Asp His Lys Leu Lys Lys Ala Ala Glu His Gly Asp Leu Pro Leu Ser Phe Ser Val Thr Asn Ile Gln P:ro Ala Ala Ala Gly Ser Ala Thr Ala Asp Val Ser Val Ser Gly Pro Lys Leu Ser Ser Pro Val Thr Gln Asn Val Thr Phe Val Asn Gln Gly Gly Trp Met Leu Ser Arg Ala Ser Ala Met Glu Leu Leu Gln Ala Ala Gly Xaa (2) INFORMATION FOR SEQ ID N0:65:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 148 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:65:
Asp Glu Val Thr Val Glu Thr Thr Ser Val Phe Arg Ala Asp Phe Leu 1 5 :LO 15 Ser Glu Leu Asp Ala Pro Ala Gln Ala Gly Thr Glu Ser Ala Val Ser Gly Val Glu Gly Leu Pro Pro Gly Ser Ala Leu Leu Val Val Lys Arg Gly Pro Asn Ala Gly Ser Arg Phe Leu Leu Asp Gln Ala Ile Thr Ser Ala Gly Arg His Pro Asp Ser Asp Ile Phe Leu Asp Asp Val Thr Val Ser Arg Arg His Ala Glu Phe Arg Leu Glu Asn Asn Glu Phe Asn Val Val Asp Val Gly Ser Leu Asn Gly Thr T'yr Val Asn Arg Glu Pro Val Asp Ser Ala Val Leu Ala Asn Gly Asp Glu Val Gln Ile Gly Lys Leu Arg Leu Val Phe Leu Thr Gly Pro Lys Gln Gly Glu Asp Asp Gly Ser Thr Gly Gly Pro (2) INFORMATION FOR SEQ ID N0:66:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 230 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:66:
Thr Ser Asn Arg Pro Ala Arg Arg Gly A:rg Arg Ala Pro Arg Asp Thr Gly Pro Asp Arg Ser Ala Ser Leu Ser Leu Val Arg His Arg Arg Gln Gln Arg Asp Ala Leu Cys Leu Ser Ser Thr Gln Ile Ser Arg Gln Ser Asn Leu Pro Pro Ala Ala Gly Gly Ala .Ala Asn Tyr Ser Arg Arg Asn Phe Asp Val Arg Ile Lys Ile Phe Met Leu Val Thr Ala Val Val Leu Leu Cys Cys Ser Gly Val Ala Thr Ala ;~la Pro Lys Thr Tyr Cys Glu Glu Leu Lys Gly Thr Asp Thr Gly Gln Ala Cys Gln Ile Gln Met Ser Asp Pro Ala Tyr Asn Ile Asn Ile Ser Leu Pro Ser Tyr Tyr Pro Asp Gln Lys Ser Leu Glu Asn Tyr Ile Ala Gln Thr Arg Asp Lys Phe Leu Ser Ala Ala Thr Ser Ser Thr Pro Arg Glu Ala Pro Tyr Glu Leu Asn Ile Thr Ser Ala Thr Tyr Gln Ser Ala 7:1e Pro Pro Arg Gly Thr Gln 165 7.70 175 Ala Val Val Leu Xaa Val Tyr His Asn Ala Gly Gly Thr His Pro Thr Thr Thr Tyr Lys Ala Phe Asp Trp Asp Gln Ala Tyr Arg Lys Pro Ile Thr Tyr Asp Thr Leu Trp Gln Ala Asp Thr Asp Pro Leu Pro Val Val Phe Pro Ile Val Ala Arg (2) INFORMATION FOR SEQ ID N0:67:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 132 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:67:
Thr Ala Ala Ser Asp Asn Phe Gln Leu Ser Gln Gly Gly Gln Gly Phe Ala Ile Pro Ile Gly Gln Ala Met Ala I.le Ala Gly Gln Ile Arg Ser Gly Gly Gly Ser Pro Thr Val His Ile G:ly Pro Thr Ala Phe Leu Gly Leu Gly Val Val Asp Asn Asn Gly Asn Gly Ala Arg Val Gln Arg Val Val Gly Ser Ala Pro Ala Ala Ser Leu Gly Ile Ser Thr Gly Asp Val Ile Thr Ala Val Asp Gly Ala Pro Ile Asn Ser Ala Thr Ala Met Ala Asp Ala Leu Asn Gly His His Pro Gly Asp Val Ile Ser Val Asn Trp Gln Thr Lys Ser Gly Gly Thr Arg Thr Gly Asn Val Thr Leu Ala Glu Gly Pro Pro Ala (2) INFORMATION FOR SEQ ID N0:68:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 100 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:Ei8:
Val Pro Leu Arg Ser Pro Ser Met Ser Pro Ser Lys Cys Leu Ala Ala 1 5 1.0 15 Ala Gln Arg Asn Pro Val Ile Arg Arg Arg Arg Leu Ser Asn Pro Pro Pro Arg Lys Tyr Arg Ser Met Pro Ser Fro Ala Thr Ala Ser Ala Gly Met Ala Arg Val Arg Arg Arg Ala Ile Trp Arg Gly Pro Ala Thr Xaa Ser Ala Gly Met Ala Arg Val Arg Arg Trp Xaa Val Met Pro Xaa Val Ile Gln Ser Thr Xaa Ile Arg Xaa Xaa Gly Pro Phe Asp Asn Arg Gly Ser Glu Arg Lys (2) INFORMATION FOR SEQ ID N0:69:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 163 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:69:
Met Thr Asp Asp Ile Leu Leu Ile Asp Thr Asp Glu Arg Val Arg Thr Leu Thr Leu Asn Arg Pro Gln Ser Arg Asn Ala Leu Ser Ala Ala Leu Arg Asp Arg Phe Phe Ala Xaa Leu Xaa Asp Ala Glu Xaa Asp Asp Asp Ile Asp Val Val Ile Leu Thr Gly Ala Asp Pro Val Phe Cys Ala Gly Leu Asp Leu Lys Val Ala Gly Arg Ala Asp Arg Ala Ala Gly His Leu 65 70 75 gp Thr Ala Val Gly Gly His Asp Gln Ala Gly Asp Arg Arg Asp Gln Arg Arg Arg Gly His Arg Arg Ala Arg Thr Gly Ala Val Leu Arg His Pro Asp Arg Leu Arg Ala Arg Pro Leu Arg Arg His Pro Arg Pro Gly Gly Ala Ala Ala His Leu Gly Thr Gln Cys Val Leu Ala Ala Lys Gly Arg His Arg Xaa Gly Pro Val Asp Glu Pro Asp Arg Arg Leu Pro Val Arg Asp Arg Arg (2) INFORMATION FOR SEQ ID N0:70:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 344 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:70:
Met Lys Phe Val Asn His Ile Glu Pro V'al Ala Pro Arg Arg Ala Gly Gly Ala Val Ala Glu Val Tyr Ala Glu Ala Arg Arg Glu Phe Gly Arg Leu Pro Glu Pro Leu Ala Met Leu Ser Pro Asp Glu Gly Leu Leu Thr Ala Gly Trp Ala Thr Leu Arg Glu Thr Leu Leu Val Gly Gln Val Pro Arg Gly Arg Lys Glu Ala Val Ala Ala Ala Val Ala Ala Ser Leu Arg Cys Pro Trp Cys Val Asp Ala His Thr Thr Met Leu Tyr Ala Ala Gly Gln Thr Asp Thr Ala Ala Ala Ile Leu Ala Gly Thr Ala Pro Ala Ala Gly Asp Pro Asn Ala Pro Tyr Val Ala T:rp Ala Ala Gly Thr Gly Thr Pro Ala Gly Pro Pro Ala Pro Phe Gly Pro Asp Val Ala Ala Glu Tyr Leu Gly Thr Ala Val Gln Phe His Phe Ile Ala Arg Leu Val Leu Val Leu Leu Asp Glu Thr Phe.Leu Pro Gly Gly Pro Arg Ala Gln Gln Leu Met Arg Arg Ala Gly Gly Leu Val Phe Ala Arg Lys Val Arg Ala Glu His Arg Pro Gly Arg Ser Thr Arg Arg :Leu Glu Pro Arg Thr Leu Pro Asp Asp Leu Ala Trp Ala Thr Pro Ser Glu Pro Ile Ala Thr Ala Phe Ala Ala Leu Ser His His Leu Asp Thr Ala Pro His Leu Pro Pro Pro Thr Arg Gln Val Val Arg Arg Val Val Gly Ser Trp His Gly Glu Pro 245 :?50 255 Met Pro Met Ser Ser Arg Trp Thr Asn Glu His Thr Ala Glu Leu Pro Ala Asp Leu His Ala Pro Thr Arg Leu Ala Leu Leu Thr Gly Leu Ala Pro His Gln Val Thr Asp Asp Asp Val Ala Ala Ala Arg Ser Leu Leu Asp Thr Asp Ala Ala Leu Val Gly Ala Leu Ala Trp Ala Ala Phe Thr Ala Ala Arg Arg Ile Gly Thr Trp Ile Gly Ala Ala Ala Glu Gly Gln Val Ser Arg Gln Asn Pro Thr Gly (2) INFORMATION FOR SEQ ID N0:71:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 485 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:71:
Asp Asp Pro Asp Met Pro Gly Thr Val Ala Lys Ala Val Ala Asp Ala Leu Gly Arg Gly Ile Ala Pro Val Glu Asp Ile Gln Asp Cys Val Glu Ala Arg Leu Gly Glu Ala Gly Leu Asp Asp Val Ala Arg Val Tyr Ile Ile Tyr Arg Gln Arg Arg Ala Glu Leu A:rg Thr Ala Lys Ala Leu Leu Gly Val Arg Asp Glu Leu Lys Leu Ser Leu Ala Ala Val Thr Val Leu 65 70 75 g0 Arg Glu Arg Tyr Leu Leu His Asp Glu Gln Gly Arg Pro Ala Glu Ser Thr Gly Glu Leu Met Asp Arg Ser Ala Arg Cys Val Ala Ala Ala Glu Asp Gln Tyr Glu Pro Gly Ser Ser Arg Arg Trp Ala Glu Arg Phe Ala Thr Leu Leu Arg Asn Leu Glu Phe Leu 1?ro Asn Ser Pro Thr Leu Met Asn Ser Gly Thr Asp Leu Gly Leu Leu Ala Gly Cys Phe Val Leu Pro Ile Glu Asp Ser Leu Gln Ser Ile Phe Ala Thr Leu Gly Gln Ala Ala Glu Leu Gln Arg Ala Gly Gly Gly Thr Czly Tyr Ala Phe Ser His Leu Arg Pro Ala Gly Asp Arg Val Ala Ser Thr Gly Gly Thr Ala Ser Gly Pro Val Ser Phe Leu Arg Leu Tyr Asp Ser Ala Ala Gly Val Val Ser Met Gly Gly Arg Arg Arg Gly Ala Cys Nlet Ala Val Leu Asp Val Ser His Pro Asp Ile Cys Asp Phe Val Thr F,la Lys Ala Glu Ser Pro Ser Glu Leu Pro His Phe Asn Leu Ser Val Gly Val Thr Asp Ala Phe Leu Arg Ala Val Glu Arg Asn Gly Leu His A.rg Leu Val Asn Pro Arg Thr Gly Lys Ile Val Ala Arg Met Pro Ala Ala Glu Leu Phe Asp Ala Ile Cys Lys Ala Ala His Ala Gly Gly Asp Pro Gly Leu Val Phe Leu Asp Thr Ile Asn Arg Ala Asn Pro Val Pro Gly Arg Gly Arg Ile Glu Ala Thr Asn Pro Cys Gly Glu Val Pro Leu Leu Pro Tyr Glu Ser Cys Asn Leu Gly Ser Ile Asn Leu Ala Arg Met Leu Ala Asp Gly Arg Val Asp Trp Asp Arg Leu Glu Glu Val Ala Gly Val Ala Val Arg Phe Leu Asp Asp Val Ile Asp Val Ser Arg Tyr Pro Plze Pro Glu Leu Gly Glu Ala Ala Arg Ala Thr Arg Lys Ile Gly Leu Gly Val Met Gly Leu Ala Glu Leu Leu Ala Ala Leu Gly Ile Pro Tyr .Asp Ser Glu Glu Ala Val Arg Leu Ala Thr Arg Leu Met Arg Arg Ile Gln Gln Ala Ala His Thr Ala Ser Arg Arg Leu Ala Glu Glu Arg Gly Ala Phe Pro Ala Phe Thr Asp Ser Arg Phe Ala Arg Ser Gly Pro Arg Arg Asn Ala Gln Val Thr Ser Val Ala Pro Thr Gly (2) INFORMATION FOR SEQ ID N0:72:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 267 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:72:
Gly Val Ile Val Leu Asp Leu Glu Pro Arg Gly Pro Leu Pro Thr Glu 1 5 7.0 15 Ile Tyr Trp Arg Arg Arg Gly Leu Ala Leu Gly Ile Ala Val Val Val Val Gly Ile Ala Val Ala Ile Val Ile Ala Phe Val Asp Ser Ser Ala Gly Ala Lys Pro Val Ser Ala Asp Lys Fro Ala Ser Ala Gln Ser His Pro Gly Ser Pro Ala Pro Gln Ala Pro Gln Pro Ala Gly Gln Thr Glu Gly Asn Ala Ala Ala Ala Pro Pro Gln Gly Gln Asn Pro Glu Thr Pro Thr Pro Thr Ala Ala Val Gln Pro Pro Pro Val Leu Lys Glu Gly Asp Asp Cys Pro Asp Ser Thr Leu Ala Val Lys Gly Leu Thr Asn Ala Pro Gln Tyr Tyr Val Gly Asp Gln Pro Lys Phe Thr Met Val Val Thr Asn Ile Gly Leu Val Ser Cys Lys Arg Asp Va l Gly Ala Ala Val Leu Ala Ala Tyr Val Tyr Ser Leu Asp Asn Lys A:rg Leu Trp Ser Asn Leu Asp 165 1'70 175 Cys Ala Pro Ser Asn Glu Thr Leu Val Lys Thr Phe Ser Pro Gly Glu Gln Val Thr Thr Ala Val Thr Trp Thr Gly Met Gly Ser Ala Pro Arg Cys Pro Leu Pro Arg Pro Ala Ile Gly Pro Gly Thr Tyr Asn Leu Val Val Gln Leu Gly Asn Leu Arg Ser Leu :Pro Val Pro Phe Ile Leu Asn Gln Pro Pro Pro Pro Pro Gly Pro Val Pro Ala Pro Gly Pro Ala Gln 245 :?50 255 Ala Pro Pro Pro Glu Ser Pro Ala Gln Gly Gly (2) INFORMATION FOR SEQ ID N0:73:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 97 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:73:
Leu Ile Ser Thr Gly Lys Ala Ser His Ala Ser Leu Gly Val Gln Val 1 5 1.0 15 Thr Asn Asp Lys Asp Thr Pro Gly Ala Lys Ile Val Glu Val Val Ala Gly Gly Ala Ala Ala Asn Ala Gly Val Fro Lys Gly Val Val Val Thr Lys Val Asp Asp Arg Pro Ile Asn Ser Ala Asp Ala Leu Val Ala Ala Val Arg Ser Lys Ala Pro Gly Ala Thr Val Ala Leu Thr Phe Gln Asp Pro Ser Gly Gly Ser Arg Thr Val Gln Val Thr Leu Gly Lys Ala Glu Gln (2) INFORMATION FOR SEQ ID N0:74:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 364 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:74:
Gly Ala Ala Val Ser Leu Leu Ala Ala G:ly Thr Leu Val Leu Thr Ala Cys Gly Gly Gly Thr Asn Ser Ser Ser Ser Gly Ala Gly Gly Thr Ser Gly Ser Val His Cys Gly Gly Lys Lys Glu Leu His Ser Ser Gly Ser Thr Ala Gln Glu Asn Ala Met Glu Gln Phe Val Tyr Ala Tyr Val Arg Ser Cys Pro Gly Tyr Thr Leu Asp Tyr Asn Ala Asn Gly Ser Gly Ala Gly Val Thr Gln Phe Leu Asn Asn Glu 'Phr Asp Phe Ala Gly Ser Asp Val Pro Leu Asn Pro Ser Thr Gly Gln Pro Asp Arg Ser Ala Glu Arg Cys Gly Ser Pro Ala Trp Asp Leu Pro '.Phr Val Phe Gly Pro Ile Ala Ile Thr Tyr Asn Ile Lys Gly Val Ser '.Chr Leu Asn Leu Asp Gly Pro Thr Thr Ala Lys Ile Phe Asn Gly Thr ile Thr Val Trp Asn Asp Pro Gln Ile Gln Ala Leu Asn Ser Gly Thr Asp Leu Pro Pro Thr Pro Ile 165 7.70 175 Ser Val Ile Phe Arg Ser Asp Lys Ser Gly Thr Ser Asp Asn Phe Gln Lys Tyr Leu Asp Gly Val Ser Asn Gly Ala Trp Gly Lys Gly Ala Ser Glu Thr Phe Ser Gly Gly Val Gly Val Gly Ala Ser Gly Asn Asn Gly Thr Ser Ala Leu Leu Gln Thr Thr Asp Gly Ser Ile Thr Tyr Asn Glu Trp Ser Phe Ala Val Gly Lys Gln Leu Asn Met Ala Gln Ile Ile Thr Ser Ala Gly Pro Asp Pro Val Ala Ile Thr Thr Glu Ser Val Gly Lys Thr Ile Ala Gly Ala Lys Ile Met Gly Gln Gly Asn Asp Leu Val Leu Asp Thr Ser Ser Phe Tyr Arg Pro Thr Gln Pro Gly Ser Tyr Pro Ile Val Leu Ala Thr Tyr Glu Ile Val Cys Ser Lys Tyr Pro Asp Ala Thr Thr Gly Thr Ala Val Arg Ala Phe Met Gln Ala Ala Ile Gly Pro Gly Gln Glu Gly Leu Asp Gln Tyr Gly Ser Ile Pro Leu Pro Lys Ser Phe Gln Ala Lys Leu Ala Ala Ala Val Asn Ala Ile Ser (2) INFORMATION FOR SEQ ID N0:75:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 309 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:'75:
Gln Ala Ala Ala Gly Arg Ala Val Arg ~Arg Thr Gly His Ala Glu Asp Gln Thr His Gln Asp Arg Leu His His Gly Cys Arg Arg Ala Ala Val Val Val Arg Gln Asp Arg Ala Ser Val Ser Ala Thr Ser Ala Arg Pro Pro Arg Arg His Pro Ala Gln Gly His Arg Arg Arg Val Ala Pro Ser Gly Gly Arg Arg Arg Pro His Pro His His Val Gln Pro Asp Asp Arg Arg Asp Arg Pro Ala Leu Leu Asp Arg Thr Gln Pro Ala Glu His Pro Asp Pro His Arg Arg Gly Pro Ala Asp E'ro Gly Arg Val Arg Gly Arg Gly Arg Leu Arg Arg Val Asp Asp Gly Arg Leu Gln Pro Asp Arg Asp Ala Asp His Gly Ala Pro Val Arg Gly Arg Gly Pro His Arg Gly Val Gln His Arg Gly Gly Pro Val Phe Val Arg Arg Val Pro Gly Val Arg Cys Ala His Arg Arg Gly His Arg Arg V'al Ala Ala Pro Gly Gln Gly Asp Val Leu Arg Ala Gly Leu Arg Val Glu Arg Leu Arg Pro Val Ala Ala Val Glu Asn Leu His Arg Gly Ser Gln Arg Ala Asp Gly Arg Val Phe Arg Pro Ile Arg Arg Gly Ala Arg Leu Pro Ala Arg Arg Ser Arg Ala Gly Pro Gln Gly Arg Leu His Leu Asp Gly Ala Gly Pro Ser Pro Leu Pro Ala Arg Ala Gly Gln Gln Gln Pro Ser Ser Ala Gly Gly Arg 245 2'50 255 Arg Ala Gly Gly Ala Glu Arg Ala Asp Pro Gly Gln Arg Gly Arg His His Gln Gly Gly His Asp Pro Gly Arg G.ln Gly Ala Gln Arg Gly Thr Ala Gly Val Ala His Ala Ala Ala Gly Pro Arg Arg Ala Ala Val Arg Asn Arg Pro Arg Arg (2) INFORMATION FOR SEQ ID N0:76:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 580 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:'76:
Ser Ala Val Trp Cys Leu Asn Gly Phe '.Chr Gly Arg His Arg His Gly 1 5 .LO 15 Arg Cys Arg Val Arg Ala Ser Gly Trp Arg Ser Ser Asn Arg Trp Cys Ser Thr Thr Ala Asp Cys Cys Ala Ser hys Thr Pro Thr Gln Ala Ala Ser Pro Leu Glu Arg Arg Phe Thr Cys C:ys Ser Pro Ala Val Gly Cys Arg Phe Arg Ser Phe Pro Val Arg Arg Leu Ala Leu Gly Ala Arg Thr 65 70 75 g0 Ser Arg Thr Leu Gly Val Arg Arg Thr Leu Ser Gln Trp Asn Leu Ser Pro Arg Ala Gln Pro Ser Cys Ala Val Thr Val Glu Ser His Thr His Ala Ser Pro Arg Met Ala Lys Leu Ala Arg Val Val Gly Leu Val Gln Glu Glu Gln Pro Ser Asp Met Thr Asn His Pro Arg Tyr Ser Pro Pro Pro Gln Gln Pro Gly Thr Pro Gly Tyr Ala Gln Gly Gln Gln Gln Thr Tyr Ser Gln Gln Phe Asp Trp Arg Tyr Pro Pro Ser Pro Pro Pro Gln Pro Thr Gln Tyr Arg Gln Pro Tyr Glu Ala Leu Gly Gly Thr Arg Pro Gly Leu Ile Pro Gly Val Ile Pro Thr Met Thr Pro Pro Pro Gly Met Val Arg Gln Arg Pro Arg Ala Gly Met Leu Ala Ile Gly Ala Val Thr Ile Ala Val Val Ser Ala Gly Ile Gly G.ly Ala Ala Ala Ser Leu Val Gly Phe Asn Arg Ala Pro Ala Gly Pro Se r Gly Gly Pro Val Ala Ala Ser Ala Ala Pro Ser Ile Pro Ala Ala Asn Met Pro Pro Gly Ser Val Glu Gln Val Ala Ala Lys Val Val Pro Ser Val Val Met Leu Glu Thr Asp Leu Gly Arg Gln Ser Glu Glu Gly ;Ser Gly Ile Ile Leu Ser Ala Glu Gly Leu Ile Leu Thr Asn Asn His 'Jal Ile Ala Ala Ala Ala Lys Pro Pro Leu Gly Ser Pro Pro Pro Lys 'Chr Thr Val Thr Phe Ser Asp Gly Arg Thr Ala Pro Phe Thr Val Val C~ly Ala Asp Pro Thr, Ser Asp Ile Ala Val Val Arg Val Gln Gly Val Ser Gly Leu Thr Pro Ile Ser Leu Gly Ser Ser Ser Asp Leu Arg Val C~ly Gln Pro Val Leu Ala Ile Gly Ser Pro Leu Gly Leu Glu Gly Thr Val Thr Thr Gly Ile Val Ser Ala Leu Asn Arg Pro Val Ser Thr Thr C~ly Glu Ala Gly Asn Gln Asn Thr Val Leu Asp Ala Ile Gln Thr Asp Ala Ala Ile Asn Pro Gly Asn Ser Gly Gly Ala Leu Val Asn Met Asn Ala Gln Leu Val Gly Val Asn Ser Ala Ile Ala Thr Leu Gly Ala Asp Ser Ala Asp Ala Gln Ser Gly Ser Ile Gly Leu Gly Phe Ala Ile Pro Val Asp Gln Ala Lys Arg Ile Ala Asp Glu Leu Ile Ser Thr Gly Lys Ala Ser His Ala Ser Leu Gly Val Gln Val Thr Asn Asp Lys Asp Thr Pro Gly Ala Lys Ile Val Glu Val Val Ala Gly Gly Ala Ala Ala Asn Ala Gly Val Pro Lys Gly Val Val Val Thr Lys Val Asp Asp Arg Pro Ile Asn Ser Ala Asp Ala Leu Val Ala Ala Val Arg Ser Lys Ala Pro Gly Ala Thr Val Ala Leu Thr Phe Gln Asp Pro Ser Gly Gly Ser Arg Thr Val Gln Val Thr Leu Gly 565 5'70 575 Lys Ala Glu Gln (2) INFORMATION FOR SEQ ID N0:77:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 233 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:'77:
Met Asn Asp Gly Lys Arg Ala Val Thr Ser Ala Val Leu Val Val Leu 1 5 :LO 15 Gly Ala Cys Leu Ala Leu Trp Leu Ser Gly Cys Ser Ser Pro Lys Pro Asp Ala Glu Glu Gln Gly Val Pro Val :ier Pro Thr Ala Ser Asp Pro Ala Leu Leu Ala Glu Ile Arg Gln Ser Leu Asp Ala Thr Lys Gly Leu Thr Ser Val His Val Ala Val Arg Thr 9'hr Gly Lys Val Asp Ser Leu 65 70 75 g0 Leu Gly Ile Thr Ser Ala Asp Val Asp Val Arg Ala Asn Pro Leu Ala 85 g0 95 Ala Lys Gly Val Cys Thr Tyr Asn Asp Glu Gln Gly Val Pro Phe Arg Val Gln Gly Asp Asn Ile Ser Val Lys L~eu Phe Asp Asp Trp Ser Asn Leu Gly Ser Ile Ser Glu Leu Ser Thr Ser Arg Val Leu Asp Pro Ala Ala Gly Val Thr Gln Leu Leu Ser Gly Val Thr Asn Leu Gln Ala Gln Gly Thr Glu Val Ile Asp Gly Ile Ser Thr Thr Lys Ile Thr Gly Thr Ile Pro Ala Ser Ser Val Lys Met Leu Asp Pro Gly Ala Lys Ser Ala Arg Pro Ala Thr Val Trp Ile Ala Gln Asp Gly Ser His His Leu Val Arg Ala Ser Ile Asp Leu Gly Ser Gly Ser Ile Gln Leu Thr Gln Ser Lys Trp Asn Glu Pro Val Asn Val Asp (2) INFORMATION FOR SEQ ID N0:78:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 66 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:78:
Val Ile Asp Ile Ile Gly Thr Ser Pro Thr Ser Trp Glu Gln Ala Ala Ala Glu Ala Val Gln Arg Ala Arg Asp Ser Val Asp Asp Ile Arg Val Ala Arg Val Ile Glu Gln Asp Met Ala Val Asp Ser Ala Gly Lys Ile Thr Tyr Arg Ile Lys Leu Glu Val Ser Phe Lys Met Arg Pro Ala Gln Pro Arg (2) INFORMATION FOR SEQ ID N0:79:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 69 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:79:
Val Pro Pro Ala Pro Pro Leu Pro Pro Leu Pro Pro Ser Pro Ile Ser 1 5 7.0 15 Cys Ala Ser Pro Pro Ser Pro Pro Leu E'ro Pro Ala Pro Pro Val Ala Pro Gly Pro Pro Met Pro Pro Leu Asp Pro Trp Pro Pro Ala Pro Pro Leu Pro Tyr Ser Thr Pro Pro Gly Ala E~ro Leu Pro Pro Ser Pro Pro Ser Pro Pro Leu Pro (2) INFORMATION FOR SEQ ID N0:80:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 355 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:80:
Met Ser Asn Ser Arg Arg Arg Ser Leu Arg Trp Ser Trp Leu Leu Ser Val Leu Ala Ala Val Gly Leu Gly Leu Ala Thr Ala Pro Ala Gln Ala Ala Pro Pro Ala Leu Ser Gln Asp Arg Phe Ala Asp Phe Pro Ala Leu Pro Leu Asp Pro Ser Ala Met Val Ala Gln Val Ala Pro Gln Val Val Asn Ile Asn Thr Lys Leu Gly Tyr Asn ,Asn Ala Val Gly Ala Gly Thr Gly Ile Val Ile Asp Pro Asn Gly Val 'Val Leu Thr Asn Asn His Val Ile Ala Gly Ala Thr Asp Ile Asn Ala Phe Ser Val Gly Ser Gly Gln Thr Tyr Gly Val Asp Val Val Gly Tyr Asp Arg Thr Gln Asp Val Ala Val Leu Gln Leu Arg Gly Ala Gly Gly Leu Pro Ser Ala Ala Ile Gly Gly Gly Val Ala Val Gly Glu Pro Val Val Ala Met Gly Asn Ser Gly Gly Gln Gly Gly Thr Pro Arg Ala Val Pro Gly Arg Val Val Ala Leu 165 7.70 175 Gly Gln Thr Val Gln Ala Ser Asp Ser Leu Thr Gly Ala Glu Glu Thr Leu Asn Gly Leu Ile Gln Phe Asp Ala Ala Ile Gln Pro Gly Asp Ser Gly Gly Pro Val Val Asn Gly Leu Gly Gln Val Val Gly Met Asn Thr Ala Ala Ser Asp Asn Phe Gln Leu Ser Gln Gly Gly Gln Gly Phe Ala Ile Pro Ile Gly Gln Ala Met Ala Ile A.la Gly Gln Ile Arg Ser Gly Gly Gly Ser Pro Thr Val His Ile Gly Pro Thr Ala Phe Leu Gly Leu Gly Val Val Asp Asn Asn Gly Asn Gly Ala Arg Val Gln Arg Val Val Gly Ser Ala Pro Ala Ala Ser Leu Gly Ile Ser Thr Gly Asp Val Ile Thr Ala Val Asp Gly Ala Pro Ile Asn Ser Ala Thr Ala Met Ala Asp Ala Leu Asn Gly His His Pro Gly Asp Val Ile Ser Val Asn Trp Gln Thr Lys Ser Gly Gly Thr Arg Thr Gly A,sn Val Thr Leu Ala Glu Gly Pro Pro Ala (2) INFORMATION FOR SEQ ID N0:81:

(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 205 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:81:
Ser Pro Lys Pro Asp Ala Glu Glu Gln Gly Val Pro Val Ser Pro Thr Ala Ser Asp Pro Ala Leu Leu Ala Glu Ile Arg Gln Ser Leu Asp Ala Thr Lys Gly Leu Thr Ser Val His Val Ala Val Arg Thr Thr Gly Lys Val Asp Ser Leu Leu Gly Ile Thr Ser Ala Asp Val Asp Val Arg Ala Asn Pro Leu Ala Ala Lys Gly Val Cys 'Phr Tyr Asn Asp Glu Gln Gly Val Pro Phe Arg Val Gln Gly Asp Asn Ile Ser Val Lys Leu Phe Asp Asp Trp Ser Asn Leu Gly Ser Ile Ser Glu Leu Ser Thr Ser Arg Val Leu Asp Pro Ala Ala Gly Val Thr Gln Leu Leu Ser Gly Val Thr Asn Leu Gln Ala Gln Gly Thr Glu Val Ile Asp Gly Ile Ser Thr Thr Lys Ile Thr Gly Thr Ile Pro Ala Ser Ser Val Lys Met Leu Asp Pro Gly Ala Lys Ser Ala Arg Pro Ala Thr Val Trp Ile Ala Gln Asp Gly Ser His His Leu Val Arg Ala Ser Ile Asp Leu Gly Ser Gly Ser Ile Gln Leu Thr Gln Ser Lys Trp Asn Glu Pro Val Asn Val Asp (2) INFORMATION FOR SEQ ID N0:82:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 286 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:82:
Gly Asp Ser Phe Trp Ala Ala Ala Asp Gln Met Ala Arg Gly Phe Val Leu Gly Ala Thr Ala Gly Arg Thr Thr L~~u Thr Gly Glu Gly Leu Gln His Ala Asp Gly His Ser Leu Leu Leu Asp Ala Thr Asn Pro Ala Val Val Ala Tyr Asp Pro Ala Phe Ala Tyr Glu Ile Gly Tyr Ile Xaa Glu Ser Gly Leu Ala Arg Met Cys Gly Glu .Asn Pro Glu Asn Ile Phe Phe Tyr Ile Thr Val Tyr Asn Glu Pro Tyr Val Gln Pro Pro Glu Pro Glu Asn Phe Asp Pro Glu Gly Val Leu Gly Gly Ile Tyr Arg Tyr His Ala Ala Thr Glu Gln Arg Thr Asn Lys Xaa c,ln Ile Leu Ala Ser Gly Val Ala Met Pro Ala Ala Leu Arg Ala Ala Gln Met Leu Ala Ala Glu Trp Asp Val Ala Ala Asp Val Trp Ser Val '.Phr Ser Trp Gly Glu Leu Asn Arg Asp Gly Val Val Ile Glu Thr Glu hys Leu Arg His Pro Asp Arg Pro Ala Gly Val Pro Tyr Val Thr Arg Ala Leu Glu Asn Ala Arg Gly Pro Val Ile Ala Val Ser Asp Trp Met Arg Ala Val Pro Glu Gln Ile Arg Pro Trp Val Pro Gly Thr Tyr Leu Thr Leu Gly Thr Asp Gly Phe Gly Phe Ser Asp Thr Arg Pro Ala Gly Arg Arg Tyr Phe Asn Thr Asp Ala Glu Ser Gln Val Gly Arg Gly Phe Gly Arg Gly Trp Pro Gly Arg Arg Val Asn Ile Asp Pro Phe Gly Ala Gly Arg Gly Pro Pro Ala Gln Leu Pro Gly Phe Asp Glu Gly Gly Gly Leu Arg Pro Xaa Lys (2) INFORMATION FOR SEQ ID N0:83:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 173 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:83:
Thr Lys Phe His Ala Leu Met Gln Glu Gln Ile His Asn Glu Phe Thr Ala Ala Gln Gln Tyr Val Ala Ile Ala Val Tyr Phe Asp Ser Glu Asp Leu Pro Gln Leu Ala Lys His Phe Tyr Ser Gln Ala Val Glu Glu Arg Asn His Ala Met Met Leu Val Gln His Leu Leu Asp Arg Asp Leu Arg Val Glu Ile Pro Gly Val Asp Thr Val .Arg Asn Gln Phe Asp Arg Pro Arg Glu Ala Leu Ala Leu Ala Leu Asp Gln Glu Arg Thr Val Thr Asp Gln Val Gly Arg Leu Thr Ala Val Ala ,~lrg Asp Glu Gly Asp Phe Leu Gly Glu Gln Phe Met Gln Trp Phe Leu Gln Glu Gln Ile Glu Glu Val Ala Leu Met Ala Thr Leu Val Arg Val Ala Asp Arg Ala Gly Ala Asn Leu Phe Glu Leu Glu Asn Phe Val Ala Arg Glu Val Asp Val Ala Pro Ala Ala Ser Gly Ala Pro His Ala Ala (~ly Gly Arg Leu (2) INFORMATION FOR SEQ ID N0:84:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 107 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:84:
Arg Ala Asp Glu Arg Lys Asn Thr Thr Niet Lys Met Val Lys Ser Ile Ala Ala Gly Leu Thr Ala Ala Ala Ala Ile Gly Ala Ala Ala Ala Gly Val Thr Ser Ile Met Ala Gly Gly Pro V'al Val Tyr Gln Met Gln Pro Val Val Phe Gly Ala Pro Leu Pro Leu Asp Pro Xaa Ser Ala Pro Xaa Val Pro Thr Ala Ala Gln Trp Thr Xaa Leu Leu Asn Xaa Leu Xaa Asp Pro Asn Val Ser Phe Xaa Asn Lys Gly Ser Leu Val Glu Gly Gly Ile Gly Gly Xaa Glu Gly Xaa Xaa Arg Arg Xaa Gln (2) INFORMATION FOR SEQ ID N0:85:
(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 125 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:85:
Val Leu Ser Val Pro Val Gly Asp Gly Phe Trp Xaa Arg Val Val Asn Pro Leu Gly Gln Pro Ile Asp Gly Arg Gly Asp Val Asp Ser Asp Thr Arg Arg Ala Leu Glu Leu Gln Ala Pro ;Ser Val Val Xaa Arg Gln Gly Val Lys Glu Pro Leu Xaa Thr Gly Ile Lys Ala Ile Asp Ala Met Thr Pro Ile Gly Arg Gly Gln Arg Gln Leu :Ile Ile Gly Asp Arg Lys Thr Gly Lys Asn Arg Arg Leu Cys Arg Thr 1?ro Ser Ser Asn Gln Arg Glu Glu Leu Gly Val Arg Trp Ile Pro Arg Ser Arg Cys Ala Cys Val Tyr Val Gly His Arg Ala Arg Arg Gly Thr Tyr His Arg Arg (2) INFORMATION FOR SEQ ID N0:86:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 117 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:86:
Cys Asp Ala Val Met Gly Phe Leu Gly Gly Ala Gly Pro Leu Ala Val 1 5 1.0 15 Val Asp Gln Gln Leu Val Thr Arg Val Fro Gln Gly Trp Ser Phe Ala Gln Ala Ala Ala Val Pro Val Val Phe Leu Thr Ala Trp Tyr Gly Leu Ala Asp Leu Ala Glu Ile Lys Ala Gly Glu Ser Val Leu Ile His Ala Gly Thr Gly Gly Val Gly Met Ala Ala Val Gln Leu Ala Arg Gln Trp Gly Val Glu Val Phe Val Thr Ala Ser Arg Gly Lys Trp Asp Thr Leu Arg Ala Xaa Xaa Phe Asp Asp Xaa Pro Tyr Arg Xaa Phe Pro His Xaa Arg Ser Ser Xaa Gly (2) INFORMATION FOR SEQ ID N0:87:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 103 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:87:
Met Tyr Arg Phe Ala Cys Arg Thr Leu Met Leu Ala Ala Cys Ile Leu Ala Thr Gly Val Ala Gly Leu Gly Val Gly Ala Gln Ser Ala Ala Gln Thr Ala Pro Val Pro Asp Tyr Tyr Trp Cys Pro Gly Gln Pro Phe Asp Pro Ala Trp Gly Pro Asn Trp Asp Pro '.Cyr Thr Cys His Asp Asp Phe His Arg Asp Ser Asp Gly Pro Asp His :ier Arg Asp Tyr Pro Gly Pro Ile Leu Glu Gly Pro Val Leu Asp Asp 1?ro Gly Ala Ala Pro Pro Pro Pro Ala Ala Gly Gly Gly Ala (2) INFORMATION FOR SEQ ID N0:88:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 88 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:88:
Val Gln Cys Arg Val Trp Leu Glu Ile Gln Trp Arg Gly Met Leu Gly Ala Asp Gln Ala Arg Ala Gly Gly Pro Ala Arg Ile Trp Arg Glu His Ser Met Ala Ala Met Lys Pro Arg Thr Gly Asp Gly Pro Leu Glu Ala Thr Lys Glu Gly Arg Gly Ile Val Met Arg Val Pro Leu Glu Gly Gly Gly Arg Leu Val Val Glu Leu Thr Pro Asp Glu Ala Ala Ala Leu Gly Asp Glu Leu Lys Gly Val Thr Ser (2) INFORMATION FOR SEQ ID N0:89:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 95 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:89:
Thr Asp Ala Ala Thr Leu Ala Gln Glu ;~la Gly Asn Phe Glu Arg Ile Ser Gly Asp Leu Lys Thr Gln Ile Asp Gln Val Glu Ser Thr Ala Gly Ser Leu Gln Gly Gln Trp Arg Gly Ala Ala Gly Thr Ala Ala Gln Ala Ala Val Val Arg Phe Gln Glu Ala Ala Asn Lys Gln Lys Gln Glu Leu Asp Glu Ile Ser Thr Asn Ile Arg Gln Ala Gly Val Gln Tyr Ser Arg Ala Asp Glu Glu Gln Gln Gln Ala Leu Ser Ser Gln Met Gly Phe (2) INFORMATION FOR SEQ ID N0:90:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 166 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:90:
Met Thr Gln Ser Gln Thr Val Thr Val Asp Gln Gln Glu Ile Leu Asn 1 5 7.0 15 Arg Ala Asn Glu Val Glu Ala Pro Met Ala Asp Pro Pro Thr Asp Val Pro Ile Thr Pro Cys Glu Leu Thr Xaa Xaa Lys Asn Ala Ala Gln Gln Xaa Val Leu Ser Ala Asp Asn Met Arg Glu Tyr Leu Ala Ala Gly Ala Lys Glu Arg Gln Arg Leu Ala Thr Ser L~eu Arg Asn Ala Ala Lys Xaa Tyr Gly Glu Val Asp Glu Glu Ala Ala Thr Ala Leu Asp Asn Asp Gly Glu Gly Thr Val Gln Ala Glu Ser Ala Gly Ala Val Gly Gly Asp Ser Ser Ala Glu Leu Thr Asp Thr Pro Arg Val Ala Thr Ala Gly Glu Pro Asn Phe Met Asp Leu Lys Glu Ala Ala Arg Lys Leu Glu Thr Gly Asp Gln Gly Ala Ser Leu Ala His Xaa Gly Asp Gly Trp Asn Thr Xaa Thr Leu Thr Leu Gln Gly Asp (2) INFORMATION FOR SEQ ID N0:91:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 5 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:91:
Arg Ala Glu Arg Met (2) INFORMATION FOR SEQ ID N0:92:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 263 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:92:
Val Ala Trp Met Ser Val Thr Ala Gly G'ln Ala Glu Leu Thr Ala Ala Gln Val Arg Val Ala Ala Ala Ala Tyr Glu Thr Ala Tyr Gly Leu Thr Val Pro Pro Pro Val Ile Ala Glu Asn Arg Ala Glu Leu Met Ile Leu Ile Ala Thr Asn Leu Leu Gly Gln Asn Thr Pro Ala Ile Ala Val Asn Glu Ala Glu Tyr Gly Glu Met Trp Ala Gln Asp Ala Ala Ala Met Phe Gly Tyr Ala Ala Ala Thr Ala Thr Ala Thr Ala Thr Leu Leu Pro Phe Glu Glu Ala Pro Glu Met Thr Ser Ala Gly Gly Leu Leu Glu Gln Ala Ala Ala Val Glu Glu Ala Ser Asp Thr Ala Ala Ala Asn Gln Leu Met Asn Asn Val Pro Gln Ala Leu Lys Gln Leu Ala Gln Pro Thr Gln Gly Thr Thr Pro Ser Ser Lys Leu Gly Gly Leu Trp Lys Thr Val Ser Pro His Arg Ser Pro Ile Ser Asn Met Val Ser Met Ala Asn Asn His Met Ser Met Thr Asn Ser Gly Val Ser Met 'Phr Asn Thr Leu Ser Ser Met Leu Lys Gly Phe Ala Pro Ala Ala Ala Ala Gln Ala Val Gln Thr Ala Ala Gln Asn Gly Val Arg Ala Met Ser ;ier Leu Gly Ser Ser Leu Gly Ser Ser Gly Leu Gly Gly Gly Val Ala Ala Asn Leu Gly Arg Ala Ala Ser Val Arg Tyr Gly His Arg Asp Gly C~ly Lys Tyr Ala Xaa Ser Gly Arg Arg Asn Gly Gly Pro Ala (2) INFORMATION FOR SEQ ID N0:93:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 303 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:93:
Met Thr Tyr Ser Pro Gly Asn Pro Gly Tyr Pro Gln Ala Gln Pro Ala Gly Ser Tyr Gly Gly Val Thr Pro Ser F'he Ala His Ala Asp Glu Gly Ala Ser Lys Leu Pro Met Tyr Leu Asn Ile Ala Val Ala Val Leu Gly Leu Ala Ala Tyr Phe Ala Ser Phe Gly Pro Met Phe Thr Leu Ser Thr Glu Leu Gly Gly Gly Asp Gly Ala Val Ser Gly Asp Thr Gly Leu Pro Val Gly Val Ala Leu Leu Ala Ala Leu Leu Ala Gly Val Val Leu Val Pro Lys Ala Lys Ser His Val Thr Val Val Ala Val Leu Gly Val Leu Gly Val Phe Leu Met Val Ser Ala Thr Phe Asn Lys Pro Ser Ala Tyr Ser Thr Gly Trp Ala Leu Trp Val Val Leu Ala Phe Ile Val Phe Gln Ala Val Ala Ala Val Leu Ala Leu Leu Val Glu Thr Gly Ala Ile Thr Ala Pro Ala Pro Arg Pro Lys Phe Asp Pro Tyr Gly Gln Tyr Gly Arg Tyr Gly Gln Tyr Gly Gln Tyr Gly Val Gln Pro Gly Gly Tyr Tyr Gly Gln Gln Gly Ala Gln Gln Ala Ala Gly Leu Gln Ser Pro Gly Pro Gln Gln Ser Pro Gln Pro Pro Gly Tyr Gly Ser Gln Tyr Gly Gly Tyr Ser Ser Ser Pro Ser Gln Ser Gly Ser Gly Tyr Thr Ala Gln Pro Pro Ala Gln Pro Pro Ala Gln Ser Gly Ser Gln C~ln Ser His Gln Gly Pro Ser Thr Pro Pro Thr Gly Phe Pro Ser Phe :>er Pro Pro Pro Pro Val Ser Ala Gly Thr Gly Ser Gln Ala Gly Ser Ala Pro Val Asn Tyr Ser Asn Pro Ser Gly Gly Glu Gln Ser Ser Ser Pro Gly Gly Ala Pro Val (2) INFORMATION FOR SEQ ID N0:94:
(i) SEQUENCE
CHARACTERISTICS:

(A) LENGTH:507 base pairs (B) TYPE:
nucleic acid (C) STRANDEDNESS:
single (D) TOPOLOGY:
linear (xi) SEQUENCE
DESCRIPTION:
SEQ
ID N0:94:

(2) INFORMATION FOR SEQ ID N0:95:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 168 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:95:

Met Lys Met Val Lys Ser Ile Ala Ala Gly Leu Thr Ala Ala Ala Ala 1 5 :LO 15 Ile Gly Ala Ala Ala Ala Gly Val Thr Ser Ile Met Ala Gly Gly Pro Val Val Tyr Gln Met Gln Pro Val Val I?he Gly Ala Pro Leu Pro Leu Asp Pro Ala Ser Ala Pro Asp Val Pro Thr Ala Ala Gln Leu Thr Ser Leu Leu Asn Ser Leu Ala Asp Pro Asn Val Ser Phe Ala Asn Lys Gly Ser Leu Val Glu Gly Gly Ile Gly Gly 7.'hr Glu Ala Arg Ile Ala Asp His Lys Leu Lys Lys Ala Ala Glu His Gly Asp Leu Pro Leu Ser Phe Ser Val Thr Asn Ile Gln Pro Ala Ala Ala Gly Ser Ala Thr Ala Asp Val Ser Val Ser Gly Pro Lys Leu Ser ~~er Pro Val Thr Gln Asn Val Thr Phe Val Asn Gln Gly Gly Trp Met Leu Ser Arg Ala Ser Ala Met Glu Leu Leu Gln Ala Ala Gly Asn (2) INFORMATION FOR SEQ ID N0:96:
(i) SEQUENCE
CHARACTERISTICS:

(A) LENGTH: 500 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE
DESCRIPTION:
SEQ
ID N0:96:

ACGGGCCGCATCCCGCGACC CGGCATCGTC GCCGGGGCT.AGGCCAGATTG CCCCGCTCCT420 (2) INFORMATION FOR SEQ ID N0:97:

(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 96 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:97:
Val Ala Met Ser Leu Thr Val Gly Ala Gly Val Ala Ser Ala Asp Pro Val Asp Ala Val Ile Asn Thr Thr Cys Asn Tyr Gly Gln Val Val Ala Ala Leu Asn Ala Thr Asp Pro Gly Ala Ala Ala Gln Phe Asn Ala Ser Pro Val Ala Gln Ser Tyr Leu Arg Asn Phe Leu Ala Ala Pro Pro Pro Gln Arg Ala Ala Met Ala Ala Gln Leu C7ln Ala Val Pro Gly Ala Ala Gln Tyr Ile Gly Leu Val Glu Ser Val Ala Gly Ser Cys Asn Asn Tyr (2) INFORMATION FOR SEQ ID N0:98:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 154 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:98:

(2) INFORMATION FOR SEQ ID N0:99:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 51 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:99:
Met Thr Glu Gln Gln Trp Asn Phe Ala Gly Ile Glu Ala Ala Ala Ser Ala Ile Gln Gly Asn Val Thr Ser Ile His Ser Leu Leu Asp Glu Gly Lys Gln Ser Leu Thr Lys Leu Ala Ala Ala Trp Gly Gly Ser Gly Ser Glu Ala Tyr (2) INFORMATION FOR SEQ ID NO:100:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 282 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:100:
CGGTCGCGCA CTTCCAGGTG ACTATGAAAG TCGGCTTCC;G NCTGGAGGAT TCCTGAACCT 60 TCAAGCGCGG CCGATAACTG AGGTGCATCA TTAAGCGAC:T TTTCCAGAAC ATCCTGACGC 120 GCTCGAAACG CGGCACAGCC GACGGTGGCT CCGNCGAGC~C GCTGNCTCCA AAATCCCTGA 180 (2) INFORMATION
FOR SEQ
ID N0:101:

(i) S EQUENCE S:
CHARACTERISTIC

(A) LENGTH:3058 basepairs (B) TYPE:
nucleic acid (C) STRANDEDNESS: le sing (D) TOPOLOGY:
linear (xi) SEQUENCE EQ ID N0:101:
DESCRIPTION:
S

CTCCGGCGGCGGCCGCCCAGGCCGTGCAAACCGCGGCGC;AAAACGGGGTCCGGGCGATGA 1260 CAGTCACCCCGGCGGCGCGGGCGCTGCCGCTGACCAGCC;TGACCAGCGCCGCGGAAAGAG 1440 CCGGCTAGGAGAGGGGGCGCAGACTGTCGTTATTTGACC;AGTGATCGGCGGTCTCGGTGT 1620 GTTCAACAAGGAGACAGGCAACATGGCCTCACGTTTTAT'GACGGATCCGCACGCGATGCG 1740 GGACATGGCGGGCCGTTTTGAGGTGCACGCCCAGACGGT'GGAGGACGAGGCTCGCCGGAT 1800 GCTAGACACCATGGCCCAGATGAATCAGGCGTTTCGCAA,CATCGTGAACATGCTGCACGG 1920 GCGGGCGGTGTCGAGGTGCTCGGCCACCGCGGGGAGTTT~GTCGGTCAGAGCGTCGAGTAC 2760 (2) INFORMATION FOR SEQ ID N0:102:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 391 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:7.02:
Met Val Asp Phe Gly Ala Leu Pro Pro C~lu Ile Asn Ser Ala Arg Met 1 5 1.0 15 Tyr Ala Gly Pro Gly Ser Ala Ser Leu Val Ala Ala Ala Gln Met Trp Asp Ser Val Ala Ser Asp Leu Phe Ser P,la Ala Ser Ala Phe Gln Ser Val Val Trp Gly Leu Thr Val Gly Ser T'rp Ile Gly Ser Ser Ala Gly Leu Met Val Ala Ala Ala Ser Pro Tyr Val Ala Trp Met Ser Val Thr Ala Gly Gln Ala Glu Leu Thr Ala Ala Gln Val Arg Val Ala Ala Ala Ala Tyr Glu Thr Ala Tyr Gly Leu Thr Val Pro Pro Pro Val Ile Ala Glu Asn Arg Ala Glu Leu Met Ile Leu Ile Ala Thr Asn Leu Leu Gly Gln Asn Thr Pro Ala Ile Ala Val Asn Glu Ala Glu Tyr Gly Glu Met Trp Ala Gln Asp Ala Ala Ala Met Phe Gly Tyr Ala Ala Ala Thr Ala Thr Ala Thr Ala Thr Leu Leu Pro Phe Glu Glu Ala Pro Glu Met Thr Ser Ala Gly Gly Leu Leu Glu Gln Ala Ala Ala Val Glu Glu Ala Ser Asp Thr Ala Ala Ala Asn Gln Leu Met Asn Asn Val Pro Gln Ala Leu Gln Gln Leu Ala Gln Pro Thr Gln Gly T:hr Thr Pro Ser Ser Lys Leu Gly Gly Leu Trp Lys Thr Val Ser Pro H.is Arg Ser Pro Ile Ser Asn Met Val Ser Met Ala Asn Asn His Met S er Met Thr Asn Ser Gly Val Ser Met Thr Asn Thr Leu Ser Ser Met Leu Lys Gly Phe Ala Pro Ala Ala Ala Ala Gln Ala Val Gln Thr Ala Ala Gln Asn Gly Val Arg Ala Met Ser Ser Leu Gly Ser Ser Leu Gly Ser Ser Gly Leu Gly Gly Gly Val Ala Ala Asn Leu Gly Arg Ala Ala Ser Val Gly Ser Leu Ser Val Pro Gln Ala Trp Ala Ala Ala Asn Gln Ala Val Thr Pro Ala Ala Arg Ala Leu Pro Leu Thr Ser Leu Thr Ser Ala Ala Glu Arg Gly Pro Gly Gln Met Leu Gly Gly Leu Pro Val Gly Gln Met Gly Ala Arg Ala Gly Gly Gly Leu Ser Gly Val Leu Arg Val Pro Pro Arg Pro Tyr Val Met Pro His Ser Pro Ala Ala Gly (2) INFORMATION FOR SEQ ID N0:103:
(i) SEQUENCE
CHARACTERISTICS:

(A) LENGTH:1725 base pairs (B) TYPE:
nucleic acid (C) STRANDEDNESS:
single (D) TOPOLOGY:
linear (xi) SEQUENCE
DESCRIPTION:
SEQ
ID N0:103:

ACGTCCCTCGGCGTGTCGCCGGCGTGGATGCAGACTCGA.TGCCGCTCTTTAGTGCAACTA 120 TCTGATGGCGGCGGCGGCCTCGCCGTATGTGGCGTGGA'.PGAGCGTCACCGCGGGGCAGGC 900 CCAGCTGACCGCCGCCCAGGTCCGGGTTGCTGCGGCGG(:CTACGAGACAGCGTATAGGCT 960 GTGGGGCCAAGACGCGGAGGCGATGTATGGCTACGCCGC:CACGGCGGCGACGGCGACCGA 1140 GGCCGTCGCGGTCGAGGAGGCCATCGACACCGCCGCGGC:GAACCAGTTGATGAACAATGT 1260 GGGTGGGCTGTGGACGGCGGTCTCGCCGCATCTGTCGCC;GCTCAGCAACGTCAGTTCGAT 1380 AGCCAACAACCACATGTCGATGATGGGCACGGGTGTGTC;GATGACCAACACCTTGCACTC 1440 GGTCTGGGCGATGAGCTCGCTGGGCAGCCAGCTGGGTTC'.GTCGCTGGGTTCTTCGGGTCT 1560 GGGCGCTGGGGTGGCCGCCAACTTGGGTCGGGCGGCCTC:GGTCGGTTCGTTGTCGGTGCC 1620 GCCAGCATGGGCCGCGGCCAACCAGGCGGTCACCCCGGC'.GGCGCGGGCGCTGCCGCTGAC 1680 CAGCCTGACCAGCGCCGCCCAAACCGCCCCCGGACACAT'GCTGGG 1725 (2} INFORMATION FOR SEQ ID N0:104:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 359 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:109:
Val Val Asp Phe Gly Ala Leu Pro Pro Glu Ile Asn Ser Ala Arg Met Tyr Ala Gly Pro Gly Ser Ala Ser Leu Val Ala Ala Ala Lys Met Trp Asp Ser Val Ala Ser Asp Leu Phe Ser Ala Ala Ser Ala Phe Gln Ser Val Val Trp Gly Leu Thr Val Gly Ser Trp Ile Gly Ser Ser Ala Gly Leu Met Ala Ala Ala Ala Ser Pro Tyr V.al Ala Trp Met Ser Val Thr Ala Gly Gln Ala Gln Leu Thr Ala Ala G.ln Val Arg Val Ala Ala Ala Ala Tyr Glu Thr Ala Tyr Arg Leu Thr Val Pro Pro Pro Val Ile Ala Glu Asn Arg Thr Glu Leu Met Thr Leu '.Chr Ala Thr Asn Leu Leu Gly Gln Asn Thr Pro Ala Ile Glu Ala Asn Gln Ala Ala Tyr Ser Gln Met Trp Gly Gln Asp Ala Glu Ala Met Tyr CJly Tyr Ala Ala Thr Ala Ala Thr Ala Thr Glu Ala Leu Leu Pro Phe Glu Asp Ala Pro Leu Ile Thr 165 7.70 175 Asn Pro Gly Gly Leu Leu Glu Gln Ala Val Ala Val Glu Glu Ala Ile Asp Thr Ala Ala Ala Asn Gln Leu Met Asn Asn Val Pro Gln Ala Leu Gln Gln Leu Ala Gln Pro Ala Gln Gly Val Val Pro Ser Ser Lys Leu Gly Gly Leu Trp Thr Ala Val Ser Pro His Leu Ser Pro Leu Ser Asn Val Ser Ser Ile Ala Asn Asn His Met ~;er Met Met Gly Thr Gly Val 245 2'50 255 Ser Met Thr Asn Thr Leu His Ser Met heu Lys Gly Leu Ala Pro Ala Ala Ala Gln Ala Val Glu Thr Ala Ala Glu Asn Gly Val Trp Ala Met Ser Ser Leu Gly Ser Gln Leu Gly Ser Ser Leu Gly Ser Ser Gly Leu Gly Ala Gly Val Ala Ala Asn Leu Gly Arg Ala Ala Ser Val Gly Ser Leu Ser Val Pro Pro Ala Trp Ala Ala A.la Asn Gln Ala Val Thr Pro Ala Ala Arg Ala Leu Pro Leu Thr Ser Leu Thr Ser Ala Ala Gln Thr Ala Pro Gly His Met Leu Gly (2) INFORMATION FOR SEQ ID N0:105:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 3027 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:105:
AGTTCAGTCG AGAATGATAC TGACGGGCTG TATCCACGA'P GGCTGAGACA ACCGAACCAC 60 CGTCGGACGCGGGGACATCGCAAGCCGACGCGATGGCG'rTGGCCGCCGAAGCCGAAGCCG 120 ACGGTCGGCATCCTGGCGACGGCGGTTGCGGGTGCGGT'.PACCAAGACTGTCCACGATTGC 360 GCAACACCATGAGGCCACCGAACGCCAGCAGCGCGCCG(:GGCGTTCGCCGCCGGAGCCAA 480 CGAATCCATGAACGAGCATTCCGCCGTGGTGCTCGTCGC:GGCGACTTCACGGGTCACCAA 720 TTCCGCTGGGGCGAAAGACGAACCACGTGCGTGGCGGC7.'CAAAGTGACCGTGACCGAAGA 780 GGGGGGACAGTACAAGATGTCGAAAGTTGAGTTCGTACC:GTGACCGATGACGTACGCGAC 840 ACGGGACAATCGCGCTGTTGTGTATTCACCCGACACGTC:GACCAAGACTTCGCTACCGCC 1200 AGGTCGCACCTCGCCGGCGATTTCCTGTCCTATACGACC'AGTTCACGCAGCAGATCGTGG 1260 CTCCGGCGGCCAAACAGAAGTCACTGAAAACCACCGCCP.,AGGTGGTGCGCGCGGCCGTGT 1320 AGGACAGCCCCAATCCGTCGATGGCGGCCAGCAGCGTGA.TGGTGACCCTAGCCAAGGTCG 1440 GGGTCTGATGGTGGCGGCGGCCTCGCCGTATGTGGCGTC~GATGAGCGTCACCGCGGGGCA 2040 GGCCGAGCTGACCGCCGCCCAGGTCCGGGTTGCTGCGG(:GGCCTACGAGACGGCGTATGG 2100 GCTGACGGTGCCCCCGCCGGTGATCGCCGAGAACCGTGC:TGAACTGATGATTCTGATAGC 2160 GATGTGGGCCCAAGACGCCGCCGCGATGTTTGGCTACGC:CGCCACGGCGGCGACGGCGAC 2280 CGAGGCGTTGCTGCCGTTCGAGGACGCCCCACTGATCAC:CAACCCCGGCGGGCTCCTTGA 2340 GCAGGCCGTCGCGGTCGAGGAGGCCATCGACACCGCCGC:GGCGAACCAGTTGATGAACAA 2400 ACTGAGTGAACTCTGGAAAGCCATCTCGCCGCATCTGTC;GCCGCTCAGCAACATCGTGTC 2520 CTCAATGTTGAAGGGCTTTGCTCCGGCGGCGGCTCAGGC;CGTGGAAACCGCGGCGCAAAA 2640 TCTGGGCGCTGGGGTGGCCGCCAACTTGGGTCGGGCGGC:CTCGGTCGGTTCGTTGTCGGT 2760 GCCGCAGGCCTGGGCCGCGGCCAACCAGGCGGTCACCCC:GGCGGCGCGGGCGCTGCCGCT 2820 (2) INFORMATION FOR SEQ ID N0:106:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 396 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:106:
Val Val Asp Phe Gly Ala Leu Pro Pro Glu Ile Asn Ser Ala Arg Met Tyr Ala Gly Pro Gly Ser Ala Ser Leu Val Ala Ala Ala Lys Met Trp Asp Ser Val Ala Ser Asp Leu Phe Ser Ala Ala Ser Ala Phe Gln Ser Val Val Trp Gly Leu Thr Thr Gly Ser Trp Ile Gly Ser Ser Ala Gly Leu Met Val Ala Ala Ala Ser Pro Tyr Val Ala Trp Met Ser Val Thr Ala Gly Gln Ala Glu Leu Thr Ala Ala G.ln Val Arg Val Ala Ala Ala Ala Tyr Glu Thr Ala Tyr Gly Leu Thr Val Pro Pro Pro Val Ile Ala Glu Asn Arg Ala Glu Leu Met Ile Leu :Lle Ala Thr Asn Leu Leu Gly Gln Asn Thr Pro Ala Ile Ala Val Asn (ilu Ala Glu Tyr Gly Glu Met Trp Ala Gln Asp Ala Ala Ala Met Phe Gly Tyr Ala Ala Thr Ala Ala Thr Ala Thr Glu Ala Leu Leu Pro Phe Glu Asp Ala Pro Leu Ile Thr 165 T_70 175 Asn Pro Gly Gly Leu Leu Glu Gln Ala Val Ala Val Glu Glu Ala Ile Asp Thr Ala Ala Ala Asn Gln Leu Met Asn Asn Val Pro Gln Ala Leu Gln Gln Leu Ala Gln Pro Thr Lys Ser l:le Trp Pro Phe Asp Gln Leu Ser Glu Leu Trp Lys Ala Ile Ser Pro His Leu Ser Pro Leu Ser Asn Ile Val Ser Met Leu Asn Asn His Val :cer Met Thr Asn Ser Gly Val Ser Met Ala Ser Thr Leu His Ser Met Leu Lys Gly Phe Ala Pro Ala Ala Ala Gln Ala Val Glu Thr Ala Ala Gln Asn Gly Val Gln Ala Met Ser Ser Leu Gly Ser Gln Leu Gly Ser Ser Leu Gly Ser Ser Gly Leu Gly Ala Gly Val Ala Ala Asn Leu Gly Arg Ala Ala Ser Val Gly Ser Leu Ser Val Pro Gln Ala Trp Ala Ala A.la Asn Gln Ala Val Thr Pro Ala Ala Arg Ala Leu Pro Leu Thr Ser Leu Thr Ser Ala Ala Gln Thr Ala Pro Gly His Met Leu Gly Gly Leu Pro Leu Gly Gln Leu Thr Asn Ser Gly Gly Gly Phe Gly Gly Val Ser Asn Ala Leu Arg Met Pro Pro Arg Ala Tyr Val Met Pro Arg Val Pro Ala Ala Gly (2) INFORMATION FOR SEQ ID N0:107:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 1616 base pairs (B) TYPE:
nucleic acid (C) STRANDEDNESS: le sing (D) TOPOLOGY:
linear (xi) S EQUENCE EQ ID 7:
DESCRIPTION: N0::10 S

CATCGGAGGGAGTGATCACCATGCTGTGGCACGCAATG(:CACCGGAGTAAATACCGCACG 60 TTCGGCGGCTCTGGACGCTCAGGCCGTCGAGTTGACCG(:GCGCCTGAACTCTCTGGGAGA 180 AGCCTGGACTGGAGGTGGCAGCGACAAGGCGCTTGCGG(:TGCAACGCCGATGGTGGTCTG 240 GGCATACACCCAGGCCATGGCCACGACGCCGTCGCTGCC:GGAGATCGCCGCCAACCACAT 360 CACCCAGGCCGTCCTTACGGCCACCAACTTCTTCGGTA7.'CAACACGATCCCGATCGCGTT 420 GACCGAGATGGATTATTTCATCCGTATGTGGAACCAGGC:AGCCCTGGCAATGGAGGTCTA 480 CCAGGCCGAGACCGCGGTTAACACGCTTTTCGAGAAGC7.'CGAGCCGATGGCGTCGATCCT 540 TGATCCCGGCGCGAGCCAGAGCACGACGAACCCGATCT7.'CGGAATGCCCTCCCCTGGCAG 600 GCTGATGTCTCAGCTGATCGAAAAGCCGGTTGCCCCCTC'GGTGATGCCGGCGGCTGCTGC 960 AACAGACTTCCCGGCCACCCGGGCCGGAAGACTTGCCAA.CATTTTGGCGAGGAAGGTAAA 1200 (2) INFORMATION FOR SEQ ID N0:108:
(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH:432 base pairs (B) TYPE:
nucleic acid (C) STRANDEDNESS:
single (D) TOPOLOGY:
linear (xi) SEQUENCE
DESCRIPTION:
SEQ
ID N0:108:

CTAGTGGATGGGACCATGGCCATTTTCTGC AGTCTCAC'.CGCCTTCTGTGTTGACATTTTG 60 GTGACGTTGCCTTCGGTCGAAGCCATTGCC TGACCGGC7.'TCGCTGATCGTCCGCGCCAGG 360 TTCTGCAGCGCGTTGTTCAGCTCGGTAGCC GTGGCGTCC;CATTTTTGCTGGACACCCTGG 420 (2) INFORMATION FOR SEQ ID N0:109:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 368 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:109:
Met Leu Trp His Ala Met Pro Pro Glu Xaa Asn Thr Ala Arg Leu Met Ala Gly Ala Gly Pro Ala Pro Met Leu Ala Ala Ala Ala Gly Trp Gln Thr Leu Ser Ala Ala Leu Asp Ala Gln A.la Val Glu Leu Thr Ala Arg Leu Asn Ser Leu Gly Glu Ala Trp Thr Gly Gly Gly Ser Asp Lys Ala Leu Ala Ala Ala Thr Pro Met Val Val Trp Leu Gln Thr Ala Ser Thr Gln Ala Lys Thr Arg Ala Met Gln Ala Thr Ala Gln Ala Ala Ala Tyr Thr Gln Ala Met Ala Thr Thr Pro Ser Leu Pro Glu Ile Ala Ala Asn His Ile Thr Gln Ala Val Leu Thr Ala Thr Asn Phe Phe Gly Ile Asn Thr Ile Pro Ile Ala Leu Thr Glu Met Asp Tyr Phe Ile Arg Met Trp Asn Gln Ala Ala Leu Ala Met Glu Val T:yr Gln Ala Glu Thr Ala Val Asn Thr Leu Phe Glu Lys Leu Glu Pro Met Ala Ser Ile Leu Asp Pro Gly Ala Ser Gln Ser Thr Thr Asn Pro :Ile Phe Gly Met Pro Ser Pro Gly Ser Ser Thr Pro Val Gly Gln Leu 1?ro Pro Ala Ala Thr Gln Thr Leu Gly Gln Leu Gly Glu Met Ser Gly I?ro Met Gln Gln Leu Thr Gln Pro Leu Gln Gln Val Thr Ser Leu Phe Ser Gln Val Gly Gly Thr Gly Gly Gly Asn Pro Ala Asp Glu Glu Ala Ala Gln Met Gly Leu Leu Gly Thr Ser Pro Leu Ser Asn His Pro Leu Ala Gly Gly Ser Gly Pro Ser Ala Gly Ala Gly Leu Leu Arg Ala Glu Ser Leu Pro Gly Ala Gly Gly Ser Leu Thr Arg Thr Pro Leu Met Ser C:ln Leu Ile Glu Lys Pro Val Ala Pro Ser Val Met Pro Ala Ala Ala Ala Gly Ser Ser Ala Thr Gly Gly Ala Ala Pro Val Gly Ala Gly Ala Nlet Gly Gln Gly Ala Gln Ser 325 ?.30 335 Gly Gly Ser Thr Arg Pro Gly Leu Val P,la Pro Ala Pro Leu Ala Gln Glu Arg Glu Glu Asp Asp Glu Asp Asp Trp Asp Glu Glu Asp Asp Trp (2) INFORMATION FOR SEQ ID NO:110:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 100 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:110:
Met Ala Glu Met Lys Thr Asp Ala Ala Thr Leu Ala Gln Glu Ala Gly Asn Phe Glu Arg Ile Ser Gly Asp Leu Lys Thr Gln Ile Asp Gln Val Glu Ser Thr Ala Gly Ser Leu Gln Gly Gln Trp Arg Gly Ala Ala Gly Thr Ala Ala Gln Ala Ala Val Val Arg Phe Gln Glu Ala Ala~Asn Lys Gln Lys Gln Glu Leu Asp Glu Ile Ser T:hr Asn Ile Arg Gln Ala Gly Val Gln Tyr Ser Arg Ala Asp Glu Glu (~ln Gln Gln Ala Leu Ser Ser Gln Met Gly Phe (2) INFORMATION FOR SEQ ID N0:111:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 396 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE
DESCRIPTION:
SEQ ID
N0:7.11:

GGGCCAGTGGCGCGGCGCGGCGGGGACGGCCGCCCAGGC;CGCGGTGGTGCGCTTCCAAGA 120 AGCAGCCAATAAGCAGAAGCAGGAACTCGACGAGATCTC;GACGAATATTCGTCAGGCCGG 180 CGTCCAATACTCGAGGGCCGACGAGGAGCAGCAGCAGGC:GCTGTCCTCGCAAATGGGCTT 240 (2) INFORMATION FOR SEQ ID N0:112:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 80 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:112:
Ile Ser Gly Asp Leu Lys Thr Gln Ile A.sp Gln Val Glu Ser Thr Ala Gly Ser Leu Gln Gly Gln Trp Arg Gly Ala Ala Gly Thr Ala Ala Gln Ala Ala Val Val Arg Phe Gln Glu Ala Ala Asn Lys Gln Lys Gln Glu Leu Asp Glu Ile Ser Thr Asn Ile Arg Gln Ala Gly Val Gln Tyr Ser Arg Ala Asp Glu Glu Gln Gln Gln Ala Leu Ser Ser Gln Met Gly Phe (2) INFORMATION FOR SEQ ID N0:113:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 387 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS:
single (D) TOPOLOGY:
linear (xi) EQUENCE
S DESCRIPTION:
SEQ ID
NO::L13:

GTGGATCCCGATCCCGTGTTTCGCTATTCTACGCGAAC'.CCGGCGTTGCCCTATGCGAACA 60 TCCCAGTGACGTTGCCTTCGGTCGAAGCCATTGCCTGAC:CGGCTTCGCTGATCGTCCGCG 120 TCCCCTCGTCAAGGAGGGAATGAATGGACGTGACATTTC:CCTGGATTGCGCTTGCCGCGG 300 CCTCGATACCCGCGAAATTCCACTGCTGCTCTGTCATG7.'TTTTGCTCCGTTTCTTTTCGT 360 ATTAGCGGGTCAGAAGCCCATTTGCGA 3g7 (2) INFORMATION FOR SEQ ID N0:114:
(i) SEQUENCE
CHARACTERISTICS:

(A) LENGTH: 272 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE
DESCRIPTION:
SEQ
ID N0:1.14:

TGTTGGGGGGCAGGCCGGGT CGGTGGTTCG GCCGGGGAC'.GCAGACGGTCT GGACGGAACG240 (2) INFORMATION FOR SEQ ID N0:115:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 20 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:115:
Asp Pro Val Asp Ala Val Ile Asn Thr Thr Cys Asn Tyr Gly Gln Val Val Ala Ala Leu (2) INFORMATION FOR SEQ ID N0:116:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 15 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:

(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0::116:
Ala Val Glu Ser Gly Met Leu Ala Leu Gly Thr Pro Ala Pro Ser 1 5 :LO 15 (2) INFORMATION FOR SEQ ID N0:117:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 19 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:7_17:
Ala Ala Met Lys Pro Arg Thr Gly Asp Gly Pro Leu Glu Ala Ala Lys 1 5 7.0 15 Glu Gly Arg (2) INFORMATION FOR SEQ ID N0:118:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 15 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:118:
Tyr Tyr Trp Cys Pro Gly Gln Pro Phe P,sp Pro Ala Trp Gly Pro (2) INFORMATION FOR SEQ ID N0:119:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 14 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:119:
Asp Ile Gly Ser Glu Ser Thr Glu Asp Gln Gln Xaa Ala Val (2) INFORMATION FOR SEQ ID N0:120:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 13 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:120:
Ala Glu Glu Ser Ile Ser Thr Xaa Glu Xaa Ile Val Pro (2) INFORMATION FOR SEQ ID N0:121:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 17 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:121:
Asp Pro Glu Pro Ala Pro Pro Val Pro Thr Thr Ala Ala Ser Pro Pro 1 5 7_0 15 Ser (2) INFORMATION FOR SEQ ID N0:122:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 15 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:1.22:
Ala Pro Lys Thr Tyr Xaa Glu Glu Leu hys Gly Thr Asp Thr Gly (2) INFORMATION FOR SEQ ID N0:123:
(i} SEQUENCE CHARACTERISTICS:
(A) LENGTH: 30 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:123:
Asp Pro Ala Ser Ala Pro Asp Val Pro Thr Ala Ala Gln Leu Thr Ser Leu Leu Asn Ser Leu Ala Asp Pro Asn Val Ser Phe Ala Asn (2) INFORMATION FOR SEQ ID N0:124:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:124:
Asp Pro Pro Asp Pro His Gln Xaa Asp Met Thr Lys Gly Tyr Tyr Pro Gly Gly Arg Arg Xaa Phe (2) INFORMATION FOR SEQ ID N0:125:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 7 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:125:
Asp Pro Gly Tyr Thr Pro Gly (2) INFORMATION FOR SEQ ID N0:126:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 10 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ix) FEATURE:
(A) NAME/KEY: Modified-site (B) LOCATION: 2 (D) OTHER INFORMATION: /product== "OTHER"
/note= "x:aa = Pro or Thr"
(xi) SEQUENCE DESCRIPTION: SEQ ID N0:126:
Xaa Xaa Gly Phe Thr Gly Pro Gln Phe Tyr (2) INFORMATION FOR SEQ ID N0:127:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 9 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ix) FEATURE:
(A) NAME/KEY: Modified-site (B) LOCATION: 3 (D) OTHER INFORMATION: /product= "OTHER"
/note= "Xaa = Gln or Leu"
(xi) SEQUENCE DESCRIPTION: SEQ ID N0:127:
Xaa Pro Xaa Val Thr Ala Tyr Ala Gly (2) INFORMATION FOR SEQ ID N0:128:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 9 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:

(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0::128:
Xaa Xaa Xaa Glu Lys Pro Phe Leu Arg (2) INFORMATION FOR SEQ ID N0:129:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 15 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:129:
Xaa Asp Ser Glu Lys Ser Ala Thr Ile Lys Val Thr Asp Ala Ser 1 5 7.0 15 (2) INFORMATION FOR SEQ ID N0:130:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 15 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:130:
Ala Gly Asp Thr Xaa Ile Tyr Ile Val Gly Asn Leu Thr Ala Asp (2) INFORMATION FOR SEQ ID N0:131:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 15 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:131:
Ala Pro Glu Ser Gly Ala Gly Leu Gly Gly Thr Val Gln Ala Gly (2) INFORMATION FOR SEQ ID N0:132:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 21 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:132:
Xaa Tyr Ile Ala Tyr Xaa Thr Thr Ala Gly Ile Val Pro Gly Lys Ile Asn Val His Leu Val (2) INFORMATION
FOR
SEQ
ID N0:133:

(i) S EQUENCE RACTERISTICS:
CHA

(A) LENGTH:882 base pairs (B) TYPE:ucleic n acid (C) STRANDEDNESS:
single (D) TOPOLOGY: linear (xi) SEQUENCE
DESCRIPTION:
SEQ
ID NO:133:

GGAAGTTCATGCCGTTGTTGCCGACGCAACAGCAGGCGC:CGGTCCCGCCGCCTCCGCCCG 180 CCGTGCCCGGTGTTGTGCCTGCCCCGGTGCCAATCCCGC~TCCCGATCATCATTCCCCCGT 360 CCACGTCGGCGACGACGCCGCCGACCACGCCGCCGACCP~CGCCGGTGACCACGCCGCCAA 480 CCACGCCACCAACGACCGTCGCCCCGACGACCGTCGCCC'.CGACGACGGTCGCTCCGACCA 600 CCGTCGCCCCGACCACGGTCGCTCCAGCCACCGCCACGC'CGACGACCGTCGCTCCGCAGC 660 CGACGCAGCAGCCCACGCAACAACCAACCCAACAGATGC'CAACCCAGCAGCAGACCGTGG 720 GGCCGGTGATGCGGTGACGGTGGTGCTGCCCTGTCTCAA.CGA 882 (2) INFORMATION FOR SEQ ID N0:134:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 815 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:134:

GGAGTGCCGCGATTAGGGCACTGACCGGCGCAACCAGCtaCAAGTACTCTCGGTCACCGAG 480 AGCGGCTAGCTGTCGGCTGCGGTCAACCTCGATCATGA'CGTCGAGGTGACCGTGACCGCG 600 (2) INFORMATION
FOR SEQ
ID N0:135:

(i) SEQUENCE S:
CHARACTERISTIC

(A) LENGTH:1152 basepairs (B) TYPE:ucleic n acid (C) STRANDEDNESS: le sing (D) TOPOLOGY: linear (xi) SEQUENCE EQ ID
DESCRIPTION: N0:7.35:
S

ACCAGCCGCCGGCTGAGGTCTCAGATCAGAGAGTCTCCC~GACTCACCGGGGCGGTTCAGC 60 CTTCTCCCAGAACAACTGCTGAAGATCCTCGCCCGCGAAP.CAGGCGCTGATTTGACGCTC 120 GGCCGGGTGATCGTGTGGAGCGAGGAGCTCGGCGAGAGC:CAGTATCCGATCGAGACGCTG 300 ACACCCGACGTGTCATACGCGCCGCGGCTCCGTCAGCAA.GTTCACCGCACCGACGATCCT 480 (2) INFORMATION FOR SEQ ID N0:136:
(i) SEQUENCE
CHARACTERISTICS:

(A) LENGTH:655 base pairs (B) TYPE:
nucleic acid (C) STRANDEDNESS:
single (D) TOPOLOGY:
linear (xi) SEQUENCE
DESCRIPTION:
SEQ
ID N0:136:

CAGCAATGCGGCAACAGCACGGATCCCGGT CAACGACGC;CACCCGGTCCACGTGGGCGAT 120 CCGCTCGAGTCCGCCCTGGGCGGCTCTTTC CTTGGGCACiGGTCATCCGACGTGTTTCCGC 180 CGTGGTTTGCCGCCATTATGCCGGCGCGCC GCGTCGGGC;GGCCGGTATGGCCGAANGTCG 240 (2) INFORMATION FOR SEQ ID N0:137:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 267 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:137:
Asn Ala Val Val Ala Phe Ala Val Ile Gly Phe Ala Ser Leu Ala Val Ala Val Ala Val Thr Ile Arg Pro Thr Ala Ala Ser Lys Pro Val Glu Gly His Gln Asn Ala Gln Pro Gly Lys Phe Met Pro Leu Leu Pro Thr Gln Gln Gln Ala Pro Val Pro Pro Pro Pro Pro Asp Asp Pro Thr Ala Gly Phe Gln Gly Gly Thr Ile Pro Ala V~sl Gln Asn Val Val Pro Arg Pro Gly Thr Ser Pro Gly Val Gly Gly 'Phr Pro Ala Ser Pro Ala Pro Glu Ala Pro Ala Val Pro Gly Val Val Pro Ala Pro Val Pro Ile Pro Val Pro Ile Ile Ile Pro Pro Phe Pro oily Trp Gln Pro Gly Met Pro Thr Ile Pro Thr Ala Pro Pro Thr Thr 1?ro Val Thr Thr Ser Ala Thr Thr Pro Pro Thr Thr Pro Pro Thr Thr I?ro Val Thr Thr Pro Pro Thr Thr Pro Pro Thr Thr Pro Val Thr Thr I?ro Pro Thr Thr Pro Pro Thr Thr Pro Val Thr Thr Pro Pro Thr Thr Val Ala Pro Thr Thr Val Ala Pro Thr Thr Val Ala Pro Thr Thr Val Ala Pro Thr Thr Val Ala Pro Ala Thr Ala Thr Pro Thr Thr Val Ala Pro Gln Pro Thr Gln Gln Pro Thr Gln Gln Pro Thr Gln Gln Met Pro Thr Gln Gln Gln Thr Val Ala Pro Gln Thr Val Ala Pro Ala Pro Gln Pro Pro Ser Gly Gly Arg Asn Gly Ser Gly Gly Gly Asp Leu Phe Gly Gly Phe (2) INFORMATION FOR SEQ ID N0:138:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 174 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:138:
Ile Asn Gln Pro Leu Ala Pro Pro Ala Pro Pro Asp Pro Pro Ser Pro Pro Arg Pro Pro Val Pro Pro Val Pro Pro Leu Pro Pro Ser Pro Pro Ser Pro Pro Thr Gly Trp Val Pro Arg Ala Leu Leu Pro Pro Trp Leu Ala Gly Thr Pro Pro Ala Pro Pro Val Pro Pro Met Ala Pro Leu Pro Pro Ala Ala Pro Leu Pro Pro Leu Pro Pro Leu Pro Pro Leu Pro Thr Ser His Pro Pro Arg Pro Pro Ala Pro Pro Ala Pro Pro Ala Pro Pro Ala Cys Pro Phe Val Pro Val Pro Pro Ala Pro Pro Leu Pro Pro Ser Pro Pro Thr Glu Leu Pro Ala Asp Ala Ala Cys Pro Pro Ala Pro Pro Ala Pro Pro Leu Ala Pro Pro Ser Pro I?ro Ala Gly Ser Ala Ala Ile Arg Ala Leu Thr Gly Ala Thr Ser Ala Ser Thr Leu Gly His Arg Ala Leu Pro Asp Asp Thr Thr Ala Arg Gly C:ys Arg Arg Thr Gly 165 7.70 (2) INFORMATION FOR SEQ ID N0:139:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 35 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:139:
Gln Pro Pro Ala Glu Val Ser Asp Gln F,rg Val Ser Gly Leu Thr Gly Ala Val Gln Pro Ser Pro Arg Thr Thr Ala Glu Asp Pro Arg Pro Arg Asn Arg Arg (2) INFORMATION FOR SEQ ID N0:140:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 104 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:140:
Arg Ala Asp Ser Ala Gly Cys Thr Cys Arg Trp Cys Xaa Pro His Glu Cys Arg Arg Pro Ala Met Arg Gln Gln His Gly Ser Arg Ser Thr Thr Pro Pro Gly Pro Arg Gly Arg Ser Ala Arg Val Arg Pro Gly Arg Leu Phe Pro Trp Ala Gly Ser Ser Asp Val P:he Pro Pro Trp Phe Ala Ala Ile Met Pro Ala Arg Arg Val Gly Arg P.ro Val Trp Pro Xaa Val Asp Gln His Thr Arg Asp Thr Gly Leu Cys L:ys Leu Phe Glu Arg Arg Ala Gly Gln Leu Arg Arg Gln Phe Tyr (2) INFORMATION FOR SEQ ID N0:141:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 53 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:191:

(2) INFORMATION FOR SEQ ID N0:142:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 42 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:7.42:

(2) INFORMATION FOR SEQ ID N0:143:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 31 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:143:

(2) INFORMATION FOR SEQ ID N0:144:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 31 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:144:

(2) INFORMATION FOR SEQ ID N0:145:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 33 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0::145:

(2) INFORMATION FOR SEQ ID N0:146:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 33 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:146:

(2) INFORMATION FOR SEQ ID N0:147:
(i)SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1993base rs pai (B) TYPE: nucleicacid (C) STRANDEDNESS:single (D) TOPOLOGY: ear lin (ix)FEATURE:

(A) NAME/KEY:
CDS

(B) LOCATION: ..1276 (xi)SEQUENCE DESCRIPTION: ID 0:147:
SEQ N

TGTTCTTCGA CCCACCC-~A ACAGCTG TTC TCCTCGCCGA 60 CGGCAGGCTG
GTGGAGGAAG
GG

AACCGCCCGA
TACGTCGCCG
GACTGT

AAGAGCACAG ATT ACG
AAAGGTATGG
C

ValLys Ile Leu HisThr Arg GCT CCG

LeuLeuAla Val Leu Thr Ala LeuLeu LeuAlaAla AlaGly Ala Pro AGC TCG

CysGlySer Lys Pro Pro Gly ProGlu ThrGlyAla GlyAla Ser Ser CCC TCG

GlyThrVal Ala Thr Thr Ala SerPro ValThrLeu AlaGlu Pro Ser TAC CTG

ThrGlySer Thr Leu Leu Pro PheAsn LeuTrpGly ProAla Tyr Leu AAC ACG

PheHisGlu Arg Tyr Pro Val IleThr AlaGlnGly ThrGly Asn Thr CAG GCC

SerGlyAla Gly Ile Ala Ala AlaGly ThrValAsn IleGly Gln Ala AlaSerAspAla TyrLeuSer GluGlyAsp MetAlaAla HisLysGly LeuMetAsnIle AlaLeuAla IleSerAla G7_nGlnVal AsnTyrAsn LeuProGlyVal SerGluHis LeuLysLeu A:>nGlyLys ValLeuAla AlaMetTyrGln GlyThrIle LysThrTrp AspAspPro GlnIleAla GCGCTCAACCCC GGCGTGAAC CTGCCCGGC AC;CGCGGTA GTTCCGCTG 700 AlaLeuAsnPro GlyValAsn LeuProGly ThrAlaVal ValProLeu HisArgSerAsp GlySerGly AspThrPhe Le~uPheThr GlnTyrLeu SerLysGlnAsp ProGluGly TrpGlyLys SeerProGly PheGlyThr ThrValAspPhe ProAlaVal ProGlyAla LeuGlyGlu AsnGlyAsn GlyGlyMetVal ThrGlyCys AlaGluThr ProGlyCys ValAlaTyr IleGlyIleSer PheLeuAsp GlnAlaSer GlnArgGly LeuGlyGlu AlaGlnLeuGly AsnSerSer GlyAsnPhe LeuLeuPro AspAlaGln SerIleGlnAla AlaAlaAla GlyPheAla SerLysThr ProAlaAsn GlnAlaIleSer MetIleAsp GlyProAla ProAspGly TyrProIle IleAsnTyrGlu TyrAlaIle ValAsnAsn ArgGlnLys AspAlaAla ThrAlaGlnThr LeuGlnAla PheLeuHis TrpAlaIle ThrAspGly AsnLysAlaSer PheLeuAsp GlnValHis Ph~~GlnPro LeuProPro Ala Val Val Lys Leu Ser Asp Ala Leu Ile A:La Thr Ile Ser Ser 360 365 3'70 TAGCCTCGTTGACCACCACGCGACAGCAACCTCCGTCGC~GCCATCGGGCTGCTTTGCGGA 1333 GCATGCTGGCCCGTGCCGGTGAAGTCGGCCGCGCTGGCC:CGGCCATCCGGTGGTTGGGTG 1393 AGGCGATGGGTGCGATCAGGCTCAACGGGTTGCATTTC~PTCACCGCCACCGAATGGAATC 1513 CTACGGGGCGTTGCCGCTGATCGTCGGGACGCTGGCGAC:CTCGGCAATCGCCCTGATCAT 1633 GGCCGAGGCTGTGGGAATAGTCCTGGAATTGCTCGCCGC~AATCCCCAGCGTGGTCGTCGG 1753 GGGCATGTTGGTGTCCGGTCTGGTGTTGGCGGTGATGG7.'CGTTCCCATTATCGCCACCAC 1933 (2) INFORMATION FOR SEQ ID N0:148:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 374 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NC>:148:
Val Lys Ile Arg Leu His Thr Leu Leu Ala Val Leu Thr Ala Ala Pro Leu Leu Leu Ala Ala Ala Gly Cys Gly Ser Lys Pro Pro Ser Gly Ser Pro Glu Thr Gly Ala Gly Ala Gly Thr Val Ala Thr Thr Pro Ala Ser Ser Pro Val Thr Leu Ala Glu Thr Gly Ser Thr Leu Leu Tyr Pro Leu Phe Asn Leu Trp Gly Pro Ala Phe His Glu Arg Tyr Pro Asn VaI Thr Ile Thr Ala Gln Gly Thr Gly Ser Gly Ala Gly Ile Ala Gln Ala Ala Ala Gly Thr Val Asn Ile Gly Ala Ser Asp Ala Tyr Leu Ser Glu Gly Asp Met Ala Ala His Lys Gly Leu Met Asn Ile Ala Leu Ala Ile Ser Ala Gln Gln Val Asn Tyr Asn Leu Pro Gly Val Ser Glu His Leu Lys Leu Asn Gly Lys Val Leu Ala Ala Met Tyr Gln Gly Thr Ile Lys Thr 145 150 1.'i5 160 Trp Asp Asp Pro Gln Ile Ala Ala Leu Asn P~_.o Gly Val Asn Leu Pro Gly Thr Ala Val Val Pro Leu His Arg Ser Asp Gly Ser Gly Asp Thr Phe Leu Phe Thr Gln Tyr Leu Ser Lys Gln A:>p Pro Glu Gly Trp Gly Lys Ser Pro Gly Phe Gly Thr Thr Val Asp Phe Pro Ala Val Pro Gly Ala Leu Gly Glu Asn Gly Asn Gly Gly Met Val Thr Gly Cys Ala Glu Thr Pro Gly Cys Val Ala Tyr Ile Gly Ile Se:r Phe Leu Asp Gln Ala Ser Gln Arg Gly Leu Gly Glu Ala Gln Leu Gl.y Asn Ser Ser Gly Asn Phe Leu Leu Pro Asp Ala Gln Ser Ile Gln Al.a Ala Ala Ala Gly Phe Ala Ser Lys Thr Pro Ala Asn Gln Ala Ile Ser Met Ile Asp Gly Pro Ala Pro Asp Gly Tyr Pro Ile Ile Asn Tyr Gl.u Tyr Ala Ile Val Asn 305 310 31.5 320 Asn Arg Gln Lys Asp Ala Ala Thr Ala Gln Thr Leu Gln,Ala Phe Leu His Trp Ala Ile Thr Asp Gly Asn Lys Ala Seer Phe Leu Asp Gln Val His Phe Gln Pro Leu Pro Pro Ala Val Val Lys Leu Ser Asp Ala Leu Ile Ala Thr Ile Ser Ser (2) INFORMATION FOR SEQ ID N0:149:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 1993 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:149:

AACCACCGAG

CGGGATCGCGCAGGCCGCCGCCGGGACGGTCAACATTG(~GGCCTCCGACGCCTATCTGTC 480 GGAAGGTGATATGGCCGCGCACAAGGGGCTGATGAACA'.CCGCGCTAGCCATCTCCGCTCA 540 GCAGGTCAACTACAACCTGCCCGGAGTGAGCGAGCACC'.CCAAGCTGAACGGAAAAGTCCT 600 GCCCGGCTTCGGCACCACCGTCGACTTCCCGGCGGTGCC:GGGTGCGCTGGGTGAGAACGG 840 CAACGGCGGCATGGTGACCGGTTGCGCCGAGACACCGGCiCTGCGTGGCCTATATCGGCAT 900 TGGCAATTTCTTGTTGCCCGACGCGCAAAGCATTCAGGC:CGCGGCGGCTGGCTTCGCATC 1020 GACGATTTCCAGCTAGCCTCGTTGACCACCACGCGACAC~CAACCTCCGTCGGGCCATCGG 1320 GCTGCTTTGCGGAGCATGCTGGCCCGTGCCGGTGAAGTC:GGCCGCGCTGGCCCGGCCATC 1380 GTGCTGGTCATCGAGGCGATGGGTGCGATCAGGCTCAAC:GGGTTGCATTTCTTCACCGCC 1500 (2) INFORMATION FOR SEQ ID N0:150:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 374 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:7.50:
Met Lys Ile Arg Leu His Thr Leu Leu Ala Val Leu Thr Ala Ala Pro 1 5 7.0 15 Leu Leu Leu Ala Ala Ala Gly Cys Gly Ser Lys Pro Pro Ser Gly Ser Pro Glu Thr Gly Ala Gly Ala Gly Thr Val Ala Thr Thr Pro Ala Ser Ser Pro Val Thr Leu Ala Glu Thr Gly ~cer Thr Leu Leu Tyr Pro Leu Phe Asn Leu Trp Gly Pro Ala Phe His Glu Arg Tyr Pro Asn Val Thr Ile Thr Ala Gln Gly Thr Gly Ser Gly Ala Gly Ile Ala Gln Ala Ala Ala Gly Thr Val Asn Ile Gly Ala Ser P,sp Ala Tyr Leu Ser Glu Gly Asp Met Ala Ala His Lys Gly Leu Met Asn Ile Ala Leu Ala Ile Ser Ala Gln Gln Val Asn Tyr Asn Leu Pro Gly Val Ser Glu His Leu Lys Leu Asn Gly Lys Val Leu Ala Ala Met Tyr Gln Gly Thr Ile Lys Thr Trp Asp Asp Pro Gln Ile Ala Ala Leu Asn Pro Gly Val Asn Leu Pro Gly Thr Ala Val Val Pro Leu His Arg Ser Asp Gly Ser Gly Asp Thr Phe Leu Phe Thr Gln Tyr Leu Ser Lys G1n Asp Pro Glu Gly Trp Gly Lys Ser Pro Gly Phe Gly Thr Thr Val Asp Phe Pro Ala Val Pro Gly Ala Leu Gly Glu Asn Gly Asn Gly Gly Met Val Thr Gly Cys Ala Glu Thr Pro Gly Cys Val Ala Tyr Ile Gly Ile Ser Phe Leu Asp Gln Ala Ser Gln Arg Gly Leu Gly Glu Ala Gln Leu Gly Asn Ser Ser Gly Asn Phe Leu Leu Pro Asp Ala Gln Ser Ile Gln Ala Ala Ala Ala Gly Phe Ala Ser Lys Thr Pro Ala Asn Gln Ala Ile Ser Met Ile Asp Gly Pro Ala Pro Asp Gly Tyr Pro Ile Ile Asn Tyr Glu Tyr Ala Ile Val Asn Asn Arg Gln Lys Asp Ala Ala Thr Ala Gln Thr Leu Gln Ala Phe Leu His Trp Ala Ile Thr Asp Gly Asn Lys Ala Ser Phe Leu Asp Gln Val His Phe Gln Pro Leu Pro Pro Ala Val Val Lys Leu Ser Asp Ala Leu Ile Ala Thr Ile Ser Ser (2) INFORMATION
FOR
SEQ
ID N0:151:

(i) SEQUENCE S:
CHARACTERISTIC

(A) LENGTH:1777 basepairs (B) TYPE:
nucleic acid (C) STRANDEDNESS: le sing (D) TOPOLOGY:
linear (xi) EQ ID
SEQUENCE N0:7.51:
DESCRIPTION:
S

GGTCTTGACCACCACCTGGGTGTCGAAGTCGGTGCCCGC~ATTGAAGTCCAGGTACTCGTG 60 CTCGTGGAAGGTGATGCCGTCGAATTGTGGCGCGCGAAC:GCTGCGGACCAGGCCGATCCG 240 CCCAACGCATACCATTATTCGAACAACCGTTCTATACTT'TGTCAACGCTGGCCGCTACCG 360 AGCGCCGCACAGGATGTGATATGCCATCTCTGCCCGCAC:AGACAGGAGCCAGGCCTTATG 420 ACAGCATTCGGCGTCGAGCCCTACGGGCAGCCGAAGTAC:CTAGAAATCGCCGGGAAGCGC 480 ATGGCGTATATCGACGAAGGCAAGGGTGACGCCATCGTC:TTTCAGCACGGCAACCCCACG 540 CACGTGGTACTGGTGCTGCACGACTGGGGCTCGGCGCTC'GGCTTCGACTGGGCTAACCAG 780 ATCAACGCCGAGCCCGGCGCGATCATCACCGGCCGCAT(:CGTGACTATGTCAGGAGCTGG 1200 CCCAACCAGACCGAAATCACAGTGCCCGGCGTGCATTT(:GTTCAGGAGGACAGCGATGGC 1260 GCCTTTCTATGGGCTCAGTTCGAGGAAGCCGAGCGGATC:ACGCGTATCCGATTGGACCTA 1560 TGGAACCGGTATCATGAAAGCTTCGAATCATTGGAACACzCGGGGGCTCCTGCGCCGTCCG 1620 ATCATCCCACAGGGCTGCTCTCACAACGCCCACATGTAC:TACGTGTTACTAGCGCCCAGC 1680 (2) INFORMATION FOR SEQ ID N0:152:
(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 324 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID
N0:7.52:

CTCCGTCCC;G

ATGCCCGGAC

GGCGGCCAC~G

AGCCCCGGTG

GACGACGCGG

(2) INFORMATION FOR SEQ ID N0:153:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1338 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID
N0:153:

CCTGTACGF,C

GTGGGTGCT'C

CGATGACCGG CGCGGCACCC GGCCACTACG CGTCGAAGA.C GTCCTCGCCG CCCGCAGCGA 180 GAGTACTGTCATCACTATTGGATGCACTGGATGACCGG(:CTGATTCAGCAGGACCAATGG 540 AACTGCCCGGGGCAAAACGTCTCGGAGATGATCGGCGTC:CCCTCGGAACCCTGCGGTGCT 600 CGCACAGCCACGCCGAGCGGGTTCGCCCCGAGCACCGCCiACCTGCTGGGCCCGGCGGCCG 840 CCGACAGCACCGACGAGTGTGTGCTACTGCGGGCCGCACiCGAAAGTTGTTGCCGCACTGC 900 CGGTTAACCGGCCAGAGGGT.CTGGACGCCATCGAGGATC;TGCACATCTGGACCGCCGAGT 960 CGGTGCGCGCCGACCGGCTCGACTTTCGGCCCAAGCACAP.ACTGGCCGTCTTGGTGGTCT 1020 GGGTCTGAGCTGTACGCCCAGTCGGCGCTGCGAGTGATC;TGCTGTCGGTTCGGTCCCTGC 1260 TGGCGTCAATTGACGGCGCGGGCAACAGCAGCATTGGCC~GCGCCATCCTCCGCGCGGCCG 1320 (2) INFORMATION FOR SEQ ID N0:154:
(i) SEQUENCE
CHARACTERISTICS:

(A) LENGTH: 321 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) EQUENCE DESCRIPTION: SEQ
S ID N0:1.54:

TAGGTGGGGCCGCGGTGACA GGCGGGGTCG CCGGCGACCzGCGGCACCGGCGGCAAAGGTG 180 GCACCGGCGGTGCCGGCGGC GCCGGCAACG ACGCCGGCP,GCACCGGCAATCCCGGCGGTA 240 (2) INFORMATION FOR SEQ ID N0:155:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 492 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:_L55:

CGTTCGCCTCCGAACTCGTCACTTCGGCGCAAGCCCGAC:GGCACCGCCGAATCACCAGGG 180 CGGTCCACGATTCGGGTGCAAAGATCCTGCTGCAAATCC:TGCACGCCGGACGCTACGCCT 240 ACCACCCACTTGCGGTCAGCGCCTCGCCGATCAAGGCGC:CGATCACCCCGTTTCGTCCGC 300 TGGCCCGCGATGCCGGCTACGACGGCGTCGAAATCATGC~GCAGCGAAGGGTATCTGCTCA 420 (2) INFORMATION FOR SEQ ID N0:156:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 536 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:1.56:
Phe Ala Gln His Leu Val Glu Gly Asp Ala Val Glu Leu Trp Arg Ala Asn Ala Ala Asp Gln Ala Asp Pro Leu Gln Pro Gly Ser Ala Arg Arg Gln Arg Ala Ser Arg Ser Pro Arg Arg L~eu Ala Gly Pro Asn Ala Tyr His Tyr Ser Asn Asn Arg Ser Ile Leu C'ys Gln Arg Trp Pro Leu Pro Ser Ala Ala Gln Asp Val Ile Cys His Leu Cys Pro His Arg Gln Glu Pro Gly Leu Met Thr Ala Phe Gly Val Glu Pro Tyr Gly Gln Pro Lys Tyr Leu Glu Ile Ala Gly Lys Arg Met Ala Tyr Ile Asp Glu Gly Lys Gly Asp Ala Ile Val Phe Gln His Gly Asn Pro Thr Ser Ser Tyr Leu Trp Arg Asn Ile Met Pro His Leu Glu Gly Leu Gly Arg Leu Val Ala Cys Asp Leu Ile Gly Met Gly Ala Ser Asp Lys Leu Ser Pro Ser Gly Pro Asp Arg Tyr Ser Tyr Gly Glu Gln Arg Asp Phe Leu Phe Ala Leu Trp Asp Ala Leu Asp Leu Gly Asp His Val Val Leu Val Leu His Asp Trp Gly Ser Ala Leu Gly Phe Asp Trp Ala Asn Gln His Arg Asp Arg Val Gln Gly Ile Ala Phe Met Glu Ala l:le Val Thr Pro Met Thr Trp Ala Asp Trp Pro Pro Ala Val Arg Gly Val Phe Gln Gly Phe Arg Ser Pro Gln Gly Glu Pro Met Ala Leu Glu His Asn Ile Phe Val Glu Arg Val Leu Pro Gly Ala Ile Leu Arg Gln Leu Ser Asp Glu Glu Met Asn His Tyr Arg Arg Pro Phe Val Asn Gly Gly Glu Asp Arg Arg Pro Thr Leu Ser Trp Pro Arg Asn Leu Pro Ile Asp Gly Glu Pro Ala Glu Val Val Ala Leu Val Asn Glu Tyr Arg Ser Trp Leu Glu Glu Thr Asp Met Pro Lys Leu Phe Ile Asn Ala Glu Pro Gly Ala Ile Ile Thr Gly Arg Ile Arg Asp Tyr Val Arg Ser Trp Pro Asn Gln Thr Glu Ile Thr Val Pro Gly Val His Phe Val Gln Glu Asp Ser Asp Gly Val Val Ser Trp Ala Gly Ala Arg Gln His Arg Arg Pro Gly Ser Ala Leu Ile Ser Arg Asp Gln Glu Cys Asp Phe Arg Arg Arg Arg Arg Pro Ala Cys Gln Leu Ile Arg Leu Pro Ala Pro Gly Arg Asp Ser Gln Gly Lys Gly His Gln Ser Gln Pro Leu Pro Ser Gln Arg Gly Arg Gln Ile Tyr Val Ala Gly Gln Arg Ser Ser Tyr Leu Pro Ser Glu Leu Val Ala Ala Phe Leu Trp Ala Gln Phe Glu Glu Ala Glu Arg Ile Thr Arg Ile Arg Leu Asp Leu Trp Asn Arg Tyr His Glu Ser Phe Glu Ser Leu Glu Gln Arg Gly Leu Leu Arg Arg Pro Ile Ile Pro Gln Gly (:ys Ser His Asn Ala His Met Tyr Tyr Val Leu Leu Ala Pro Ser Ala Asp Arg Glu Glu Val Leu Ala Arg Leu Thr Ser Glu Gly Ile Gly Ala Val Phe His Tyr Val Pro Leu His Asp Ser Pro Ala Gly Arg Arg (2) INFORMATION FOR SEQ ID N0:157:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 284 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1.57:
Asn Glu Ser Ala Pro Arg Ser Pro Met Leu Pro Ser Ala Arg Pro Arg 1 5 7.0 15 Tyr Asp Ala Ile Ala Val Leu Leu Asn C~lu Met His Ala Gly His Cys Asp Phe Gly Leu Val Gly Pro Ala Pro Asp Ile Val Thr Asp Ala Ala Gly Asp Asp Arg Ala Gly Leu Gly Val Asp Glu Gln Phe Arg His Val Gly Phe Leu Glu Pro Ala Pro Val Leu Val Asp Gln Arg Asp Asp Leu Gly Gly Leu Thr Val Asp Trp Lys Val Ser Trp Pro Arg Gln Arg Gly Ala Thr Val Leu Ala Ala Val His Glu Trp Pro Pro Ile Val Val His Phe Leu Val Ala Glu Leu Ser Gln Asp Arg Pro Gly Gln His Pro Phe Asp Lys Asp Val Val Leu Gln Arg His Trp Leu Ala Leu Arg Arg Ser Glu Thr Leu Glu His Thr Pro His Gly A.rg Arg Pro Val Arg Pro Arg His Arg Gly Asp Asp Arg Phe His Glu A.rg Asp Pro Leu His Ser Val Ala Met Leu Val Ser Pro Val Glu Ala Glu Arg Arg Ala Pro Val Val Gln His Gln Tyr His Val Val Ala Glu Val Glu Arg Ile Pro Glu Arg Glu Gln Lys Val Ser Leu Leu Ala Ile Ala Ile Ala Val Gly Ser Arg Trp Ala Glu Leu Val Arg Arg Ala His I?ro Asp Gln Ile Ala Gly His Gln Pro Ala Gln Pro Phe Gln Val Arg His Asp Val Ala Pro Gln Val 245 :?50 255 Arg Arg Arg Gly Val Ala Val Leu Lys Asp Asp Gly Val Thr Leu Ala Phe Val Asp Ile Arg His Ala Leu Pro Gly Asp Phe (2) INFORMATION FOR SEQ ID N0:158:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 264 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:158:

GCCATGCACGCGATCGCCGGTTTCTCCGATGCGTTGCGC;CAAGAGCTGCGGGGTAGCGGA 120 CCCGCCGACATGCCGCCGCCGTTTCGCAGCCTCACGCCC;ATTCCCGTTCACTGGGTCGCG 240 (2) INFORMATION FOR SEQ ID N0:159:
(i) SEQUENCE
CHARACTERISTICS:

(A) LENGTH:1171 basepairs (B) TYPE:
nucleic acid (C) STRANDEDNESS: le sing (D) TOPOLOGY:
linear (xi) EQUENCE
S DESCRIPTION:
SEQ ID
N0:1.59:

AAGCCGGTGCGATCCTTACCCGCGAAGCAGTGGGTGAGC:ACCGGGCGTCCGGCGGCAAGC 120 ATCTCCTCGCCGCCCATCGTCAGATCCCGCTCGTGCGT'.CGACAAGAACGGCCGCAGATGT 600 GCCAGCGGGTATCGGAGATTGAACCGCGCACGCAGTTC'.PTCAATCGCTGCGCGCTGCCGC 660 ACTATTGGCACTTTCCGGCGGTCGCGGTATTCAGCAAG(:ATGCGAGTCTCGACGAACTCG 720 ACCATCGGCACCGGCACCAAGGTGCCGCACCTGACCTAC:GTCGGCGACGCCGACATCGGC 960 GAGTACAGCAACATCGGCGCCTCCAGCGTGTTCGTCAAC:TACGACGGTACGTCCAAACGG 1020 CGCACCACCGTCGGTTCGCACGTACGGACCGGGTCCGAC:ACCATGTTCGTGGCCCCAGTA 1080 (2) INFORMATION FOR SEQ ID N0:160:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 227 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:7.60:

ACGGCGGCCA AGGCGGCACC GGCGGCACCG GCGGCAACC~C CGGCGCCGGC GGCACCAGCT 120 (2) INFORMATION FOR SEQ ID N0:161:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 304 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:161:
CCTCGCCACC ATGGGCGGGC AGGGCGGTAG CGGTGGCGC'C GGCTCTACCC CAGGCGCCAA 60 CAACGCCACC AACCCTGGTG AAAACGGGCC AAACGGTAA.C CCCGGCGGCA ACGGTGGCGC 300 (2) INFORMATION
FOR
SEQ
ID N0:162:

(i) SEQUENCE
CHARACTERISTICS:

(A) LENGTH:1439 base pairs (B) TYPE:
nucleic acid (C) STRANDEDNESS:
single (D) TOPOLOGY:
linear (xi) SEQUENCE
DESCRIPTION:
SEQ
ID N0:162:

CGAGTGGGCGGGTGTATGACCCGTGCTGCGGTTCCGGAC~GCATGTTTGTGCAGACCGAGA 300 AGTTCATCTACGAACACGACGGCGATCCGAAGGATGTC7.'CGATCTATGGCCAGGAAAGCA 360 TTGAGGAGACCTGGCGGATGGC;GAAGATGAACCTCGCCATCCACGGCATCGACAACAAGG 420 GGCTCGGCGCCCGATGGAGTGATACCTTCGCCCGCGACC:AGCACCCGGACGTGCAGATGG 480 CCGGCTCCGGTGGTGCCGGCGGTAATGGGGGCACTGGCC:TCAACGGCGCGGGCGGTGCTG 1020 (2) INFORMATION FOR SEQ ID N0:163:
(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 329 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE
DESCRIPTION:
SEQ
ID N0:7_63:

GTGGTAACGGCGGGATGGGC GGGGCTGGCG GGGCTGGC<7GCCCCGGCGGGGCCGGCGGCC120 TGATCAGCCTGCTGGGCGGC CAAGGCGCCG GCGGGGCCC~GCGGGACCGGCGGGGCCGGCG180 GTGTTGGCGGTGACGGCGGG GCCGGCGGCC CCGGCAACC:AGGCCTTCAACGCAGGTGCCG240 (2) INFORMATION FOR SEQ ID N0:164:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 80 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO::L64:

(2) INFORMATION FOR SEQ ID N0:165:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 392 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO::L65:

TCAAGGTCAT CGACCGCGAC GGGCATCGAG GCCGTCGT(:G CGCGGCTCGG GCAGGATCCG 180 CCCCGGCGCA CTTCGCGCGC CAAGCGGGCT CATCGCTC(:G AACGGCGGCG ATCCTGTGAG 240 (2) INFORMATION FOR SEQ ID N0:166:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 535 base pairs (B) TYPE:
nucleic acid (C) STRANDEDNESS:
single (D) TOPOLOGY:
linear (xi) SEQUENCE
DESCRIPTION:
SEQ ID
N0:166:

GCTACCGGTGGCGCCGGGTTCGCCGGCGGCGCCGGCGGi~GAAGGCGGACCGGGCGGCAAC 420 AGCGGTGTGGGCGGCACCAACGGCTCCGGCGGCGCCGG(:GGTGCAGGCGGCAAGGGCGGC 480 (2) INFORMATION
FOR
SEQ
ID N0:167:

(i) SEQUENCE RACTERISTICS:
CHA

(A) LENGTH:690 base pairs (B) TYPE:
nucleic acid (C) STRANDEDNESS:
single (D) TOPOLOGY: linear (xi) SEQUENCE
DESCRIPTION:
SEQ
ID N0:7.67:

CATCGCCGATGCCCTGGCCGCCGGAACACAAGAAGGCAT'CCTTGACTTCA CGGCCGACCT300 TCTGGTGGCCGCGGTGGCCGCCGCACCGACGCCGGCCGA.GGTGGTGAACA CGCTCGCCAG420 (2) INFORMATION FOR SEQ ID N0:168:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 407 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS:
single (D) TOPOLOGY: linear (xi) SEQUENCE
DESCRIPTION:
SEQ
ID N0:168:

(2) INFORMATION FOR SEQ ID N0:169:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 468 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID 9:
N0:16 GCGATTCCGC

GCTGCGGCC~C

ACACGTCGGT

ACGCCCGCGC

GCCCGGCGAA

GGATGTGCC'G

TCCCGCTGGC

ACAGGCCGGC

(2) INFORMATION FOR SEQ ID N0:170:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 219 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID
N0:170:

GGCGCCGGCG

AACGGCGGTA

GGCAACGCGC

(2) INFORMATION FOR SEQ ID N0:171:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 494 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:171:

CAGCGGCTTT TTCGGCGGCA AGGGCGGCTT CGGCGGCGi~C GGCGGTCAGG GCGGCCCCAA 180 GGGCGGCGAC GGCGTCTTTG CCGGTGCCGG CGGCCAGG(~C GGCCTCGGTG GGCAGGGCGG 300 (2) INFORMATION FOR SEQ ID N0:172:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 220 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:172:

(2) INFORMATION FOR SEQ ID N0:173:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 388 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:173:

ACGCCCGCGC

TGATCGGCCTAGCCGCACCCGGGAAAGCCGATCCAACA.GGCGACGATGCCGCCTTCCTTG 180 (2) INFORMATION
FOR
SEQ
ID N0:174:

(i) SEQUENCE
CHARACTERISTICS:

(A) LENGTH: 400 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE
DESCRIPTION:
SEQ
ID N0::174:

GCGGAAACGGCGGAAACGGC GCAGACAACA CCACCACCCiCCGCCGCCGGC ACCACAGGCG240 (2) INFORMATION
FOR
SEQ
ID N0:175:

(i) S EQUENCE CHARACTERISTICS:

(A) LENGTH: 538 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE
DESCRIPTION:
SEQ
ID N0:175:

(2) INFORMATION
FOR SEQ
ID N0:176:

(i) SEQUENCE
CHARACTERISTICS:

(A) LENGTH: 239 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE
DESCRIPTION:
SEQ ID
N0:176:

CGCGGCGGGT GCCGTTGGGG

GCCACGGCGGCAACGCCATT GCCGGCGGCA TCAACGGC'PCCGGTGGTGCC GGCGGCACC239 (2) INFORMATION
FOR SEQ
ID N0:177:

(i) S EQUENCE CHARACTERISTICS:

(A) LENGTH: 985 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE
DESCRIPTION:
SEQ ID
N0:177:

AGCAGCGCTACCGGTGGCGC CGGGTTCGCC GGCGGCGCC;GGCGGAGAAGG CGGAGCGGGC60 GGCAACAGCGGTGTGGGCGG CACCAACGGC TCCGGCGGC;GCCGGCGGTGC AGGCGGCAAG120 GGCGGCACCGGAGGTGCCGG CGGGTCCGGC GCGGACAAC:CCCACCGGTGC TGGTTTCGCC180 GGTGGCGCCGGCGGCACAGG TGGCGCGGCC GGCGCCGGC'.GGGGCCGGCGG GGCGACCGGT240 ACCGGCGGCACCGGCGGCGT TGTCGGCGCC ACCGGTAGT'GCAGGCATCGG CGGGGCCGGC300 TCGGCCTAGCCGCACCCGGG AAAGCCGATC CAACAGGCG.~CGATGCCGCC TTCCTTGCCG780 CGTTGGACCAGGCCGGCATC ACCTACGCTG ACCCAGGCC:~1CGCCATAACG GCCGCCAAGG840 AATACAATCCCGGGCTGACC ATGGACAGCG CGGCCAAGT'PCGCTGCCATC GCATCAGGCG960 CGTACTGCCCCGAACACCTG GAACA g85 (2) INFORMATION
FOR SEQ
ID N0:178:

(i) S EQUENCE
CHARACTERISTICS:

(A) LENGTH:2138 basepairs (B) TYPE:
nucleic acid (C) STRANDEDNESS:
single (D) TOPOLOGY: linear (xi) S EQUENCE CRIPTION:EQ ID 8:
DES S N0:17 CGGCCGAACTAACCGATACGCCGAGGGTGGCCACGGCCCiGTGAACCCAACTTCATGGATC 600 TCAAAGAAGCGGCAAGGAAGCTCGAAACGGGCGACCAAC~GCGCATCGCTCGCGCACTTTG 660 CGGATGGGTGGAACACTTTCAACCTGACGCTGCAAGGCC~ACGTCAAGCGGTTCCGGGGGT 720 TTGACAACTGGGAAGGCGATGCGGCTACCGCTTGCGAGC~CTTCGCTCGATCAACAACGGC 780 AACGGCTTTACGCGGAAAACCCTTCGGCCCGCGACCAAP,TTCTCCCGGTGTACGCGGAGT 960 GCCAGGACAGTAAGGAGTCGAAGTGAGCATGGACGAAT'TGGACCCGCATGTCGCCCGGGC1620 AA.TGGCCTAAGCCCATTGTTGCGGTGGTAGCGACTACGCACCGAATGAGCGCCGCAATGC1980 GCCGGGTTCGGAGGGCGCCATAGTCCTGGTCGCCAATA'PTGCCGCAGCTAGCTGGTCTTA2100 (2) INFORMATION FOR SEQ ID N0:179:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 460 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:179:
Met Thr Gln Ser Gln Thr Val Thr Val Asp Gln Gln Glu Ile Leu Asn 1 5 7.0 15 Arg Ala Asn Glu Val Glu Ala Pro Met Ala Asp Pro Pro Thr Asp Val Pro Ile Thr Pro Cys Glu Leu Thr Ala Ala Lys Asn Ala Ala Gln Gln Leu Val Leu Ser Ala Asp Asn Met Arg Glu Tyr Leu Ala Ala Gly Ala Lys Glu Arg Gln Arg Leu Ala Thr Ser Leu Arg Asn Ala Ala Lys Ala 65 70 75 g0 Tyr Gly Glu Val Asp Glu Glu Ala Ala Thr Ala Leu Asp Asn Asp Gly Glu Gly Thr Val Gln Ala Glu Ser Ala Gly Ala Val Gly Gly Asp Ser Ser Ala Glu Leu Thr Asp Thr Pro Arg Val Ala Thr Ala Gly Glu Pro Asn Phe Met Asp Leu Lys Glu Ala Ala Arg Lys Leu Glu Thr Gly Asp Gln Gly Ala Ser Leu Ala His Phe Ala Asp Gly Trp Asn Thr Phe Asn Leu Thr Leu Gln Gly Asp Val Lys Arg Phe Arg Gly Phe Asp Asn Trp 165 1'70 175 Glu Gly Asp Ala Ala Thr Ala Cys Glu Ala Ser Leu Asp Gln Gln Arg Gln Trp Ile Leu His Met Ala Lys Leu Ser Ala Ala Met Ala Lys Gln Ala Gln Tyr Val Ala Gln Leu His Val Trp Ala Arg Arg Glu His Pro Thr Tyr Glu Asp Ile Val Gly Leu Glu Arg Leu Tyr Ala Glu Asn Pro Ser Ala Arg Asp Gln Ile Leu Pro Val Tyr Ala Glu Tyr Gln Gln Arg Ser Glu Lys Val Leu Thr Glu Tyr Asn Asn Lys Ala Ala Leu Glu Pro Val Asn Pro Pro Lys Pro Pro Pro Ala Ile Lys Ile Asp Pro Pro Pro Pro Pro Gln Glu Gln Gly Leu Ile Pro Gly Phe Leu Met Pro Pro Ser Asp Gly Ser Gly Val Thr Pro Gly Thr c;ly Met Pro Ala Ala Pro Met Val Pro Pro Thr Gly Ser Pro Gly Gly (ily Leu Pro Ala Asp Thr Ala 325 :330 335 Ala Gln Leu Thr Ser Ala Gly Arg Glu Ala Ala Ala Leu Ser Gly Asp Val Ala Val Lys Ala Ala Ser Leu Gly CJly Gly Gly Gly Gly Gly Val Pro Ser Ala Pro Leu Gly Ser Ala Ile Gly Gly Ala Glu Ser Val Arg Pro Ala Gly Ala Gly Asp Ile Ala Gly Leu Gly Gln Gly Arg Ala Gly Gly Gly Ala Ala Leu Gly Gly Gly Gly Met Gly Met Pro Met Gly Ala Ala His Gln Gly Gln Gly Gly Ala Lys Ser Lys Gly Ser Gln Gln Glu Asp Glu Ala Leu Tyr Thr Glu Asp Arg Ala Trp Thr Glu Ala Val Ile Gly Asn Arg Arg Arg Gln Asp Ser Lys Glu Ser Lys (2) INFORMATION FOR SEQ ID N0:180:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 277 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:180:

Ala Gly Asn Val Thr Ser Ala Ser Gly Pro His Arg Phe Gly Ala Pro Asp Arg Gly Ser Gln Arg Arg Arg Arg His Pro Ala Ala Ser Thr Ala Thr Glu Arg Cys Arg Phe Asp Arg His Val Ala Arg Gln Arg Cys Gly Phe Pro Pro Ser Arg Arg Gln Leu Arg Arg Arg Val Ser Arg Glu Ala Thr Thr Arg Arg Ser Gly Arg Arg Asn His Arg Cys Gly Trp His Pro Gly Thr Gly Ser His Thr Gly Ala Val Arg Arg Arg His Gln Glu Ala Arg Asp Gln Ser Leu Leu Leu Arg Arg .~lrg Gly Arg Val Asp Leu Asp Gly Gly Gly Arg Leu Arg Arg Val Tyr Arg Phe Gln Gly Cys Leu Val Val Val Phe Gly Gln His Leu Leu Arg Pro Leu Leu Ile Leu Arg Val His Arg Glu Asn Leu Val Ala Gly Arg Arg Val Phe Arg Val Lys Pro Phe Glu Pro Asp Tyr Val Phe Ile Ser Arg Met Phe Pro Pro Ser Pro His Val Gln Leu Arg Asp Ile Leu Ser Leu Leu Gly His Arg Ser Ala Gln Phe Gly His Val Glu Tyr Pro Leu Pro Leu Leu Ile Glu Arg Ser Leu Ala Ser Gly Ser Arg Ile Ala Phe F'ro Val Val Lys Pro Pro Glu Pro Leu Asp Val Ala Leu Gln Arg Gln V'al Glu Ser Val Pro Pro Ile Arg Lys Val Arg Glu Arg Cys Ala Leu Val Ala Arg Phe Glu Leu Pro Cys Arg Phe Phe Glu Ile His Glu Val Gly Phe Thr Gly Arg Gly His Pro Arg Arg Ile Gly (2) INFORMATION FOR SEQ ID N0:181:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 192 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:181:
Arg Val Ala Ala Ser Phe Ile Asp Trp Leu Asp Ser Pro Asp Ser Pro Leu Asp Pro Ser Leu Val Ser Ser Leu Leu Asn Ala Val Ser Cys Gly Ala Glu Ser Ser Ala Ser Ser Ser Ala Arg Ser Gly Asn Gly Ser Arg Trp Thr Ser Met Pro Ser Gly Thr Arg Pro Gly Pro Arg Arg Ala Thr Ser Arg Asp Asp Arg Arg Ser Ala Thr Ser Val Ile Pro Ser Arg Arg Ser Val Ala Pro Arg Ala Glu Phe Gly 'Thr Arg Leu Ala Ser His Arg Ala Ser Pro Ser Asn Ala Cys Pro Val ;erg Ile Val Thr Ser Ala Ser Gly Arg Pro Ile Ser Ser Pro Pro Ile 'Jal Arg Ser Arg Ser Cys Val Asp Lys Asn Gly Arg Arg Cys Ala Ser Gly Tyr Arg Arg Leu Asn Arg Ala Arg Ser Ser Ser Ile Ala Ala Arg (:ys Arg Thr Ile Gly Thr Phe Arg Arg Ser Arg Tyr Ser Ala Ser Met Arg Val Ser Thr Asn Ser Pro 165 7.70 175 His Val Thr His Gly Val Ala Pro Gly Val Thr Arg Arg Ile Gly Gly (2) INFORMATION FOR SEQ ID N0:182:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 196 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:182:
Gln Glu Arg Pro Gln Met Cys Gln Arg Val Ser Glu Ile Glu Pro Arg Thr Gln Phe Phe Asn Arg Cys Ala Leu Pro His Tyr Trp His Phe Pro Ala Val Ala Val Phe Ser Lys His Ala Ser Leu Asp Glu Leu Ala Pro Arg Asn Pro Arg Arg Ser Ser Arg Arg Asp Ala Glu Asp Arg Arg Val Ile Phe Ala Ala Thr Leu Val Ala Val A;sp Pro Pro Leu Arg Gly Ala Gly Gly Glu Ala Asp Gln Leu Ile Asp Leu Gly Val Cys Arg Arg Gln Ala Gly Arg Val Arg Arg Gly Gln Glu Leu His His Arg His Arg His Gln Gly Ala Ala Pro Asp Leu Arg Arg Arg Arg Arg His Arg Arg Val Gln Gln His Arg Arg Leu Gln Arg Val Arg Gln Leu Arg Arg Tyr Val Gln Thr Ala His His Arg Arg Phe Ala Arg Thr Asp Arg Val Arg His His Val Arg Gly Pro Ser Asn His Arg .Arg Arg Arg Val Tyr Arg Gly Arg His Ser Gly Ala Gly Gly Cys Pro Ala Gly Gly Ala Gly Ser Val Gly Gly Ser Ala (2) INFORMATION FOR SEQ ID N0:183:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 311 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:183:
Val Arg Cys Gly Thr Leu Val Pro Val Pro Met Val Glu Phe Leu Thr 1 5 7.0 15 Ser Thr Asn Ala Pro Ser Leu Pro Ser Ala Tyr Ala Glu Val Asp Lys Leu Ile Gly Leu Pro Ala Gly Thr Ala Lys Arg Trp Ile Asn Gly Tyr Glu Arg Gly Gly Lys Asp His Pro Pro Ile Leu Arg Val Thr Pro Gly Ala Thr Pro Trp Val Thr Trp Gly Glu Fhe Val Glu Thr Arg Met Leu Ala Glu Tyr Arg Asp Arg Arg Lys Val Pro Ile Val Arg Gln Arg Ala Ala Ile Glu Glu Leu Arg Ala Arg Phe Asn Leu Arg Tyr Pro Leu Ala His Leu Arg Pro Phe Leu Ser Thr His Glu Arg Asp Leu Thr Met Gly Gly Glu Glu Ile Gly Leu Pro Asp Ala Glu Val Thr Ile Arg Thr Gly Gln Ala Leu Leu Gly Asp Ala Arg Trp L~~u Ala Ser Leu Val Pro Asn Ser Ala Arg Gly Ala Thr Leu Arg Arg Leu Gly Ile Thr Asp Val Ala Asp Leu Arg Ser Ser Arg Glu Val Ala Arg Arg Gly Pro Gly Arg Val Pro Asp Gly Ile Asp Val His Leu Leu Pro Phe Pro Asp Leu Ala Asp Asp Asp Ala Asp Asp Ser Ala Pro His Glu Thr Ala Phe Lys Arg Leu Leu Thr Asn Asp Gly Ser Asn Gly Glu Ser Gly Glu Ser Ser Gln Ser Ile Asn Asp Ala Ala Thr Arg Tyr Met 'rhr Asp Glu Tyr Arg Gln Phe Pro Thr Arg Asn Gly Ala Gln Arg Ala :Leu His Arg Val Val Thr Leu Leu Ala Ala Gly Arg Pro Val Leu Thr 1-Iis Cys Phe Ala Gly Lys Asp Arg Thr Gly Phe Val Val Ala Leu Val Leu Glu Ala Val Gly Leu Asp Arg Asp Val Ile Val Ala Asp (2) INFORMATION FOR SEQ ID N0:184:
(i) SEQUENCE
CHARACTERISTICS:

(A) LENGTH:2072 basepairs (B) TYPE:
nucleic acid (C) STRANDEDNESS: le sing (D) TOPOLOGY:
linear (xi) SEQUENCE
DESCRIPTION:
SEQ ID
N0:1.84:

CTCGTGCCGATTCGGCACGAGCTGAGCAGCCCAAGGGGC:CGTTCGGCGAAGTCATCGAGG 60 CGTTCGGCCT GAACGTGGCC AGCACCGCCT CGACACTC:CCTAAAGAGATCGCGTACTCCG720 AGCCCCGCTT GCAGCCGCCC AACGGGTACA AGGACACC:ACGGTGCCCGGCATCTGGGTGC780 TCCAGAACCG AGCGGTCGCG CAGGCCAACA TGACGATG;~CGGTGCTCTCCCTCGGGCTGT1380 GAGCGATGAT GGACCGACGG GGACCGGCCA AGATCGTG(:TGGTTGGGATCATGCTGATCG1560 GGGCGGCAGT GCAGACCCTG GCCCCACATC AGATCGCTC:GCGGTTCGACGCTGATCAGCG1740 AGTCATCGAA

(2) INFORMATION FOR SEQ ID N0:185:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1923 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID :
N0:185 TCACCCCGGA GAAGTCGTTC GTCGACGACC TGGACATCG.A 60 CTCGCTGTCG ATGGTCGAGA

CGACGAGGAC CTCGCCGGTC

TGCGTACCGT CGGTGACGTT GTCGCCTACA TCCAGAAGC'T 180 CGAGGAAGAA AACCCGGAGG

CGGAGAAC;CC
CGATGCGGCA
CGAGCAGATC

ACGCCCGTCG
TCCTCTTGCA
CGCTCAGCCA

ACGAAGGGAC

CTGACAATTG

TCACCCCAGCTCACTGGTGCACCATCCGGGTGTCGGTG,~GCGTGCAACTCAAACACACTC780 GTGCCCTTCGTGCCAGGTCGCGAATCCGGCAACCAGCAC:GCTGGTGTCTGGTGCGATCAC1200 TCAATCTCGATGCGCCCATCGCGCTCGGTGATCTCCACC:TGGTCGTTCCCGCGCAAGCCA1380 TCGAACGGGT

GCGTGATCGC GCATTTCCAT
CCTGGCGGCG

ACCCCCAGCG GGCAACGGT'rCCGCAGACAA 1920 AGGTCAAGGC GGCTCAGGTC
GGCGGTCACT

ACC

(2) INFORMATION FOR SEQ ID N0:186:

(i) SEQUENCE
CHARACTERISTICS:

(A) LENGTH:1055 basepairs (B) TYPE: ucleic n acid (C) STRANDEDNESS:
single (D) TOPOLOGY: linear (xi) SEQUENCE CRIPTION:EQ ID 6:
DES S N0:18 CCACCCGATGATTATGACCACTGGGCGCCTGCGCCGGA(iGACGGCGCCGATGTCGATGTC 600 GCGTGGAACGAGTGGGTGGCGGAGAACGCTGAACCCCGC:TTTGAGGTGCCACGGAGTAGC 720 CATGACAAGTTACAGGTATTAGGTCCAGGTTCAACAAGC~AGACAGGCAACATGGCAACAC 900 (2) INFORMATION FOR SEQ ID N0:187:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 359 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:187:

TCCGGGCTGA CCACCGGGAT CGCCGAACCA TCCGAGATC,A CCTCGCAATG ATCCACCTCG 120 GAGAAGTTCA GGGTGAAGGT CGGCATGTCG CCGCCGAGG'P AGTTGACCCG GAAAACCAGA 300 (2) INFORMATION FOR SEQ ID N0:188:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 350 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: $EQ ID
N0:188:

(2) INFORMATION FOR SEQ ID N0:189:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 679 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1.89:
Glu Gln Pro Lys Gly Pro Phe Gly Glu Val Ile Glu Ala Phe Ala Asp 1 5 1.0 15 Gly Leu Ala Gly Lys Gly Lys Gln Ile Asn Thr Thr Leu Asn Ser Leu Ser Gln Ala Leu Asn Ala Leu Asn Glu G'ly Arg Gly Asp Phe Phe Ala Val Val Arg Ser Leu Ala Leu Phe Val A.sn Ala Leu His Gln Asp Asp Gln Gln Phe Val Ala Leu Asn Lys Asn Leu Ala Glu Phe Thr Asp Arg Leu Thr His Ser Asp Ala Asp Leu Ser Asn Ala Ile Gln Gln Phe Asp Ser Leu Leu Ala Val Ala Arg Pro Phe Phe Ala Lys Asn Arg Glu Val Leu Thr His Asp Val Asn Asn Leu Ala T:hr Val Thr Thr Thr Leu Leu Gln Pro Asp Pro Leu Asp Gly Leu Glu Tlzr Val Leu His Ile Phe Pro Thr Leu Ala Ala Asn Ile Asn Gln Leu Tyr His Pro Thr His Gly Gly Val Val Ser Leu Ser Ala Phe Thr Asn Phe Ala Asn Pro Met Glu Phe Ile Cys Ser Ser Ile Gln Ala Gly Ser Arg Leu Gly Tyr Gln Glu Ser Ala Glu Leu Cys Ala Gln Tyr Leu Ala Pro Val Leu Asp Ala Ile Lys Phe Asn Tyr Phe Pro Phe Gly Leu Asn Val Ala Ser Thr Ala Ser Thr Leu Pro Lys Glu Ile Ala Tyr Ser Glu Pro Arg Leu Gln Pro Pro Asn Gly Tyr Lys Asp Thr Thr Val Pro Gly Ile Trp Val Pro Asp Thr Pro Leu Ser His Arg Asn Thr Gln Pro Gly 'Trp Val Val Ala Pro Gly Met Gln Gly Val Gln Val Gly Pro Ile Thr Gln Gly Leu Leu Thr Pro Glu Ser Leu Ala Glu Leu Met Gly Gly Pro Asp Ile Ala Pro Pro Ser Ser Gly Leu Gln Thr Pro Pro Gly Pro Pro Asn Ala Tyr Asp Glu Tyr Pro Val Leu Pro Pro Ile Gly Leu Gln Ala Pro Gln Val Pro Ile Pro Pro Pro Pro Pro Gly Pro Asp Val Ile Pro CJly Pro Val Pro Pro Val Leu Ala Ala Ile Val Phe Pro Arg Asp Arg Pro Ala Ala Ser Glu Asn Phe Asp Tyr Met Gly Leu Leu Leu Leu Ser F'ro Gly Leu Ala Thr Phe Leu Phe Gly Val Ser Ser Ser Pro Ala Arg Gly Thr Met Ala Asp Arg His Val Leu Ile Pro Ala Ile Thr Gly Leu Ala Leu Ile Ala Ala Phe Val Ala His Ser Trp Tyr Arg Thr Glu His Pro Leu Ile Asp Met Arg Leu Phe Gln Asn Arg Ala Val Ala Gln Ala Asn Met Thr Met Thr Val Leu Ser Leu Gly Leu Phe Gly Ser Phe Leu Leu Leu Pro Ser Tyr Leu Gln Gln Val Leu His Gln Ser Pro Met Gln S~~r Gly Val His Ile Ile Pro Gln Gly Leu Gly Ala Met Leu Ala Met P:ro Ile Ala Gly Ala Met Met Asp Arg Arg Gly Pro Ala Lys Ile Val Leu Val Gly Ile Met Leu Ile Ala Ala Gly Leu Gly Thr Phe Ala Phe Gly Val Ala Arg Gln Ala Asp Tyr Leu Pro Ile Leu Pro Thr Gly Leu Ala Ile Met Gly Met Gly Met Gly Cys Ser Met Met Pro Leu Ser Gly Ala Ala Val Gln Thr Leu Ala Pro His Gln Ile Ala Arg Gly Ser Thr Leu Ile Ser Val Asn Gln Gln Val Gly Gly Ser Ile Gly Thr Ala Leu Met Ser Val Leu Leu Thr Tyr Gln Phe Asn His Ser Glu Ile Ile Ala 'Phr Ala Lys Lys Val Ala Leu Thr Pro Glu Ser Gly Ala Gly Arg Gly Ala Ala Val Asp Pro Ser Ser Leu Pro Arg Gln Thr Asn Phe Ala Ala Gln Leu Leu His Asp Leu Ser His Ala Tyr Ala Val Val Phe Val Ile Ala Thr Ala Leu Val Val Ser 645 Ei50 655 Thr Leu Ile Pro Ala Ala Phe Leu Pro hys Gln Gln Ala Ser His Arg Arg Ala Pro Leu Leu Ser Ala (2) INFORMATION FOR SEQ ID N0:190:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 120 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:190:
Thr Pro Glu Lys Ser Phe Val Asp Asp Leu Asp Ile Asp Ser Leu Ser Met Val Glu Ile Ala Val Gln Thr Glu Asp Lys Tyr Gly Val Lys Ile Pro Asp Glu Asp Leu Ala Gly Leu Arg Thr Val Gly Asp Val Val Ala Tyr Ile Gln Lys Leu Glu Glu Glu Asn Pro Glu Ala Ala Gln Ala Leu Arg Ala Lys Ile Glu Ser Glu Asn Pro Asp Ala Ala Arg Ala Asp Arg Cys Val Ser Pro Thr Ser Gln Ala Arg Asp Ala Arg Arg Pro Leu Ala Arg Ser Ala Arg Leu Ala Cys Arg Arg Leu Pro Ala Ser Val Pro Thr Thr Arg Arg Asp Pro Arg Glu Arg (2) INFORMATION FOR SEQ ID N0:191:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 89 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:191:
Leu Ala Cys Gln Cys His Arg Arg Tyr .Asp Val Gly Ile Gln Phe Arg Gly Pro Ala Gly Pro Val Ala Thr Gln Ser Gly Pro Pro Gly Pro Ser Ile Ala Glu Gly Arg Gln Val Arg Ala ciln Cys Gly Ala Gly Phe Leu Glu Arg Arg Pro Ala Val Ser Gly Ala Leu Pro Pro Asn Asn Ala Ser Pro Gly Ile Arg Ser Arg Ala Ala Asp Ser Gln Arg His Leu Leu Ala Gly Asp Gly Ser Asp Val Thr Val Gly (2) INFORMATION FOR SEQ ID N0:192:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 119 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:192:
Ala Ser Leu Leu Ala Tyr Ser Ala Ala A.la Ala Ser Thr Ala Leu Ala Val Ala Cys Val Arg Ala Asp His Arg Asp Arg Arg Thr Ile Arg Asp His Leu Ala Met Ile His Leu Ala Gln Leu Val Thr Gln Pro Pro Gly Gly Val Arg Gln Arg Leu His His Leu Gly Ile Ala Val Ala Pro Gln Pro Gln Glu Val Val Val Leu Ala His His Leu Val Thr Gly Thr Gly Glu Val Gln Gly Glu Gly Arg His Val Ala Ala Glu Val Val Asp Pro Glu Asn Gln Ile Leu Arg Gln Val Leu Gly Pro Ala Pro His Asp Lys Pro Asp Ala Gly Ile Gly Gln (2) INFORMATION FOR SEQ ID N0:193:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 116 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:193:
Arg Ala Arg Gly His Arg Ser Ser Lys Gly Ser Arg Trp Ser His Glu Val Leu Glu Gly Cys Ile Leu Ala Asp S er Arg Gln Ser Lys Thr Ala Ala Ser Pro Ser Pro Ser Arg Pro Gln Ser Ser Ser Asn Asn Ser Val Pro Gly Ala Pro Asn Arg Val Ser Phe Ala Lys Leu Arg Glu Pro Leu Glu Val Pro Gly Leu Leu Asp Val Gln Thr Asp Ser Phe Glu Trp Leu Ile Gly Ser Pro Arg Trp Arg Glu Ser Ala Ala Glu Arg Gly Asp Val 85 '-30 95 Asn Pro Val Gly Gly Leu Glu Glu Val Leu Tyr Glu Leu Ser Pro Ile Glu Asp Phe Ser (2) INFORMATION FOR SEQ ID N0:194:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 811 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:194:

GTGAAAGCCGCCGACGTGTTCGCCGCATTCGGGGAGAAC.ATCGAACTGCTCAAAAGGCTG 120 GTGCGGGCCGCCATCGATCGGGTCGCCGACGAGCGCACG'TGCACGCACTGTCAACACCAC 180 GCCGGTGTTCCGTTGCCGTTCGAGCTGCCATGAGGGTGC'rGCTGACCGGCGCGGCCGGCT 240 ACCCGGTGCT

TCGACGTGCGCGACGCCAGCGCGCTGGCCCCGTTGTTG'~GCCGGTGTCGATCTGGTGTGTC 420 (2) INFORMATION
FOR SEQ
ID N0:195:

(i) S EQUENCE S:
CHARACTERISTIC

(A) LENGTH:966 base airs p (B) TYPE:ucleic n acid (C) STRANDEDNESS: le sing (D) TOPOLOGY: linear (xi) S EQUENCE CRIPTION: 5:
DES SEQ ID
N0:19 GTCCCGCGATGTGGCCGAGCATGACTTTCGGCAACACCC~GCGTAGTAGTCGAAGATATCG 60 GACTTTGTGGTCCCGGTGGCGGGATAGAGCACCTGTCGC~CGTTGGTCAGCGTCACCCGTT 120 TGCCGGTCAAGGTGTACAGCGCTACCGCAGACCACGACF~TCAGGTTCCACCAGGTGCACG 360 GCGGCGCTATAGAAGCCGCTCTGCGCGATTATCAAACGC.AAAATACGCTTACTCATGCCA 840 (2) INFORMATION
FOR SEQ
ID N0:196:

(i) SEQUENCE
CHARACTERISTICS:

(A) LENGTH:2367 basepairs (B) TYPE:
nucleic acid (C) STRANDEDNESS:
single (D) TOPOLOGY:
linear (xi) S EQUENCE 6:
DESCRIPTION:
SEQ ID
N0:19 CGTTACCGCC

CACCCACGCCACCGGCTCCGCCCACCCCGCCGACACCA;~GCGAGCTGCCGCCGGAGCCAC 300 TGCCGCCATCACCACCCTTGCCGCCGACCACATCGGGT~PCTGCCTCGGGGTCTGGGCTGT 600 CAAACCTCGCGATGCCAGCGTTGCCGCCGCTTCCCCCGC~GCCCCCCCGTGGCGCCGTCAC 660 CACCGATACCACCCGCGCCACCGGCGCCACCGTTGCCGC:CATCACCGAATAGCAACCCGC 720 CGGCGCCACCATTGCCGCCAGCTCCCCCTGCGCCACCG7.'CGGCGCCGGAGGCGGCACTGG 780 CGAAAGCGCCGCCTCCGGCGCCGCCGCTACCACCCCCAC',TGCCGGCGGCTACACCGTCGG 900 ACCCGTTGCCACCATCACCGCCAAAGGCGCTCGCAATGT'CGCCCTGCGCGACTCCGCCGT 960 CGCCGGTACCACCGGCCCCGCCGTTGCCGCCGTTGCCGA'TCAACCCGGCCGCGCCTCCGC 1440 ACCGTTGCCA

GCCAGGCTGC GCCGTTTCCG
ATCAACGGGC

CGCCTCGGTG CAGACTCCGC

CTTCAGTGCTGGCATACCGACCCGCGGCCGCAGTCAAC'GCCTGCACAAACTGCTCGTGAA1680 ACGCTGCCACCTGTACGCTGAGCGCCTGATACTGCCGA.GCATGGGCCCCGAACAACCCCG1790 CGGCCGCATTAGCCGCGCTCACCTGCGAACCAATAGTCGATAAATCCP.AAGCCGCAGTTG1860 GGGAGGACAGGCCGAGCTTGGTGTAGACGTGGGTCAAG'TGGGAATGCACGGTCCGCGGCG2100 GGCCTCGTTGCGCGTACGCGATCGCCTCATCGATCGATi'~ACGCAGTTCCTTCGGCCCAGG2280 (2) INFORMATION FOR SEQ ID N0:197:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 376 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:1.97:
Gln Pro Ala Gly Ala Thr Ile Ala Ala w~er Ser Pro Cys Ala Thr Val 1 5 1.0 15 Gly Ala Gly Gly Gly Thr Gly Ser Pro V'al Thr Thr Glu Thr Ala Ala Thr Thr Gly Arg Gly Gly Ser Gly Asp Val Tyr Glu Ser Ala Ala Ser Gly Ala Ala Ala Thr Thr Pro Thr Ala Gly Gly Tyr Thr Val Gly Pro Val Ala Thr Ile Thr Ala Lys Gly Ala Arg Asn Val Ala Leu Arg Asp Ser Ala Val Ala Ala Val Ala Ala Ala Ala Thr Gly Ser Gly Gly Thr Ala Val Thr Thr Gly Thr Ala Gly Gly Leu Ala Arg Ala Cys Arg Arg Gly Gly Thr Val Ala Ala Gly Ala Thr G.ly Arg Arg Ala Gly Ser Ala Met Ala Ala Arg Ala Ala Val Ala Ala G:Ly Leu Ile Thr Asp Ala Gly His Ile Cys Arg Ala Val Pro Gly Ala Gly Arg Gly Ala Gly Arg Gly Ile Asp Pro Val Cys Pro Gly Glu Ala Gly Ala Ala Gly Thr Thr Gly Ala Ala Met Ala Glu Gln Pro Gly Val Ala Ala Val Thr Ala Arg Thr Pro Asp Ala Cys Gly His Ala Gly Ala Ala Asp Thr Ala Val Ala Ala Val Ala Pro Gln Pro Pro Pro Val Pro Thr Gly Thr Ala Gly Arg Ala Gly Thr Thr Gly Pro Ala Val Ala Ala Val Ala Asp Gln Pro Gly Arg Ala Ser Ala Ala Ala Gly Leu Thr Glu Pro Ala Ser Arg Ala Val Ala Thr Val Ala Lys Gln Gln Pro Ala Gly Arg Ala Arg Leu Pro Gly Cys Arg Pro Val Gly Ala Val Ser Asp Gln Arg Ala Pro Gln Lys Arg Leu Gly Gly Arg Ile His Arg Thr Gln Gln '.Chr Pro Leu Asn Ser Gly Phe Ser Ala Gly Ile Pro Thr Arg Gly Arg ;ier Gln Arg Leu His Lys Leu Leu Val Lys Arg Cys His Leu Tyr Ala Glu Arg Leu Ile Leu Pro Ser Met Gly Pro Glu Gln Pro Arg Asn Arg Arg Arg His Phe Ile Gly Ser Arg Ser His His Phe Arg Arg Arg Asp Arg Arg Gly Arg Ile Ser Arg Ala His Leu Arg Thr Asn Ser Arg (2) INFORMATION FOR SEQ ID N0:198:
(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 2852 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID
N0:198:

GGCCAAAACG CCCCGGCGAT CGCGGCCACC GAGGCCGCC'rACGACCAGATGTGGGCCCAG 60 GCTCAGGTGA CCACGCGGGT CTTCCGCAAC CTGGGCTTG(3CGAACGTCCGCGAGGGCAAC 240 CTCGGCTC;GG
CCAACATCGG
CAACGGCAAC

ATCGGGTTTG
GCAACGTGGG
TCCTGGGTTG

AACACCGGCAGCAACAACATCGGGTTCGGCAATACCGG'AG ACGGCAACCGAGGTATCGGG480 CTCACGGGTAGCGGTTTGTTGGGGTTCGGCGGCCTGAA.CT CGGGCACCGGCAACATCGGT540 GGCTACCTGAACAGCGGCAACTACAACACCGGCTTGGC.AA ACTCCGGCAATGTCAACACC890 CTGATTTTCGGGAGCCCCGGCTTCTTCAACTCGACCAG'rG CGCCGTCGTCGGGATTCTTC960 ATCACAACGCCGGCCTTGATCTCGGGCTTCTTCAACAC(:G GAAGCAACATGTCGGGATTT1200 TTCGGTGGCCCACCGGTCTTCAATCTCGGCCTGGCAAAC:C GGGGCGTCGTGAACATTCTC1260 GGCAACGCCAACATCGGCAATTACAACATTCTCGGCAGC:G GAAACGTCGGTGACTTCAAC1320 TTCAATATCGGCAGTGGAAACATCGGAGTATTCAATGTC;G GTTCCGGAAGCCTGGGAAAC1440 TACAACATCGGATCCGGAAACCTCGGGATCTACAACATC;G GTTTTGGAAACGTCGGCGAC1500 AACAACATCGGGTTCGCCAACACCGGCAACAACAACATC'G GCATCGGGCTGTCCGGCGAC1620 GTGACACCAA

GCAACGTCAA CAATGGCTTC
TACCGGCGCT

GCGATAACCA
GGGCCAGATT
GCCATCGATC
TCTCGGTCAC
CACTCCATTC

ACGAGCAGAT
GGTCATTGAC
GTACACAACG
TAATGACCTT
CGGCGGCAAC

ATGATCACGGTCACCGAGGCCTCGACCGTTTTCCCCCP,AACCTTCTATCTGAGCGGTTTG2220 TTCTTCTTCGGCCCGGTCAATCTCAGCGCATCCACGCT'GACCGTTCCGACGATCACCCTC2280 (2) INFORMATION FOR SEQ ID N0:199:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 943 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:1.99:
Gly Gln Asn Ala Pro Ala Ile Ala Ala Thr Glu Ala Ala Tyr Asp Gln Met Trp Ala Gln Asp Val Ala Ala Met Phe Gly Tyr His Ala Gly Ala Ser Ala Ala Val Ser Ala Leu Thr Pro Phe Gly Gln Ala Leu Pro Thr Val Ala Gly Gly Gly Ala Leu Val Ser A.la Ala Ala Ala Gln Val Thr Thr Arg Val Phe Arg Asn Leu Gly Leu Ala Asn Val Arg Glu Gly Asn Val Arg Asn Gly Asn Val Arg Asn Phe Asn Leu Gly Ser Ala Asn Ile Gly Asn Gly Asn Ile Gly Ser Gly Asn Ile Gly Ser Ser Asn Ile Gly Phe Gly Asn Val Gly Pro Gly Leu Thr Ala Ala Leu Asn Asn Ile Gly Phe Gly Asn Thr Gly Ser Asn Asn Ile G.ly Phe Gly Asn Thr Gly Ser Asn Asn Ile Gly Phe Gly Asn Thr Gly A;sp Gly Asn Arg Gly Ile Gly Leu Thr Gly Ser Gly Leu Leu Gly Phe Gly Gly Leu Asn Ser Gly Thr Gly Asn Ile Gly Leu Phe Asn Ser Gly Thr Gly Asn Val Gly Ile Gly Asn Ser Gly Thr Gly Asn Trp Gly Ile Gly Asn Ser Gly Asn Ser Tyr Asn Thr Gly Phe Gly Asn Ser Gly Asp Ala Asn Thr Gly Phe Phe Asn Ser Gly Ile Ala Asn Thr Gly Val Gly Asn Ala Gly Asn Tyr Asn Thr Gly Ser Tyr Asn Pro Gly Asn Ser Asn Thr Gly Gly Phe Asn Met Gly Gln Tyr Asn Thr Gly Tyr Leu Asn Ser Gly Asn Tyr Asn Thr Gly Leu Ala Asn Ser Gly Asn Val Asn Thr Gly Ala Phe Ile Thr Gly Asn Phe Asn Asn Gly Phe Leu Trp Arg Gly Asp l3is Gln Gly Leu Ile Phe Gly Ser Pro Gly Phe Phe Asn Ser Thr Ser Ala Pro Ser Ser Gly Phe Phe Asn Ser Gly Ala Gly Ser Ala Ser Gly F?he Leu Asn Ser Gly Ala Asn Asn Ser Gly Phe Phe Asn Ser Ser Ser Gly Ala Ile Gly Asn Ser Gly Leu Ala Asn Ala Gly Val Leu Val Ser C~ly Val Ile Asn Ser Gly Asn Thr Val Ser Gly Leu Phe Asn Met Ser Leu Val Ala Ile Thr Thr Pro Ala Leu Ile Ser Gly Phe Phe Asn Thr Gly Ser Asn Met Ser Gly Phe Phe Gly Gly Pro Pro Val Phe Asn Leu Gly Leu Ala Asn Arg Gly Val Val Asn Ile Leu Gly Asn Ala Asn Ile Gly Asn Tyr Asn Ile Leu Gly Ser Gly Asn Val Gly Asp Phe Asn Ile Leu Gly Ser Gly Asn Leu Gly Ser Gln Asn Ile Leu Gly Ser Gly Asn Val Gly Ser Phe Asn Ile Gly Ser Gly Asn Ile Gly Val Phe Asn Val Gly Ser Gly Ser Leu Gly Asn Tyr Asn Ile Gly Ser Gly Asn Leu Gly Ile Tyr Asn Ile Gly Phe Gly Asn Val Gly Asp Tyr Asn Val Gly Phe Gly Asn Ala Gly Asp Phe Asn Gln Gly Phe Ala Asn Thr Gly Asn Asn Asn Ile Gly Phe Ala Asn Thr Gly Asn Asn Asn Ile Gly Ile Gly Leu Ser Gly Asp Asn Gln Gln Gly Phe Asn Ile Ala Ser Gly Trp Asn Ser Gly Thr Gly Asn Ser Gly Leu Phe Asn Ser Gly Thr Asn Asn Val Gly Ile Phe Asn Ala Gly Thr Gly Asn Val Gly Ile Ala Asn Ser Gly Thr Gly Asn Trp Gly Ile Gly Asn Pro Gly Thr Asp Asn Thr Gly Ile Leu Asn Ala Gly Ser Tyr Asn Thr Gly Ile Leu Asn Ala Gly Asp Phe Asn 'rhr Gly Phe Tyr Asn Thr Gly Ser Tyr Asn Thr Gly Gly Phe Asn Val Gly Asn Thr Asn Thr Gly Asn Phe Asn Val Gly Asp Thr Asn Thr Gly Ser Tyr Asn Pro Gly Asp Thr 695 (i50 655 Asn Thr Gly Phe Phe Asn Pro Gly Asn Val Asn Thr Gly Ala Phe Asp Thr Gly Asp Phe Asn Asn Gly Phe Leu Val Ala Gly Asp Asn Gln Gly Gln Ile Ala Ile Asp Leu Ser Val Thr Thr Pro Phe Ile Pro Ile Asn Glu Gln Met Val Ile Asp'Val His Asn Val Met Thr Phe Gly Gly Asn Met Ile Thr Val Thr Glu Ala Ser Thr Val Phe Pro Gln Thr Phe Tyr Leu Ser Gly Leu Phe Phe Phe Gly Pro Val Asn Leu Ser Ala Ser Thr Leu Thr Val Pro Thr Ile Thr Leu Thr Ile Gly Gly Pro Thr Val Thr Val Pro Ile Ser Ile Val Gly Ala Leu Glu Ser Arg Thr Ile Thr Phe Leu Lys Ile Asp Pro Ala Pro Gly Ile Gly Asn Ser Thr Thr Asn Pro Ser Ser Gly Phe Phe Asn Ser Gly Thr Gly Gly Thr Ser Gly Phe Gln Asn Val Gly Gly Gly Ser Ser Gly Val T:rp Asn Ser Gly Leu Ser Ser Ala Ile Gly Asn Ser Gly Phe Gln Asn Leu Gly Ser Leu Gln Ser Gly Trp Ala Asn Leu Gly Asn Ser Val Ser Gly Phe Phe Asn Thr Ser Thr Val Asn Leu Ser Thr Pro Ala Asn Val Ser Gly Leu Asn Asn Ile Gly Thr Asn Leu Ser Gly Val Phe Arg Gly Pro Thr Gly Thr Ile Phe Asn Ala Gly Leu Ala Asn Leu Gly Gln Leu Asn Ile Gly Ser Ala Ser Cys Arg Ile Arg His Glu Leu Asp Thr Val Ser Thr Ile Ile Ser Ala Phe Cys Gly Ser Ala Ser Asp Glu Ser Asn Pro Gly Ser Val Ser Glu (2) INFORMATION FOR SEQ ID N0:200:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 53 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:200:

(2) INFORMATION FOR SEQ ID N0:201:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 42 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:201:

(2) INFORMATION FOR SEQ ID N0:202:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 31 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:202:

(2) INFORMATION FOR SEQ ID N0:203:
(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 31 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:203:

(2) INFORMATION FOR SEQ ID N0:.204:
(ij SEQUENCE CHARACTERISTICS:
(A) LENGTH: 33 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:204:

(2) INFORMATION FOR SEQ ID N0:205:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 38 base pairs (B) TYPE: nucleic acid (Cj STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:205:

(2) INFORMATION FOR SEQ ID N0:206:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 30 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:206:

(2) INFORMATION FOR SEQ ID N0:207:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 37 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:207:

(2) INFORMATION FOR SEQ ID N0:208:

(i) SEQUENCE
CHARACTERISTICS:

(A) LENGTH:7676 basepairs (B) TYPE:
nucleic acid (C) STRANDEDNESS:
single (D) TOPOLOGY: linear (xi) S EQUENCE CRIPTION: 8:
DES SEQ ID
N0:20 CTTTCTCGCCACGTTCGCCGGCTTTCCCCGTCAAGCTC'TAAATCGGGGGCTCCCTTTAGG 180 GTTCCGATTTAGTGCTTTACGGCACCTCGACCCCAAAA,?~ACTTGATTAGGGTGATGGTTC 240 CTTTAATAGTGGACTCTTGTTCCAAACTGGAACAACAC'PCAACCCTATCTCGGTCTATTC 360 ACAAAAATTTAACGCGAATTTTAACAAAATATTAACGT'CTACAATTTCAGGTGGCACTTT 480 TCGGGGAAATGTGCGCGGAACCCCTATTTGTTTATTTT'.CCTAAATACATTCAAATATGTA 540 TCATATCAGGATTATCAATACCATATTTTTGAAAAAGCC:GTTTCTGTAATGAAGGAGAAA 660 ACTCACCGAGGCAGTTCCATAGGATGGCAAGATCCTGG7.'ATCGGTCTGCGATTCCGACTC 720 AGACTTGTTCAACAGGCCAGCCATTACGCTCGTCATCAAP.ATCACTCGCATCAACCAAAC 900 TGGTGAGTAACCATGCATCATCAGGAGTACGGATAAAAT'GCTTGATGGTCGGAAGAGGCA 1140 AGAGCGCAGATACCAAATACTGTCCTTCTAGTGTAGCCG'T CCACTTCAAG 1680 AGTTAGGCCA

TGTTACCAGT

GCTTGGAGCG

AAGGCGGACAGGTATCCGGTAAGCGGCAGGGTCGGAAC:AGGAGAGCGCACGAGGGAGCTT1980 GCCTTTTTACGGTTCCTGGCCTTTTGCTGGCCTTTTGC'TCACATGTTCTTTCCTGCGTTA2160 GTGAAGCGATTCACAGATGTCTGCCTGTTCATCCGCGTC:CAGCTCGTTGAGTTTCTCCAG2640 AAGCGTTAATGTCTGGCTTCTGATAAAGCGGGCCATGT7.'AAGGGCGGTTTTTTCCTGTTT2700 GGTCACTGATGCCTCCGTGTAAGGGGGATTTCTGTTCA7.'GGGGGTAATGATACCGATGAA2760 TCAATGCCAGCGCTTCGTTAATACAGATGTAGGTGTTCC:ACAGGGTAGCCAGCAGCATCC2940 TGCGATGCAGATCCGGAACATAATGGTGCAGGGCGCTGP,CTTCCGCGTTTCCAGACTTTA3000 CGAAACACGGAAACCGAAGACCATTCATGTTGTTGCTCF,GGTCGCAGACGTTTTGCAGCA3060 TAATTGCGTT AGTCGGGAAA

AATGAATCGG GTTTGCGTAT
CCAACGCGCG

TGTGCACCGCCGCTTTACAGGCTTCGACGCCGCTTCGT'PCTACCATCGACACCACCACGC4320 TGGCACCCAGTTGATCGGCGCGAGATTTAATCGCCGCGi~CAATTTGCGACGGCGCGTGCA4380 GGGCCAGACTGGAGGTGGCAACGCCAATCAGCAACGAC'CGTTTGCCCGCCAGTTGTTGTG4440 CATACTCTGCGACATCGTATAACGTTACTGGTTTCACA'.CTCACCACCCTGAATTGACTCT4620 CTTCCGGGCGCTATCATGCCATACCGCGAAAGGTTTTGC:GCCATTCGATGGTGTCCGGGA4680 AATTAATACGACTCACTATAGGGGAATTGTGAGCGGATP~ACAATTCCCCTCTAGAAATAA5040 GGCGCGGGATAGCGTCGATGACATCCGCGTCGCTCGGGT'CATTGAGCAGGACATGGCCGT5220 CAGGCCGCCG

ACTCGGCGAGGCCCAACTAGGCAATAGCTCTGGCAATT'TCTTGTTGCCCGACGCGCAAAG6060 GATCGACGGGCCCGCCCCGGACGGCTACCCGATCATCA;~CTACGAGTACGCCATCGTCAA6180 CACCGACGGCAACAAGGCCTCGTTCCTCGACCAGGTTCi~TTTCCAGCCGCTGCCGCCCGC6300 TGCCGCTACCCTCGCGCAGGAGGCAGGTAATTTCGAGC(~GATCTCCGGCGACCTGAAAAC6420 GCCGCCGTCGACCGCTGCAGCGCCACCCGCACCGGCGAC:ACCTGTTGCCCCCCCACCACC6720 GGCCGCCGCCAACACGCCGAATGCCCAGCCGGGCGATCC;CAACGCAGCACCTCCGCCGGC6780 CGACAACCCGGTTGGAGGATTCAGCTTCGCGCTGCCTGC;TGGCTGGGTGGAGTCTGACGC6900 CGCCCACTTCGACTACGGTTCAGCACTCCTCAGCAAAAC;CACCGGGGACCCGCCATTTCC6960 GCTTTACGCCAGCGCCGAAGCCACCGACTCCAAGGCCGC'.GGCCCGGTTGGGCTCGGACAT7080 GGGTGAGTTCTATATGCCCTACCCGGGCACCCGGATCAP,CCAGGAAACCGTCTCGCTTGA7140 CCGAAAGGAAGCTGAGTTGGCTGCTGCCACCGCTGAGC.AATAACTAGCATAACCCCTTGG7620 (2) INFORMATION FOR SEQ ID N0:209:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 802 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0:209:
Met Gly His His His His His His Val :Lle Asp Ile Ile Gly Thr Ser 1 5 :LO 15 Pro Thr Ser Trp Glu Gln Ala Ala Ala (~lu Ala Val Gln Arg Ala Arg Asp Ser Val Asp Asp Ile Arg Val Ala Arg Val Ile Glu Gln Asp Met Ala Val Asp Ser Ala Gly Lys Ile Thr Tyr Arg Ile Lys Leu Glu Val Ser Phe Lys Met Arg Pro Ala Gln Pro Arg Gly Ser Lys Pro Pro Ser Gly Ser Pro Glu Thr Gly Ala Gly Ala Gly Thr Val Ala Thr Thr Pro Ala Ser Ser Pro Val Thr Leu Ala Glu Thr Gly Ser Thr Leu Leu Tyr Pro Leu Phe Asn Leu Trp Gly Pro Ala F~he His Glu Arg Tyr Pro Asn Val Thr Ile Thr Ala Gln Gly Thr Gly S'er Gly Ala Gly Ile Ala Gln Ala Ala Ala Gly Thr Val Asn Ile Gly A.la Ser Asp Ala Tyr Leu Ser Glu Gly Asp Met Ala Ala His Lys Gly Leu Met Asn Ile Ala Leu Ala Ile Ser Ala Gln Gln Val Asn Tyr Asn Leu Pro Gly Val Ser Glu His Leu Lys Leu Asn Gly Lys Val Leu Ala Ala Met Tyr Gln Gly Thr Ile Lys Thr Trp Asp Asp Pro Gln Ile Ala Ala Leu Asn Pro Gly Val Asn Leu Pro Gly Thr Ala Val Val Pro Leu His Arg Ser Asp Gly Ser Gly Asp 'Thr Phe Leu Phe Thr Gln Tyr Leu Ser Lys Gln Asp Pro Glu Gly Trp Gly Lys Ser Pro Gly Phe Gly Thr Thr Val Asp Phe Pro Ala Val Pro Gly Ala Leu Gly Glu Asn Gly Asn Gly Gly Met Val Thr Gly Cys Ala Glu Thr Pro Gly Cys Val Ala Tyr Ile Gly Ile Ser Phe Leu Asp Gln Ala Ser Gln Arg Gly Leu Gly Glu ;~11a Gln Leu Gly Asn Ser Ser Gly Asn Phe Leu Leu Pro Asp Ala Gln Ser Ile Gln Ala Ala Ala Ala 325 :330 335 Gly Phe Ala Ser Lys Thr Pro Ala Asn Gln Ala Ile Ser Met Ile Asp Gly Pro Ala Pro Asp Gly Tyr Pro Ile :Cle Asn Tyr Glu Tyr Ala Ile Val Asn Asn Arg Gln Lys Asp Ala Ala Thr Ala Gln Thr Leu Gln Ala Phe Leu His Trp Ala Ile Thr Asp Gly Asn Lys Ala Ser Phe Leu Asp Gln Val His Phe Gln Pro Leu Pro Pro Ala Val Val Lys Leu Ser Asp Ala Leu Ile Ala Thr Ile Ser Ser Ala C~lu Met Lys Thr Asp Ala Ala Thr Leu Ala Gln Glu Ala Gly Asn Phe Glu Arg Ile Ser Gly Asp Leu Lys Thr Gln Ile Asp Gln Val Glu Ser Thr Ala Gly Ser Leu Gln Gly Gln Trp Arg Gly Ala Ala Gly Thr Ala Ala Gln Ala Ala Val Val Arg Phe Gln Glu Ala Ala Asn Lys Gln Lys Gln Glu Leu Asp Glu Ile Ser Thr Asn Ile Arg Gln Ala Gly Val Gln T'yr Ser Arg Ala Asp Glu Glu Gln Gln Gln Ala Leu Ser Ser Gln Met Gly Phe Val Pro Thr Thr Ala Ala Ser Pro Pro Ser Thr Ala Ala Ala Pro Pro Ala Pro Ala Thr Pro Val Ala Pro Pro Pro Pro Ala Ala Ala Asn Thr Pro Asn Ala Gln Pro Gly Asp Pro Asn Ala Ala Pro Pro Pro Ala Asp Pro Asn Ala Pro Pro Pro Pro Val Ile Ala Pro Asn Ala Pro Gln Pro Val Arg Ile Asp Asn Pro Val Gly Gly Phe Ser Phe Ala Leu Pro Ala Gly Trp Val Glu Ser Asp Ala Ala His Phe Asp Tyr Gly Ser Ala Leu Leu Ser Lys Thr Thr Gly Asp Pro Pro Phe Pro Gly Gln Pro Pro Pro Val Ala Asn Asp Thr Arg Ile Val Leu Gly Arg Leu Asp Gln Lys Leu Tyr Ala Ser Ala Glu Ala Thr Asp Ser Lys Ala Ala Ala Arg :Leu Gly Ser Asp Met Gly Glu Phe Tyr Met Pro Tyr Pro Gly Thr Arg :Ile Asn Gln Glu Thr Val Ser Leu Asp Ala Asn Gly Val Ser Gly Ser i~la Ser Tyr Tyr Glu Val Lys Phe Ser Asp Pro Ser Lys Pro Asn Gly Gln Ile Trp Thr Gly Val Ile Gly Ser Pro Ala Ala Asn Ala Pro Asp Ala Gly Pro Pro Gln Arg Trp 725 '130 735 Phe Val Val Trp Leu Gly Thr Ala Asn Asn Pro Val Asp Lys Gly Ala Ala Lys Ala Leu Ala Glu Ser Ile Arg F?ro Leu Val Ala Pro Pro Pro Ala Pro Ala Pro Ala Pro Ala Glu Pro Ala Pro Ala Pro Ala Pro Ala Gly Glu Val Ala Pro Thr Pro Thr Thr Pro Thr Pro Gln Arg Thr Leu Pro Ala

Claims (54)

We claim:

1. A polypeptide comprising an antigenic portion of a soluble M. tuberculosis antigen, or a variant of said antigen that differs only in conservative substitutions and/or modifications, wherein said antigen has an N-terminal sequence selected from the group consisting of:
(a) Asp-Pro-Val-Asp-Ala-Val-Ile-Asn-Thr-Thr-Cys-Asn-Tyr-Gly-Gln-Val-Val-Ala-Ala-Leu (SEQ ID NO: 115);
(b) Ala-Val-Glu-Ser-Gly-Met-Leu-Ala-Leu-Gly-Thr-Pro-Ala-Pro-Ser (SEQ ID NO: 116);
(c) Ala-Ala-Met-Lys-Pro-Arg-Thr-Gly-Asp-Gly-Pro-Leu-Glu-Ala-Ala-Lys-Glu-Gly-Arg (SEQ ID NO: 17);
(d) Tyr-Tyr-Trp-Cys-Pro-Gly-Gln-Pro-Phe-Asp-Pro-Ala-Trp-Gly-Pro (SEQ ID NO: 118);
(e) Asp-Ile-Gly-Ser-Glu-Ser-Thr-Glu-Asp-Gln-Gln-Xaa-Ala-Val (SEQ ID
NO: 119);
(f) Ala-Glu-Glu-Ser-Ile-Ser-Thr-Xaa-Glu-Xaa-Ile-Val-Pro (SEQ ID
NO: 120);
(g) Asp-Pro-Glu-Pro-Ala-Pro-Pro-Val-Pro-Thr-Thr-Ala-Ala-Ser-Pro-Pro-Ser (SEQ ID NO: 121);
(h) Ala-Pro-Lys-Thr-Tyr-Xaa-Glu-Glu-Leu-Lys-Gly-Thr-Asp-Thr-Gly (SEQ ID NO: 122);
(i) Asp-Pro-Ala-Ser-Ala-Pro-Asp-Val-Pro-Thr-Ala-Ala-Gln-Leu-Thr-Ser-Leu-Leu-Asn-Ser-Leu-Ala-Asp-Pro-Asn-Val-Ser-Phe-Ala-Asn (SEQ
ID NO: 123); and (j) Ala-Pro-Glu-Ser-Gly-Ala-Gly-Leu-Gly-Gly-Thr-Val-Gln-Ala-Gly;
(SEQ ID NO: 131) wherein Xaa may be any amino acid.

2. A polypeptide comprising an immunogenic portion of an M. tuberculosis antigen, or a variant of said antigen that differs only in conservative substitutions and/or modifications, wherein said antigen has an N-terminal sequence selected from the group consisting of:
(a) Asp-Pro-Pro-Asp-Pro-His-Gln-Xaa-Asp-Met-Thr-Lys-Gly-Tyr-Tyr-Pro-Gly-Gly-Arg-Arg-Xaa-Phe; (SEQ ID NO: 124) and (b) Xaa-Tyr-Ile-Ala-Tyr-Xaa-Thr-Thr-Ala-Gly-Ile-Val-Pro-Gly-Lys-Ile-Asn-Val-His-Leu-Val; (SEQ ID NO: 132), wherein Xaa may be any amino acid.

3. A polypeptide comprising an antigenic portion of a soluble M. tuberculosis antigen, or a variant of said antigen that differs only in conservative substitutions and/or modifications, wherein said antigen comprises an amino acid sequence encoded by a DNA sequence selected from the group consisting of the sequences recited in SEQ ID NOS: 1, 2, 4-10, 13-25, 52, 94 and 96, the complements of said sequences, and DNA
sequences that hybridize to a sequence recited in SEQ ID NOS: 1, 2, 4-10, 13-25, 52, 94 and 96 or a complement thereof under moderately stringent conditions.

4. A polypeptide comprising an antigenic portion of a M. tuberculosis antigen, or a variant of said antigen that differs only in conservative substitutions and/or modifications, wherein said antigen comprises an amino acid sequence encoded by a DNA
sequence selected from the group consisting of the sequences recited in SEQ ID
NOS: 26-51, 133, 134, 158-178 and 196, the complements of said sequences, and DNA
sequences that hybridize to a sequence recited in SEQ ID NOS: 26-51, 133, 134, 158-178 and 196 or a complement thereof under moderately stringent conditions.

5. A DNA molecule comprising a nucleotide sequence encoding a polypeptide according to any one of claims 1-4.

6. A recombinant expression vector comprising a DNA molecule according to claim 5.

7. A host cell transformed with an expression vector according to claim 6.

8. The host cell of claim 7 wherein the host cell is selected from the group consisting of E. coli, yeast and mammalian cells.

9. A method for detecting M. tuberculosis infection in a biological sample, comprising:
(a) contacting a biological sample with one or more polypeptides according to any of claims 1-4; and (b) detecting in the sample the presence of antibodies that bind to at least one of the polypeptides, thereby detecting M. tuberculosis infection in the biological sample.

10. A method for detecting M. tuberculosis infection in a biological sample, comprising:
(a) contacting a biological sample with a polypeptide having an N-terminal sequence selected from the group consisting of sequences provided in SEQ ID NO:
129 and 130; and (b) detecting in the sample the presence of antibodies that bind to at least one of the polypeptides, thereby detecting M. tuberculosis infection in the biological sample.

11. A method for detecting M. tuberculosis infection in a biological sample, comprising:
(a) contacting a biological sample with one or more polypeptides encoded by a DNA sequence selected from the group consisting of SEQ ID NOS: 3, 11, 12, 135, 136, 151-155, 184-188, 194-195 and 198, the complements of said sequences, and DNA
sequences that hybridize to a sequence recited in SEQ ID NOS: 3, 11, 12, 135, 136, 151-155, 184-188, 194-195 and 198; and (b) detecting in the sample the presence of antibodies that bind to at least one of the polypeptides, thereby detecting M. tuberculosis infection in the biological sample.

12. The method of any one of claims 9-11 wherein step (a) additionally comprises contacting the biological sample with a 38 kD M. tuberculosis antigen and step (b) additionally comprises detecting in the sample the presence of antibodies that bind to the 38 kD M. tuberculosis antigen.

13. The method of any one of claims 9-11 wherein the polypeptide(s) are bound to a solid support.

14. The method of claim 13 wherein the solid support comprises nitrocellulose, latex or a plastic material.

15. The method of any one of claims 9-11 wherein the biological sample is selected from the group consisting of whole blood, serum, plasma, saliva, cerebrospinal fluid and urine.

16. The method of claim 15 wherein the biological sample is whole blood or serum.

17. A method for detecting M. tuberculosis infection in a biological sample, comprising:
(a) contacting the sample with at least two oligonucleotide primers in a polymerase chain reaction, wherein at least one of the oligonucleotide primers is specific for a DNA molecule according to claim 5; and (b) detecting in the sample a DNA sequence that amplifies in the presence of the oligonucleotide primers, thereby detecting M. tuberculosis infection.

18. The method of claim 17, wherein at least one of the oligonucleotide primers comprises at least about 10 contiguous nucleotides of a DNA molecule according to claim 5.

19. A method for detecting M. tuberculosis infection in a biological sample, comprising:
(a) contacting the sample with at least two oligonucleotide primers in a polymerase chain reaction, wherein at least one of the oligonucleotide primers is specific for a DNA sequence selected from the group consisting of SEQ ID NOS: 3, 11, 12, 135, 136, 151-155, 184-188, 194-195 and 198; and (b) detecting in the sample a DNA sequence that amplifies in the presence of the first and second oligonucleotide primers, thereby detecting M.
tuberculosis infection.

20. The method of claim 19, wherein at least one of the oligonucleotide primers comprises at least about 10 contiguous nucleotides of a DNA sequence selected from the group consisting of SEQ ID NOS: 3, 11, 12, 135, 136, 151-155, 184-188, 194-195 and 198.

21. The method of claims 17 or 19 wherein the biological sample is selected from the group consisting of whole blood, sputum, serum, plasma, saliva, cerebrospinal fluid and urine.

22. A method for detecting M. tuberculosis infection in a biological sample, comprising:
(a) contacting the sample with one or more oligonucleotide probes specific for a DNA molecule according to claim 5; and (b) detecting in the sample a DNA sequence that hybridizes to the oligonucleotide probe, thereby detecting M. tuberculosis infection.

23. The method of claim 22 wherein the probe comprises at least about 15 contiguous nucleotides of a DNA molecule according to claim 5.

24. A method for detecting M. tuberculosis infection in a biological sample, comprising:
(a) contacting the sample with one or more oligonucleotide probes specific for a DNA sequence selected from the group consisting of SEQ ID NOS: 3, 11, 12, 135, 136, 151-155, 184-188, 194-195 and 198; and (b) detecting in the sample a DNA sequence that hybridizes to the oligonucleotide probe, thereby detecting M. tuberculosis infection.

25. The method of claim 24 wherein the oligonucleotide probe comprises at least about 15 contiguous nucleotides of a DNA sequence selected from the group consisting of SEQ ID NOS: 3, 11, 12, 135, 136, 151-155, 184-188, 194-195 and 198.

26. The method of claims 22 or 24 wherein the biological sample is selected from the group consisting of whole blood, sputum, serum, plasma, saliva, cerebrospinal fluid and urine.

27. A method for detecting M. tuberculosis infection in a biological sample, comprising:
(a) contacting the biological sample with a binding agent which is capable of binding to a polypeptide according to any one of claims 1-4; and (b) detecting in the sample a protein or polypeptide that binds to the binding agent, thereby detecting M. tuberculosis infection in the biological sample.

28. A method for detecting M. tuberculosis infection in a biological sample, comprising:

(a) contacting the biological sample with a binding agent which is capable of binding to a polypeptide having an N-terminal sequence selected from the group consisting of sequences provided in SEQ ID NO: 129 and 130; and (h) detecting in the sample a protein or polypeptide that binds to the binding agent, thereby detecting M. tuberculosis infection in the biological sample.

29. A method for detecting M. tuberculosis infection in a biological sample, comprising:
(a) contacting the biological sample with a binding agent which is capable of binding to a polypeptide encoded by a DNA sequence selected from the group consisting of SEQ ID NOS: 3, 1 l, 12, 135, 136, 151-155, 184-188, 194-195 and 198, the complements of said sequences, and DNA sequences that hybridize to a sequence recited in SEQ ID
NOS: 3, 11, 12, 135, 136, 151-155, 184-188, 194-195 and 198; and (b) detecting in the sample a protein or polypeptide that binds to the binding agent, thereby detecting M. tuberculosis infection in the biological sample.

30. The method of any one of claims 27-29 wherein the binding agent is a monoclonal antibody.

31. The method of any one of claims 27-29 wherein the binding agent is a polyclonal antibody.

32. A diagnostic kit comprising:
(a) one or more polypeptides according to any of claims 1-4; and (b) a detection reagent.

33. A diagnostic kit comprising:
(a) one or more polypeptides having an N-terminal sequence selected from the group consisting of sequences provided in SEQ ID NO: 129 and 130; and (b) a detection reagent.

34. A diagnostic kit comprising:
(a) one or more polypeptides encoded by a DNA sequence selected from the group consisting of SEQ ID NOS: 3, 11, 12, 135, 136, 151-155, 184-188, 194-195 and 198, the complements of said sequences, and DNA sequences that hybridize to a sequence recited in SEQ ID NOS: 3, 11, 12, 135, 136, 151-155, 184-188, 194-195 and 198;
and (b) a detection reagent.

35. The kit of any one of claims 32-34 wherein the polypeptide(s) are immobilized on a solid support.

36. The kit of claim 35 wherein the solid support comprises nitrocellulose, latex or a plastic material.

37. The kit of any one of claims 32-34 wherein the detection reagent comprises a reporter group conjugated to a binding agent.

38. The kit of claim 37 wherein the binding agent is selected from the group consisting of anti-immunoglobulins, Protein G, Protein A and lectins.

39. The kit of claim 37 wherein the reporter group is selected from the group consisting of radioisotopes, fluorescent graups, luminescent groups, enzymes, biotin and dye particles.

40. A diagnostic kit comprising at least two oligonucleotide primers, at least one of the oligonucleotide primers being specific for a DNA molecule according to claim 5.

41. A diagnostic kit according to claim 40, wherein at least one of the oligonucleotide primers comprises at least about 10 contiguous nucleotide of a DNA
molecule according to claim 5.

42. A diagnostic kit comprising a at least two oligonucleotide primers, at least one of the primers being specific for a DNA sequence selected from the group consisting of SEQ ID NOS: 3, 11, 12, 135, 136, 151-155, 184-188, 194-195 and I98.

43. A diagnostic kit according to claim 42, wherein at least one of the oligonucleotide primers comprises at least about 10 contiguous nucleotide of a DNA
sequence selected from the group consisting of SEQ ID NOS: 3, 11, 12, 135, 136, 151-155, 184-188, 194-195 and 198.

44. A diagnostic kit comprising at least one oligonucleotide probe, the oligonucleotide probe being specific for a DNA molecule according to claim 5.

45. A kit according to claim 44, wherein the oligonucleotide probe comprises at least about 15 contiguous nucleotides of a DNA molecule according to claim 5.

46. A diagnostic kit comprising at least one oligonucleotide probe, the oligonucleotide probe being specific for a DNA sequence selected from the group consisting of SEQ ID NOS: 3, 11, 12, 135, 136, 151-155, 184-188, 194-195 and 198.

47. A kit according to claim 46, wherein the oligonucleotide probe comprises at least about 15 contiguous nucleotides of a DNA sequence selected from the group consisting of SEQ ID NOS: 3, 11, 12, 135, 136, 151-155, 184-188, 194-195 and 198.

48. A monoclonal antibody that binds to a polypeptide according to any of claims 1 -4.

49. A polyclonal antibody that binds to a polypeptide according to any of claims 1-4.

50. A fusion protein comprising two or more polypeptides according to any one of claims 1-4.

51. A fusion protein comprising one or more polypeptides according to any one of claims 1-4 and ESAT-6 (SEQ ID NO: 99).

52. A fusion protein comprising a polypeptide having an N-terminal sequence selected from the group of sequences provided in SEQ ID NOS: 129 and 130.

53. A fusion protein comprising one or more polypeptides according to any one of claims 1-4 and the M. tuberculosis antigen 38 kD (SEQ ID NO: 150).

54. A diagnostic kit comprising:
(a) one or more fusion proteins according to any one of claims 50-53; and (b) a detection reagent.