Abstract
Analysis of the telomeric region of chromosome 14q has enabled us to complete a map of the immunoglobulin VH locus which accounts for almost all VH segments known to rearrange in B-lymphocytes. The human germline VH repertoire consists of approximately 50 functional VH segments — the exact number depending on the haplotype — spanning 1,100 kilobases upstream of the JH segments. A yeast artificial chromosome used to map these segments was isolated by its ability to provide telomere activity in yeast, suggesting that the VH locus may be located within a few kilobases of the 14q telomere. The limited structural diversity encoded by the functional VH segments demonstrates the importance of combinatorial diversity produced by VDJ joining and the association of heavy and light chains in producing the human antibody repertoire.
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References
Tonegawa, S. Somatic generation of antibody diversity. Nature 302, 575–581 (1983).
McBride, O.W. et al. Localisation of human variable and constant region immunoglobulin heavy chain genes on subtelomeric band q32 of chromosome 14. Nucl. Acids Res. 10, 8155–8169 (1982).
Cox, D.W., Markovic, V.D. & Teshima, I.E. Genes for immunoglobulin heavy chains and for a1-antitrypsin are localised to specific regions of chromosome 14. Nature 297, 428–430 (1982).
Cherif, D. & Berger, R. New localisations of VH sequences by in situ hybridisation with biotinylated probes. Genes Chrom. Cancer 2, 103–108 (1990).
Matsuda, F. et al. Organisation of variable region segments of the human immunoglobulin heavy chain: duplication of the D5 cluster within the locus and interchromosomal translocation of variable region segments. EMBO J. 9, 2501–2506 (1990).
Tomlinson, I.M. et al. Human immunoglobulin VH and D segments on chromosomes 15q11.2 and 16p11.2. Hum. molec. Genet. 3, 853–860 (1994).
Tomlinson, I.M., Walter, G., Marks, J.D., Llewelyn, M.B. & Winter, G. The repertoire of human germline VH segments reveals about fifty groups of VH segments with different hypervariable loops. J. molec. Biol. 227, 776–798 (1992).
Willems van Dijk, K., Mortari, F., Kirkham, P.M., Schroeder, H.W. & Milner, E.C.B. The human immunoglobulin VH7 gene family consists of a small, polymorphic group of six to eight gene segments dispersed throughout the VH locus. Eur. J. Immunol. 23, 832–839 (1993).
Kodaira, M. et al. Organisation and evolution of variable region genes of the human immunoglobulin heavy chain. J. molec. Biol. 190, 529–541 (1986).
Berman, J.E. et al. Content and organisation of the human Ig VH locus: definition of three new VH families and linkage to the Ig CH locus. EMBO J. 7, 727–738 (1988).
Walter, M.A., Surti, U., Hofker, M.H. & Cox, D.W. The physical organisation of the human immunoglobulin heavy chain gene complex. EMBO J. 9, 3303–3313 (1990).
Shin, E.K. et al. Physical map of the 3′ region of the human immunoglobulin heavy-chain locus: clustering of autoantibody-related variable segments in one haplotype. EMBO J. 10, 3641–3645 (1991).
Matsuda, F. et al. Structure and physical map of 64 variable segments in the 3′ 0.8-megabase region of the human immunoglobulin heavy-chain locus. Nature Genet. 3, 88–94 (1993).
Walter, G. et al. HAPPY mapping of a YAC reveals alternative haplotypes in the human immunoglobulin VH locus. Nucl. Acids Res. 21, 4524–4529 (1993).
Mengle-Gaw, L., Albertson, D.G., Sherrington, P.D. & Rabbitts, T.H. Analysis of a T-cell tumor-specific breakpoint cluster at human chromosome 14q32. Proc. natn. Acad. Sci. U.S.A. 85, 9171–9175 (1988).
Haluska, F., Tsujimoto, Y. & Croce, C.M. The t(8;14) chromosome translocation of the Burkitt lymphoma cell line Daudi occured during immunoglobulin gene rearrangement and involved the heavy chain diversity region. Proc. natn. Acad. Sci. U.S.A. 84, 6835–6839 (1987).
Buluwela, L. et al. The use of chromosomal translations to study human immunoglobulin gene organisation: mapping DH segments within 35 kb of the Cμm gene and idenification of a new DH locus. EMBO J. 7, 2003–2020 (1988).
Brown, W.R.A. Molecular cloning of human telomeres in yeast. Nature 338, 774–776 (1989).
Cheng, J.-F., Smith, C.L. & Cantor, C.R. Isolation and characterisation of a human telomere. Nucl. Acids Res. 17, 6109–6127 (1989).
Cross, S.H., Allshire, R.C., McKay, S.J., McGill, N.I. & Cooke, H.J. Cloning of human telomeres by complementation in yeast. Nature 338, 771–774 (1989).
Riethman, H.C., Moyzis, R.K., Meyne, J., Burke, D.T. & Olson, M.V. Cloning human telomeric DNA fragments into Saccharomyces cerevisiae using a yeast-artificial-chromosome vector. Proc. natn. Acad. Sci. U.S.A. 86, 6240–6244 (1989).
Pavan, W.J., Hieter, P. & Reeves, R.J. Generation of deletion deivatives by targeted transformation of human-derived yeast artificial chromosomes. Proc. natn. Acad. Sci. U.S.A. 87, 1300–1304 (1990).
Schroeder, H.J., Hillson, J.L. & Perlmutter, R.M. Early restriction of the human antibody repertoire. Science 238, 791–793 (1987).
Willems van Dijk, K., Milner, L.A., Sasso, E.H. & Milner, E.C.B. Chromosomal organisation of the heavy chain variable region gene segments comprising the human fetal antibody repertoire. Proc. natn. Acad. Sci. U.S.A. 89, 10430–10434 (1992).
Matsuda, F. et al. Dispersed localisation of D segments in the human immunoglobulin heavy chain locus. EMBO J. 7, 1047–1051 (1988).
Sasso, E.H., Willems van Dijk, K., Bull, A.P. & Milner, E.C.B. A fetally expressed immunoglobulin VH1 gene belongs to a complex set of alleles. J. clin. Invest. 91, 2358–2367 (1993).
Walter, M.A., Dosch, H.M. & Cox, D.W. A deletion map of the human immunoglobulin heavy chain variable region. J. exp. Med. 174, 335–349 (1991).
Moyzis, R.K. et al. A highly conserved repetitive DNA sequence, (TTAGGG)n, present at the telomeres of human chromosomes. Proc. natn. Acad. Sci. U.S.A. 85, 6622–6626 (1988).
Baer, R., Forster, A., Lavenir, I. & Rabbitts, T.H. Immunoglobulin VH genes are transcribed in T cells in association with a new 5′ exon. J. exp. Med. 167, 2011–2016 (1988).
Fisch, P. et al. Immunoglobulin VH-T cell receptor Cα fusion mRNA resulting from chromosome inversion include the T cell-associated 5′ exon ET. Eur. J. Immunol. 22, 2745–2748 (1992).
Chothia, C. et al. Structural repertoire of the human VH segments. J. molec. Biol. 227, 799–817 (1992).
Winter, G., Griffiths, A.D., Hawkins, R. & Hoogenboom, H.R. Making antibodies by phage display technology. Ann. Rev. Immunol. 12, 433–455 (1994).
Brüggemann, M. et al. A repertoire of monoclonal antibodies with human heavy chains from transgenic mice. Proc. natn. Acad. Sci. U.S.A. 86, 6709–6713 (1989).
Carter, N.P. et al. Reverse chromosome painting: a method for the analysis of aberrant chromosomes in clinical cytogenetics. J. med. Genet. 29, 299–307 (1992).
Reeves, R.H., Pavan, W.J. & Hieter, P. Yeast artificial chromosome modification and manipulation. Meth. Enzym. 216, 584–603 (1992).
Sanz, I. et al. The smaller human VH gene families display remarkably little polymorphism. EMBO J. 8, 3741–3748 (1989).
Baer, R., Chen, K.-C., Smith, S.D. & Rabbitts, T.H. Fusion of an immunoglobulin variable region gene and a T cell receptor constant region gene in the chromosome 14 inversion associated with T cell tumours. Cell 43, 705–713 (1985).
Van Es, J.H., Aanstoot, H., Gmelig-Meyling, F.H.J., Derksen, R.H.W.M. & Logtenberg, T. A human systemic lupus erythematosus-related anti-cardiolipin/single-stranded DNA autoantibody is encoded by a somatically mutated variant of the developmentally restricted 51 p1 VH gene. J. Immunol. 149, 2234–2240 (1992).
Zelenetz, A.D., Chen, T.T. & Levy, R. Clonal expansion in follicular lymphoma occurs subsequent to antigenic selection. J. exp. Med. 176, 1137–1148 (1992).
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Cook, G., Tomlinson, I., Walter, G. et al. A map of the human immunoglobulin VH locus completed by analysis of the telomeric region of chromosome 14q. Nat Genet 7, 162–168 (1994). https://doi.org/10.1038/ng0694-162
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DOI: https://doi.org/10.1038/ng0694-162
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