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Complete sequence and gene map of a human major histocompatibility complex

Nature volume 401, pages 921–923 (1999)Cite this article

Abstract

Here we report the first complete sequence and gene map of a human major histocompatibility complex (MHC), a region on chromosome 6 which is essential to the immune system (reviewed in ref. 1). When it was discovered over 50 years ago the region was thought to specify histocompatibility genes, but their nature has been resolved only in the last two decades. Although many of the 224 identified gene loci (128 predicted to be expressed) are still of unknown function, we estimate that about 40% of the expressed genes have immune system function. Over 50% of the MHC has been sequenced twice, in different haplotypes, giving insight into the extraordinary polymorphism and evolution of this region. Several genes, particularly of the MHC class II and III regions, can be traced by sequence similarity and synteny to over 700 million years ago, clearly predating the emergence of the adaptive immune system some 400 million years ago. The sequence is expected to be invaluable for the identification of many common disease loci. In the past, the search for these loci has been hampered by the complexity of high gene density and linkage disequilibrium.

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Figure 1: Complete gene map of the MHC reference sequence reported here.

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Acknowledgements

Sequencing of the class I region in the US was funded by a Department of Energy grant to M. Olson and by US NIH grants to D.G. Sequencing of the class I region in Japan was funded by the Japanese Science and Technology Corporation (JST). Sequencing of the class II region at the Sanger Centre was funded by the Wellcome Trust. Early stages of the class II sequence were funded by the Imperial Cancer Research Fund and the EU BioMed1 programme. Sequencing of the class III region at the University of Washington Multimegabase Sequencing Center was funded by the US NIH and Department of Energy. We thank all members past and present of the University of Washington Genome Center (http://www.genome.washington.edu/uwgc/), the Genome Sequencing Group at Tokai University (http://www.alis.tokyo.jst.go.jp/HGS/top.html), the Chromosome 6 Project Group at the Sanger Centre (http://www.sanger.ac.uk/HGP/Chr6) and the University of Washington Multimegabase Sequencing Center (http:/chroma.mbt.washington.edu/msg_www/) for their contributions. R.D.C. was funded by the UK Medical Research Council and J.T. was funded by the Wellcome Trust. The work was divided as follows: The Sanger Centre, Hinxton, UK: HSET to TSBP, 1.2 Mb; Tokai University, Isehara, Japan: HSPA1B to P5-15, 2.2 Mb; Fred Hutchinson Cancer Research Center and the University of Washington Genome Center (UWGC), Seattle, USA: NFKBIL1 to HLA-F and beyond, 2.2 Mb; University of Washington Multimegabase Sequencing Center (UWMSC), Seattle, USA: NOTCH4 to LTA, 0.76 Mb. From these sequences a 3,673,800-base-long consensus was assembled covering P5-15 to HSET (http://www.sanger.ac.uk/HGP/Chr6/MHC_990719.fasta).

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The MHC sequencing consortium

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Corresponding authors representing the four sequencing centres: S. Beck (The Sanger Centre, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK); D. Geraghty (Fred Hutchinson Cancer Research Center, Seattle, Washington 98104, USA); H. Inoko (Tokai University School of Medicine, Department of Molecular Life Science, Bohseidai, Isehara, Kanagawa 259-11, Japan); and L. Rowen (University of Washington, Seattle, Washington 98195, USA). A full list of contributors appears at the end of the paper.

Correspondence and requests for materials should be addressed to D. Geraghty (e-mail: geraghty@fhcrc.org) or H. Inoko (e-mail: hinoko@is.icc.u-tokai.ac.jp) for the class I region, S. Beck (e-mail: beck@sanger.ac.uk) or J. Trowsdale (e-mail: jt233@mole.bio.cam.ac.uk) for the class II region and D. Campbell (e-mail: rcampbel@hgmp.mrc.ac.uk) or L. Rowen (e-mail: leerowen@u.washington.edu) for the class III region.

Contributors in alphabetical order (numbers in parentheses indicate addresses): B. Aguado (5), S. Bahram (7), S. Beck (1), R. D. Campbell (5), S. A. Forbes (6), D. Geraghty (2), T. Guillaudeux (2), L. Hood (4), R. Horton (1), H. Inoko (3), M. Janer (2), C. Jasoni (2), A. Madan (4), S. Milne (1), M. Neville (5), A. Oka (3), S. Qin (4), G. Ribas-Despuig (5), J. Rogers (1), L. Rowen (4), T. Shiina (3), T. Spies (2), G. Tamiya (3), H. Tashiro (8), J. Trowsdale (6), Q. Vu (2), L. Williams (2), M. Yamazaki (8) (1)The Sanger Centre, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK (2)Fred Hutchinson Cancer Research Center, Seattle, Washington 98104, USA (3)Tokai University School of Medicine, Department of Molecular Life Science, Bohseidai, Isehara, Kanagawa 259-11, Japan (4)University of Washington, Seattle, Washington 98195, USA (5)HGMP Resource Centre, Wellcome Trust Genome Campus, Hinxton CB10 1SB, UK (6)Cambridge University, Department of Pathology, Division of Immunology, Tennis Court Road, Cambridge CB2 1QP, UK (7)Centre de Recherche d'Immunologie et d'Hematologie, 4 Rue Kirschleger, 67085 Strasbourg, France (8)Bioscience Research Laboratory, Fujiya Co., Ltd., 228 Soya, Hadano, Kanagawa 257, Japan

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The MHC sequencing consortium. Complete sequence and gene map of a human major histocompatibility complex. Nature 401, 921–923 (1999). https://doi.org/10.1038/44853

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