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  • Review Article
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Gene map of the extended human MHC

Key Points

  • The gene map for the extended major histocompatibility complex (xMHC) comprises 421 loci (excluding RNA genes) in a sequence length of 7.6 Mb — extending the previous gene map of the classical MHC, which was 3.6 Mb long and contained 224 loci.

  • All 421 xMHC loci have been assigned definitive and approved gene symbols.

  • About 50% of the xMHC gene loci are present in clusters or superclusters that are not restricted only to immune genes. The two largest clusters, comprising histone and tRNA genes are the largest of their type in the genome.

  • Transcription hotspot analysis indicates that it is just as likely that the classical MHC is hitch-hiking with gene clusters of the xMHC as the reverse.

  • About 22% of the expressed xMHC genes show a higher than average number of non-synonymous coding polymorphisms.

  • About 28% of the xMHC genes can be associated with immune system function.

  • About 10% of the xMHC genes are currently known to be disease-causing or disease-associated.

  • About 20% of the xMHC genes have putative paralogues elsewhere in the genome, indicating considerable potential for functional redundancy.

  • The gene map of the xMHC provides an invaluable resource for the study of the most important genetic region of the human genome in relation to infectious, inflammatory and autoimmune diseases.

Abstract

The major histocompatibility complex (MHC) is the most important region in the vertebrate genome with respect to infection and autoimmunity, and is crucial in adaptive and innate immunity. Decades of biomedical research have revealed many MHC genes that are duplicated, polymorphic and associated with more diseases than any other region of the human genome. The recent completion of several large-scale studies offers the opportunity to assimilate the latest data into an integrated gene map of the extended human MHC. Here, we present this map and review its content in relation to paralogy, polymorphism, immune function and disease.

The gene map of the xMHC is also available as a poster, which accompanies this issue and is available at http://www.nature.com/nrg/posters/mhcmap/index.html.

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Figure 1: Gene map of the extended major histocompatibility complex (xMHC).
Figure 2: Distribution of major histocompatibility complex (MHC) paralogues in the human genome.

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References

  1. Gorer, P. A. The detection of a hereditary antigenic difference in the blood of mice by means of human group A serum. J. Genet. 32, 17–31 (1936).

    Google Scholar 

  2. Klein, J. Seeds of time: fifty years ago Peter A. Gorer discovered the H-2 complex. Immunogenetics 24, 331–338 (1986).

    CAS  PubMed  Google Scholar 

  3. Klein, J. Natural History of the Major Histocompatibility Complex (Wiley & Sons, New York, 1986).

    Google Scholar 

  4. Campbell, R. D. & Trowsdale, J. Map of the human MHC. Immunol. Today 14, 349–352 (1993).

    CAS  PubMed  Google Scholar 

  5. The MHC sequencing consortium. Complete sequence and gene map of a human major histocompatibility complex. Nature 401, 921–923 (1999). Describes the first sequence-based gene map of a (mosaic) human MHC.

  6. Malfroy, L. et al. Heterogeneity in rates of recombination in the 6-Mb region telomeric to the human major histocompatibility complex. Genomics 43, 226–231 (1997). This paper describes the first evidence (linkage disequilibrium) for the existence of an extended MHC.

    CAS  PubMed  Google Scholar 

  7. Yoshino, M. et al. Genomic evolution of the distal Mhc class I region on mouse Chr 17. Hereditas 127, 141–148 (1997).

    CAS  PubMed  Google Scholar 

  8. Stephens, R. et al. Gene organisation, sequence variation and isochore structure at the centromeric boundary of the human MHC. J. Mol. Biol. 291, 789–799 (1999).

    CAS  PubMed  Google Scholar 

  9. Mungall, A. J. et al. The DNA sequence and analysis of human chromosome 6. Nature 425, 805–811 (2003).

    CAS  PubMed  Google Scholar 

  10. Stewart, C. A. et al. Complete MHC haplotype sequencing for common disease gene mapping. Genome Res. 14, 1176–1187 (2004). The authors describe the sequences in the MHC from single haplotypes.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Kumanovics, A., Takada, T. & Lindahl, K. F. Genomic organization of the mammalian MHC. Annu. Rev. Immunol. 21, 629–657 (2003).

    CAS  PubMed  Google Scholar 

  12. Freemont, P. S., Hanson, I. M. & Trowsdale, J. A novel cysteine-rich sequence motif. Cell 64, 483–484 (1991).

    CAS  PubMed  Google Scholar 

  13. Wain, H. M., Lush, M. J., Ducluzeau, F., Khodiyar, V. K. & Povey, S. Genew: the human gene nomenclature database, 2004 updates. Nucleic Acids Res. 32, D255–257 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Robinson, J. et al. IMGT/HLA and IMGT/MHC: sequence databases for the study of the major histocompatibility complex. Nucleic Acids Res. 31, 311–314 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Ehlers, A. et al. MHC-linked olfactory receptor loci exhibit polymorphism and contribute to extended HLA/OR-haplotypes. Genome Res. 10, 1968–1978 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Xie, T. et al. Analysis of the gene-dense major histocompatibility complex class III region and its comparison to mouse. Genome Res. 13, 2621–2636 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Eddy, S. R. Non-coding RNA genes and the modern RNA world. Nature Rev. Genet. 2, 919–929 (2001).

    CAS  PubMed  Google Scholar 

  18. Yang, Z., Mendoza, A. R., Welch, T. R., Zipf, W. B. & Yu, C. Y. Modular variations of the human major histocompatibility complex class III genes for serine/threonine kinase RP, complement component C4, steroid 21-hydroxylase CYP21, and tenascin TNX (the RCCX module). A mechanism for gene deletions and disease associations. J. Biol. Chem. 274, 12147–12156 (1999).

    CAS  PubMed  Google Scholar 

  19. Bergstrom, T. F. et al. Phylogenetic history of hominoid DRB loci and alleles inferred from intron sequences. Immunol. Rev. 167, 351–365 (1999).

    CAS  PubMed  Google Scholar 

  20. Kulski, J. K. & Dawkins, R. L. The P5 multicopy gene family in the MHC is related in sequence to human endogenous retroviruses HERV-L and HERV-16. Immunogenetics 49, 404–412 (1999).

    CAS  PubMed  Google Scholar 

  21. Bailey, J. A. et al. Recent segmental duplications in the human genome. Science 297, 1003–1007 (2002). This paper shows that duplication is a common feature of the human genome and that it is not restricted to known (for example, immune) multigene families.

    CAS  PubMed  Google Scholar 

  22. Gu, X., Wang, Y. & Gu, J. Age distribution of human gene families shows significant roles of both large- and small-scale duplications in vertebrate evolution. Nature Genet. 31, 205–209 (2002).

    CAS  PubMed  Google Scholar 

  23. Trowsdale, J. The gentle art of gene arrangement: the meaning of gene clusters. Genome Biol. 3, COMMENT2002 (2002).

  24. Paule, M. R. & White, R. J. Survey and summary: transcription by RNA polymerases I and III. Nucleic Acids Res. 28, 1283–1298 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Marzluff, W. F., Gongidi, P., Woods, K. R., Jin, J. & Maltais, L. J. The human and mouse replication-dependent histone genes. Genomics 80, 487–498 (2002).

    CAS  PubMed  Google Scholar 

  26. Zhang, E. Y., Knipp, G. T., Ekins, S. & Swaan, P. W. Structural biology and function of solute transporters: implications for identifying and designing substrates. Drug Metab. Rev. 34, 709–750 (2002).

    CAS  PubMed  Google Scholar 

  27. Ruddy, D. A. et al. A 1.1-Mb transcript map of the hereditary hemochromatosis locus. Genome Res. 7, 441–456 (1997).

    CAS  PubMed  Google Scholar 

  28. Shibui, A. et al. Isolation and chromosomal mapping of a novel human gene showing homology to Na+/PO4 cotransporter. J. Hum. Genet. 44, 190–192 (1999).

    CAS  PubMed  Google Scholar 

  29. Radosavljevic, M. & Bahram, S. In vivo immunogenetics: from MIC to RAET1 loci. Immunogenetics 55, 1–9 (2003).

    CAS  PubMed  Google Scholar 

  30. Bahram, S. MIC genes: from genetics to biology. Adv. Immunol. 76, 1–60 (2000).

    CAS  PubMed  Google Scholar 

  31. Hopper, A. K. & Phizicky, E. M. tRNA transfers to the limelight. Genes Dev. 17, 162–180 (2003).

    CAS  PubMed  Google Scholar 

  32. Buckland, R. A., Maule, J. C. & Sealey, P. G. A cluster of transfer RNA genes (TRM1, TRR3, and TRAN) on the short arm of human chromosome 6. Genomics 35, 164–171 (1996).

    CAS  PubMed  Google Scholar 

  33. Rhodes, D. A., Stammers, M., Malcherek, G., Beck, S. & Trowsdale, J. The cluster of BTN genes in the extended major histocompatibility complex. Genomics 71, 351–362 (2001).

    CAS  PubMed  Google Scholar 

  34. Stammers, M., Rowen, L., Rhodes, D., Trowsdale, J. & Beck, S. BTL-II: a polymorphic locus with homology to the butyrophilin gene family, located at the border of the major histocompatibility complex class II and class III regions in human and mouse. Immunogenetics 51, 373–382 (2000).

    CAS  PubMed  Google Scholar 

  35. Jack, L. J. & Mather, I. H. Cloning and analysis of cDNA encoding bovine butyrophilin, an apical glycoprotein expressed in mammary tissue and secreted in association with the milk-fat globule membrane during lactation. J. Biol. Chem. 265, 14481–14486 (1990).

    CAS  PubMed  Google Scholar 

  36. Giorgi, D., Friedman, C., Trask, B. J. & Rouquier, S. Characterization of nonfunctional V1R-like pheromone receptor sequences in human. Genome Res. 10, 1979–1985 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Volz, A. et al. Complex transcription and splicing of odorant receptor genes. J. Biol. Chem. 278, 19691–19701 (2003).

    CAS  PubMed  Google Scholar 

  38. Ziegler, A., Dohr, G. & Uchanska-Ziegler, B. Possible roles for products of polymorphic MHC and linked olfactory receptor genes during selection processes in reproduction. Am. J. Reprod. Immunol. 48, 34–42 (2002).

    PubMed  Google Scholar 

  39. Coleman, J. E. Zinc proteins: enzymes, storage proteins, transcription factors, and replication proteins. Annu. Rev. Biochem. 61, 897–946 (1992).

    CAS  PubMed  Google Scholar 

  40. Lee, P. L. et al. Three genes encoding zinc finger proteins on human chromosome 6p21.3: members of a new subclass of the Kruppel gene family containing the conserved SCAN box domain. Genomics 43, 191–201 (1997).

    CAS  PubMed  Google Scholar 

  41. Meyer, M., Gaudieri, S., Rhodes, D. A. & Trowsdale, J. Cluster of TRIM genes in the human MHC class I region sharing the B30.2 domain. Tissue Antigens 61, 63–71 (2003).

    CAS  PubMed  Google Scholar 

  42. Matthews, J. M. & Sunde, M. Zinc fingers — folds for many occasions. IUBMB Life 54, 351–355 (2002).

    CAS  PubMed  Google Scholar 

  43. Gruss, H. J. & Dower, S. K. The TNF ligand superfamily and its relevance for human diseases. Cytokines Mol. Ther. 1, 75–105 (1995).

    CAS  PubMed  Google Scholar 

  44. Mallya, M., Campbell, R. D. & Aguado, B. Transcriptional analysis of a novel cluster of LY-6 family members in the human and mouse major histocompatibility complex: five genes with many splice forms. Genomics 80, 113–123 (2002).

    CAS  PubMed  Google Scholar 

  45. Milner, C. M. & Campbell, R. D. Structure and expression of the three MHC-linked HSP70 genes. Immunogenetics 32, 242–251 (1990).

    CAS  PubMed  Google Scholar 

  46. Gleimer, M. & Parham, P. Stress management: MHC class I and class I-like molecules as reporters of cellular stress. Immunity 19, 469–477 (2003).

    CAS  PubMed  Google Scholar 

  47. Alfonso, C. & Karlsson, L. Nonclassical MHC class II molecules. Annu. Rev. Immunol. 18, 113–142 (2000).

    CAS  PubMed  Google Scholar 

  48. Ohno, S. Evolution by Gene Duplication (Springer, New York, 1970).

    Google Scholar 

  49. Mazet, F. & Shimeld, S. M. Gene duplication and divergence in the early evolution of vertebrates. Curr. Opin. Genet. Dev. 12, 393–396 (2002).

    CAS  PubMed  Google Scholar 

  50. Flajnik, M. F. & Kasahara, M. Comparative genomics of the MHC: glimpses into the evolution of the adaptive immune system. Immunity 15, 351–362 (2001).

    CAS  PubMed  Google Scholar 

  51. Sidow, A. Gen(om)e duplications in the evolution of early vertebrates. Curr. Opin. Genet. Dev. 6, 715–722 (1996).

    CAS  PubMed  Google Scholar 

  52. International Human Genome Sequencing Consortium. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001).

  53. Hughes, A. L. Phylogenetic tests of the hypothesis of block duplication of homologous genes on human chromosomes 6, 9, and 1. Mol. Biol. Evol. 15, 854–870 (1998).

    CAS  PubMed  Google Scholar 

  54. Abi-Rached, L., Gilles, A., Shiina, T., Pontarotti, P. & Inoko, H. Evidence of en bloc duplication in vertebrate genomes. Nature Genet. 31, 100–105 (2002). The latest hypothesis to explain the MHC paralogy.

    CAS  PubMed  Google Scholar 

  55. Rand, V. Genome evolution: a study of MHC paralogous genes in the human genome. Ph.D. Thesis, University of Cambridge, UK (2003). Access through http://www.sanger.ac.uk/Info/theses/

  56. Kaufman, J. et al. The chicken B locus is a minimal essential major histocompatibility complex. Nature 401, 923–925 (1999).

    CAS  PubMed  Google Scholar 

  57. Rogers, S. & Kaufman, J. (personal communication).

  58. Teng, M. S. et al. A human TAPBP (TAPASIN)-related gene, TAPBP-R. Eur. J. Immunol. 32, 1059–1068 (2002).

    CAS  PubMed  Google Scholar 

  59. Wagner, A. Selection and gene duplication: a view from the genome. Genome Biol. 3, R1012 (2002).

    Google Scholar 

  60. Clamp, M. et al. Ensembl 2002: accommodating comparative genomics. Nucleic Acids Res. 31, 38–42 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Marsh, S. G. E., Parham, P. & Barber, L. D. The HLA Factsbook (Academic Press, San Diego, California, 2000).

    Google Scholar 

  62. Ahmad, T. et al. Haplotype-specific linkage disequilibrium patterns define the genetic topography of the human MHC. Hum. Mol. Genet. 12, 647–656 (2003).

    Article  CAS  PubMed  Google Scholar 

  63. Walsh, E. C. et al. An integrated haplotype map of the human major histocompatibility complex. Am. J. Hum. Genet. 73, 580–590 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Stenzel, A. et al. Patterns of linkage disequilibrium in the MHC region on human chromosome 6p. Hum. Genet. 114, 377–385 (2004).

    CAS  PubMed  Google Scholar 

  65. Trowsdale, J. & Parham, P. Mini-review: defense strategies and immunity-related genes. Eur. J. Immunol. 34, 7–17 (2004).

    CAS  PubMed  Google Scholar 

  66. Zdobnov, E. M. et al. Comparative genome and proteome analysis of Anopheles gambiae and Drosophila melanogaster. Science 298, 149–159 (2002).

    CAS  PubMed  Google Scholar 

  67. Christophides, G. K. et al. Immunity-related genes and gene families in Anopheles gambiae. Science 298, 159–165 (2002).

    CAS  PubMed  Google Scholar 

  68. Lazarus, R. et al. Single nucleotide polymorphisms in innate immunity genes: abundant variation and potential role in complex human disease. Immunol. Rev. 190, 9–25 (2002).

    CAS  PubMed  Google Scholar 

  69. Hewitt, E. W. The MHC class I antigen presentation pathway: strategies for viral immune evasion. Immunology 110, 163–169 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Vivier, E., Tomasello, E. & Paul, P. Lymphocyte activation via NKG2D: towards a new paradigm in immune recognition? Curr. Opin. Immunol. 14, 306–311 (2002).

    CAS  PubMed  Google Scholar 

  71. Lechler, R. & Warrens, A. HLA in Health and Disease (Academic Press, London, 2000).

    Google Scholar 

  72. Feder, J. N. et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nature Genet. 13, 399–408 (1996). The authors describe a novel role for an MHC class I molecule. This is a landmark paper that illustrates the problems posed by linkage disequilibrium in disease mapping in the MHC.

    CAS  PubMed  Google Scholar 

  73. von Kempis, J. Arthropathy in hereditary hemochromatosis. Curr. Opin. Rheumatol. 13, 80–83 (2001).

    CAS  PubMed  Google Scholar 

  74. Rubio, J. P. et al. Extended haplotype analysis in the HLA complex reveals an increased frequency of the HFE-C282Y mutation in individuals with multiple sclerosis. Hum. Genet. 114, 573–580 (2004).

    CAS  PubMed  Google Scholar 

  75. Hellerbrand, C., Poppl, A., Hartmann, A., Scholmerich, J. & Lock, G. HFE C282Y heterozygosity in hepatocellular carcinoma: evidence for an increased prevalence. Clin. Gastroenterol. Hepatol. 1, 279–284 (2003).

    CAS  PubMed  Google Scholar 

  76. Pal, D. K. et al. BRD2 (RING3) is a probable major susceptibility gene for common juvenile myoclonic epilepsy. Am. J. Hum. Genet. 73, 261–270 (2003). Identification of a promoter mutation within the MHC that is strongly linked to a common form of epilepsy.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Okamoto, K. et al. Identification of IκBL as the second major histocompatibility complex-linked susceptibility locus for rheumatoid arthritis. Am. J. Hum. Genet. 72, 303–312 (2003).

    CAS  PubMed  Google Scholar 

  78. Schmidt, A. M., Yan, S. D., Yan, S. F. & Stern, D. M. The biology of the receptor for advanced glycation end products and its ligands. Biochim. Biophys. Acta 1498, 99–111 (2000).

    CAS  PubMed  Google Scholar 

  79. Hofmann, M. A. et al. RAGE and arthritis: the G82S polymorphism amplifies the inflammatory response. Genes Immun. 3, 123–135 (2002).

    CAS  PubMed  Google Scholar 

  80. Bjorkman, P. J. et al. Structure of the human class I histocompatibility antigen, HLA-A2. Nature 329, 506–512 (1987).

    CAS  PubMed  Google Scholar 

  81. Brown, J. H. et al. Three-dimensional structure of the human class II histocompatibility antigen HLA-DR1. Nature 364, 33–39 (1993).

    CAS  PubMed  Google Scholar 

  82. Siebold, C. et al. Crystal structure of HLA-DQ0602 that protects against type 1 diabetes and confers strong susceptibility to narcolepsy. Proc. Natl Acad. Sci. USA 101, 1999–2004 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Hulsmeyer, M. et al. Dual, HLA-B27 subtype-dependent conformation of a self-peptide. J. Exp. Med. 199, 271–281 (2004).

    PubMed  PubMed Central  Google Scholar 

  84. Gao, X. et al. Effect of a single amino acid change in MHC class I molecules on the rate of progression to AIDS. N. Engl. J. Med. 344, 1668–1675 (2001). Along with reference 83, this paper shows how a single amino-acid change can influence structural and functional properties of HLA-B27 antigens, and in HLA-B35 molecules is associated with rate of progression from HIV infection to AIDS.

    CAS  PubMed  Google Scholar 

  85. Ferrara, G. B. et al. Bone marrow transplantation from unrelated donors: the impact of mismatches with substitutions at position 116 of the human leukocyte antigen class I heavy chain. Blood 98, 3150–3155 (2001).

    CAS  PubMed  Google Scholar 

  86. Doxiadis, I. I. et al. Association between specific HLA combinations and probability of kidney allograft loss: the taboo concept. Lancet 348, 850–853 (1996).

    CAS  PubMed  Google Scholar 

  87. Chen, T. C., Waldmann, H. & Fairchild, P. J. Induction of dominant transplantation tolerance by an altered peptide ligand of the male antigen Dby. J. Clin. Invest. 113, 1754–1762 (2004). This paper shows that the balance of destructive and protective T cells in a transplant setting can be changed by using altered peptides for presentation by MHC molecules

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Hansen, J. A. & Dupont, B. in Proceedings of the 13th International Histocompatibility Workshop and Congress (IHWG Press, Seattle, in the press).

  89. Cohen, M. L. Changing patterns of infectious disease. Nature 406, 762–767 (2000).

    CAS  PubMed  Google Scholar 

  90. Vyse, T. J. & Todd, J. A. Genetic analysis of autoimmune disease. Cell 85, 311–318 (1996).

    CAS  PubMed  Google Scholar 

  91. Novik, K. L. et al. Epigenomics: genome-wide study of methylation phenomena. Curr. Issues Mol. Biol. 4, 111–128 (2002).

    CAS  PubMed  Google Scholar 

  92. Teitell, M. & Richardson, B. DNA methylation in the immune system. Clin. Immunol. 109, 2–5 (2003).

    CAS  PubMed  Google Scholar 

  93. Soen, Y., Chen, D. S., Kraft, D. L., Davis, M. M. & Brown, P. O. Detection and characterizationof cellular immune responses using peptide-MHC microarrays. PLoS Biol. 1, E65 (2003).

    PubMed  PubMed Central  Google Scholar 

  94. Bartel, D. P. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297 (2004).

    CAS  PubMed  Google Scholar 

  95. Vance, V. & Vaucheret, H. RNA silencing in plants — defense and counterdefense. Science 292, 2277–2280 (2001).

    CAS  PubMed  Google Scholar 

  96. Lecellier, C. H. & Voinnet, O. RNA silencing: no mercy for viruses? Immunol. Rev. 198, 285–303 (2004).

    CAS  PubMed  Google Scholar 

  97. Bock, G. & Goode, J. Immunoinformatics — Strategies for Better Understanding of Immune Function (Novartis Foundation, Chichester, UK, 2003).

    Google Scholar 

  98. Chabas, D., Taheri, S., Renier, C. & Mignot, E. The genetics of narcolepsy. Annu. Rev. Genomics Hum. Genet. 4, 459–483 (2003).

    CAS  PubMed  Google Scholar 

  99. Sollid, L. M. Coeliac disease: dissecting a complex inflammatory disorder. Nature Rev. Immunol. 2, 647–655 (2002).

    CAS  Google Scholar 

  100. Brown, N. P., Whittaker, A. J., Newell, W. R., Rawlings, C. J. & Beck, S. Identification and analysis of multigene families by comparison of exon fingerprints. J. Mol. Biol. 249, 342–359 (1995).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We wish to thank S. Rogers and J. Kaufman for sharing prepublication data. The work of the HUGO Gene Nomenclature Committee is supported by the US National Institutes of Health, the UK Medical Research Council and the Wellcome Trust.

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Correspondence to Stephan Beck.

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Related links

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DATABASES

Entrez

HFE

MICA

MICB

B2M

TRIM

TNF

LTA

LTB

OMIM

Ankylosing spondylitis

FURTHER INFORMATION

Anthony Nolan Research Institute

Beck's laboratory

ENSEMBL

HUGO Gene Nomenclature Committee (HGNC)

Human Annotation Workshop (HAWK)

Human Genome Mapping Project resource centre

IMGT/HLA Sequence Database

International Histocompatiblity Working Group

International ImMunoGeneTics Information System

MHC Haplotype Project

MHCPEP database of MHC-binding peptides

NCBI MHC database

NCBI Single Nucleotide Polymorphism database

Poster of the xMHC map

Trowsdale's laboratory

UCSC Genome Browser

VEGA

Ziegler's laboratory

Glossary

T CELLS

These are lymphocytes that have an important role in the primary immune response, so named because their final stages of development occur in the thymus. CD8+ killer or cytotoxic T cells destroy infected cells, whereas CD4+ or helper T-cells regulate the function of other lymphocytes.

CLASS III COMPLEMENT PROTEINS

Proteins that are involved in a cascade of proteolytic cleavage of glycoproteins, ultimately leading to the induction of inflammatory responses and damage to pathogens.

CYTOKINE GENES

These encode a wide array of proteins that mediate signalling between cells either at close range or at a distance.

HAPLOTYPE

The combination of alleles at several loci on a single chromosome of a given individual. For example, for a marker with alleles M and m that is linked to another locus with alleles Q and q, possible haplotypes are MQ, Mq, mQ and mq.

LINKAGE DISEQUILIBRIUM

The non-random association of alleles at adjacent loci.

CONSERVED SYNTENY

The occurrence of genomic collinearity between homologous genes in different organisms.

PGF CELL LINE

A consanguineous B-lymphoblastoid cell line, derived from a European caucasoid male, with a homozygous HLA haplotype.

IMMUNO-PROTEASOME

Large protease complexes that degrade proteins into peptides for association with MHC class I molecules. The immuno-proteasome contains some subunits that are induced by γ interferon, two of which are encoded in the MHC.

NATURAL KILLER CELL

Large granular non-T, non-B-type lymphocytes. Natural killer cells are important for the early response to viruses. They produce cytokines, kill certain tumour cells and have appropriate receptors for antibody-dependent cell-mediated cytotoxicity.

LEUKOCYTE RECEPTOR COMPLEX

A cluster of genes on chromosome 19q13.4. The products of some of the IgSF genes in the LRC are expressed on natural killer cells and serve as receptors for MHC class I molecules.

NATURAL KILLER COMPLEX

A cluster of genes on chromosome 12. The products of some of the lectin-related genes in the NKC are expressed on natural killer cells and serve as receptors for MHC class I ligands.

SPERM-RECEPTOR SELECTION HYPOTHESIS

This theory proposes that olfactory receptors that are expressed on spermatozoa and polymorphic antigens (for example, MHC class I molecules) might be functionally connected, ensuring that spermatozoa have a higher chance to fertilize a genetically different oocyte than spermatozoa that share alleles with the female, in particular on the MHC.

PURIFYING SELECTION

Alternatively known as negative selection. A process in which more non-synonymous (amino-acid changing) than synonymous substitutions have been eliminated. It is observed, for example, when a substitution is deleterious and therefore has been eliminated from a population.

POSITIVE SELECTION

A process in which more non-synonymous (amino-acid changing) than synonymous substitutions have been preserved. It is observed when non-synonymous substitutions in a gene are selectively advantageous, for example, increasing the fitness of the species.

POLYGENY

The presence of several different but related genes with similar function. Polygeny of MHC class I genes ensures that each individual produces different MHC molecules.

MULTIFACTORIAL DISEASE

A disease that is influenced by multiple genetic, epigenetic or environmental factors.

ADVANCED GLYCATION

Non-enzymatic glycoxidation process involving sugars and basic amino acids of various proteins. The end products (AGEs) are chemically diverse, stable and implicated in various diseases in which deposits are formed, including amyloidosis, atherosclerosis and rheumatoid arthritis.

microRNAs

A class of small (approximately 22-bp) non-coding RNAs that have an important role in gene regulation.

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Horton, R., Wilming, L., Rand, V. et al. Gene map of the extended human MHC. Nat Rev Genet 5, 889–899 (2004). https://doi.org/10.1038/nrg1489

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