Conservation Versus Polymorphism of the MHC in Relation to Transplantation, Immune Responses and Autoimmune Disease

  • Roger L. Dawkins
  • Mariapia P. Degli-Esposti
  • Lawrence J. Abraham
  • Wenjie Zhang
  • Frank T. Christiansen
Part of the NATO ASI Series book series (volume 59)


The MHC comprises three megabases and includes both HLA and central polymorphic non HLA genes which are relevant to the immune response. Alleles at all MHC genes occur together in specific combinations or haplotypes inherited within families. The vast majority of these nuclear haplotypes are either conserved ancestral haplotypes (AHs) or recombinants between them. In our population approximately twenty such AHs occur with frequency of greater than 1% (some as frequent as 13%) and at least 70% of the population have at least 500 kilobases of one or more of these AHs. Many MHC alleles are specific for one AH whilst other alleles apparently shared between AHs can be split. It appears that within the MHC there are at least three conserved regions containing at least two or more contiguous loci which exhibit extensive polymorphism. Recombination between these regions can be identified but is rare within them. However, these frozen regions seem to be non randomly associated, perhaps through a cascade of protein peptide interaction.


Major Histocompatibility Complex Major Histocompatibility Complex Gene Major Histocompatibility Complex Allele Ancestral Haplotype Major Histocompatibility Complex Haplotype 
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  1. Abraham, L.J., ChinDu, D., Zahedi, K., Dawkins, R.L., and Whitehead, A.S.: Haplotypic polymorphisms of the TNFB gene. Immunogenetics 33: 50–53, 1991PubMedCrossRefGoogle Scholar
  2. Alper, C.A., Raum, D., Karp, S., Awdeh, Z.L., and Yunis, E.J.: Serum complement ‘Super-genes’ of the major histocompatibility complex in man (complotypes). Vox Sang 45: 62–67, 1983PubMedCrossRefGoogle Scholar
  3. Awdeh, Z.L., Raum, L.D., Yunis, E.J., and Alper, C.A.: Extended HLA/complement allele haplotypes: evidence for T/t-like complex in man. Proc Natl Acad Sci USA 80: 259, 1983PubMedCrossRefGoogle Scholar
  4. Banerji, J., Sands, J., Strominger, J.L., and Spies, T.: Gene pair from the human major histo-compatibility complex encodes large proline-rich proteins with multiple repeated motifs and a single ubiquitin-like domain. Proc Natl Acad Sci USA 87: 2374–2378, 1990PubMedCrossRefGoogle Scholar
  5. Bidwell, J.L. and Hui, K.M.: Human HLA-DR/Dw allotype matching by analysis of HLA-DRB gene PCR product polymorphism (PCR “fingerprints”). Technique 2(2): 93–100, 1990Google Scholar
  6. Carroll, M.C., Campbell, R.D., Bentley, D.R., and Porter, R.R.: A molecular map of the human major histocompatibility complex class III region linking complement genes C4, C2 and factor B. Nature 307: 237–241, 1984PubMedCrossRefGoogle Scholar
  7. Carroll, M.C., Katzman, P., Alicot, E.M., Koller, B.H., Geraghty, D.E., Orr, H.T., Strominger, J.L., and Spies, T.: Linkage map of the human major hisotcompatibility complex including the tumor necrosis factor genes. Proc Natl Acad Sci USA 84: 8535–8539, 1987PubMedCrossRefGoogle Scholar
  8. Christiansen, F.T. and Dawkins, R.L.: Questions in marrow matching: The implications of ancestral haplotypes for routine pracitice. Bone Marrow Transpl (submitted 1991)Google Scholar
  9. Christiansen, F.T., Saueracker, G.C., Leaver, A.L., Tokunaga, K., Cameron, P.U., and Dawkins, R.L.: Characterization of MHC ancestral haplotypes in insulin-dependent diabetes mellitus: evidence for involvement of non-HLA genes. Immunogenetics 17: (submitted 1990)Google Scholar
  10. Collins, M. and Myers, R.M.: Alterations in DNA helix stability due to base modifications can be evaluated using denaturing gradient gel electrophoresis. J Mol Biol 198: 737–744, 1987PubMedCrossRefGoogle Scholar
  11. Cotton, R.G.H.: Detection of single base changes in nucleic acids. Biochem J 263: 1–10, 1989PubMedGoogle Scholar
  12. Cotton, R.G.H., Rodrigues, N.R., and Campbell, R.D.: Reactivity of cytosine and thymine in single-base-pair mismatches with hydroxylamine and osmium tetroxide and its application to the study of mutations. Proc Natl Acad Sci USA 85: 4397–4401, 1988PubMedCrossRefGoogle Scholar
  13. Dawkins, R.L., Christiansen, F.T., Kay, P.H., Garlepp, M.J., McCluskey, J., Hollingsworth, P.N., and Zilko, P.J.: Disease associations with complotypes, supratypes and haplotypes. Immunol Revs 70: 5–22, 1983CrossRefGoogle Scholar
  14. Dawkins, R.L., Leaver, A., Cameron, P.U., Martin, E., Kay, P.H., and Christiansen, F.T.: Some disease-associated ancestral haplotypes carry a polymorphism of TNF. Human Immunol 26: 91–97, 1989CrossRefGoogle Scholar
  15. Dawkins, R.L., Zhang, W.J., Degli-Esposti, M.A., Abraham, L., McCann, V., and Christiansen, F.T.: Studies of haplotypes by pulsed field gel electrophoresis. In Clinical Endocrinology and Metabolism. Bailliere Tindall Limited, London (submitted 1991)Google Scholar
  16. Dupont, B.: Immunobiology of HLA. Histocompatibility Testing 1987. Springer-Verlag, New York 1989CrossRefGoogle Scholar
  17. Egea, G.E., Yunis, I., Spies, T., Strominger, J., Awdeh, Z.L., Alper, C.A., and Yunis, E.J.: Association of polymorphisms in the HLA-B region with extended haplotypes. Immunogenetics 33: 4–11, 1991PubMedCrossRefGoogle Scholar
  18. French, M.A.H. and Dawkins, R.L.: Central MHC genes, IgA deficiency and autoimmune disease. Immunol Today 11: 271–274, 1990PubMedCrossRefGoogle Scholar
  19. Klein, J. and Takahata, N.: The Major Histocompatibility Complex and the Quest for Origins. Immunol Revs 113: 5–25, 1990CrossRefGoogle Scholar
  20. Messer, G., Spengler, U., Jung, M.C., Honold, G., Blomer, K., Pape, G.R., Riethmuller, G., and Weiss, E.H.: Polymorphic structure of the tumor necrosis factor (TNF) locus: An Ncol polymorphism in the first intron of the human TNF-B gene correlates with a variant amino acid in position 26 and a reduced level of TNF-B production. J Exp Med 173: 209–219, 1991PubMedCrossRefGoogle Scholar
  21. Sargent, C.A., Dunham, I., and Campbell, R.D.: Identification of multiple HTF-island associated genes in the human major histocompatibility complex class III region. EMBO J 8: 2305–2312, 1989PubMedGoogle Scholar
  22. Sargent, C.A., Dunham, I., Trowsdale, J., and Campbell, R.D.: Human major histocompatibility complex contains genes for the major heat shock proiem HSP70. Proc Natl Acad Sci USA 86: 1968–1972, 1989PubMedCrossRefGoogle Scholar
  23. Spies, T., Blanck, G., Bresnahan, M., Sands, J., and Strominger, J.L.: A new cluster of genes within the human major histocompatibility complex. Science 243: 214–217, 1989PubMedCrossRefGoogle Scholar
  24. Spies, T., Bresnahan, M., Bahram, S., Arnold, D., Blanck, G., Mellins, E., Pious, D., and DeMars, R.: A gene in the human major histocompatibility complex class II region controlling the class I antigen presentation pathway. Nature 348: 744–747, 1990PubMedCrossRefGoogle Scholar
  25. Tokunaga, K., Saueracker, G., Kay, P.H., Christiansen, F.T., Anand, R., and Dawkins, R.L.: Extensive deletions and insertions in different MHC supratypes detected by pulsed field gel electrophoresis. J Exp Med 168: 933–940, 1988PubMedCrossRefGoogle Scholar
  26. Trowsdale, J., Hanson, I., Mockridge, I., Beck, S., Townsend, A., and Kelly, A.: Sequences encoded in the class II region of the MHC related to the ’ABC’ superfamily of transporters. Nature 348: 741–744, 1990PubMedCrossRefGoogle Scholar
  27. White, P.C., Grossberger, D., Onufer, B.J., Chaplin, D.D., New, M.I., Dupont, B., and Strominger, J.L.: Two genes encoding steroid 21-hydroxylase are located near the genes encoding the fourth component in man. Proc Natl Acad Sci USA 82: 1089–1093, 9185CrossRefGoogle Scholar
  28. Yang, S.Y.: Assisgnment of HLA-A and HLA-B antigens for the reference panel of B-lymphoblastoid cell lines determined by one-dimensional isoelectric focusing (1D-IEF) gel electrophoresis. In B. Dupont (ed.): Immunobiology of HLA, Volume 1: Histo-compatibility Testing 1987, p. 43. Springer-Verlag, New York 1989CrossRefGoogle Scholar
  29. Zhang, W.J., Degli-Esposti, M.A., Cobain, T.J., Cameron, P.U., Christiansen, F.T., and Dawkins, R.L.: Differences in gene copy number carried by different MHC ancestral haplotypes: quantitation after physical separation of haplotypes by Pulsed Field Gel Electrophoresis. J Exp Med 171: 2101–2114, 1990PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1991

Authors and Affiliations

  • Roger L. Dawkins
    • 1
  • Mariapia P. Degli-Esposti
    • 1
  • Lawrence J. Abraham
    • 1
  • Wenjie Zhang
    • 1
  • Frank T. Christiansen
    • 1
  1. 1.Department of Clinical ImmunologyRoyal Perth HospitalPerthAustralia

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