Frozen Haplotypes in Mhc Evolution

  • Jan Klein
  • Colm O’hUigin
  • Masanori Kasahara
  • Vladimir Vincek
  • Dagmar Klein
  • Felipe Figueroa
Part of the NATO ASI Series book series (volume 59)


An odd feature of the HLA-DRB region is its remarkable haplotype polymorphism: At least five groups of haplotypes differing both in length and in number of genes exist in the human population at appreciable frequencies. We have demonstrated that similar DRB haplotype polymorphism exists also in the apes - the chimpanzee and the gorilla. Moreover, certain haplotype segments have apparently remained intact since the human-chimpanzee (gorilla) divergence more than five million years ago. Hence, not only allelic but also haplotype polymorphisms evolve trans-specifically at the DRB region. The evolutionary origins of the individual haplotype groups and the possible reasons for the extreme linkage disequilibrium between certain DRB genes (the frozen haplotypes) are discussed.


Major Histocompatibility Complex Restriction Fragment Length Polymorphism Analysis Major Haplotype Human Major Histocompatibility Complex Haplotype Polymorphism 
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  1. Andersson, G., Larhammar, D., Widmark, E., Servenius, B., Peterson, P.A., and Rask, L.A.: Class II genes of the human major histocompatibility complex: Organization and evolutionary relationship of the DRß genes. J Biol Chem 262: 8748–8758, 1987PubMedGoogle Scholar
  2. Arden, B. and Klein, J.: Biochemical comparison of major histocompatibility complex molecules from different subspecies of Mus musculus: Evidence for trans-specific evolution of alleles. Proc Natl Acad Sci USA 79: 2342–2346, 1982PubMedCrossRefGoogle Scholar
  3. Awdeh, Z.L., Raum, 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: 259–263, 1983PubMedCrossRefGoogle Scholar
  4. Batchelor, J.R., Curtoni, S., Mervart, H., Noreen, H., Davey, N.J., Moses, J.H., and Amoroso, A. Antigen Society No. 22 Report (DR2). In B. Dupont (ed.) Immunobiology of HLA. Vol. I. Histocompatibility Testing 1987, pp. 240–242. Springer-Verlag, New York 1989Google Scholar
  5. Bidwell, J.: DNA-RFLP analysis and genotyping of HLA-DR and DQ antigens. Immunol Today 9: 18–23, 1988PubMedCrossRefGoogle Scholar
  6. Bidwell, J.F., Bidwell, E.A., Savage, D.A., Middleton, D., Klouda, P.T., and Bradley, B.A.: A DNA-RFLP typing system that positively identifies serologically well-defined and ill-defined HLA-DR and DQ alleles, including DRwl0. Transplantation 45: 640–646, 1988PubMedCrossRefGoogle Scholar
  7. Blanck, G. and Strominger, J.L.: Molecular organization of the DQ subregion (DO-DX-DV- DQ) of the human MHC and its evolutionary implications. J Immunol 141: 1734–1737, 1988PubMedGoogle Scholar
  8. Bodmer, W.F. and Cavalli-Sforza, L.L.: Genetics, Evolution, and Man. W.H. Freeman, San Francisco 1976Google Scholar
  9. Bodmer, J.G., Pickbourne, P., and Richards, S.: Ia Serology. In W.F. Bodmer et al. (eds.) Histocompatibility Testing 1977, pp. 35–84, Munksgaard, Copenhagen 1977Google Scholar
  10. Böhme, J., Andersson, M., Andersson, G., Möller, E., Peterson, P.A., and Rask, L.: HLA- DR ß genes vary in number between different DR specificities whereas the number of DQ ß genes is constant. J Immunol 135: 2149–2155, 1985PubMedGoogle Scholar
  11. Bontrop, R.E., Broos, L.A.M., Pham, K., Bakas, R.M., Otting, N., and Jonker, M.: The chimpanzee major histocompatibility complex class II DR subregion contains an unexpectedly high number of beta chain genes. Immunogenetics 52: 272–280, 1990Google Scholar
  12. Brändle, U., Ono, H., Figueroa, F., and Klein, J.: Organization of major histocompatibility complex DRB genes in the chimpanzee. Submitted BridgesGoogle Scholar
  13. Bridges, C.B., Skoog, E.N., and Li, J.-C.: Genetical and cytological studies of a deficiency (Notopleurat) in the second chromosome of Drosophila melanogaster. Genetics 2 1:788–795, 1936Google Scholar
  14. Cepellini, R., Curtoni, E.S., Mattiuz, P.L., Miggiano, V., Scudeller, G., and Serra, A.: Genetics of leukocyte antigens: A family study of segregation and linkage. In E.S. Curtoni, P.L. Mattiuz, and R.M. Tosi (eds.): Histocompatibility Testing 1967, pp. 149–184, Munksgaard, Copenhagen 1967Google Scholar
  15. Corell, A., Martin-Villa, J.M., Morales, P., De Juan, M.D., Varela, P., Vicario, J.L., Martinez-Laso, A., and Arnaiz-Villena, A.: Exon-2 nucleotide sequences, polymorphism and haplotype distribution of a new HLA-DRB gene: HLA-DRB6. Mol Immunol 28: 533–543, 1991PubMedCrossRefGoogle Scholar
  16. Dausset, J. and Pla, M. HLA complexe majeur d’histocompatibilité de l’hommes. Flammarion, Paris 1989Google Scholar
  17. Deevey, E.S., Jr.: The human population. Sci Am 203 (3): 195–204, 1960PubMedCrossRefGoogle Scholar
  18. Didier, D.K., Schiffenbauer, J., Shuman, S., Abruzzini, L.F., Gorski, J., Watling, D.L., Tieber, V.L., and Schwartz, B.D.: Characterization of two distinct DRß chain alleles at the ßIII locus of the DR5 haplotype: ßIII alleles are highly conserved. J Immunol 137: 2627–2631, 1986PubMedGoogle Scholar
  19. Dupont, B. (ed.): Immunobiology of HLA, Vol. 2: Immunogenetics and Histocompatibility. Springer-Verlag, New York 1989Google Scholar
  20. Dunham, I., Sargent, C.A., Dawkins, R.L., and Duncan Campbell, R.: An analysis of variation in the long-range genomic organization of the human major histocompatibility complex class II region by pulsed-field gel electrophoresis. Genomics 5: 787–796, 1989PubMedCrossRefGoogle Scholar
  21. Erlich, H.A., Scharf, S.J., Long, C.M., and Horn, C.T.: Analysis of isotypic and allotypic sequence variation in the HLA-DRß region using the in vitro enzymatic amplification of specific DNA segments. In B. Dupont (ed.): Immunobiology of HLA. Vol. II, pp. 181–185, Springer-Verlag, New York 1989Google Scholar
  22. Fan, W., Kasahara, M., Gutknecht, J., Klein, D., Mayer, W.E., Jonker, M., and Klein, J.: Shared class II Mhc polymorphisms between humans and chimpanzees. Hum Immunol 26:107–121, 1989PubMedCrossRefGoogle Scholar
  23. Felsenstein, J.: Phylogenies from molecular sequences: Inference and reliability. Annu Rev Genet 22: 521–565, 1988PubMedCrossRefGoogle Scholar
  24. Figueroa, F., Günther, E., and Klein, J.: Mhc polymorphism pre-dating speciation. Nature 335: 265–267, 1988PubMedCrossRefGoogle Scholar
  25. Figueroa, F., O’hUigin, C., Inoko, H., and Klein, J.: Primate DRB6 pseudogenes -- clue to the evolutionary origin of the HLA-DR2 haplotype. Immunogenetics, in press 1991Google Scholar
  26. Gorski, J.: HLA-DR ß-chain polymorphism. Second domain polymorphism reflects evolutionary relatedness of alleles and may explain public serologic epitopes. J Immunol 143: 329–333, 1989aPubMedGoogle Scholar
  27. Gorski, J.: The HLA-DRw8 lineage was generated by a deletion in the DRB region followed by first domain diversification. J Immunol 142: 4041–4045, 1989PubMedGoogle Scholar
  28. Gorski, J. and Mach, B.: Polymorphism of human Ia antigens: gene conversion between two DRß loci results in a new HLA-D/DR specificity. Nature 322: 6110, 1986CrossRefGoogle Scholar
  29. Grahovac, B., Mayer, W., Vincek, V., Figueroa, F., O’hUigin, C., Tichy, H., and Klein, J.: Major histocompatibility complex DRB genes of a new world monkey, the cottontop tamarin (Saguinus oedipus). Mol Biol Evol, in press 1991Google Scholar
  30. Groves, C.P.: Systematics of great apes. In D.R. Swindler and J. Erwin (eds.): Comparative Primate Biology. Vol. I. Systematics, Evolution, and Anatomy, pp. 187–217, Alan R. Liss, New York 1986Google Scholar
  31. Grumet, F.C. and Ness, D.B.: Joint report: DRw10. In P. Terasaki (ed.): Histocompatibility Testing 1980, p. 542–545, Springer-Verlag, New York 1980Google Scholar
  32. Gustafsson, K., Wiman, K., Emmoth, E., Larhammar, D., Böhme, J., Hyldig-Nielsen, J.J., Ronnne, H., Peterson, P.A., and Rask, L.: Mutations and selection in the generation of class Π histocompatibility antigen polymorphism. EMBO J 3: 1655–1661, 1984PubMedGoogle Scholar
  33. Gyllensten, U.B. and Erlich, H.A.: Ancient roots for polymorphism at the HLA-DQ alpha locus in primates. Proc Natl Acad Sci USA 86: 9986–9990, 1989PubMedCrossRefGoogle Scholar
  34. Gyllensten, U.B., Lashkari, D., and Erlich, H.A.: Allelic diversification at the class II DQB locus of the mammalian major histocompatibility complex. Proc Natl Acad Sci USA 87: 1835–1839, 1990PubMedCrossRefGoogle Scholar
  35. Hartl, D.L. and Clark, A.G.: Principles of Population Genetics. 2nd. ed. Sinauer, Sunderland, MA 1989Google Scholar
  36. Holmes, E.C., Pesole, G., and Saccone, C.: Stochastic models of molecular evolution and the estimation of phylogeny and rates of nucleotide substitution in the hominoid primates. J Hum Evol 18: 775–794, 1989CrossRefGoogle Scholar
  37. Hurley, C.K., Giles, R.C., Nunez, G., DeMars, R., Nadler, L., Winchester, R., Stastny, P., and Capra, D.C.: Molecular localization of human class II MT2 and MT3 determinants. J Exp Med 160: 472–493, 1984PubMedCrossRefGoogle Scholar
  38. Jarman, A.P. and Well, R.A.: Hypervariable ministatellites: recombinators or innocent bystanders? Trends Genet 5: 367–371, 1989PubMedCrossRefGoogle Scholar
  39. Jonsson, A.-K., Andersson, L., and Rask, L.: A cellular and functional split in the DRw8 haplotype is due to a single amino acid replacement (DRßser57-asp57). Immunogenetics 29: 308–316, 1989PubMedCrossRefGoogle Scholar
  40. Kasahara, M., Klein, D., Fan, W., and Gutknecht, J.: Evolution of the class II major histocompatibility complex alleles in higher primates. Immunol Rev. 113: 65–82, 1990PubMedCrossRefGoogle Scholar
  41. Kasahara, M., Klein, D., Vincek, V., Sarapata, D.E., and Klein, J.: The DRB subregion of the gorilla major histocompatibility complex: Evidence for linkage disequilibrium conserved across species. J Immunol., submitted 1991Google Scholar
  42. Kawai, J. Ando, A., Sato, T., Nakatsuji, T., Tsuji, K., and Inoko, H.: Analysis of gene structure and antigen determinants of DR2 antigens using DR gene transfer into mouse L cells. J Immunol 142: 312–317, 1989PubMedGoogle Scholar
  43. Kendall, E., Todd, J.A., and Campbell, R.D.: Molecular analysis of the MHC class II region in DR4, DR7, and DR9 haplotypes. Immunogenetics, in press 1991Google Scholar
  44. Kimura, M.: Estimation of evolutionary distances between homologous nucleotide sequences. Proc Natl Acad Sci USA 78:454–458, 1981PubMedCrossRefGoogle Scholar
  45. Kimura, M.: The Neutral Theory of Molecular Evolution. Cambridge University Press, Cambridge 1983Google Scholar
  46. Klein, J.: Generation of diversify at MHC loci: Implications for T cell receptor repertoires. In M. Fougereau and J. Dausset (eds.): Immunology 80: Progress in Immunology TV, pp. 239–253. Academic Press, London 1980Google Scholar
  47. Klein, J. and Schönbach, C.: Origins of Mhc diversity. In B.G. Solheim, E. Möller, and S. Ferrone (eds.): The HLA System. Basic Concepts and Clinical Importance in Transplantation Immunology. Springer-Verlag, Heidelberg, in press 1991Google Scholar
  48. Klein, J. and Takahata, N.: The major histocompatibility complex and the quest for origins. Immunol Rev 113: 5–25,1990PubMedCrossRefGoogle Scholar
  49. Klein, J., Kasahara, M., Gutknecht, J., and Figueroa, F.: Origin and function of Mhc polymorphism. Chem Immunol 49: 35–50,1990PubMedCrossRefGoogle Scholar
  50. Klein, D., Vincek, V., Kasahara, M., Schönbach, C., O’hUigin, C., and Klein, J.: Gorilla Mhc-DRB pseudogene orthologous to HLA-DRBVIII. Hum Immunol, in press 1991Google Scholar
  51. Lawlor, D.A., Ward, F.E., Ennis, P.D., Jackson, A.P., and Parham, P.: HLA-A and B polymorphisms predate the divergence of humans and chimpanzees. Nature 335: 268–271, 1988PubMedCrossRefGoogle Scholar
  52. Lee, S., Nunez-Roldan, A., Dwyer, E., Pompeo, L., and Winchester, R.: Definition of DRw10 by restriction fragment length polymorphism. Tissue Antigens 33: 466–474, 1989PubMedCrossRefGoogle Scholar
  53. Long, E.O., Wake, C.T., Gorski, J., and Mach, B.: Complete sequence of an HLA-DR ß chain deduced from a cDNA clone and identification of multiple non-allelic DR ß chain genes. EMBO J 2: 389–394, 1983PubMedGoogle Scholar
  54. Marsh, S.G.E. and Bodmer, J.G.: HLA class II nucleotide sequences, 1991. Immunogenetics 33: 321–334 1991PubMedCrossRefGoogle Scholar
  55. Martin, R.D.: Primate Origins and Evolution: A Phylogenetic Reconstruction. Chapman and Hall, London 1990Google Scholar
  56. Matsuyama, T., Schwenzer, J., Silver, J., and Winchester, R.: Structural relationships between the DRß1 and DRß2 subunits in DR4, 7, and w9 haplotypes and the DRw53 (MT3) specificity. J Immunol 137: 934–940, 1986PubMedGoogle Scholar
  57. Matsuyama, T., Winchester, R., Lee, S., Shookster, L., and Nunez-Roldan, A.: Identification of the DRw10 DRß1-chain allele as encoding a polymorphic class II major histocompatibility complex epitope otherwise restricted to DRß2 molecules of the DRw53 type. / Immunol 140: 537–543, 1988Google Scholar
  58. O’hUigin, C. and Klein, J. The age and evolution of the HLA-DRB pseudogene. In J. Klein and D. Klein (eds.): Molecular Evolution of the Major Histocompatibility Complex. Springer-Verlag, Heidelberg 1991Google Scholar
  59. Mayer, W.E., Jonker, M., Klein, D., Ivanyi, P., van Seventer, G., and Klein, J.: Nucleotide sequences of chimpanzee MHC class I alleles: Evidence for trans-species mode of evolution. EMBO J 7: 2765–2774, 1988PubMedGoogle Scholar
  60. McConnell, T.J., Talbot, W.S., Mclndoe, R.A., and Wakeland, E.K.: The origin of Mhc class II gene polymorphism within the genus Mus. Nature 332: 651–654, 1988PubMedCrossRefGoogle Scholar
  61. Mellars, P. and Stringer, C. (eds.): The Human Revolution. Princeton University Press, Princeton, New Jersey 1989Google Scholar
  62. Merryman, P., Gregersen, P.K., Lee, S., Silver, J., Nunez-Roldan, N., Crapper, R., and Winchester, R.: Nucleotide sequence of a DRw10 ß chain cDNA clone. Identity of the third D region with that of the DRw53 allele of the ß2 locus and as the probable site encoding a polymorphic MHC class II epitope. J Immunol 140: 2447–2452, 1988PubMedGoogle Scholar
  63. Nei, M.: Human evolution at the molecular level. In T. Ohta and K. Aoki (eds.): Population Genetics and Molecular Evolution, pp. 41–64, Springer-Verlag, Berlin 1985Google Scholar
  64. Navarette, C., Seki, T., Miranda, A., Winchester, R., and Gregersen, P.K.: DNA sequence analysis of the HLA-DRw12 allele. Hum Immunol 25: 51–58, 1989CrossRefGoogle Scholar
  65. Niven, M.J., Hitman, G.A., Pearce, H., Marshal, B., and Sachs, J.A.: Large haplotype- specific differences in inter-genic distances in human MHC shown by pulsed field electrophoresis mapping of healthy and Type 1 diabetic subjects. Tissue Antigens 35: 19–24, 1990CrossRefGoogle Scholar
  66. Riisome, K., Sorensen, I.J., Moller, B., Kruse, T.A., Grangaard, B., and Lamm, L.U.: HLA- DR typing using restriction fragment length polymorphism (RFLP) with one enzyme. Tissue Antigens 31: 141–150, 1988CrossRefGoogle Scholar
  67. Rollini, P., Mach, B., and Gorski, J.: Linkage map of three HLA-DR ß chain genes: Evidence for a recent duplication event. Proc Natl Acad Sci USA 82: 7197–7201, 1985PubMedCrossRefGoogle Scholar
  68. Saitou, N. and Nei, M.: The neighbor-joining method. A new method for reconstructing phylogenetic trees. Mol Biol Evol 4: 406–425, 1987PubMedGoogle Scholar
  69. Satta, Y., Takahata, N., Schönbach, C., Gutknecht, J., and Klein, J.: Calibrating evolutionary rates at major histocompatibility loci. In J. Klein and D. Klein (eds.): Molecular Evolution of the Major Histocompatibility Complex. Springer-Verlag, Heidelberg, 1991Google Scholar
  70. Satyanarayana, K. and Strominger, J.L.: DNA sequences near a meiotic recombination breakpoint within the human HLA-DQ region. Immunogenetics, in press 1991Google Scholar
  71. Schwartz, J.H.: The Red Ape. Orang-utans and Human Origins. Houghton Mifflin Co., Boston 1987Google Scholar
  72. Semana, G., Bignon, J.D., Quillivic, F., Cheneau, M.L., Hernion, E., Muller, J.Y., Genetet, B., and Fauchet, R.: Definition of DRw10 specificity by restriction fragment length polymorphism. Tissue Antigens 32: 113–120, 1988PubMedCrossRefGoogle Scholar
  73. Simons, M.J., Wheeler, R., Cohen, D., Lalonel, J.-M., and Dupont, B.: Restriction fragment length polymorphism of HLA genes: Summary of the Tenth International Workshop Southern Blot Analysis. In B. Dupont (ed.) Immunobiology of HLA. Vol. I. Histocompatibility Testing 1987, pp. 959–1023. Springer-Verlag, New York 1989CrossRefGoogle Scholar
  74. Sorrentino, R., Lillie, J., and Strominger, J.L.: Molecular characterization of MT3 antigens by two-dimensional gel electrophoresis, NH2-terminal amino acid sequence analysis and Southern-blot analysis. Proc Natl Acad Sci USA 82: 3794–3798, 1985PubMedCrossRefGoogle Scholar
  75. Spies, T., Sorrentino, R., Boss, J.M., Okada, K., and Strominger, J.L.: Structural organization of the DR subregion of the human major histocompatibility complex. Proc Natl Acad Sci USA 82: 5165–5169,1985PubMedCrossRefGoogle Scholar
  76. Steinmetz, M., Uematsu, Y., and Fischer Lindahl, K.: Hotspots of homologous recombination in mammalian genomes. Trends Genet 3: 7–10, 1987CrossRefGoogle Scholar
  77. Stormont, C.: Linked genes, pseudoalleles, and blood groups. Amer Nat 89: 105–116, 1955CrossRefGoogle Scholar
  78. Taylor, C.J., Ugozzoli, L., Tanigaki, N., Tosi, R., Bunce, M., Ting, A., and Ferrara, G.B.: Antigen Society No. 29 Report (DRw52). In B. DuPont (ed.): Immunobiology of HLA. Vol. 2: Immunogenetics and Histocompatibility. Springer-Verlag, New York 1989Google Scholar
  79. Tieber, V.L., Abruzzini, L.F., Didier, D.K., Schwartz, B.D., and Rotwein, P.: Complete characterization and sequence of an HLA class II DRß chain cDNA from the DR5 haplotype. J Biol Chem 261: 2738–2742, 1986PubMedGoogle Scholar
  80. Toguchi, T., Burmester, G., Nunez-Roldan, A., Gregersen, P., Seremetis, S., Lee, S., Szer, I., and Winchester, R.: Evidence for the separate molecular expression of four distinct polymorphic Ia epitopes on cells of DR4 homozygous individuals. Hum Immunol 10: 69–81, 1984PubMedCrossRefGoogle Scholar
  81. 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
  82. Tokunaga, K., Kay, P.H., Christiansen, F.T., Saueracker, G., and Dawkins, R.L.: Comparative mapping of the human major histocompatibility complex in different racial groups by pulsed-field gel electrophoresis. Hum Immunol 26: 99–106, 1989PubMedCrossRefGoogle Scholar
  83. Vincek, V., Klein, D., Figueroa, F., Hauptfeld, V., Kasahara, M., O’hUigin, C., Mach, B., and Klein, J.: The evolutionary origin of the HLA-DR3 haplotype. Immunogenetics, in press 1991Google Scholar
  84. WHO Nomenclature Committee for Factors of the HLA System: Nomenclature for factors of the HLA system, 1990 Immunogenetics 33: 301–309, 1991CrossRefGoogle Scholar
  85. Zhu, Z., Vincek, V., Figueroa, F., Schönbach, C., and Klein, J.: Mhc-DRB genes of the pigtail macaque (Macaca nemestrina): Implications for the evolution of human DRB genes. Mol Biol Evol, in press 1991Google Scholar

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© Springer-Verlag Berlin Heidelberg 1991

Authors and Affiliations

  • Jan Klein
    • 1
    • 2
  • Colm O’hUigin
    • 1
  • Masanori Kasahara
    • 2
  • Vladimir Vincek
    • 2
  • Dagmar Klein
    • 2
  • Felipe Figueroa
    • 1
  1. 1.Abteilung ImmungenetikMax-Planck-Institut für BiologieTübingenGermany
  2. 2.Department of Microbiology and ImmunologyUniversity of Miami School of MedicineMiamiUSA

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