Calibrating Evolutionary Rates at Major Histocompatibility Complex Loci

  • Yoko Satta
  • Naoyuki Takahata
  • Christian Schönbach
  • Jutta Gutknecht
  • Jan Klein
Part of the NATO ASI Series book series (volume 59)


Unlike alleles at many other loci, major histocompatibility complex (Mhc) locus alleles often differ by nucleotide substitutions at more than one site, often as many as 88 sites. The substitutions accumulate gradually during evolution by the same process that leads to the divergence of genes in two biological species. The difference between the inter- and intraspecific variation is that in the former, substitutions become fixed in the population (reach a frequency of 1.0), whereas in the latter, they reach polymorphic frequencies (≥ 0.01, < 1.0). Since accumulation of interspecific differences is believed by many geneticists to proceed with a clock-like regularity within certain taxonomic groups, there is no a priori reason why the same should not be true for the accumulation of polymorphic differences. Here we demonstrate the validity of this assumption by comparing alleles at the Mhc-DRB and Mhc-DQB loci of different primate species. We then estimate the evolutionary rates at the DRB and DQB loci; the overall rates of these loci are 0.97 ± 0.17 and 1.2 ± 0.39 (site/billion years), respectively. However, the rate of the sites (both synonymous and nonsynonymous) encoding the peptide (antigen)-binding region (PBR) is 4 to 7 times higher than in the rest of the gene. As previously suggested, the enhanced nonsynonymous rate at the PBR is most likely due to balancing selection, but the PBR as a whole may be a hot spot of nucleotide substitutions.


Major Histocompatibility Complex Substitution Rate Major Histocompatibility Complex Locus Relative Rate Test Synonymous Rate 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 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
  2. Britten, R. J.: Rates of DNA sequence evolution differ between taxonomic groups. Science 231:1393–1398, 1986PubMedCrossRefGoogle Scholar
  3. Cowen, R.: History of Life. Blackwell, Cambridge 1990Google Scholar
  4. Fan, W., Kasahara, M., Gutknecht, J., Klein, D., Mayer, W. E., Jonker, M., and Klein, J.: Shared class Ή polymorphisms between human and chimpanzees. Hum Immunol 26:107–121, 1989PubMedCrossRefGoogle Scholar
  5. Figueroa, F., Günther, E., and Klein, J.: MHC polymorphism predating speciation. Nature 335: 265–267, 1988PubMedCrossRefGoogle Scholar
  6. 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 cotton-top tamarin (Saguinus oedipus). Mol Biol Evol, in press 1991Google Scholar
  7. Groenen, M.A.M., van der Poel, J.J., Dijkhof, R.J.M., and Giphart, M.J.: The nucleotide sequence of bovine MHC class II DQB and DRB genes. Immunogenetics 31: 37–44, 1990PubMedCrossRefGoogle Scholar
  8. Gyllensten, U.B. and Erlich, H. A.: Ancient roots for polymorphism at the HLA-DQa locus in primates. Proc Natl Acad Sci USA 86: 9986–9990, 1989PubMedCrossRefGoogle Scholar
  9. 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, 1990CrossRefGoogle Scholar
  10. Hasegawa, M., Kishino, H., and Yano, T.: Estimation of branching dates among primates by molecular clocks of nuclear DNA which slowed down in Hominoidea. J Hum Evol 18: 461–476, 1989CrossRefGoogle Scholar
  11. Hasegawa, M. and Kishino, H.: DNA sequence analysis and evolution of Hominoidea. In M. Kimura and N. Takahata (eds.): New Aspects of the Genetics of Molecular Evolution, pp. 303–317, Springer Verlag, Tokyo/Berlin 1991Google Scholar
  12. Hayashida, H. and Miyata, T.: Unusual evolutionary conservation and frequent DNA segment exchange in class I genes of the major histocompatibility complex. Proc Natl Acad Sci USA 80: 2671–2675, 1983PubMedCrossRefGoogle Scholar
  13. Hudson, R. R.: Testing the constant-rate of neutral allele model with protein sequence data. Evolution 37: 203–217, 1983CrossRefGoogle Scholar
  14. Hughes, A.L. and Nei, M.: Pattern of nucleotide substitution at major histocompatibility complex class I loci reveals overdominant selection. Nature 335: 167–170, 1988PubMedCrossRefGoogle Scholar
  15. Hughes, A.L. and Nei, M.: Nucleotide substitution at major histocompatibility complex class Π loci: Evidence for overdominant selection. Proc Natl Acad Sci USA 86: 958– 962, 1989PubMedCrossRefGoogle Scholar
  16. Jukes, T.H. and Cantor, C.H.: Evolution of protein molecules. In H. N. Munro (ed): Mammalian Protein Metabolism, pp. 21–132, Academic Press, New York 1969Google Scholar
  17. Kimura, M.: Molecular evolutionary clock and the neutral theory. J Mol Evol 26: 24–33, 1987PubMedCrossRefGoogle Scholar
  18. Klein, J.: Generation of diversity at MHC loci: Implications for T cell receptor repertoires. In M. Fougereau and J. Dausset (eds.): Immunology 80: Progress in Immunology IV, pp. 239–253, Academic Press, New York 1980Google Scholar
  19. Klein, J.: Natural History of the Major Histocompatibility Complex, Wiley, New York 1986Google Scholar
  20. Klein, J. and Figueroa, F.: Evolution of the major histocompatibility complex. CRC Crit. Rev. Immunol. 6: 295–386, 1986Google Scholar
  21. Lawlor, D.A., Zenmour, J., Ennis, P.P., and Parham, P.: HLA-A and B polymorphisms predated the divergence of humans and chimpanzees. Nature 335: 268–271, 1988PubMedCrossRefGoogle Scholar
  22. Li, W-H., Luo, C.C., and Wu, C.I.: Evolution of DNA sequences. In R.J. MacIntyre (ed.): Molecular Evolutionary Genetics, pp. 1–94 Plenum, New York 1985Google Scholar
  23. Marsh, S.G.E. and Bodmer, J.G.: HLA-DRB nucleotide sequences. Immunogenetics 31: 141–144, 1990PubMedCrossRefGoogle Scholar
  24. Marsh, S.G.E. and Bodmer, J.G.: HLA class II nucleotide sequences. Immunogenetics 55:321–334, 1991CrossRefGoogle Scholar
  25. 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
  26. McConnell, T.J., Talbot, W.S., McIndoe, R.A., and Wakeland, E.K.: The origin of MHC class II gene polymorphism within the genus Mus. Nature 332: 651–654, 1988PubMedCrossRefGoogle Scholar
  27. Miyamoto, M.M., Koop, B.F., Slightom, J.L., Goodman, M., and Tennant, M.R.: Molecular systematics of higher primates: Genealogical relations and classification. Proc Natl Acad Sci USA 85: 7627–7631, 1988PubMedCrossRefGoogle Scholar
  28. Nei, M.: Molecular Evolutionary Genetics, Columbia University Press, New York 1987Google Scholar
  29. Nei, M. and Li, W.-H.: Mathematical model for studying genetic variation in terms of restriction endonucléases. Proc Natl Acad Sci USA 76: 5269–5273, 1979PubMedCrossRefGoogle Scholar
  30. Sarmiento, U.M., Sarmiento, J.I., and Storb, R.: Allelic variation in the DR subregion of the canine major histocompatibility complex. Immunogenetics 32: 13–19, 1990PubMedCrossRefGoogle Scholar
  31. Takahata, N.: A simple genealogical structure of strongly balanced allelic lines and transspecies evolution of polymorphism. Proc Natl Acad Sci USA 87: 2419–2423, 1990PubMedCrossRefGoogle Scholar
  32. Takahata, N. and Nei, M.: Gene genealogy and variance of interpopulational nucleotide differences. Genetics 110: 325–344, 1985PubMedGoogle Scholar
  33. Takahata, N. and Nei, M.: Allelic genealogy under overdominant and frequency-dependent selection and polymorphism of major histocompatibility complex loci. Genetics 124: 967–978, 1990PubMedGoogle Scholar
  34. Tavaré, S.: Lines of descent and genealogical processes, and their applications in population genetics models. Theor Popul Biol 26: 119–164, 1984PubMedCrossRefGoogle Scholar
  35. Wilson, A.C., Carlson, S.S., and White, T.J.: Biochemical evolution. Annu Rev Biochem 46: 573–639, 1977PubMedCrossRefGoogle Scholar
  36. Wu, C.-I. and Li, W.H.: Evidence for higher rates of nucleotide substitution in rodents than in man. Proc Natl Acad Sci USA 82: 1741–1745, 1985PubMedCrossRefGoogle Scholar
  37. 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

Copyright information

© Springer-Verlag Berlin Heidelberg 1991

Authors and Affiliations

  • Yoko Satta
    • 1
  • Naoyuki Takahata
    • 1
  • Christian Schönbach
    • 2
  • Jutta Gutknecht
    • 2
  • Jan Klein
    • 2
    • 3
  1. 1.Department of Population GeneticsNational Institute of GeneticsMishima 411Japan
  2. 2.Abteilung ImmungenetikMax-Planck-Institut für BiologieTübingenGermany
  3. 3.Department of Microbiology and ImmunologyUniversity of Miami School of MedicineMiamiUSA

Personalised recommendations