Calibrating Evolutionary Rates at Major Histocompatibility Complex Loci
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.
KeywordsMajor Histocompatibility Complex Substitution Rate Major Histocompatibility Complex Locus Relative Rate Test Synonymous Rate
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- Cowen, R.: History of Life. Blackwell, Cambridge 1990Google Scholar
- 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
- 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
- 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
- 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
- Klein, J.: Natural History of the Major Histocompatibility Complex, Wiley, New York 1986Google Scholar
- Klein, J. and Figueroa, F.: Evolution of the major histocompatibility complex. CRC Crit. Rev. Immunol. 6: 295–386, 1986Google Scholar
- 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
- Nei, M.: Molecular Evolutionary Genetics, Columbia University Press, New York 1987Google Scholar
- 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