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Genetics. Apr 1992; 130(4): 925–938.
PMCID: PMC1204941

Polymorphism and Balancing Selection at Major Histocompatibility Complex Loci


Amino acid replacements in the peptide-binding region (PBR) of the functional major histocompatibility complex (Mhc) genes appear to be driven by balancing selection. Of the various types of balancing selection, we have examined a model equivalent to overdominance that confers heterozygote advantage. As discussed by A. Robertson, overdominance selection tends to maintain alleles that have more or less the same degree of heterozygote advantage. Because of this symmetry, the model makes various testable predictions about the genealogical relationships among different alleles and provides ways of analyzing DNA sequences of Mhc alleles. In this paper, we analyze DNA sequences of 85 alleles at the HLA-A, -B, -C, -DRB1 and -DQB1 loci with respect to the number of alleles and extent of nucleotide differences at the PBR, as well as at the synonymous (presumably neutral) sites. Theory suggests that the number of alleles that differ at the sites targeted by selection (presumably the nonsynonymous sites in the PBR) should be equal to the mean number of nucleotide substitutions among pairs of alleles. We also demonstrate that the nucleotide substitution rate at the targeted sites relative to that of neutral sites may be much larger than 1. The predictions of the presented model are in surprisingly good agreement with the actual data and thus provide means for inferring certain population parameters. For overdominance selection in a finite population at equilibrium, the product of selection intensity (s) against homozygotes and the effective population size (N) is estimated to be 350-3000, being largest at the B locus and smallest at the C locus. We argue that N is of the order of 10(5) and s is several percent at most, if the mutation rate per site per generation is 10(-8).

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Selected References

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  • Black FL, Salzano FM. Evidence for heterosis in the HLA system. Am J Hum Genet. 1981 Nov;33(6):894–899. [PMC free article] [PubMed]
  • Bjorkman PJ, Saper MA, Samraoui B, Bennett WS, Strominger JL, Wiley DC. Structure of the human class I histocompatibility antigen, HLA-A2. Nature. 1987 Oct 8;329(6139):506–512. [PubMed]
  • Bjorkman PJ, Saper MA, Samraoui B, Bennett WS, Strominger JL, Wiley DC. The foreign antigen binding site and T cell recognition regions of class I histocompatibility antigens. Nature. 1987 Oct 8;329(6139):512–518. [PubMed]
  • Clark AG, Kao TH. Excess nonsynonymous substitution of shared polymorphic sites among self-incompatibility alleles of Solanaceae. Proc Natl Acad Sci U S A. 1991 Nov 1;88(21):9823–9827. [PMC free article] [PubMed]
  • Degos L, Colombani J, Chaventre A, Bengtson B, Jacquard A. Selective pressure on HL-A polymorphism. Nature. 1974 May 3;249(452):62–63. [PubMed]
  • Denniston C, Crow JF. Alternative fitness models with the same allele frequency dynamics. Genetics. 1990 May;125(1):201–205. [PMC free article] [PubMed]
  • Doherty PC, Zinkernagel RM. Enhanced immunological surveillance in mice heterozygous at the H-2 gene complex. Nature. 1975 Jul 3;256(5512):50–52. [PubMed]
  • Figueroa F, Günther E, Klein J. MHC polymorphism pre-dating speciation. Nature. 1988 Sep 15;335(6187):265–267. [PubMed]
  • Hedrick PW, Thomson G. Evidence for balancing selection at HLA. Genetics. 1983 Jul;104(3):449–456. [PMC free article] [PubMed]
  • Hill AV, Allsopp CE, Kwiatkowski D, Anstey NM, Twumasi P, Rowe PA, Bennett S, Brewster D, McMichael AJ, Greenwood BM. Common west African HLA antigens are associated with protection from severe malaria. Nature. 1991 Aug 15;352(6336):595–600. [PubMed]
  • Howard JC. Immunology. Disease and evolution. Nature. 1991 Aug 15;352(6336):565–567. [PubMed]
  • Hughes AL, Nei M. Pattern of nucleotide substitution at major histocompatibility complex class I loci reveals overdominant selection. Nature. 1988 Sep 8;335(6186):167–170. [PubMed]
  • Hughes AL, Nei M. Nucleotide substitution at major histocompatibility complex class II loci: evidence for overdominant selection. Proc Natl Acad Sci U S A. 1989 Feb;86(3):958–962. [PMC free article] [PubMed]
  • Jin L, Nei M. Limitations of the evolutionary parsimony method of phylogenetic analysis. Mol Biol Evol. 1990 Jan;7(1):82–102. [PubMed]
  • Kimura M. Evolutionary rate at the molecular level. Nature. 1968 Feb 17;217(5129):624–626. [PubMed]
  • Klein J. Of HLA, tryps, and selection: an essay on coevolution of MHC and parasites. Hum Immunol. 1991 Apr;30(4):247–258. [PubMed]
  • Klein J, Gutknecht J, Fischer N. The major histocompatibility complex and human evolution. Trends Genet. 1990 Jan;6(1):7–11. [PubMed]
  • Lawlor DA, Ward FE, Ennis PD, Jackson AP, Parham P. HLA-A and B polymorphisms predate the divergence of humans and chimpanzees. Nature. 1988 Sep 15;335(6187):268–271. [PubMed]
  • Lewontin RC, Ginzburg LR, Tuljapurkar SD. Heterosis as an explanation for large amounts of genic polymorphism. Genetics. 1978 Jan;88(1):149–169. [PMC free article] [PubMed]
  • Marsh SG, Bodmer JG. HLA class II nucleotide sequences, 1991. Immunogenetics. 1991;33(5-6):321–334. [PubMed]
  • Maruyama T, Nei M. Genetic variability maintained by mutation and overdominant selection in finite populations. Genetics. 1981 Jun;98(2):441–459. [PMC free article] [PubMed]
  • Mayer WE, Jonker M, Klein D, Ivanyi P, van Seventer G, Klein J. Nucleotide sequences of chimpanzee MHC class I alleles: evidence for trans-species mode of evolution. EMBO J. 1988 Sep;7(9):2765–2774. [PMC free article] [PubMed]
  • McConnell TJ, Talbot WS, McIndoe RA, Wakeland EK. The origin of MHC class II gene polymorphism within the genus Mus. Nature. 1988 Apr 14;332(6165):651–654. [PubMed]
  • Potts WK, Manning CJ, Wakeland EK. Mating patterns in seminatural populations of mice influenced by MHC genotype. Nature. 1991 Aug 15;352(6336):619–621. [PubMed]
  • ROBERTSON A. Selection for heterozygotes in small populations. Genetics. 1962 Sep;47:1291–1300. [PMC free article] [PubMed]
  • Savatier P, Trabuchet G, Chebloune Y, Faure C, Verdier G, Nigon VM. Nucleotide sequence of the beta-globin genes in gorilla and macaque: the origin of nucleotide polymorphisms in human. J Mol Evol. 1987;24(4):309–318. [PubMed]
  • Serjeantson SW. The reasons for MHC polymorphism in man. Transplant Proc. 1989 Feb;21(1 Pt 1):598–601. [PubMed]
  • Spencer HG, Marks RW. The maintenance of single-locus polymorphism. I. Numerical studies of a viability selection model. Genetics. 1988 Oct;120(2):605–613. [PMC free article] [PubMed]
  • Tajima F. Evolutionary relationship of DNA sequences in finite populations. Genetics. 1983 Oct;105(2):437–460. [PMC free article] [PubMed]
  • Takahata N. A simple genealogical structure of strongly balanced allelic lines and trans-species evolution of polymorphism. Proc Natl Acad Sci U S A. 1990 Apr;87(7):2419–2423. [PMC free article] [PubMed]
  • Takahata N, Nei M. Gene genealogy and variance of interpopulational nucleotide differences. Genetics. 1985 Jun;110(2):325–344. [PMC free article] [PubMed]
  • Thomson G. HLA disease associations: models for insulin dependent diabetes mellitus and the study of complex human genetic disorders. Annu Rev Genet. 1988;22:31–50. [PubMed]
  • Uzzell T, Corbin KW. Fitting discrete probability distributions to evolutionary events. Science. 1971 Jun 11;172(3988):1089–1096. [PubMed]
  • Wright S. Evolution in Mendelian Populations. Genetics. 1931 Mar;16(2):97–159. [PMC free article] [PubMed]
  • Wright S. The Distribution of Self-Sterility Alleles in Populations. Genetics. 1939 Jun;24(4):538–552. [PMC free article] [PubMed]
  • Yokoyama S, Nei M. Population dynamics of sex-determining alleles in honey bees and self-incompatibility alleles in plants. Genetics. 1979 Mar;91(3):609–626. [PMC free article] [PubMed]
  • Zemmour J, Parham P. HLA class I nucleotide sequences, 1991. Immunogenetics. 1991;33(5-6):310–320. [PubMed]

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