Skip to main content
PMC home page
Genetics logoLink to Genetics
. 1990 Apr;124(4):967–978. doi: 10.1093/genetics/124.4.967

Allelic Genealogy under Overdominant and Frequency-Dependent Selection and Polymorphism of Major Histocompatibility Complex Loci

N Takahata 1, M Nei 1
PMCID: PMC1203987  PMID: 2323559

Abstract

To explain the long-term persistence of polymorphic alleles (trans-specific polymorphism) at the major histocompatibility complex (MHC) loci in rodents and primates, a computer simulation study was conducted about the coalescence time of different alleles sampled under various forms of selection. At the same time, average heterozygosity, the number of alleles in a sample, and the rate of codon substitution were examined to explain the mechanism of maintenance of polymorphism at the MHC loci. The results obtained are as follows. (1) The coalescence time for neutral alleles is too short to explain the trans-specific polymorphism at the MHC loci. (2) Under overdominant selection, the coalescence time can be tens of millions of years, depending on the parameter values used. The average heterozygosity and the number of alleles observed are also high enough to explain MHC polymorphism. (3) The pathogen adaptation model proposed by Snell is incapable of explaining MHC polymorphism, since the coalescence time for this model is too short and the expected heterozygosity and the expected number of alleles are too small. (4) From the mathematical point of view, the minority advantage model of frequency-dependent selection is capable of explaining a high degree of polymorphism and trans-specific polymorphism. (5) The molecular mimicry hypothesis also gives a sufficiently long coalescence time when the mutation rate is low in the host but very high in the parasite. However, the expected heterozygosity and the expected number of alleles tend to be too small. (6) Consideration of the molecular mechanism of the function of MHC molecules and other biological observations suggest that the most important factor for the maintenance of MHC polymorphism is overdominant selection. However, some experiments are necessary to distinguish between the overdominance and frequency-dependent selection hypotheses.

Full Text

The Full Text of this article is available as a PDF (1.2 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bjorkman P. J., Saper M. A., Samraoui B., Bennett W. S., Strominger J. L., Wiley D. C. The foreign antigen binding site and T cell recognition regions of class I histocompatibility antigens. Nature. 1987 Oct 8;329(6139):512–518. doi: 10.1038/329512a0. [DOI] [PubMed] [Google Scholar]
  2. Bodmer W. F. Evolutionary significance of the HL-A system. Nature. 1972 May 19;237(5351):139–passim. doi: 10.1038/237139a0. [DOI] [PubMed] [Google Scholar]
  3. Braciale T. J., Sweetser M. T., Morrison L. A., Kittlesen D. J., Braciale V. L. Class I major histocompatibility complex-restricted cytolytic T lymphocytes recognize a limited number of sites on the influenza hemagglutinin. Proc Natl Acad Sci U S A. 1989 Jan;86(1):277–281. doi: 10.1073/pnas.86.1.277. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Doherty P. C., Zinkernagel R. M. Enhanced immunological surveillance in mice heterozygous at the H-2 gene complex. Nature. 1975 Jul 3;256(5512):50–52. doi: 10.1038/256050a0. [DOI] [PubMed] [Google Scholar]
  5. EWENS W. J. THE MAINTENANCE OF ALLELES BY MUTATION. Genetics. 1964 Nov;50:891–898. doi: 10.1093/genetics/50.5.891. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Hughes A. L., 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. doi: 10.1073/pnas.86.3.958. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Hughes A. L., Nei M. Pattern of nucleotide substitution at major histocompatibility complex class I loci reveals overdominant selection. Nature. 1988 Sep 8;335(6186):167–170. doi: 10.1038/335167a0. [DOI] [PubMed] [Google Scholar]
  8. KIMURA M., CROW J. F. THE NUMBER OF ALLELES THAT CAN BE MAINTAINED IN A FINITE POPULATION. Genetics. 1964 Apr;49:725–738. doi: 10.1093/genetics/49.4.725. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Kimura M. Evolutionary rate at the molecular level. Nature. 1968 Feb 17;217(5129):624–626. doi: 10.1038/217624a0. [DOI] [PubMed] [Google Scholar]
  10. Kimura M. Theoretical foundation of population genetics at the molecular level. Theor Popul Biol. 1971 Jun;2(2):174–208. doi: 10.1016/0040-5809(71)90014-1. [DOI] [PubMed] [Google Scholar]
  11. Klein J., Figueroa F. Evolution of the major histocompatibility complex. Crit Rev Immunol. 1986;6(4):295–386. [PubMed] [Google Scholar]
  12. Klein J. Origin of major histocompatibility complex polymorphism: the trans-species hypothesis. Hum Immunol. 1987 Jul;19(3):155–162. doi: 10.1016/0198-8859(87)90066-8. [DOI] [PubMed] [Google Scholar]
  13. Lawlor D. A., Ward F. E., Ennis P. D., Jackson A. P., Parham P. HLA-A and B polymorphisms predate the divergence of humans and chimpanzees. Nature. 1988 Sep 15;335(6187):268–271. doi: 10.1038/335268a0. [DOI] [PubMed] [Google Scholar]
  14. Maruyama T., Nei M. Genetic variability maintained by mutation and overdominant selection in finite populations. Genetics. 1981 Jun;98(2):441–459. doi: 10.1093/genetics/98.2.441. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Mayer W. E., 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. doi: 10.1002/j.1460-2075.1988.tb03131.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. McConnell T. J., Talbot W. S., McIndoe R. A., Wakeland E. K. The origin of MHC class II gene polymorphism within the genus Mus. Nature. 1988 Apr 14;332(6165):651–654. doi: 10.1038/332651a0. [DOI] [PubMed] [Google Scholar]
  17. Nei M., Roychoudhury A. K. Probability of fixation and mean fixation time of an overdominant mutation. Genetics. 1973 Jun;74(2):371–380. doi: 10.1093/genetics/74.2.371. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Ohta T., Kimura M. A model of mutation appropriate to estimate the number of electrophoretically detectable alleles in a finite population. Genet Res. 1973 Oct;22(2):201–204. doi: 10.1017/s0016672300012994. [DOI] [PubMed] [Google Scholar]
  19. Sette A., Buus S., Colon S., Miles C., Grey H. M. I-Ad-binding peptides derived from unrelated protein antigens share a common structural motif. J Immunol. 1988 Jul 1;141(1):45–48. [PubMed] [Google Scholar]
  20. Sher A., Hall B. F., Vadas M. A. Acquisition of murine major histocompatibility complex gene products by schistosomula of Schistosoma mansoni. J Exp Med. 1978 Jul 1;148(1):46–57. doi: 10.1084/jem.148.1.46. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Sibley C. G., Ahlquist J. E. The phylogeny of the hominoid primates, as indicated by DNA-DNA hybridization. J Mol Evol. 1984;20(1):2–15. doi: 10.1007/BF02101980. [DOI] [PubMed] [Google Scholar]
  22. Simpson A. J., Singer D., McCutchan T. F., Sacks D. L., Sher A. Evidence that schistosome MHC antigens are not synthesized by the parasite but are acquired from the host as intact glycoproteins. J Immunol. 1983 Aug;131(2):962–965. [PubMed] [Google Scholar]
  23. Tajima F. Evolutionary relationship of DNA sequences in finite populations. Genetics. 1983 Oct;105(2):437–460. doi: 10.1093/genetics/105.2.437. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Takahata N., Nei M. Gene genealogy and variance of interpopulational nucleotide differences. Genetics. 1985 Jun;110(2):325–344. doi: 10.1093/genetics/110.2.325. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Watterson G. A. Heterosis or neutrality? Genetics. 1977 Apr;85(4):789–814. doi: 10.1093/genetics/85.4.789. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Wright S. Polyallelic random drift in relation to evolution. Proc Natl Acad Sci U S A. 1966 May;55(5):1074–1081. doi: 10.1073/pnas.55.5.1074. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Wright S. The Distribution of Self-Sterility Alleles in Populations. Genetics. 1939 Jun;24(4):538–552. doi: 10.1093/genetics/24.4.538. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. 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. doi: 10.1093/genetics/91.3.609. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Genetics are provided here courtesy of Oxford University Press

RESOURCES