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MHC polymorphism under host-pathogen coevolution

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Abstract

The genes encoding major histocompatibility (MHC) molecules are among the most polymorphic genes known for vertebrates. Since MHC molecules play an important role in the induction of immune responses, the evolution of MHC polymorphism is often explained in terms of increased protection of hosts against pathogens. Two selective pressures that are thought to be involved are (1) selection favoring MHC heterozygous hosts, and (2) selection for rare MHC alleles by host-pathogen coevolution. We have developed a computer simulation of coevolving hosts and pathogens to study the relative impact of these two mechanisms on the evolution of MHC polymorphism. We found that heterozygote advantage per se is insufficient to explain the high degree of polymorphism at the MHC, even in very large host populations. Host-pathogen coevolution, on the other hand, can easily account for realistic polymorphisms of more than 50 alleles per MHC locus. Since evolving pathogens mainly evade presentation by the most common MHC alleles in the host population, they provide a selective pressure for a large variety of rare MHC alleles. Provided that the host population is sufficiently large, a large set of MHC alleles can persist over many host generations under host-pathogen coevolution, despite the fact that allele frequencies continuously change.

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References

  • Aoki K (1980) A criterion for the establishment of a stable polymorphism of higher order with an application to the evolution of polymorphism. J Math Biol 9:133–146

    CAS  PubMed  Google Scholar 

  • Apanius V, Penn D, Slev PR, Ruff LR, Potts WK (1997) The nature of selection on the major histocompatibility complex. Crit Rev Immunol 17:179–224

    CAS  PubMed  Google Scholar 

  • Barouch D, Friede T, Stevanovic S, Tussey L, Smith K, Rowland-Jones S, Braud V, McMichael A, Rammensee HG (1995) HLA-A2 subtypes are functionally distinct in peptide binding and presentation. J Exp Med 182:1847–1856

    CAS  PubMed  Google Scholar 

  • Beck K (1984) Coevolution: mathematical analysis of host-parasite interactions. J Math Biol 19:63–77

    CAS  PubMed  Google Scholar 

  • Beltman JB, Borghans JAM, De Boer RJ (2002) Major histocompatibility complex: polymorphism from coevolution. In: Dieckmann U, Metz JAJ, Sabelis MW, Sigmund K (eds) Adaptive dynamics of infectious diseases. In pursuit of virulence management. Cambridge University Press, Cambridge, pp 210–221

  • Black FL (1992) Why did they die? Science 258:1739–1740

    CAS  PubMed  Google Scholar 

  • Bodmer WF (1972) Evolutionary significance of the HL-A system. Nature 237:139–145

    CAS  PubMed  Google Scholar 

  • Borghans JAM, De Boer RJ (2001) Diversity in the immune system. In: Segel LA, Cohen IR (eds) Design principles for the immune system and other distributed autonomous systems. Oxford University Press, Oxford, pp 161–183

  • Carrington M, Nelson GW, Martin MP, Kissner T, Vlahov D, Goedert JJ, Kaslow R, Buchbinder S, Hoots K, O’Brien SJ (1999) HLA and HIV-1: Heterozygote advantage and B*35-Cw*04 disadvantage. Science 283:1748–1752

    Article  CAS  PubMed  Google Scholar 

  • De Boer RJ, Borghans JAM, Van Boven M, Keşmir C, Weissing FJ (2004) Heterozygote advantage fails to explain the high degree of polymorphism of the MHC. Immunogenetics. DOI 10.1007/s00251-003-0629-y

  • Doherty PC, Zinkernagel RM (1975) Enhanced immunological surveillance in mice heterozygous at the H-2 gene complex. Nature 256:50–52

    CAS  PubMed  Google Scholar 

  • Dybdahl MF, Lively CM (1998) Host-parasite coevolution: evidence for rare advantage and time-lagged selection in a natural population. Evolution 52:1057–1066

    Google Scholar 

  • Hamilton WD, Axelrod R, Tanese R (1990) Sexual reproduction as an adaptation to resist parasites (a review). Proc Natl Acad Sci USA 87:3566–3573

    CAS  PubMed  Google Scholar 

  • Hedrick PW (2002) Pathogen resistance and genetic variation at MHC loci. Evolution 56:1902–1908

    PubMed  Google Scholar 

  • Hill AV, Allsopp CE, Kwiatkowski D, Anstey NM, Twumasi P, Rowe PA, Bennett S, Brewster D, McMichael AJ, Greenwood BM (1991) Common west African HLA antigens are associated with protection from severe malaria. Nature 352:595–600

    CAS  PubMed  Google Scholar 

  • Holland JH (1975) Adaptation in natural and artificial systems. University of Michigan Press, Ann Arbor

  • Hughes AL, Nei M (1988) Pattern of nucleotide substitution at major histocompatibility complex class I loci reveals overdominant selection. Nature 335:167–170

    PubMed  Google Scholar 

  • Hughes AL, Nei M (1989) Nucleotide substitution at major histocompatibility complex class II loci: evidence for overdominant selection. Proc Natl Acad Sci USA 86:958–962

    PubMed  Google Scholar 

  • Hughes AL, Nei M (1992) Models of host-parasite interaction and MHC polymorphism. Genetics 132:863–864

    CAS  PubMed  Google Scholar 

  • Jeffery KJ, Siddiqui AA, Bunce M, Lloyd AL, Vine AM, Witkover AD, Izumo S, Usuku K, Welsh KI, Osame M, Bangham CR (2000) The influence of HLA class I alleles and heterozygosity on the outcome of human T cell lymphotropic virus type I infection. J Immunol 165:7278–7284

    CAS  PubMed  Google Scholar 

  • Kast WM, Brandt RM, Sidney J, Drijfhout JW, Kubo RT, Grey HM, Melief CJ, Sette A (1994) Role of HLA-A motifs in identification of potential CTL epitopes in human papillomavirus type 16 E6 and E7 proteins. J Immunol 152:3904–3912

    CAS  PubMed  Google Scholar 

  • Klein J (1980) Generation of diversity to MHC loci: implications for T cell receptor repertoires. In: Fougereau M, Dausset J (eds) Immunology 80. Academic Press, London

  • Klein J, Klein D (1991) Molecular evolution of the MHC complex. Springer, Berlin Heidelberg New York

  • Korber B, Gaschen B, Yusim K, Thakallapally R, Keşmir C, Detours V (2001) Evolutionary and immunological implications of contemporary HIV-1 variation. Br Med Bull 58:19–42

    Article  CAS  PubMed  Google Scholar 

  • Lawlor DA, Ward FE, Ennis PD, Jackson AP, Parham P (1988) HLA-A and B polymorphisms predate the divergence of humans and chimpanzees. Nature 335:268–271

    CAS  PubMed  Google Scholar 

  • Lawlor DA, Zemmour J, Ennis PD, Parham P (1990) Evolution of class-I MHC genes and proteins: From natural selection to thymic selection. Annu Rev Immunol 8:23–63

    Article  CAS  PubMed  Google Scholar 

  • Lewontin RC, Ginzburg LR, Tuljapurkar SD (1978) Heterosis as an explanation for large amounts of genic polymorphism. Genetics 88:149–170

    Google Scholar 

  • Lively CM, Dybdahl MF (2000) Parasite adaptation to locally common host genotypes. Nature 405:679–681

    Article  CAS  PubMed  Google Scholar 

  • Mayer WE, Jonker M, Klein D, Ivanyi P, Van Seventer G, Klein J (1988) Nucleotide sequences of chimpanzee MHC class I alleles: evidence for trans-species mode of evolution. EMBO J 7:2765–2774

    CAS  PubMed  Google Scholar 

  • Moore CB, John M, James IR, Christiansen FT, Witt CS, Mallal SA (2002) Evidence of HIV-1 adaptation to HLA-restricted immune responses at a population level. Science 296:1439–1443

    Article  Google Scholar 

  • Nagylaki T (1992) Introduction to Theoretical Population Genetics. Springer, Berlin Heidelberg New York

  • Parham P, Ohta T (1996) Population biology of antigen presentation by MHC class I molecules. Science 272:67–74

    PubMed  Google Scholar 

  • Parham P, Benjamin RJ, Chen BP, Clayberger C, Ennis PD, Krensky AM, Lawlor DA, Littman DR, Norment AM, Orr HT, Salter RD, Zemmour J (1989a) Diversity of class I HLA molecules: functional and evolutionary interactions with T cells. Cold Spring Harbor Symp Quant Biol 54:529–543

    CAS  PubMed  Google Scholar 

  • Parham P, Lawlor DA, Lomen CE, Ennis PD (1989b) Diversity and diversification of HLA-A, B, C alleles. J Immunol 142:3937–3950

    PubMed  Google Scholar 

  • Penn DJ, Damjanovich K, Potts WK (2002) MHC heterozygosity confers a selective advantage against multiple-strain infections. Proc Natl Acad Sci USA 99:11260–11264

    Article  CAS  PubMed  Google Scholar 

  • Penn DJ, Potts WK (1999) The evolution of mating preferences and major histocompatibility complex genes. Am Nat 153:145–164

    Article  Google Scholar 

  • Slade RW, McCallum HI (1992) Overdominant versus frequency-dependent selection at MHC loci. Genetics 132:861–864

    PubMed  Google Scholar 

  • Snell GD (1968) The H-2 locus of the mouse: observations and speculations concerning its comparative genetics and its polymorphism. Folia Biol Praha 14:335–358

    CAS  PubMed  Google Scholar 

  • Takahata N, Nei M (1990) Allelic genealogy under overdominant and frequency-dependent selection and polymorphism of major histocompatibility complex loci. Genetics 124:967–978

    Google Scholar 

  • Trachtenberg E, Korber B, Sollars C, Kepler TB, Hraber PT, Hayes E, Funkhouser R, Fugate M, Theiler J, Hsu YS, Kunstman K, Wu S, Phair J, Erlich H, Wolinsky S (2003) Advantage of rare HLA supertype in HIV disease progression. Nat Med 9:928–935

    Article  CAS  PubMed  Google Scholar 

  • Vogel TU, Evans DT, Urvater JA, O’Connor DH, Hughes AL, Watkins DI (1999) Major histocompatibility complex class I genes in primates: Coevolution with pathogens. Immunol Rev 167:327–337

    CAS  PubMed  Google Scholar 

  • Weidt G, Deppert W, Buchhop S, Dralle H, Lehmann-Grube F (1995) Antiviral protective immunity induced by major histocompatibility complex class I molecule-restricted viral T-lymphocyte epitopes inserted in various positions in immunologically self and nonself proteins. J Virol 69:2654–2658

    CAS  PubMed  Google Scholar 

  • Wills C (1991) Maintenance of multiallelic polymorphism at the MHC region. Immunol Rev 124:165–220

    CAS  PubMed  Google Scholar 

  • Yusim K, Keşmir C, Gaschen B, Addo MM, Altfeld M, Brunak S, Chigaev A, Detours V, Korber BT (2002) Clustering patterns of cytotoxic T-lymphocyte epitopes in human immunodeficiency virus type 1 (HIV-1) proteins reveal imprints of immune evasion on HIV-1 global variation. J Virol 76:8757–8768

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Wayne Potts, Dustin Penn, Can Keşmir, Paulien Hogeweg, and Ludo Pagie for useful discussions and comments on earlier versions of this manuscript. J.A.M.B. acknowledges financial support by the EC (Marie Curie Fellowship, Quality of Life, contract 1999-01548).

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Correspondence to José A. M. Borghans.

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Borghans, J.A.M., Beltman, J.B. & De Boer, R.J. MHC polymorphism under host-pathogen coevolution. Immunogenetics 55, 732–739 (2004). https://doi.org/10.1007/s00251-003-0630-5

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  • DOI: https://doi.org/10.1007/s00251-003-0630-5

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