MHC polymorphism under host-pathogen coevolution

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 hostpathogen coevolution, despite the fact that allele frequencies continuously change.

MHC influences infection with parasites and winter survival in the root vole Microtus oeconomus

“…According to the heterozygote advantage hypothesis, heterozygotes can be expected to have higher fitness than homozygotes, as they express more MHC alleles and thus can recognise a wider array of pathogen-derived antigens (Doherty and Zinkernagel 1975;Hughes and Nei 1988). The second mechanism, rare-allele advantage, assumes that parasites are most likely to adapt to the most frequent host genotypes, and thus rare alleles are more often associated with parasite resistance (Bodmer 1972;Potts and Wakeland 1990;Borghans et al 2004). If the selective pressure from a parasite changes temporally (Hill et al 1991) or spatially (Kloch et al 2010;Loiseau et al 2011), this change may drive the third mechanism, fluctuating selection (Hedrick 2002).…”

Sexual selection and the evolutionary dynamics of the major histocompatibility complex

“…Pathogen populations were derived under three mutation rates: 5 Â 10 23 , 2 Â 10 23 or 10 23 per antigen, per pathogen generation. Previous analyses have demonstrated that model results are robust to alternative forms of host and pathogen mutation, including point mutation, recombination and/or randomly constituted alleles [30]. Pathogen mutation rates directly influence the potential for host-pathogen coevolution: at low mutation rates, pathogens may not evolve quickly enough to rspb.royalsocietypublishing.org Proc.…”

“…Mutations in host MHC molecules were simulated by micro-recombination (10 25 mutations per allele, per host generation), the dominant mode of MHC mutation [36]. The parameter settings of our model are based on extensive sensitivity analyses of earlier simulation models [30,33,34], and are designed to explore the full range of host-pathogen dynamics predicted under such conditions. Our model explicitly incorporates the two major explanations for the high genetic diversity observed at MHC loci: pathogen-mediated natural selection and disassortative mating during reproduction.…”

“…Our model is based on the theoretical framework of Borghans et al [30] and adapted from Ejsmond et al [33,34], considering a population of sexually reproducing hosts (N e ¼ 50-10 000), with non-overlapping generations and a 1 : 1 sex ratio. Each host carried two MHC alleles represented as 16-bit binary strings, with bits corresponding to the amino acids involved in antigen binding and T cell presentation (approx.…”

“…Previous efforts to model the effects of selection on patterns of MHC variation have investigated the effects of natural and sexual selection in isolation, and have been unable to address the key question of how these two forms of selection are likely to interact in natural systems [30][31][32][33]. Such interactions may not only determine levels of MHC polymorphism maintained in populations, but also may impact the resistance of host populations to prevalent pathogen genotypes, for example when alleles conferring resistance to infection are disfavoured during mate choice.…”