The evolution of MHC diversity in house mice

Abstract

The genes of the major histocompatibility complex (MHC) appear to be the most polymorphic loci in vertebrates, and explaining how natural selection maintains such genetic diversity (‘population allelic richness’) is a major unsolved problem in evolutionary biology. There is accumulating evidence that MHC polymorphisms are maintained by balancing selection (Apanius et al., 1997; Spurgin and Richardson, 2010); however, the nature of this selection is still unclear. MHC genes encode cell-surface glycoproteins (class I and II molecules) that present peptide antigens to T cells, and thereby play an important role in the development of the T cell receptor (TCR) repertoire, immunological self/non-self recognition, and resistance to pathogens and parasites. Many MHC alleles increase susceptibility to infectious and autoimmune diseases, which makes MHC polymorphisms especially puzzling, as these harmful alleles should be eliminated by natural selection. The evolutionary origin of MHC diversity is generated by mutation, recombination, and gene conversion (Martinsohn et al., 1999); however, these mechanisms do not explain how selection maintains polymorphisms. In this chapter, we review theoretical and empirical studies on the evolution of MHC diversity, with a particular focus on house mice (Mus musculus). There are two general hypotheses proposed to explain how selection maintains MHC polymorphisms. One hypothesis suggests that MHC polymorphisms are maintained by selection from pathogens and parasites (pathogen-mediated selection (PMS)) (Apanius et al., 1997; Spurgin and Richardson, 2010). This idea is the most likely explanation, given the role MHC molecules play in immune recognition of pathogens. The most viable models for PMS include negative frequency-dependent