How selection shapes variation of the human major histocompatibility complex: a review

Abstract

summaryThe nature of polymorphism and molecular sequence variation in the genes of the human major histocompatibility complex (MHC) provides strong support for the idea that these genes are under selection. With the understanding that selection shapes MHC variation new questions have become the focus of study. What is the mode of selection that accounts for MHC polymorphism? Is variation maintained by pathogen pressure or by reproductive mechanisms? Discerning between these requires drawing on information from studies on association between HLA genes and infectious diseases, reproductive success and mating preferences relative to HLA genotypes, and theoretical studies that compare the outcomes of different selection regimes. The pattern that has emerged suggests that several types of selection are plausible for the maintenance of HLA polymorphism.

A long-term genetic survey of an ungulate population reveals balancing selection acting on MHC through spatial and temporal fluctuations in selection

“…Three nonexclusive mechanisms have been proposed: (i) Negative frequency-dependent selection: MHC genotypes with a rare allele are supposed to have a strong selective advantage as few pathogens have been exposed and adapted to it. Conversely, once alleles become frequent, pathogens adapt to them and are selected for, which decreases the fitness of MHC genotypes bearing these alleles (Meyer and Thomson, 2001). In support of this model, many associations between MHC alleles and resistance to parasitism have been found in natural populations (Hill et al, 1991;Paterson et al, 1998).…”

“…This pattern could be explained by some form of balancing selection (Hedrick and Thompson, 1983). Pathogens and parasites have been viewed as the main obvious agents driving this balancing selection (see for reviews Hughes and Yeager, 1998;Meyer and Thomson, 2001;Bernatchez and Landry, 2003). Three nonexclusive mechanisms have been proposed: (i) Negative frequency-dependent selection: MHC genotypes with a rare allele are supposed to have a strong selective advantage as few pathogens have been exposed and adapted to it.…”

Balancing selection and heterogeneity across the classical human leukocyte antigen loci: A meta-analytic review of 497 population studies

“…Population-level studies of HLA allelic diversity have provided insight into the selective forces that have acted to generate and maintain polymorphism in the human species [2,3]. Historical and evolutionary relationships among modern human populations have been inferred from comparisons of HLA allele and haplotype frequency distributions [4][5][6][7].…”

Human population structure and the adaptive response to pathogen-induced selection pressures

“…This is particularly relevant for variants that exist in the HLA region, where there are high levels of genetic diversity and evidence for balancing selection. For a relevant review, see [75]. We have instead focused on the impact of directional selection for pathogen resistance.…”