Pathogen-Driven Selection and Worldwide HLA Class I Diversity

Abstract

The human leukocyte antigen (HLA; known as MHC in other vertebrates) plays a central role in the recognition and presentation of antigens to the immune system and represents the most polymorphic gene cluster in the human genome [1]. Pathogen-driven balancing selection (PDBS) has been previously hypothesized to explain the remarkable polymorphism in the HLA complex, but there is, as yet, no direct support for this hypothesis [2 and 3]. A straightforward prediction coming out of the PDBS hypothesis is that populations from areas with high pathogen diversity should have increased HLA diversity in relation to their average genomic diversity. We tested this prediction by using HLA class I genetic diversity from 61 human populations. Our results show that human colonization history explains a substantial proportion of HLA genetic diversity worldwide. However, between-population variation at the HLA class I genes is also positively correlated with local pathogen richness (notably for the HLA B gene), thus providing support for the PDBS hypothesis. The proportion of variations explained by pathogen richness is higher for the HLA B gene than for the HLA A and HLA C genes. This is in good agreement with both previous immunological and genetic data suggesting that HLA B could be under a higher selective pressure from pathogens.

A population genetics study of the Familial Mediterranean Fever gene: evidence of balancing selection under an overdominance regime

“…For example, these include cytokine genes or their receptors, as exemplified by CCR5, IL1F10, IL1F7, IL18RAP, IL7R and IL4R; [47][48][49] similarly, b-defensisns 50,51 and genes encoding bloodgroup antigens 23 have been shown to be frequently subjected to balancing selection. In all these cases, the underlying selective pressure has not been ascribed to one specific infective agent; rather, in analogy to MHC genes, 52 it has been hypothesized 23,48 that pathogen diversity in terms of different species or genera might underly the maintenance of balanced polymorphisms at some blood group antigen and interleukin genes. These observations are consistent with the fact that one possible reason for the establishment of balancing selection is represented by variable environmental conditions (for example different pathogens being active in different times and places) and therefore that different alleles might afford protection from different pathogens.…”

Gene dynamics of toll-like receptor 4 through a population bottleneck in an insular population of water voles (Arvicola amphibius)

“…If the starting allele frequencies were more skewed then our simulation studies highlighted a greater propensity for extinction. For example, if we change our simulation parameters from the observed starting allele frequencies to a scenario where one is 0.9 and the other is 0.1 then ex- It has been demonstrated in loci such as the MHC that balancing selection can be mediated through host-parasite interaction, with differences between genotypes and parasite load (Altizer et al 2003;Prugnolle et al 2005;Zueva et al 2014). Indeed, within this population of water voles, MHC variation explained significant variance in gamasid mites (Gamasidae), M. walkeri fleas, I. ricinus tick nymphs and overall co-infection (Oliver et al 2009a, b).…”

Spatial pattern of adaptive and neutral genetic diversity across different biomes in the lesser anteater (Tamandua tetradactyla)

“…Studies in humans both on MHC (Prugnolle et al. 2005) and on several genomic SNPs with signs for positive selection (Fumagalli et al. 2011), correlating with pathogen pressure, showed a strong signature of demography despite the observed influence of pathogen‐mediated selection.…”