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Excess of Deleterious Mutations around HLA Genes Reveals Evolutionary Cost of Balancing Selection.

ABSTRACT: Deleterious mutations are expected to evolve under negative selection and are usually purged from the population. However, deleterious alleles segregate in the human population and some disease-associated variants are maintained at considerable frequencies. Here, we test the hypothesis that balancing selection may counteract purifying selection in neighboring regions and thus maintain deleterious variants at higher frequency than expected from their detrimental fitness effect. We first show in realistic simulations that balancing selection reduces the density of polymorphic sites surrounding a locus under balancing selection, but at the same time markedly increases the population frequency of the remaining variants, including even substantially deleterious alleles. To test the predictions of our simulations empirically, we then use whole-exome sequencing data from 6,500 human individuals and focus on the most established example for balancing selection in the human genome, the major histocompatibility complex (MHC). Our analysis shows an elevated frequency of putatively deleterious coding variants in nonhuman leukocyte antigen (non-HLA) genes localized in the MHC region. The mean frequency of these variants declined with physical distance from the classical HLA genes, indicating dependency on genetic linkage. These results reveal an indirect cost of the genetic diversity maintained by balancing selection, which has hitherto been perceived as mostly advantageous, and have implications both for the evolution of recombination and also for the epidemiology of various MHC-associated diseases.

SUBMITTER: Lenz TL

PROVIDER: S-EPMC5026253 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Balancing selection can maintain different alleles over long evolutionary times. Beyond this direct effect on the molecular targets of selection, balancing selection is also expected to increase neutral polymorphism in linked genome regions, in inverse proportion to their genetic map distances from the selected sites. The genes controlling plant self-incompatibility are subject to one of the strongest forms of balancing selection, and they show clear signatures of balancing selection. The genome region containing those genes (the S-locus) is generally described as nonrecombining, and the physical size of the region with low recombination has recently been established in a few species. However, the size of the region showing the indirect footprints of selection due to linkage to the S-locus is only roughly known. Here, we improved estimates of this region by surveying synonymous polymorphism and estimating recombination rates at 12 flanking region loci at known physical distances from the S-locus region boundary, in two closely related self-incompatible plants Arabidopsis halleri and A. lyrata. In addition to studying more loci than previous studies and using known physical distances, we simulated an explicit demographic scenario for the divergence between the two species, to evaluate the extent of the genomic region whose diversity departs significantly from neutral expectations. At the closest flanking loci, we detected signatures of both recent and ancient indirect effects of selection on the S-locus flanking genes, finding ancestral polymorphisms shared by both species, as well as an excess of derived mutations private to either species. However, these effects are detected only in a physically small region, suggesting that recombination in the flanking regions is sufficient to quickly break up linkage disequilibrium with the S-locus. Our approach may be useful for distinguishing cases of ancient versus recently evolved balancing selection in other systems.

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Excess of Deleterious Mutations around HLA Genes Reveals Evolutionary Cost of Balancing Selection.

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