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The highly polymorphic genes of the major histocompatibility complex (MHC) play a key role in adaptive immunity. Divergent allele advantage, a mechanism of balancing selection, is proposed to contribute to their exceptional polymorphism. It assumes that MHC genotypes with more divergent alleles allow for broader antigen-presentation to immune effector cells, by that increasing immunocompetence. However, the direct correlation between pairwise sequence divergence and the corresponding repertoire of bound peptides has not been studied systematically across different MHC genes. Here, we investigated this relationship for five key classical human MHC genes (human leukocyte antigen; HLA-A, -B, -C, -DRB1, and -DQB1), using allele-specific computational binding prediction to 118,097 peptides derived from a broad range of human pathogens. For all five human MHC genes, the genetic distance between two alleles of a heterozygous genotype was positively correlated with the total number of peptides bound by these two alleles. In accordance with the major antigen-presentation pathway of MHC class I molecules, HLA-B and HLA-C alleles showed particularly strong correlations for peptides derived from intracellular pathogens. Intriguingly, this bias coincides with distinct protein compositions between intra- and extracellular pathogens, possibly suggesting adaptation of MHC I molecules to present specifically intracellular peptides. Eventually, we observed significant positive correlations between an allele's average divergence and its population frequency. Overall, our results support the divergent allele advantage as a meaningful quantitative mechanism through which pathogen-mediated selection leads to the evolution of MHC diversity.

Divergent Allele Advantage at Human MHC Genes: Signatures of Past and Ongoing Selection