Oral Presentation Society for Molecular Biology and Evolution Conference 2016

Functional characterization of evolutionarily advantageous sequence divergence between MHC alleles (#25)

Federica Pierini 1 , Tobias L. Lenz 1
  1. Department of Evolutionary Ecology, Max Planck Institute for Evolutionary Biology, Ploen, Germany

The highly polymorphic genes of the major histocompatibility complex (MHC) encode for cell-surface glycoproteins with a key role in adaptive immunity. Divergent allele advantage, a mechanism of balancing selection, has been proposed to maintain the exceptional sequence divergence and ancient allelic lineages at these genes. Heterozygous individuals with more divergent MHC allele combinations (i.e. larger sequence difference along the antigen-binding domains) are thought to carry glycoproteins presenting a wider array of antigens to immune effector cells, conferring an advantage against pathogen infections. As quantification of the MHC-bound antigen repertoire is unfeasible in natural populations, different measures of MHC sequence divergence are commonly used as a proxy. However, the direct correlation between sequence divergence and the corresponding repertoire of bound peptides has not been studied systematically across the different MHC genes. Here, we investigated the relationship between sequence divergence and peptide binding properties for the five key classical human MHC genes (human leukocyte antigen; HLA): HLA-A, -B, -C, -DRB1, and -DQB1. Pairwise sequence divergence was correlated with allele-specific binding properties obtained by established computational HLA binding prediction of 115,752 pathogen-derived peptides. For all five HLA genes, the genetic distance between two alleles of a heterozygous genotype showed a significant positive correlation with the combined number of bound peptides. In accordance with the major biological function of MHC class I and class II molecules, we observed for HLA-B and HLA-DQB1 alleles particularly strong correlations for peptides derived from intracellular and extracellular pathogens, respectively. Finally, we observed significant correlations between an allele’s population frequency and its average pairwise sequence divergence for four of the investigated HLA genes, suggesting still ongoing selection for divergent HLA genotypes in modern human populations. Overall, our results support the divergent allele advantage hypothesis as a meaningful scenario, contributing to the exceptional genetic diversity in classical MHC genes.