“Balancing” balancing selection? Assortative mating at the major histocompatibility complex despite molecular signatures of balancing selection

Abstract

In vertebrate animals, genes of the major histocompatibility complex (MHC) determine the set of pathogens to which an individual's adaptive immune system can respond. MHC genes are extraordinarily polymorphic, often showing elevated nonsynonymous relative to synonymous sequence variation and sharing presumably ancient polymorphisms between lineages. These patterns likely reflect pathogen‐mediated balancing selection, for example, rare‐allele or heterozygote advantage. Such selection is often reinforced by disassortative mating at MHC. We characterized exon 2 of MHC class II, corresponding to the hypervariable peptide‐binding region, in song sparrows ( Melospiza melodia ). We compared nonsynonymous to synonymous sequence variation in order to identify positively selected sites; assessed evidence for trans‐species polymorphisms indicating ancient balancing selection; and compared MHC similarity of socially mated pairs to expectations under random mating. Six codons showed elevated ratios of nonsynonymous to synonymous variation, consistent with balancing selection, and we characterized several alleles similar to those occurring in at least four other avian families. Despite this evidence for historical balancing selection, mated pairs were significantly more similar at MHC than were randomly generated pairings. Nonrandom mating at MHC thus appears to partially counteract, not reinforce, pathogen‐mediated balancing selection in this system. We suggest that in systems where individual fitness does not increase monotonically with MHC diversity, assortative mating may help to avoid excessive offspring heterozygosity that could otherwise arise from long‐standing balancing selection.

Only rare classical MHC-I alleles are highly expressed in the European house sparrow

“…Since rare alleles are more likely to occur at heterozygous loci, while common alleles are more likely to occur at homozygous loci, heterozygote advantage can potentially promote rare alleles and disfavour common alleles, similar to negative frequency-dependent selection. Consistent with PMBS theory, many studies have found high rates of positive selection in classical MHC genes (reviewed in [ 8 , 9 ]) and correlations between MHC genotype and resistance to infection [ 10 – 13 ]. Moreover, studies in humans have reported direct mechanistic links between MHC antigen presentation and disease resistance [ 14 ].…”

Discordant results among major histocompatibility complex binding affinity prediction tools

“…[2][3][4][5][6][7][8] There is large diversity in the antigenic peptide sequences which individual HLA alleles can recognize and ultimately present to the adaptive immune system, 9 with a positive correlation between increased sequence diversity recognition and fitness. 10 Tools that can predict the extent to which a given HLA allele may have an affinity for a given peptide have critical implications for our ability to understand and translationally leverage antigen-specific immune response pathways. For instance, MHC binding affinity predictors have beenor otherwise have the potential to beused to evaluate an individual or population's susceptibility to viral infection, 11 to develop an understanding of specific autoimmune conditions, 12 to improve transplantation technologies, 13 or even to assist in the development of personalized cancer vaccines.…”

Discordant results among MHC binding affinity prediction tools

“…Infectious diseases in particular are thought to be a major source of selective pressure on the Major Histocompatibility Complex (MHC) region which encodes HLA alleles and is one of the most diverse regions of the human genome (2)(3)(4)(5)(6)(7)(8). There is large diversity in the antigenic peptide sequences which individual HLA alleles can recognize and ultimately present to the adaptive immune system (9), with a positive correlation between increased sequence diversity recognition and fitness (10).…”