Meta‐analysis of major histocompatibility complex (MHC) class IIA reveals polymorphism and positive selection in many vertebrate species

Pathogen‐mediated selection and sexual selection are important drivers of evolution. Both processes are known to target genes of the major histocompatibility complex (MHC), a gene family encoding cell‐surface proteins that display pathogen peptides to the immune system. The MHC is also a model for understanding processes such as gene duplication and trans‐species allele sharing. The class II MHC protein is a heterodimer whose peptide‐binding groove is encoded by an MHC‐IIA gene and an MHC‐IIB gene. However, our literature review found that class II MHC papers on infectious disease or sexual selection included IIA data only 18% and 9% of the time, respectively. To assess whether greater emphasis on MHC‐IIA is warranted, we analysed MHC‐IIA sequence data from 50 species of vertebrates (fish, amphibians, birds, mammals) to test for polymorphism and positive selection. We found that the number of MHC‐IIA alleles within a species was often high, and covaried with sample size and number of MHC‐IIA genes assayed. While MHC‐IIA variability tended to be lower than that of MHC‐IIB, the difference was only ~25%, with ~3 fewer IIA alleles than IIB. Furthermore, the unexpectedly high MHC‐IIA variability showed clear signatures of positive selection in most species, and positive selection on MHC‐IIA was stronger in fish than in other surveyed vertebrate groups. Our findings underscore that MHC‐IIA can be an important target of selection. Future studies should therefore expand the characterization of MHC‐IIA at both allelic and genomic scales, and incorporate MHC‐IIA into models of fitness consequences of MHC variation.