Ancient Trans-Species Polymorphism at the Major Histocompatibility Complex in Primates

Abstract

AbstractClassical genes within the Major Histocompatibility Complex (MHC) are responsible for peptide presentation to T cells, thus playing a central role in immune defense against pathogens. These genes are subject to strong selective pressures including both balancing and directional selection, resulting in exceptional genetic diversity—thousands of alleles per gene. Moreover, some alleles appear to be shared between primate species, a phenomenon known astrans-species polymorphism (TSP)orincomplete lineage sorting, which is rare in the genome overall. However, despite the clinical and evolutionary importance of MHC diversity, we currently lack a full picture of primate MHC evolution. To start addressing this gap, we used Bayesian phylogenetic methods to determine the extent of TSP at six classical MHC genes. We find strong support for TSP in all six genes, including between humans and old-world monkeys in HLA-DRB1 and even— remarkably—between humans and new-world monkeys in HLA-DQB1. Despite the long-term persistence of ancient lineages, we additionally observe rapid evolution at amino acids within the peptide-binding domain. The most rapidly-evolving positions are also strongly enriched for autoimmune and infectious disease associations. Together, these results suggest complex selective forces arising from differential peptide binding, which drive short-term allelic turnover within lineages while also maintaining deeply divergent lineages for at least 45 million years.