Cis ‐regulatory evolution in a wild primate: Infection‐associated genetic variation drives differential expression of MHC ‐ DQA 1 in vitro

Abstract

Few studies have combined genetic association analyses with functional characterization of infection‐associated SNP s in natural populations of nonhuman primates. Here, we investigate the relationship between host genetic variation, parasitism and natural selection in a population of red colobus ( Procolobus rufomitratus tephrosceles ) in Kibale National Park, Uganda. We collected parasitological, cellular and genomic data to test the following hypotheses: (i) MHC ‐ DQA 1 regulatory genetic variation is associated with control of whipworm ( Trichuris ) infection in a natural population of red colobus; (ii) infection‐associated SNP s are functional in driving differential gene expression in vitro; and (iii) balancing selection has shaped patterns of variation in the MHC ‐ DQA 1 promoter. We identified two SNP s in the MHC ‐ DQA 1 promoter, both in transcription factor binding sites, and both of which are associated with decreased control of Trichuris infection. We characterized the function of both SNP s by testing differences in gene expression between the two alleles of each SNP in two mammalian cell lines. Alleles of one of the SNP s drove differential gene expression in both cell lines, while the other SNP drove differences in expression in one of the cell lines. Additionally, we found evidence of balancing selection acting on the MHC ‐ DQA 1 promoter, including extensive trans‐species polymorphisms between red colobus and other primates, and an excess of intermediate‐frequency alleles relative to genome‐wide, coding and noncoding RAD seq data. Our data suggest that balancing selection provides adaptive regulatory flexibility that outweighs the consequences of increased parasite infection intensity in heterozygotes.

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