Genetic Architecture of Immune Cell DNA Methylation in the Rhesus Macaque

Abstract

Genetic variation that impacts gene regulation, rather than protein function, can have strong effects on trait variation both within and between species. Epigenetic mechanisms, such as DNA methylation, are often an important intermediate link between genotype and phenotype, yet genetic effects on DNA methylation remain understudied in natural populations. To address this gap, we used reduced representation bisulfite sequencing to measure DNA methylation levels at 555,856 CpGs in peripheral whole blood of 573 samples collected from free‐ranging rhesus macaques ( Macaca mulatta ) living on the island of Cayo Santiago, Puerto Rico. We used allele‐specific methods to map cis ‐methylation quantitative trait loci (meQTL) and tested for effects of 243,389 single nucleotide polymorphisms (SNPs) on local DNA methylation levels. Of 776,092 tested SNP–CpG pairs, we identified 516,213 meQTL, with 69.12% of CpGs having at least one meQTL (FDR cis ‐expression QTL (eQTL) in the population, and found meQTL–eQTL genes were enriched for immune response functions, like antigen presentation and inflammation. Overall, our study takes an important step towards understanding the genetic architecture of DNA methylation in natural populations, and more generally points to the biological mechanisms driving phenotypic variation in our close relatives.

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