A genomic study of the contribution of DNA methylation to regulatory evolution in primates

A long-standing hypothesis is that changes in gene regulation play an important role in adaptive evolution, notably in primates. Yet, in spite of the evidence accumulated in the past decade that regulatory changes contribute to many species-specific adaptations, we still know remarkably little about the mechanisms of regulatory evolu tion. In this study we focused on DNA methylation, an epigenetic mechanism whose contribution to the evolution of gene expression remains unclear. To interrogate the methylation status of the vast majority of cytosines in the genome, we performed whole-genome bisulfite conversion followed by high-throughput sequencing across 4 tissues (heart, kidney, liver and lung) in 3 primate species (human, chimpanzee and macaque). In parallel, we collected gene expression profiles using RNA-seq from the same tissue samples, allowing us to perform a high resolution scan for genes and pathways whose regulation evolved under natural selection. We integrated these datasets to characterize better the genome features whose methylation status leads to expression changes, and we developed a statistical model to quantify the proportion of variation in gene expression levels across tissues and species. Overall design: We extracted RNA and genomic DNA followed by high-throughput sequencing across 4 tissues (heart, kidney, liver and lung) in 4 individuals per primate species (human, chimpanzee and macaque).