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

Speaker: Julien Roux, MCSA postdoc fellow, University of Lausanne, Switzerland
Host: Albin Sandelin, Section for Computational and RNA biology

Abstract
A long-standing hypothesis is that changes in gene regulation play an important role in adaptive evolution, with a potential impact on human evolution. 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 evolution. In this study, we use cross-tissues and cross-species comparisons to study the contribution of DNA methylation changes to the evolution of gene expression.

To interrogate the CpG methylation status in the genome, we performed whole-genome bisulfite conversion followed by high-throughput sequencing across 4 tissues (heart, kidney, liver and lung) in human and two primate species (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.

The integration of both datasets allowed us to characterize better the genome features whose methylation status leads to expression changes. We developed a statistical model to quantify the proportion of variation in gene expression levels across tissues and species that can be explained by changes in methylation, which provided a better understanding of how epigenetic divergence contributes to gene expression evolution. We discovered that, compared to the relatively strong negative association between gene expression and methylation changes across tissues, the correlation was greatly reduced across species, questioning the importance of epigenetic modifications as a general mechanism causing regulatory changes and adaptations in primates. Interestingly, tissue-specificity is helpful to refine the subset of between-species differentially methylated regions showing a stronger association with expression changes.