The interplay between DNA methylation and sequence divergence in recent human evolution

Abstract

Despite the increasing knowledge about DNA methylation, the understanding of human epigenome evolution is in its infancy. Using whole genome bisulfite sequencing we identified hundreds of differentially methylated regions (DMRs) in humans compared to non-human primates and estimated that ∼25% of these regions were detectable throughout several human tissues. Human DMRs were enriched for specific histone modifications and the majority were located distal to transcription start sites, highlighting the importance of regions outside the direct regulatory context. We also found a significant excess of endogenous retrovirus elements in human-specific hypomethylated.We reported for the first time a close interplay between inter-species genetic and epigenetic variation in regions of incomplete lineage sorting, transcription factor binding sites and human differentially hypermethylated regions. Specifically, we observed an excess of human-specific substitutions in transcription factor binding sites located within human DMRs, suggesting that alteration of regulatory motifs underlies some human-specific methylation patterns. We also found that the acquisition of DNA hypermethylation in the human lineage is frequently coupled with a rapid evolution at nucleotide level in the neighborhood of these CpG sites. Taken together, our results reveal new insights into the mechanistic basis of human-specific DNA methylation patterns and the interpretation of inter-species non-coding variation.

Recently evolved human-specific methylated regions are enriched in schizophrenia signals

“…Furthermore, while the DMRs utilized here were obtained from bone samples, the authors of the original study (28) referred to the report by HernandoHerraez et al (40) which demonstrated that species-specific DMRs tend to be conserved across tissues and as such should not represent tissue-specific variations. Other studies also showed that neurological systems were enriched for methylation differences even when the tissue samples analyzed were not neurological (41)(42)(43). Therefore, we believe that our results are valid for a 'brain' phenotype even though the DMRs were derived from non-brain tissues.…”

A comparison of gene expression and DNA methylation patterns across tissues and species

“…This trend is robust with respect to the species used to initially locate T-DMRs (Additional File 2: Figures S8-S9). Thus, our results suggest that in general, inter-tissue methylation differences within a species tend to be conserved, consistent with the observations of previous studies [7, 13, 15, 53, 54].…”

“…We also found a large number of pairwise tissue DMRs and tissue-specific DMRs to be conserved in the three primates we studied. Our observations are qualitatively consistent with those of previous studies that mostly used microarrays to measure methylation levels [7, 13, 41]. However, the high resolution of our sequence-based DMR data allowed us to examine a much larger number of CpG sites.…”

“…Over the past decade, dozens of comparative genomic studies focused on characterizing mRNA expression level differences between primates in a large number of tissues (e.g., [2-6]), typically focusing on differences between humans and other primates. A few studies have also characterized inter-primate differences in regulatory mechanisms and phenotypes other than gene expression levels, such as DNA methylation levels, chromatin modifications and accessibility, and protein expression levels [7-15].…”

Insights in human epigenomic dynamics through comparative primate analysis

“…This study estimated that ~10% of the CGI regions differed significantly between human and chimpanzee. A recent paper was performed with whole-genome bisulphite sequencing (BiS-seq) generating data for ~6 million well-covered CpGs, in peripheral blood across human, chimpanzee, gorilla, and orang-utan [88]. This identified that sDMRs were also enriched for species-specific nucleotide changes and hypomethylated s-DMRs were specifically enriched twofold for endogenous retroviruses (ERVs).…”