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. 2015 Sep 30;43(17):8204-14.
doi: 10.1093/nar/gkv693. Epub 2015 Jul 13.

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

Irene Hernando-Herraez  1 , Holger Heyn  2 , Marcos Fernandez-Callejo  3 , Enrique Vidal  2 , Hugo Fernandez-Bellon  4 , Javier Prado-Martinez  5 , Andrew J Sharp  6 , Manel Esteller  7 , Tomas Marques-Bonet  8
Affiliations

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

Irene Hernando-Herraez et al. Nucleic Acids Res. .

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.

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Figures

Figure 1.
Figure 1.
Global DNA methylation patterns. (A) DNA methylation profile of 5 946 947 CpG sites shared among the four species. (B) Pairwise-correlation analysis in different regions of the genome (right). Genome-wide n = 5 946 947, promoter n = 1 466 948, CpG Island n = 740 153, repeats n = 2 310 842, LINE n = 433 317, LTR n = 385 009, SINE 141 380, Alu 1 160 930, other n = 190 206. Density scatterplot of DNA methylation levels between human and chimpanzee genome-wide and in Alu elements (left), R indicates the Pearson correlation coefficient. (C) Hierarchical cluster tree and pairwise-correlation analysis based of methylation data from incomplete lineage sorting regions. O(G(C,H) n = 922 701, O(H(C,G)) n = 221 908, O(C(H,G)) n = 142 231.
Figure 2.
Figure 2.
Differentially methylated regions. (A) Heat maps showing species specific hypo- (top) and hypermethylated (bottom) DRMs. Each vertical line represents the mean methylation value of a region. (B) Browser representation of human hypomethylated DMR (C) human hypermethylated DMR, within SEMA6C. Each vertical bar shows the methylation value of a single CpG site. Black blocks correspond to hypomethylated regions (HMRs) called by the Hidden Markov Model algorithm. Human samples: WB (whole blood), monocyte and neutrophil (myeloid lineage), CD19+ and CD4+ (lymphoid lineage), liver, brain and placenta. Non-human samples: WB: whole blood. The bottom panel displays the chromatin-state segmentation track (ChromHMM) for 7 different cell types (B-lymphocyte, lung fibroblast, HMEC: mammary epithelial cells, skeletal muscle myoblasts, HUVEC: umbilical vein endothelial cells, hESC: embryonic stem cells, epidermal keratinocytes). (D) Pearson correlation matrix of human hypo- and hypermethylated DMRs.
Figure 3.
Figure 3.
Nucleotide divergence at human hypermethylated DMRs. (A) Top, nucleotide changes of human hypermethylated DMRs estimated in each species lineage. The color plot represents the methylation state of the lineage species, red hypermethylated and blue hypomethylated. Data are represented as mean ± 2 standard deviations above and below the mean. Bottom, PhastCons score (Cons 46-Way) from all species (vertebrate) and two subsets (primate and placental mammal). (B) Number of CpG sites per kb in human hypermethylated DMRs estimated at each species lineage. (C) Classification of human-specific substitutions showing an excess of C>G mutations at human hypermethylated DMRs compared to the flanking regions.
Figure 4.
Figure 4.
Characteristics of human DMRs. (A) Increase of human-specific substitutions in TFBS within DMRs compared with TFBS in the background set. Conserved binding sites (gray) and binding sites with human-specific changes (orange). (B) Fraction of CpG sites overlapping with ERV elements (C) Distribution of human hypo- and hypermethylated DMRs. (D) Histone modification enrichment at human hypo- and hyper DMRs. Active promoter: H3K9ac, enhancer: H3K4me1, repressive promoter: H3K27me3, gene body: H3K36me3 and heterochromatin: H3K9me3 **denotes P < 0.001 and * denotes P < 0.01 (permutation test).
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