Evolutionary expansion of DNA hypomethylation in the mammalian germline genome

Abstract

DNA methylation in the germline is among the most important factors influencing the evolution of mammalian genomes. Yet little is known about its evolutionary rate or the fraction of the methylome that has undergone change. We compared whole-genome, single-CpG DNA methylation profiles in sperm of seven species-human, chimpanzee, gorilla, rhesus macaque, mouse, rat, and dog-to investigate epigenomic evolution. We developed a phylo-epigenetic model for DNA methylation that accommodates the correlation of states at neighboring sites and allows for inference of ancestral states. Applying this model to the sperm methylomes, we uncovered an overall evolutionary expansion of the hypomethylated fraction of the genome, driven both by the birth of new hypomethylated regions and by extensive widening of hypomethylated intervals in ancestral species. This expansion shows strong lineage-specific aspects, most notably that hypomethylated intervals around transcription start sites have evolved to be considerably wider in primates and dog than in rodents, whereas rodents show evidence of a greater trend toward birth of new hypomethylated regions. Lineage-specific hypomethylated regions are enriched near sets of genes with common developmental functions and significant overlap across lineages. Rodent-specific and primate-specific hypomethylated regions are enriched for binding sites of similar transcription factors, suggesting that the plasticity accommodated by certain regulatory factors is conserved, despite substantial change in the specific sites of regulation. Overall our results reveal substantial global epigenomic change in mammalian sperm methylomes and point to a divergence in -epigenetic mechanisms that govern the organization of epigenetic states at gene promoters.

Unusual sequence characteristics of human chromosome 19 are conserved across 11 nonhuman primates

“…Germline DNA methylation can potentially leave an evolutionary signature in the genome due to the hypermutability of methylated cytosines and less mutable nature of unmethylated cytosines. A comparison of sperm methylome data across human, chimpanzee, gorilla, rhesus, mouse, rat and dog found a genome wide evolutionary expansion of hypomethylation at CpG sites [29]. Primates and dog show a pattern of widening hypomethylation around transcription start sites into promoter flanking regions while rodents evolve new hypomethylated regions.…”

“…Primates and dog show a pattern of widening hypomethylation around transcription start sites into promoter flanking regions while rodents evolve new hypomethylated regions. We compared methylation levels of promoter, promoter flanking, enhancer and general genomic regions between primate chromosome 19 orthologs and whole genomes using the methylation data from Qu, et al [29]. The promoter flanking and general genomic regions showed hypomethylation of chromosome 19 relative to genome wide levels in all the examined primates consisting of human, chimpanzee, gorilla and rhesus (Table S20), with an average methylation level 0.09 lower, while promoter and enhancer methylation was similar between chromosome 19 and the genome wide levels in all the examined primates consisting of human, chimpanzee, gorilla and rhesus (Table S20).…”

“…Extensive hypomethylation of chromosome 19 promoter flanking regions may represent an extreme case of the primate pattern of expanding hypomethylation around promoters. In all the examined primates consisting of human, chimpanzee, gorilla and rhesus the average size of hypomethylated regions (HMRs) [29] were longer on chromosome 19 than the genome wide average by an average across species of 222 bp (see Table S21 for HMR lengths by species). Furthermore, the average size of Ensembl promoter flanking regions on human chromosome 19 (1519 bp) is 207 bp longer than the genome wide average (1311 bp).…”

Maternal DNMT3A-dependent de novo methylation of the zygotic paternal genome inhibits gene expression in the early embryo

“…CpG islands (CGIs), short stretches of CpG-rich regions, are an exception to the widespread DNAme observed in spermatozoa. Indeed, the vast majority of CGIs, which encompass the promoter regions of most housekeeping genes, are hypomethylated in mature male and female germ cells, as well as in early embryonic development 18,[28][29][30][31][32][33] . In addition, CGIs retain nucleosomes in spermatozoa, foregoing the exchange for protamines [28][29][30] .…”

Continuous-trait probabilistic model for comparing multi-species functional genomic data

“…Our new method incorporates the evolutionary affinity among multiple species into the hidden Markov model (HMM) for exploiting both temporal dependencies across species in the context of evolution and spatial dependencies along the genome in a continuous-trait model. Note that our Phylo-HMGP is fundamentally different from the existing models that are restricted to discrete state space of the studied traits (Siepel and Haussler, 2005;Hobolth et al, 2007;Liu et al, 2014;Jensen and Pedersen, 2000;Lunter and Hein, 2004;Qu et al, 2018). In particular, Phylo-HMMs define a stochastic process of discrete-trait character changes (Siepel and Haussler, 2005), where different states estimated by Phylo-HMMs can reflect different patterns of substitutions or background distributions.…”