Genome-wide genetic variations are highly correlated with proximal DNA methylation patterns

Abstract

5-methyl-cytosines at CpG sites frequently mutate into thymines, accounting for a large proportion of spontaneous point mutations. The repair system would leave substantial numbers of errors in neighboring regions if the synthesis of erased gaps around deaminated 5-methyl-cytosines is error-prone. Indeed, we identified an unexpected genome-wide role of the CpG methylation state as a major determinant of proximal natural genetic variation. Specifically, 507 Mbp (~18%) of the human genome was within 10 bp of a CpG site; in these regions, the single nucleotide polymorphism (SNP) rate significantly increased by~50% (P < 10 -566 by a two-proportion z-test) if the neighboring CpG sites are methylated. To reconfirm this finding in another vertebrate, we compared six single-base resolution methylomes in two inbred medaka (Oryzias latipes) strains with sufficient genetic divergence (3.4%). We found that the SNP rate also increased by~50% (P < 10 -2170), and the substitution rates in all dinucleotides increased simultaneously (P < 10 -441 ) around methylated CpG sites. In the hypomethylated regions, the ''CGCG'' motif was significantly enriched (P < 10 -680) and evolutionarily conserved (P =~0.203%), and slow CpG deamination rather than fast CpG gain was seen, indicating a possible role of CGCG as a candidate cis-element for the hypomethylation state. In regions that were hypermethylated in germline-like tissues but were hypomethylated in somatic liver cells, the SNP rate was significantly smaller than that in hypomethylated regions in both tissues, suggesting a positive selective pressure during DNA methylation reprogramming. This is the first report of findings showing that the CpG methylation state is significantly correlated with the characteristics of evolutionary change in neighboring DNA.

BDNF rs6265 methylation and genotype interact on risk for schizophrenia

“…5 Briefly, 'N-back' refers to how far back in the sequence of stimuli the subject had to recall. The stimuli consisted of numbers (1)(2)(3)(4) shown in random sequence and displayed at the points of a diamond-shaped box. There was a visually paced motor task, which also served as a non-memory guided control condition (0-back) that simply required subjects to identify the stimulus currently seen.…”

“…1 CpG methylation state is recognized as a major determinant of natural genetic variation, 2 and a strong genetic component underlies inter-individual variation in DNA-methylation profiles. 3 While it has been argued that many SNPs contribute to geneexpression changes and phenotypes relevant for diseases via epigenetic mechanisms, 3,4 the possibility that DNA methylation changes may compensate and/or modulate the effect of genetic variation has been less studied.…”

Large hypomethylated domains serve as strong repressive machinery for key developmental genes in vertebrates

“…To obtain the global genomic distribution of epigenetic modifications in medaka blastula embryos, we performed ChIP-seq analyses using antibodies against H3K27me3, H3K4me1, H3K4me2, H3K4me3 and H3K27ac (supplementary material Table S1), and integrated these results with previously established medaka single-base DNA methylomes (Qu et al, 2012). At the blastula stage, methylation frequency of individual CpG sites has a clear bimodal distribution (supplementary material Fig.…”

“…To address whether HMD shortening at active gene loci is a general feature in adult tissues, we compared the epigenomes of the adult dorsal myotome and liver with that of blastula embryos. For liver epigenome data, we generated histone modification maps (supplementary material Table S1), and integrated these with methylome data from a previous study (Qu et al, 2012). We found that the majority of K27HMDs have unchanged methylation levels in adult tissues, but a significant proportion of HMDs were subjected to DNA hypermethylation in which more than 5% of their CpG sites became highly methylated (>0.4) ( Fig.…”

“…Here, we investigate the epigenomic profiles of medaka blastula embryos ( pluripotent cells) and adult tissues by using single-base resolution DNA methylomes from our previous study (Qu et al, 2012) and also by generating genome-wide histone modification maps and additional methylomes. In blastula embryos, large compartmentalized genomic domains with H3K27me3 and DNA hypomethylation (K27HMDs) were found at developmental transcription factor genes.…”