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

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 methylationreprogramming. This is the first report of findings showing that the CpGmethylation state is significantly correlated with the characteristics of evolutionary change in neighboring DNA.