Methylation at CpG dinucleotides is generally mutagenic and may increase the level of sequence divergence. However, methylated genes are also reported to evolve more slowly than unmethylated genes. A controversy on whether DNA methylation may be correlated with increase or decrease in protein evolutionary rate thus results. We hypothesize that DNA methylation has significant influences on the within-gene variations in evolutionary rates. To test this hypothesis, we compare human-mouse and human-macaque exonic evolutionary rates against experimentally determined single-base-resolution human DNA methylation data derived from different cell types. We show that the uneven distribution of DNA methylation is significantly related to within-gene variations in evolutionary rates. First, DNA methylation level is more strongly correlated with CpG dinucleotide mutations in first coding exons than in internal and last exons, although it is positively correlated with synonymous substitution rate regardless of the positions of the exons. Second, for first exons, highly methylated regions tend to have lower levels of expression, higher levels of sample specificity of DNA methylation level, and higher nonsynonymous substitution rates, whereas the reverse are true for internal and last exons. Our results suggest that DNA methylation level is differentially correlated with the biological features of different coding exons - first exons appear more liable to the methylation-associated increase in mutation rate, whereas other coding exons may be affected more by the regulatory effects of DNA methylation.
Reference: Proc Natl Acad Sci USA, 109(39):15841-15846, September 2012.