Dynamic landscape and evolution of m6A methylation in human

m(6)A is a prevalent internal modification in mRNAs and has been linked to the diverse effects on mRNA fate. To explore the landscape and evolution of human m(6)A, we generated 27 m(6)A methylomes across major adult tissues. These data reveal dynamic m(6)A methylation across tissue types, uncover both broadly or tissue-specifically methylated sites, and identify an unexpected enrichment of m(6)A methylation at non-canonical cleavage sites. A comparison of fetal and adult m(6)A methylomes reveals that m(6)A preferentially occupies CDS regions in fetal tissues. Moreover, the m(6)A sub-motifs vary between fetal and adult tissues or across tissue types. From the evolutionary perspective, we uncover that the selection pressure on m(6)A sites varies and depends on their genic locations. Unexpectedly, we found that similar to 40% of the 3'UTR m(6)A sites are under negative selection, which is higher than the evolutionary constraint on miRNA binding sites, and much higher than that on A-to-I RNA modification. Moreover, the recently gained m(6)A sites in human populations are clearly under positive selection and associated with traits or diseases. Our work provides a resource of human m(6)A profile for future studies of m(6)A functions, and suggests a role of m(6)A modification in human evolutionary adaptation and disease susceptibility.