Dynamic landscape and evolution of m6A methylation in human.

Xueni Zhao,Hui Zhang,Xinrui Shi,Nannan Gu,Rui Zhang,Wanying Chen,Tao Huang

doi:10.1093/nar/gkaa347

Xueni Zhao, Hui Zhang + Show 5 more

Open Access

https://doi.org/10.1093/nar/gkaa347

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Abstract

m6A 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 m6A, we generated 27 m6A methylomes across major adult tissues. These data reveal dynamic m6A methylation across tissue types, uncover both broadly or tissue-specifically methylated sites, and identify an unexpected enrichment of m6A methylation at non-canonical cleavage sites. A comparison of fetal and adult m6A methylomes reveals that m6A preferentially occupies CDS regions in fetal tissues. Moreover, the m6A sub-motifs vary between fetal and adult tissues or across tissue types. From the evolutionary perspective, we uncover that the selection pressure on m6A sites varies and depends on their genic locations. Unexpectedly, we found that ∼40% of the 3′UTR m6A 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 m6A sites in human populations are clearly under positive selection and associated with traits or diseases. Our work provides a resource of human m6A profile for future studies of m6A functions, and suggests a role of m6A modification in human evolutionary adaptation and disease susceptibility.

Highlights

(adenosine to inosine) RNA editing, which is the predominant type of RNA deamination in animals [7–12], less is known about the dynamics and evolution of most RNA
We found that m6A sites had an older age than the control sites in all bins, suggesting that 3 UTR m6A sites are generally subject to negative selection (Figure 4D)
As m6A is known to affect mRNA stability, to further understand the potential regulatory effects of these SNPs, we examined the overlaps between these variants and eQTL SNPs from the Genotype-Tissue Expression (GTEx) project

Summary

INTRODUCTION

Chemical modifications on RNA have been recently appreciated as an important regulatory feature [1]. M6A RNA methylation is catalyzed by a multicomponent methyltransferase complex, including METTL3, METTL14 and WTAP [17,18]. A fundamental question in biology is to understand how natural selection has shaped the evolution of gene regulation [27,28], including RNA modifications. A recent study suggested that most m6A sites in CDS regions are evolutionarily unconserved [31]. Those studies were limited in scope and scale, a systematic investigation of the selection pressure on individual m6A sites is needed

MATERIALS AND METHODS

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DISCUSSION