Allele-specific RNAN6-methyladenosine modifications reveal functional genetic variants in human tissues
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Published:2023-08
Issue:8
Volume:33
Page:1369-1380
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ISSN:1088-9051
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Container-title:Genome Research
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language:en
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Short-container-title:Genome Res.
Author:
Cao Shuo,Zhu Haoran,Cui Jinru,Liu Sun,Li Yuhe,Shi Junfang,Mo Junyuan,Wang Zihan,Wang Hailan,Hu Jiaxin,Chen Lizhi,Li Yuan,Xia Laixin,Xiao Shan
Abstract
An intricate network ofcis- andtrans-elements acts on RNAN6-methyladenosine (m6A), which in turn may affect gene expression and, ultimately, human health. A complete understanding of this network requires new approaches to accurately measure the subtle m6A differences arising from genetic variants, many of which have been associated with common diseases. To address this gap, we developed a method to accurately and sensitively detect transcriptome-wide allele-specific m6A (ASm6A) from MeRIP-seq data and applied it to uncover 12,056 high-confidence ASm6A modifications from 25 human tissues. We also identified 1184 putative functional variants for ASm6A regulation, a subset of which we experimentally validated. Importantly, we found that many of these ASm6A-associated genetic variants were enriched for common disease–associated and complex trait–associated risk loci, and verified that two disease risk variants can change m6A modification status. Together, this work provides a tool to detangle the dynamic network of RNA modifications at the allelic level and highlights the interplay of m6A and genetics in human health and disease.
Funder
National Key R&D Program of China
National Natural Science Foundation of China
Guangdong Basic and Applied Basic Research Foundation
Science and Technology Program of Guangzhou, China
Publisher
Cold Spring Harbor Laboratory
Subject
Genetics (clinical),Genetics