Allele-specific RNA N6-methyladenosine modifications reveal functional genetic variants in human tissues
- Shuo Cao1,3,
- Haoran Zhu1,3,
- Jinru Cui1,3,
- Sun Liu1,3,
- Yuhe Li1,
- Junfang Shi1,
- Junyuan Mo1,
- Zihan Wang1,
- Hailan Wang1,
- Jiaxin Hu1,
- Lizhi Chen1,
- Yuan Li1,
- Laixin Xia1 and
- Shan Xiao1,2
- 1Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China;
- 2Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Guangzhou 510515, China
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↵3 These authors contributed equally to this work.
Abstract
An intricate network of cis- and trans-elements acts on RNA N6-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.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at https://www.genome.org/cgi/doi/10.1101/gr.277704.123.
- Received January 15, 2023.
- Accepted June 13, 2023.
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