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研究揭示m6A修饰对人类疾病遗传力的贡献
2020-06-30 21:31

美国芝加哥大学何川、Xin He、Matthew Stephens等研究人员合作揭示N6-甲基腺苷(m6A)修饰对人类疾病遗传力的贡献。这一研究成果于2020年6月29日在线发表于《自然—遗传学》。

研究人员绘制了60个约鲁巴(YRI)淋巴母细胞样细胞系中m6A峰的定量特征位点(QTL)。研究人员发现,m6A QTL很大程度上不依赖于表达和剪接QTL,并且富含RNA结合蛋白的结合位点、RNA结构改变变体和转录特征。对m6A的QTL及其相关分子性状的联合分析表明,m6A的下游效应是异质的,且取决于背景。
 
研究人员鉴定了介导m6A影响翻译的蛋白质。通过与全基因组关联研究数据的整合,研究人员发现m6A QTL以与剪接QTL以及表达QTL约一半相当的水平促进了各种免疫和血液相关性状的遗传。通过在整个转录组关联研究框架中利用m6A QTL,研究人员鉴定了这些特征的潜在风险基因。
 
据了解,N6-甲基腺苷(m6A)在调节信使RNA加工中起重要作用。尽管在该领域取得了快速进展,但对m6A修饰的遗传决定因素及其在常见疾病中的作用了解甚少。
 
附:英文原文

Title: Genetic analyses support the contribution of mRNA N 6 -methyladenosine (m 6 A) modification to human disease heritability

Author: Zijie Zhang, Kaixuan Luo, Zhongyu Zou, Maguanyun Qiu, Jiakun Tian, Laura Sieh, Hailing Shi, Yuxin Zou, Gao Wang, Jean Morrison, Allen C. Zhu, Min Qiao, Zhongshan Li, Matthew Stephens, Xin He, Chuan He

Issue&Volume: 2020-06-29

Abstract: N6-methyladenosine (m6A) plays important roles in regulating messenger RNA processing. Despite rapid progress in this field, little is known about the genetic determinants of m6A modification and their role in common diseases. In this study, we mapped the quantitative trait loci (QTLs) of m6A peaks in 60 Yoruba (YRI) lymphoblastoid cell lines. We found that m6A QTLs are largely independent of expression and splicing QTLs and are enriched with binding sites of RNA-binding proteins, RNA structure-changing variants and transcriptional features. Joint analysis of the QTLs of m6A and related molecular traits suggests that the downstream effects of m6A are heterogeneous and context dependent. We identified proteins that mediate m6A effects on translation. Through integration with data from genome-wide association studies, we show that m6A QTLs contribute to the heritability of various immune and blood-related traits at levels comparable to splicing QTLs and roughly half of expression QTLs. By leveraging m6A QTLs in a transcriptome-wide association study framework, we identified putative risk genes of these traits. Quantitative trait locus (QTL) mapping of N6-methyladenosine (m6A) in human cells highlights the role of RNA-binding proteins, RNA secondary structure and context-dependent m6A effects. m6A QTLs are enriched in loci associated with immune and blood-related traits.

DOI: 10.1038/s41588-020-0644-z

Source: https://www.nature.com/articles/s41588-020-0644-z

Nature Genetics:《自然—遗传学》,创刊于1992年。隶属于施普林格·自然出版集团,最新IF:25.455
官方网址:https://www.nature.com/ng/
投稿链接:https://mts-ng.nature.com/cgi-bin/main.plex


本期文章:《自然—遗传学》:Online/在线发表

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