Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China;
Genome Res. 2023 Aug;33(8):1369-1380. doi: 10.1101/gr.277704.123. Epub 2023 Sep 15.
An intricate network of - and -elements acts on RNA -methyladenosine (mA), 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 mA 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 mA (ASmA) from MeRIP-seq data and applied it to uncover 12,056 high-confidence ASmA modifications from 25 human tissues. We also identified 1184 putative functional variants for ASmA regulation, a subset of which we experimentally validated. Importantly, we found that many of these ASmA-associated genetic variants were enriched for common disease-associated and complex trait-associated risk loci, and verified that two disease risk variants can change mA 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 mA and genetics in human health and disease.
一个复杂的 RNA -甲基腺苷（mA）的 -和 -元素网络发挥作用，反过来，这可能会影响基因表达，最终影响人类健康。要全面了解这个网络，需要采用新的方法来准确测量由遗传变异引起的微妙的 mA 差异，其中许多变异与常见疾病有关。为了解决这一差距，我们开发了一种从 MeRIP-seq 数据中准确而灵敏地检测全转录组等位基因特异性 mA（ASmA）的方法，并将其应用于从 25 个人体组织中发现 12056 个高可信度的 ASmA 修饰。我们还确定了 1184 个用于 ASmA 调节的假定功能变体，其中一部分我们进行了实验验证。重要的是，我们发现这些与 ASmA 相关的遗传变异中有许多富集了常见疾病相关和复杂性状相关的风险位点，并且验证了两个疾病风险变体可以改变 mA 修饰状态。总的来说，这项工作提供了一种工具，可以在等位基因水平上解开 RNA 修饰的动态网络，并强调了 mA 和遗传学在人类健康和疾病中的相互作用。
