小柯机器人

多聚腺苷酸化（poly A）定量性状位点图有助于解释复杂性状和疾病遗传，这一成果由美国德克萨斯大学李蔚和Eric J. Wagner研究团队合作经过不懈努力而取得。相关论文于2021年5月13日发表于国际学术期刊《自然-遗传学》杂志。

研究人员构建了人3'UTR替代多腺苷酸化（APA）定量性状基因座（3'aQTL）的多组织图谱，其中包含与靶基因APA相关的约40万种常见遗传变异，这些遗传变异在从467个个体的46个分离组织中鉴定（基因型组织表达计划）。从机制上讲，3'aQTL可以改变poly（A）结构、RNA二级结构和RNA结合蛋白结合位点，从而导致数千次APA变化。基于CRISPR的实验表明，此类3'aQTL可以改变APA调控。

此外，研究人员证明这些3'aQTLs可以识别APA调节因子，例如La相关蛋白4。最后，3'aQTLs与大约16.1％的性状相关变体共定位，并且在很大程度上与其他QTL（例如表达QTLs）不同。总的来说，该研究结果表明3'aQTL很大程度上有助于揭示人类复杂性状和疾病的分子机制。

据悉，全基因组关联研究已经鉴定出数千种与人类特征和疾病相关的非编码变异。然而，解释这些变体的功能解释仍存在挑战。

附：英文原文

Title: An atlas of alternative polyadenylation quantitative trait loci contributing to complex trait and disease heritability

Author: Lei Li, Kai-Lieh Huang, Yipeng Gao, Ya Cui, Gao Wang, Nathan D. Elrod, Yumei Li, Yiling Elaine Chen, Ping Ji, Fanglue Peng, William K. Russell, Eric J. Wagner, Wei Li

Issue&Volume: 2021-05-13

Abstract: Genome-wide association studies have identified thousands of noncoding variants associated with human traits and diseases. However, the functional interpretation of these variants is a major challenge. Here, we constructed a multi-tissue atlas of human 3′UTR alternative polyadenylation (APA) quantitative trait loci (3′aQTLs), containing approximately 0.4 million common genetic variants associated with the APA of target genes, identified in 46 tissues isolated from 467 individuals (Genotype-Tissue Expression Project). Mechanistically, 3′aQTLs can alter poly(A) motifs, RNA secondary structure and RNA-binding protein–binding sites, leading to thousands of APA changes. Our CRISPR-based experiments indicate that such 3′aQTLs can alter APA regulation. Furthermore, we demonstrate that mapping 3′aQTLs can identify APA regulators, such as La-related protein 4. Finally, 3′aQTLs are colocalized with approximately 16.1% of trait-associated variants and are largely distinct from other QTLs, such as expression QTLs. Together, our findings show that 3′aQTLs contribute substantially to the molecular mechanisms underlying human complex traits and diseases.

DOI: 10.1038/s41588-021-00864-5

Source: https://www.nature.com/articles/s41588-021-00864-5

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