美国哈佛医学院布莱根妇女医院Shamil Sunyaev研究组利用群体测序数据揭示了人类生殖系突变过程的概要。相关论文于2021年8月12日发表于国际顶尖学术期刊《科学》杂志上。

他们使用体积正则化非负矩阵分解来统计分解沿基因组的突变率和谱的变化。对测序数据集 (TOPMed) 的分析揭示了解释基因座之间突变特性变化的九个过程。他们为其中七个过程提供了生物学解释。他们将一个过程与庞大的 DNA 损伤联系起来，这些损伤在转录和复制方面不对称。两个进程分别跟踪复制叉的方向和复制时间。他们确定了主要作用于调节区域的主动去甲基化的诱变作用和 LINE 重复的诱变作用。他们从群体测序数据中定位了特定于卵母细胞的诱变过程。这个过程出现转录不对称。

据介绍，人类生殖系突变的生物学机制在很大程度上仍不清楚。

附：英文原文

Title: Population sequencing data reveal a compendium of mutational processes in the human germ line

Author: Vladimir B. Seplyarskiy, Ruslan A. Soldatov, Evan Koch, Ryan J. McGinty, Jakob M. Goldmann, Ryan D. Hernandez, Kathleen Barnes, Adolfo Correa, Esteban G. Burchard, Patrick T. Ellinor, Stephen T. McGarvey, Braxton D. Mitchell, Ramachandran S. Vasan, Susan Redline, Edwin Silverman, Scott T. Weiss, Donna K. Arnett, John Blangero, Eric Boerwinkle, Jiang He, Courtney Montgomery, D.C. Rao, Jerome I. Rotter, Kent D. Taylor, Jennifer A Brody, Yii-Der Ida Chen, Lisa de las Fuentes, Chii-Min Hwu, Stephen S. Rich, Ani W. Manichaikul, Josyf C. Mychaleckyj, Nicholette D. Palmer, Jennifer A. Smith, Sharon L.R. Kardia, Patricia A. Peyser, Lawrence F. Bielak, Timothy D. O’Connor, Leslie S. Emery, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Population Genetics Working Group, Christian Gilissen, Wendy S. W. Wong, Peter V. Kharchenko, Shamil Sunyaev

Issue&Volume: 2021/08/12

Abstract: Biological mechanisms underlying human germline mutations remain largely unknown. We statistically decompose variation in the rate and spectra of mutations along the genome using volume-regularized nonnegative matrix factorization. The analysis of a sequencing dataset (TOPMed) reveals nine processes that explain the variation in mutation properties between loci. We provide a biological interpretation for seven of these processes. We associate one process with bulky DNA lesions that resolve asymmetrically with respect to transcription and replication. Two processes track direction of replication fork and replication timing, respectively. We identify a mutagenic effect of active demethylation primarily acting in regulatory regions and a mutagenic effect of LINE repeats. We localize a mutagenic process specific to oocytes from population sequencing data. This process appears transcriptionally asymmetric.

DOI: 10.1126/science.aba7408

Source: https://science.sciencemag.org/content/early/2021/08/11/science.aba7408