美国科学家绘制SV参考图谱，对群体遗传学等研究贡献巨大

科技号消息，近日，美国麻省理工学院和哈佛大学广泛研究所Michael E. Talkowski研究团队取得一项新突破。他们构建了医学和群体遗传学的结构变异（SV）参考。该项研究成果发表在2020年5月27日出版的《自然》杂志上。

他们介绍了基因组聚合数据库（gnomAD）中由全球不同群体（54％非欧洲人）的14,891个基因组构建的序列解析SV的参考。他们发现了433,371个SV的丰富而复杂图谱，据此他们估计SV占每个基因组所有罕见蛋白质截短事件的25-29％。他们发现自然选择与破坏性单核苷酸变异（SNV）和破坏或复制蛋白质编码序列的稀有SV之间有很强的相关性，这表明对功能丧失高度不耐受的基因也对剂量增加敏感。

他们还发现了顺式调控元件中针对非编码SV的适度选择，尽管针对蛋白质截短SV的选择比所有非编码效果都强。最后，他们在3.9％的样本中发现了非常大（超过1兆碱基）的稀有SV，并估计有0.13％的携带SV的个体符合临床上重要的偶然发现的现有标准。该SV资源可通过gnomAD浏览器自由分配，并将在群体遗传学、疾病关联研究和诊断筛查中具有广泛的用途。

据了解，SV重新排列了DNA的大片段，可能对进化和人类疾病产生深远的影响。随着国家生物银行、疾病关联研究和临床基因测试越来越依赖于基因组测序，诸如gnomAD之类的群体参考资料已成为SNV注释的组成部分。但是，尚无与SNV相比可比的高覆盖度基因组测序的SV参考图谱。

附：英文原文

Title: A structural variation reference for medical and population genetics

Author: Ryan L. Collins, Harrison Brand, Konrad J. Karczewski, Xuefang Zhao, Jessica Alfldi, Laurent C. Francioli, Amit V. Khera, Chelsea Lowther, Laura D. Gauthier, Harold Wang, Nicholas A. Watts, Matthew Solomonson, Anne ODonnell-Luria, Alexander Baumann, Ruchi Munshi, Mark Walker, Christopher W. Whelan, Yongqing Huang, Ted Brookings, Ted Sharpe, Matthew R. Stone, Elise Valkanas, Jack Fu, Grace Tiao, Kristen M. Laricchia, Valentin Ruano-Rubio, Christine Stevens, Namrata Gupta, Caroline Cusick, Lauren Margolin, Kent D. Taylor, Henry J. Lin, Stephen S. Rich, Wendy S. Post, Yii-Der Ida Chen, Jerome I. Rotter, Chad Nusbaum, Anthony Philippakis, Eric Lander, Stacey Gabriel, Benjamin M. Neale, Sekar Kathiresan, Mark J. Daly, Eric Banks, Daniel G. MacArthur, Michael E. Talkowski

Issue&Volume: 2020-05-27

Abstract: Structural variants (SVs) rearrange large segments of DNA1 and can have profound consequences in evolution and human disease2,3. As national biobanks, disease-association studies, and clinical genetic testing have grown increasingly reliant on genome sequencing, population references such as the Genome Aggregation Database (gnomAD)4 have become integral in the interpretation of single-nucleotide variants (SNVs)5. However, there are no reference maps of SVs from high-coverage genome sequencing comparable to those for SNVs. Here we present a reference of sequence-resolved SVs constructed from 14,891 genomes across diverse global populations (54% non-European) in gnomAD. We discovered a rich and complex landscape of 433,371 SVs, from which we estimate that SVs are responsible for 25–29% of all rare protein-truncating events per genome. We found strong correlations between natural selection against damaging SNVs and rare SVs that disrupt or duplicate protein-coding sequence, which suggests that genes that are highly intolerant to loss-of-function are also sensitive to increased dosage6. We also uncovered modest selection against noncoding SVs in cis-regulatory elements, although selection against protein-truncating SVs was stronger than all noncoding effects. Finally, we identified very large (over one megabase), rare SVs in 3.9% of samples, and estimate that 0.13% of individuals may carry an SV that meets the existing criteria for clinically important incidental findings7. This SV resource is freely distributed via the gnomAD browser8 and will have broad utility in population genetics, disease-association studies, and diagnostic screening.

DOI: 10.1038/s41586-020-2287-8

Source: https://www.nature.com/articles/s41586-020-2287-8