Journal Article

A structural variation reference for medical and population genetics

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

2020

Overview

Structural variants (SVs) rearrange large segments of DNA 1 and can have profound consequences in evolution and human disease 2 , 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 dosage 6 . 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 findings 7 . This SV resource is freely distributed via the gnomAD browser 8 and will have broad utility in population genetics, disease-association studies, and diagnostic screening. A large empirical assessment of sequence-resolved structural variants from 14,891 genomes across diverse global populations in the Genome Aggregation Database (gnomAD) provides a reference map for disease-association studies, population genetics, and diagnostic screening.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 45/23 / 631/114/2785 / 631/208/212 / 631/208/2489/1381 / 631/208/726/649/2157 / 631/208/737 / Amino acid sequence / Analysis / Autism / Basic Medicine / Biologi / Biological Sciences / Deoxyribonucleic acid / Diagnostic systems / Disease / Disease - genetics / DNA / Female / Gene mapping / Gene sequencing / Genetic screening / Genetic Testing / Genetic Variation / Genetics / Genetics and Genomics / Genetics, Medical - standards / Genetics, Population - standards / Genetik och genomik / Genome, Human - genetics / Genomes / Genomic libraries / Genomic structural variations / Genomics / Genotyping Techniques / Human population genetics / Humanities and Social Sciences / Humans / Life Sciences / Male / Medical and Health Sciences / Medical genetics / Medical Genetics and Genomics (including Gene Therapy) / Medicin och hälsovetenskap / Medicinsk genetik och genomik (Här ingår: Genterapi) / Medicinska och farmaceutiska grundvetenskaper / Middle Aged / multidisciplinary / Mutation / Natural Sciences / Natural selection / Naturvetenskap / Nucleotides / Pipelines / Polymorphism, Single Nucleotide - genetics / Population genetics / Population studies / Properties / Proteins / Quality / Racial Groups - genetics / Reference Standards / Regulatory sequences / Science / Science (multidisciplinary) / Selection, Genetic / Whole Genome Sequencing