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Collins, Ryan L.; Brand, Harrison; Karczewski, Konrad J.; Zhao, Xuefang; Alföldi, Jessica; Francioli, Laurent C.; Khera, Amit V.; Lowther, Chelsea; Gauthier, Laura D.; Wang, Harold; Watts, Nicholas A.; Solomonson, Matthew; O’Donnell-Luria, Anne; Baumann, Alexander; Munshi, Ruchi; Walker, Mark; Whelan, Christopher W.; Huang, Yongqing; Brookings, Ted; Sharpe, Ted; Stone, Matthew R.; Valkanas, Elise; Fu, Jack; Tiao, Grace; [...]

A structural variation reference for medical and population genetics

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  • Media type: E-Article
  • Title: A structural variation reference for medical and population genetics
  • Contributor: Collins, Ryan L.; Brand, Harrison; Karczewski, Konrad J.; Zhao, Xuefang; Alföldi, Jessica; Francioli, Laurent C.; Khera, Amit V.; Lowther, Chelsea; Gauthier, Laura D.; Wang, Harold; Watts, Nicholas A.; Solomonson, Matthew; O’Donnell-Luria, Anne; Baumann, Alexander; Munshi, Ruchi; Walker, Mark; Whelan, Christopher W.; Huang, Yongqing; Brookings, Ted; Sharpe, Ted; Stone, Matthew R.; Valkanas, Elise; Fu, Jack; Tiao, Grace; [...]
  • imprint: Springer Science and Business Media LLC, 2020
  • Published in: Nature
  • Language: English
  • DOI: 10.1038/s41586-020-2287-8
  • ISSN: 0028-0836; 1476-4687
  • Origination:
  • Footnote:
  • Description: <jats:title>Abstract</jats:title><jats:p>Structural variants (SVs) rearrange large segments of DNA<jats:sup>1</jats:sup> and can have profound consequences in evolution and human disease<jats:sup>2,3</jats:sup>. 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)<jats:sup>4</jats:sup> have become integral in the interpretation of single-nucleotide variants (SNVs)<jats:sup>5</jats:sup>. 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<jats:sup>6</jats:sup>. We also uncovered modest selection against noncoding SVs in <jats:italic>cis</jats:italic>-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<jats:sup>7</jats:sup>. This SV resource is freely distributed via the gnomAD browser<jats:sup>8</jats:sup> and will have broad utility in population genetics, disease-association studies, and diagnostic screening.</jats:p>