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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<\/jats:sup> have become integral in the interpretation of single-nucleotide variants (SNVs)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\u201329% 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<\/jats:sup>. We also uncovered modest selection against noncoding SVs in 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 findings7<\/jats:sup>. This SV resource is freely distributed via the gnomAD browser8<\/jats:sup> and will have broad utility in population genetics, disease-association studies, and diagnostic screening.<\/jats:p>","DOI":"10.1038\/s41586-020-2287-8","type":"journal-article","created":{"date-parts":[[2020,5,27]],"date-time":"2020-05-27T16:02:53Z","timestamp":1590595373000},"page":"444-451","update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":700,"title":["A structural variation reference for medical and population genetics"],"prefix":"10.1038","volume":"581","author":[{"ORCID":"http:\/\/orcid.org\/0000-0003-1268-9995","authenticated-orcid":false,"given":"Ryan L.","family":"Collins","sequence":"first","affiliation":[]},{"given":"Harrison","family":"Brand","sequence":"additional","affiliation":[]},{"ORCID":"http:\/\/orcid.org\/0000-0003-2878-4671","authenticated-orcid":false,"given":"Konrad 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He is a member of the scientific advisory boards for Regeneron Genetics Center and Corvidia Therapeutics; he has served as a consultant for Acceleron, Eli Lilly, Novartis, Merck, Novo Nordisk, Novo Ventures, Ionis, Alnylam, Aegerion, Haug Partners, Noble Insights, Leerink Partners, Bayer Healthcare, Illumina, Color Genomics, MedGenome, Quest, and Medscape; he reports patents related to a method of identifying and treating a person having a predisposition to or afflicted with cardiometabolic disease (20180010185) and a genetics risk predictor (20190017119).","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}