A structural variation reference for medical and population genetics

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Genome Aggregation Database Prod T , Genome Aggregation Database Consor , Collins , R L , Brand , H , Karczewski , K J , Talkowski , M E , Färkkilä , M , Groop , L , Holi , M M , Kaprio , J , Palotie , A , Ripatti , S , Tuomi , T , Wessman , M & Kallela , M 2020 , ' A structural variation reference for medical and population genetics ' , Nature , vol. 581 , no. 7809 , pp. 444-+ . https://doi.org/10.1038/s41586-020-2287-8

Title: A structural variation reference for medical and population genetics
Author: Genome Aggregation Database Prod T; Genome Aggregation Database Consor; Collins, Ryan L.; Brand, Harrison; Karczewski, Konrad J.; Talkowski, Michael E.; Färkkilä, Martti; Groop, Leif; Holi, Matti M.; Kaprio, Jaakko; Palotie, Aarno; Ripatti, Samuli; Tuomi, Tiinamaija; Wessman, Maija; Kallela, Mikko
Other contributor: University of Helsinki, Centre of Excellence in Complex Disease Genetics
University of Helsinki, Centre of Excellence in Complex Disease Genetics
University of Helsinki, HUS Psychiatry
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Centre of Excellence in Complex Disease Genetics
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Centre of Excellence in Complex Disease Genetics
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, HUS Neurocenter


















Date: 2020-05-28
Language: eng
Number of pages: 17
Belongs to series: Nature
ISSN: 0028-0836
DOI: https://doi.org/10.1038/s41586-020-2287-8
URI: http://hdl.handle.net/10138/325139
Abstract: 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.
Subject: COPY NUMBER VARIATION
GENOME
IMPACT
REARRANGEMENTS
EVOLUTION
VARIANTS
PATTERNS
DELETION
3111 Biomedicine
1184 Genetics, developmental biology, physiology
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