^aCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
^bDivision of Medical Sciences, Harvard Medical School, Boston, MA, USA
^cProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
^dDepartment of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
^eAnalytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
^fDepartment of Medicine, Harvard Medical School, Boston, MA, USA
^gData Science Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA
^hDepartment of Pediatrics, Harvard Medical School, Boston, MA, USA
ⁱDivision of Genetics and Genomics, Boston Children’s Hospital, Boston, MA, USA

Nature Nature Portfolio2020-05-27 1,035 citations50 references

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Abstract

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.

TL;DRA 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. (Semantic Scholar)

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A structural variation reference for medical and population genetics

Abstract

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