A structural variation reference for medical and population genetics

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A structural variation reference for medical and population genetics. / Genome Aggregation Database Production Team; Genome Aggregation Database Consortium; Collins, Ryan; Groop, Leif (Medarbetare); Haiman, Christopher (Medarbetare); Melander, Olle (Medarbetare); Nilsson, Peter M (Medarbetare); Talkowski, Michael E.

I: Nature, Vol. 581, 27.05.2020, s. 444-451.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Harvard

Genome Aggregation Database Production Team, Genome Aggregation Database Consortium, Collins, R, Groop, L, Haiman, C, Melander, O, Nilsson, PM & Talkowski, ME 2020, 'A structural variation reference for medical and population genetics', Nature, vol. 581, s. 444-451. https://doi.org/10.1038/s41586-020-2287-8

APA

Genome Aggregation Database Production Team, Genome Aggregation Database Consortium, Collins, R., Groop, L., Haiman, C., Melander, O., Nilsson, P. M., & Talkowski, M. E. (2020). A structural variation reference for medical and population genetics. Nature, 581, 444-451. https://doi.org/10.1038/s41586-020-2287-8

CBE

Genome Aggregation Database Production Team, Genome Aggregation Database Consortium, Collins R, Groop L, Haiman C, Melander O, Nilsson PM, Talkowski ME. 2020. A structural variation reference for medical and population genetics. Nature. 581:444-451. https://doi.org/10.1038/s41586-020-2287-8

MLA

Vancouver

Genome Aggregation Database Production Team, Genome Aggregation Database Consortium, Collins R, Groop L, Haiman C, Melander O et al. A structural variation reference for medical and population genetics. Nature. 2020 maj 27;581:444-451. https://doi.org/10.1038/s41586-020-2287-8

Author

Genome Aggregation Database Production Team ; Genome Aggregation Database Consortium ; Collins, Ryan ; Groop, Leif ; Haiman, Christopher ; Melander, Olle ; Nilsson, Peter M ; Talkowski, Michael E. / A structural variation reference for medical and population genetics. I: Nature. 2020 ; Vol. 581. s. 444-451.

RIS

TY - JOUR

T1 - A structural variation reference for medical and population genetics

AU - Genome Aggregation Database Production Team

AU - Genome Aggregation Database Consortium

AU - Collins, Ryan

AU - Talkowski, Michael E

A2 - Groop, Leif

A2 - Haiman, Christopher

A2 - Melander, Olle

A2 - Nilsson, Peter M

PY - 2020/5/27

Y1 - 2020/5/27

N2 - Structural variants (SVs) rearrange large segments of DNA1 and can have profound consequences in evolution and human disease2,3. 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 dosage6. 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 findings7. This SV resource is freely distributed via the gnomAD browser8 and will have broad utility in population genetics, disease-association studies, and diagnostic screening.

AB - Structural variants (SVs) rearrange large segments of DNA1 and can have profound consequences in evolution and human disease2,3. 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 dosage6. 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 findings7. This SV resource is freely distributed via the gnomAD browser8 and will have broad utility in population genetics, disease-association studies, and diagnostic screening.

UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-85085567000&origin=inward&txGid

U2 - 10.1038/s41586-020-2287-8

DO - 10.1038/s41586-020-2287-8

M3 - Article

C2 - 32461652

VL - 581

SP - 444

EP - 451

JO - Nature

JF - Nature

SN - 0028-0836

ER -