A structural variation reference for medical and population genetics
Open accessPublished version of a preprint
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.
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Previous short-read, linear reference studies have discovered 7,500-9,500 SVs per sample, whereas long-read sequencing efforts have routinely discovered around 25,000.
“Previous short-read, linear reference studies have discovered 7,500–9,500 SVs per sample19,68, whereas long-read sequencing efforts have routinely discovered around 25,000.”
From A draft human pangenome reference. (2023) · cites this paper as [68]
The SV discovery and genotyping section reports a median of 7,439 SVs per genome using short-read WGS, close to the claimed lower bound of 7,500. It does not substantiate the upper bound of 9,500; the cited comparison with an earlier WGS study instead gives 3,441 per genome. The citation is attached to the short-read clause, not the long-read figure. (LLM, conf=0.85)
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- Authors
- Collins, R. L., Brand, H., Karczewski, K. J., Zhao, X., Alföldi, J., Francioli, L. C., Khera, A. V., Lowther, C., Gauthier, L. D., Wang, H., Watts, N. A., Solomonson, M., O’Donnell-Luria, A., Baumann, A., Munshi, R., Walker, M., Whelan, C. W., Huang, Y., Brookings, T., Sharpe, T., Stone, M. R., Valkanas, E., Fu, J., Tiao, G., Laricchia, K. M., Ruano-Rubio, V., Stevens, C., Gupta, N., Cusick, C., Margolin, L., Genome Aggregation Database Production Team, Alföldi, J., Armean, I. M., Banks, E., Bergelson, L., Cibulskis, K., Collins, R. L., Connolly, K. M., Covarrubias, M., Cummings, B., Daly, M. J., Donnelly, S., Farjoun, Y., Ferriera, S., Francioli, L., Gabriel, S., Gauthier, L. D., Gentry, J., Gupta, N., Jeandet, T., Kaplan, D., Karczewski, K. J., Laricchia, K. M., Llanwarne, C., Minikel, E. V., Munshi, R., Neale, B. M., Novod, S., O’Donnell-Luria, A. H., Petrillo, N., Poterba, T., Roazen, D., Ruano-Rubio, V., Saltzman, A., Samocha, K. E., Schleicher, M., Seed, C., Solomonson, M., Soto, J., Tiao, G., Tibbetts, K., Tolonen, C., Vittal, C., Wade, G., Wang, A., Wang, Q., Ware, J. S., Watts, N. A., Weisburd, B., Whiffin, N., Genome Aggregation Database Consortium, Salinas, C. A. A., Ahmad, T., Albert, C. M., Ardissino, D., Atzmon, G., Barnard, J., Beaugerie, L., Benjamin, E. J., Boehnke, M., Bonnycastle, L. L., Bottinger, E. P., Bowden, D. W., Bown, M. J., Chambers, J. C., Chan, J. C., Chasman, D., Cho, J., Chung, M. K., Cohen, B., Correa, A., Dabelea, D., Daly, M. J., Darbar, D., Duggirala, R., Dupuis, J., Ellinor, P. T., Elosua, R., Erdmann, J., Esko, T., Färkkilä, M., Florez, J., Franke, A., Getz, G., Glaser, B., Glatt, S. J., Goldstein, D., Gonzalez, C., Groop, L., Haiman, C., Hanis, C., Harms, M., Hiltunen, M., Holi, M. M., Hultman, C. M., Kallela, M., Kaprio, J., Kathiresan, S., Kim, B.-J., Kim, Y. J., Kirov, G., Kooner, J., Koskinen, S., Krumholz, H. M., Kugathasan, S., Kwak, S. H., Laakso, M., Lehtimäki, T., Loos, R. J. F., Lubitz, S. A., Ma, R. C. W., MacArthur, D. G., Marrugat, J., Mattila, K. M., McCarroll, S., McCarthy, M. I., McGovern, D., McPherson, R., Meigs, J. B., Melander, O., Metspalu, A., Neale, B. M., Nilsson, P. M., O’Donovan, M. C., Ongur, D., Orozco, L., Owen, M. J., Palmer, C. N. A., Palotie, A., Park, K. S., Pato, C., Pulver, A. E., Rahman, N., Remes, A. M., Rioux, J. D., Ripatti, S., Roden, D. M., Saleheen, D., Salomaa, V., Samani, N. J., Scharf, J., Schunkert, H., Shoemaker, M. B., Sklar, P., Soininen, H., Sokol, H., Spector, T., Sullivan, P. F., Suvisaari, J., Tai, E. S., Teo, Y. Y., Tiinamaija, T., Tsuang, M., Turner, D., Tusie-Luna, T., Vartiainen, E., Vawter, M. P., Ware, J. S., Watkins, H., Weersma, R. K., Wessman, M., Wilson, J. G., Xavier, R. J., Taylor, K. D., Lin, H. J., Rich, S. S., Post, W. S., Chen, Y.-D. I., Rotter, J. I., Nusbaum, C., Philippakis, A., Lander, E., Gabriel, S., Neale, B. M., Kathiresan, S., Daly, M. J., Banks, E., MacArthur, D. G., & Talkowski, M. E.
- Affiliations
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- University of Parma (IT)
- Albert Einstein College of Medicine (US)
- Cleveland Clinic (US)
- Boston University (US)
- National Institutes of Health (US)
- University of Leicester (GB)
- Imperial College Healthcare NHS Trust (GB)
- Harvard University (US)
- Colorado School of Public Health (US)
- Texas Biomedical Research Institute (US)
- SUNY Upstate Medical University (US)
- Columbia University Irving Medical Center (US)
- University of Helsinki (FI)
- Lund University (SE)
- Columbia University (US)
- University of Eastern Finland (FI)
- Helsinki University Hospital (FI)
- Korea National Institute of Health (KR)
- MRC London Institute of Medical Sciences (GB)
- Yale New Haven Hospital (US)
- Seoul National University (KR)
- Tampere University (FI)
- Massachusetts General Hospital (US)
- Cedars-Sinai Medical Center (US)
- National Institute of Genomic Medicine (MX)
- University of Dundee (GB)
- University of Southern California (US)
- Institute of Cancer Research (GB)
- Montreal Heart Institute (CA)
- University of Pennsylvania (US)
- Finnish Institute for Health and Welfare (FI)
- Vanderbilt University (US)
- King's College London (GB)
- University of North Carolina at Chapel Hill (US)
- National University of Singapore (SG)
- Hebrew University of Jerusalem (IL)
- University of California, Irvine (US)
- University Medical Center Groningen (NL)
- The Lundquist Institute (US)
- Johns Hopkins University (US)
- Corresponding author
- Talkowski, Michael E.
- ORCID
- Brand, Harrison
- Zhao, Xuefang
- Francioli, Laurent C.
- Khera, Amit V.
- Lowther, Chelsea
- O’Donnell-Luria, Anne
- Walker, Mark
- Whelan, Christopher W.
- Huang, Yongqing
- Stone, Matthew R.
- Valkanas, Elise
- Fu, Jack
- Stevens, Christine
- Cusick, Caroline
- Armean, Irina M.
- Cibulskis, Kristian
- Cummings, Beryl
- Donnelly, Stacey
- Farjoun, Yossi
- Minikel, Eric V.
- Poterba, Timothy
- Saltzman, Andrea
- Samocha, Kaitlin E.
- Wang, Qingbo
- Weisburd, Ben
- Whiffin, Nicola
- Ahmad, Tariq
- Albert, Christine M.
- Ardissino, Diego
- Atzmon, Gil
- Beaugerie, Laurent
- Benjamin, Emelia J.
- Boehnke, Michael
- Bonnycastle, Lori L.
- Bowden, Donald W.
- Bown, Matthew J.
- Chambers, John C.
- Chan, Juliana C.
- Chasman, Daniel
- Cho, Judy
- Chung, Mina K.
- Cohen, Bruce
- Correa, Adolfo
- Dabelea, Dana
- Darbar, Dawood
- Duggirala, Ravindranath
- Dupuis, Josée
- Ellinor, Patrick T.
- Erdmann, Jeanette
- Esko, Tõnu
- Färkkilä, Martti
- Getz, Gad
- Glatt, Stephen J.
- Goldstein, David
- Groop, Leif
- Haiman, Christopher
- Hanis, Craig
- Harms, Matthew
- Hiltunen, Mikko
- Holi, Matti M.
- Kallela, Mikko
- Kaprio, Jaakko
- Kim, Bong-Jo
- Kim, Young Jin
- Kirov, George
- Kooner, Jaspal
- Krumholz, Harlan M.
- Kugathasan, Subra
- Kwak, Soo Heon
- Laakso, Markku
- Lehtimäki, Terho
- Loos, Ruth J. F.
- Lubitz, Steven A.
- Marrugat, Jaume
- McCarroll, Steven
- McCarthy, Mark I.
- McGovern, Dermot
- McPherson, Ruth
- Meigs, James B.
- Melander, Olle
- Metspalu, Andres
- Nilsson, Peter M.
- O’Donovan, Michael C.
- Orozco, Lorena
- Owen, Michael J.
- Palotie, Aarno
- Park, Kyong Soo
- Pato, Carlos
- Pulver, Ann E.
- Rahman, Nazneen
- Rioux, John D.
- Ripatti, Samuli
- Roden, Dan M.
- Saleheen, Danish
- Salomaa, Veikko
- Samani, Nilesh J.
- Scharf, Jeremiah
- Schunkert, Heribert
- Shoemaker, Moore B.
- Sklar, Pamela
- Soininen, Hilkka
- Sokol, Harry
- Spector, Tim
- Sullivan, Patrick F.
- Suvisaari, Jaana
- Tai, E. Shyong
- Tsuang, Ming
- Turner, Dan
- Vartiainen, Erkki
- Vawter, Marquis P.
- Watkins, Hugh
- Weersma, Rinse K.
- Xavier, Ramnik J.
- Taylor, Kent D.
- Lin, Henry J.
- Rich, Stephen S.
- Post, Wendy S.
- Chen, Yii-Der Ida
- Rotter, Jerome I.
- Nusbaum, Chad
- Philippakis, Anthony
- Lander, Eric
- Talkowski, Michael E.
- Venue
- Nature
- Published
- 2020-05-27
- Volume
- 581
- Issue
- 7809
- Pages
- 444-451
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC7334194
- OpenAlex
- W3032034316
- Cited by
- 1,037
- References
- 50
- Citations by year
- 2026: 133 · 2025: 149 · 2024: 188 · 2023: 184 · 2022: 174 · 2021: 157 · 2020: 49 · 2017: 1 · 2012: 1
- FWCI
- 86.20
- Type
- journal article
- Language
- en
- Update notices
- correction (2021-02-03)
- Open access
- hybrid
- doi.org
- Locations
- Nature (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, cc-by)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- HAL (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Työväentutkimus Vuosikirja (submittedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion, cc-by)
- Tampere University Institutional Repository (Tampere University) (submittedVersion, cc-by)
- STM:n Hallinnonalan avoin julkaisuarkisto (Julkari) (submittedVersion)
- Funders
- National Science Foundation (UL1-TR-000040, 2017240332, GRFP #2017240332)
- Simons Foundation (573206)
- Wellcome Trust (107469/Z/15/Z)
- Broad Institute
- Simons Foundation Autism Research Initiative (573206)
- British Heart Foundation (RG/18/10/33842, CS/14/2/30841)
- Rosetrees Trust
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (177853)
- National Institutes of Health (n01hc95164-17-0-1, 1ul1rr033176-01, UL1TR001420, 573206, n01hc95165-34-0-1, n01hc95161-24-0-1, n01hc095169-003, N01-HC- 95166, n01hc95166-21-0-1, N01-HC9-5168, n01hc95162-31-0-1, n01hc95168-27-0-1, n01hc95160-18-0-1, n01hc095167-000, N01-HC- 95159, UL1TR001079, n01hc95163-22-0-1, HHSN268201500003I, n01hc95159-40-0-1, UL1TR003098, KL2TR000107, UL1TR000040, UL1-TR-, N01‐HC‐95161, N01- HC-95163, N01- HC-95165, N01‐HC‐95160, N01 HC95164, N01-HC-95167, N01-HC95162, N01‐HC‐95169, DK-063491, ULTR001881, UL1TR001881)
- National Heart, Lung, and Blood Institute (DK-063491, R01HL071205, N01 HC-95159, N01-HC-95160, N01-HC095169, N01 HC-95168, N01-HC-095165, N01 HC95167, (N01-HC-95163, N01 HC095163, R01HL071259, N01 HC-95161, N01 HC95165, N01HC95164, HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95167, N01-HC-95168, N01-HC-95169, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, R01HL071251, N01-HC-95167, N01-HC-95168, UL1-TR-, N01-HC-095159, N01-HC, N01 HC095168, N01-HC-095162, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95161, N01-HC-95162, N01-HC-95163, HC-95168, N01-HC-095161, R01HL071051, R01HL071250, HHSN268201500003C, HHSN26820150 0003I, HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01, N01 HC095167, N01-HC-095160, N01 HC095166, HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01 HC095164, N01‐HC‐95166, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, R01HL071258, N01-HC-95159, N01-HC-95160, N01 HC-95162, HC95159, UL1RR033176, N01 HC95169)
- National Institute of Mental Health (R01MH111776, U01MH105669, R01MH085548, R01MH104964, R01MH115957, R01MH123451)
- National Human Genome Research Institute (K08HG010155, UM1HG008895, T32HG002295)
- National Institute of General Medical Sciences (P01GM061354)
- National Institute of Diabetes and Digestive and Kidney Diseases (U01DK078616, UM1DK078616, P30DK020572, P30DK063491)
- National Institute of Dental and Craniofacial Research (R00DE026824, K99DE026824)
- National Center for Research Resources (N01-HC-95166, N01-HC-95164, N01-HC-95168, N01-HC-95160, N01 HC 95169, N01-HC-95162, UL1-RR-033176, N01-HC-95163, N01 HC 95161, N01-HC-95159, N01 HC 95165, N01-HC-95167)
- National Center for Advancing Translational Sciences (N01-HC-95161, ULTR001881, N01-HC-95168, UL1-TR, N01-HC-95162, UL1RR033176, and UL1‐TR‐001420, N01-HC-95159, DK063491, N01-HC-95160, HHSN268201500003I, N01-HC-95166, N01-HC-95169, N01-HC-95163, N01-HC-95167, N01-HC-95165, N01-HC-95164)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD091797, R03HD099547, R01HD096326, P50HD028138, P01HD068250, R01HD081256)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genome Rearrangement Algorithms
- Keywords
- structural variants, gnomAD, population genomics, natural selection, truncating mutations, dosage sensitivity, cis-regulatory elements, incidental finding, rare variants, loss-of-function intolerance
- MeSH terms
- Whole Genome Sequencing, Disease, Female, Genetic Testing, Genetics, Medical, Genetics, Population, Humans, Male, Middle Aged, Mutation, Reference Standards, Selection, Genetic, Genetic Variation, Genome, Human, Polymorphism, Single Nucleotide, Racial Groups, Genotyping Techniques
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