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A structural variation reference for medical and population genetics

Author

Listed:
  • Ryan L. Collins

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Harvard Medical School)

  • Harrison Brand

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Massachusetts General Hospital and Harvard Medical School)

  • Konrad J. Karczewski

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Xuefang Zhao

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Massachusetts General Hospital and Harvard Medical School)

  • Jessica Alföldi

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Laurent C. Francioli

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Harvard Medical School)

  • Amit V. Khera

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Chelsea Lowther

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Massachusetts General Hospital and Harvard Medical School)

  • Laura D. Gauthier

    (Broad Institute of MIT and Harvard
    Broad Institute of MIT and Harvard)

  • Harold Wang

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Nicholas A. Watts

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Matthew Solomonson

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Anne O’Donnell-Luria

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Alexander Baumann

    (Broad Institute of MIT and Harvard)

  • Ruchi Munshi

    (Broad Institute of MIT and Harvard)

  • Mark Walker

    (Broad Institute of MIT and Harvard
    Broad Institute of MIT and Harvard)

  • Christopher W. Whelan

    (Broad Institute of MIT and Harvard)

  • Yongqing Huang

    (Broad Institute of MIT and Harvard)

  • Ted Brookings

    (Broad Institute of MIT and Harvard)

  • Ted Sharpe

    (Broad Institute of MIT and Harvard)

  • Matthew R. Stone

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Elise Valkanas

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Harvard Medical School)

  • Jack Fu

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Massachusetts General Hospital and Harvard Medical School)

  • Grace Tiao

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Kristen M. Laricchia

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Valentin Ruano-Rubio

    (Broad Institute of MIT and Harvard)

  • Christine Stevens

    (Broad Institute of MIT and Harvard)

  • Namrata Gupta

    (Broad Institute of MIT and Harvard)

  • Caroline Cusick

    (Broad Institute of MIT and Harvard)

  • Lauren Margolin

    (Broad Institute of MIT and Harvard)

  • Kent D. Taylor

    (Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center)

  • Henry J. Lin

    (Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center)

  • Stephen S. Rich

    (University of Virginia)

  • Wendy S. Post

    (Johns Hopkins University School of Medicine)

  • Yii-Der Ida Chen

    (Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center)

  • Jerome I. Rotter

    (Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center)

  • Chad Nusbaum

    (Broad Institute of MIT and Harvard
    Cellarity Inc.)

  • Anthony Philippakis

    (Broad Institute of MIT and Harvard)

  • Eric Lander

    (Broad Institute of MIT and Harvard
    Harvard Medical School
    MIT)

  • Stacey Gabriel

    (Broad Institute of MIT and Harvard)

  • Benjamin M. Neale

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Massachusetts General Hospital
    Broad Institute of MIT and Harvard)

  • Sekar Kathiresan

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Harvard Medical School
    Massachusetts General Hospital)

  • Mark J. Daly

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Massachusetts General Hospital
    Broad Institute of MIT and Harvard)

  • Eric Banks

    (Broad Institute of MIT and Harvard)

  • Daniel G. MacArthur

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Massachusetts General Hospital
    Harvard Medical School)

  • Michael E. Talkowski

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Massachusetts General Hospital and Harvard Medical School
    Broad Institute of MIT and Harvard)

Abstract

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.

Suggested Citation

  • Ryan L. Collins & Harrison Brand & Konrad J. Karczewski & Xuefang Zhao & Jessica Alföldi & Laurent C. Francioli & Amit V. Khera & Chelsea Lowther & Laura D. Gauthier & Harold Wang & Nicholas A. Watts , 2020. "A structural variation reference for medical and population genetics," Nature, Nature, vol. 581(7809), pages 444-451, May.
  • Handle: RePEc:nat:nature:v:581:y:2020:i:7809:d:10.1038_s41586-020-2287-8
    DOI: 10.1038/s41586-020-2287-8
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    Citations

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    Cited by:

    1. Sook Wah Yee & Luis Ferrández-Peral & Pol Alentorn-Moron & Claudia Fontsere & Merve Ceylan & Megan L. Koleske & Niklas Handin & Virginia M. Artegoitia & Giovanni Lara & Huan-Chieh Chien & Xujia Zhou &, 2024. "Illuminating the function of the orphan transporter, SLC22A10, in humans and other primates," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Parithi Balachandran & Isha A. Walawalkar & Jacob I. Flores & Jacob N. Dayton & Peter A. Audano & Christine R. Beck, 2022. "Transposable element-mediated rearrangements are prevalent in human genomes," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    3. Xiaoling Tong & Min-Jin Han & Kunpeng Lu & Shuaishuai Tai & Shubo Liang & Yucheng Liu & Hai Hu & Jianghong Shen & Anxing Long & Chengyu Zhan & Xin Ding & Shuo Liu & Qiang Gao & Bili Zhang & Linli Zhou, 2022. "High-resolution silkworm pan-genome provides genetic insights into artificial selection and ecological adaptation," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    4. Wenmin Sun & Dan Xiong & Jiamin Ouyang & Xueshan Xiao & Yi Jiang & Yingwei Wang & Shiqiang Li & Ziying Xie & Junwen Wang & Zhonghui Tang & Qingjiong Zhang, 2024. "Altered chromatin topologies caused by balanced chromosomal translocation lead to central iris hypoplasia," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    5. Zhikun Wu & Zehang Jiang & Tong Li & Chuanbo Xie & Liansheng Zhao & Jiaqi Yang & Shuai Ouyang & Yizhi Liu & Tao Li & Zhi Xie, 2021. "Structural variants in the Chinese population and their impact on phenotypes, diseases and population adaptation," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    6. Arthur S. Lee & Lauren J. Ayers & Michael Kosicki & Wai-Man Chan & Lydia N. Fozo & Brandon M. Pratt & Thomas E. Collins & Boxun Zhao & Matthew F. Rose & Alba Sanchis-Juan & Jack M. Fu & Isaac Wong & X, 2024. "A cell type-aware framework for nominating non-coding variants in Mendelian regulatory disorders," Nature Communications, Nature, vol. 15(1), pages 1-26, December.
    7. Robert Schöpflin & Uirá Souto Melo & Hossein Moeinzadeh & David Heller & Verena Laupert & Jakob Hertzberg & Manuel Holtgrewe & Nico Alavi & Marius-Konstantin Klever & Julius Jungnitsch & Emel Comak & , 2022. "Integration of Hi-C with short and long-read genome sequencing reveals the structure of germline rearranged genomes," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    8. Ramesh Rajaby & Dong-Xu Liu & Chun Hang Au & Yuen-Ting Cheung & Amy Yuet Ting Lau & Qing-Yong Yang & Wing-Kin Sung, 2023. "INSurVeyor: improving insertion calling from short read sequencing data," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    9. Zhuoran Xu & Quan Li & Luigi Marchionni & Kai Wang, 2023. "PhenoSV: interpretable phenotype-aware model for the prioritization of genes affected by structural variants," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    10. Cristian Groza & Carl Schwendinger-Schreck & Warren A. Cheung & Emily G. Farrow & Isabelle Thiffault & Juniper Lake & William B. Rizzo & Gilad Evrony & Tom Curran & Guillaume Bourque & Tomi Pastinen, 2024. "Pangenome graphs improve the analysis of structural variants in rare genetic diseases," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    11. Ludovica Montanucci & David Lewis-Smith & Ryan L. Collins & Lisa-Marie Niestroj & Shridhar Parthasarathy & Julie Xian & Shiva Ganesan & Marie Macnee & Tobias Brünger & Rhys H. Thomas & Michael Talkows, 2023. "Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    12. Jinlong Shi & Zhilong Jia & Jinxiu Sun & Xiaoreng Wang & Xiaojing Zhao & Chenghui Zhao & Fan Liang & Xinyu Song & Jiawei Guan & Xue Jia & Jing Yang & Qi Chen & Kang Yu & Qian Jia & Jing Wu & Depeng Wa, 2023. "Structural variants involved in high-altitude adaptation detected using single-molecule long-read sequencing," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    13. Joanna Hui Juan Tan & Zhihui Li & Mar Gonzalez Porta & Ramesh Rajaby & Weng Khong Lim & Ye An Tan & Rodrigo Toro Jimenez & Renyi Teo & Maxime Hebrard & Jack Ling Ow & Shimin Ang & Justin Jeyakani & Ya, 2024. "A Catalogue of Structural Variation across Ancestrally Diverse Asian Genomes," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    14. Yirong Shi & Yiwei Niu & Peng Zhang & Huaxia Luo & Shuai Liu & Sijia Zhang & Jiajia Wang & Yanyan Li & Xinyue Liu & Tingrui Song & Tao Xu & Shunmin He, 2023. "Characterization of genome-wide STR variation in 6487 human genomes," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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