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An integrated map of structural variation in 2,504 human genomes

Author

Listed:
  • Peter H. Sudmant

    (University of Washington)

  • Tobias Rausch

    (European Molecular Biology Laboratory (EMBL), Genome Biology Unit)

  • Eugene J. Gardner

    (Institute for Genome Sciences, University of Maryland School of Medicine)

  • Robert E. Handsaker

    (Harvard Medical School
    Program in Medical and Population Genetics, Broad Institute of MIT and Harvard)

  • Alexej Abyzov

    (Center for Individualized Medicine, Mayo Clinic)

  • John Huddleston

    (University of Washington
    Howard Hughes Medical Institute, University of Washington)

  • Yan Zhang

    (Program in Computational Biology and Bioinformatics, Yale University
    School of Medicine, Yale University)

  • Kai Ye

    (The Genome Institute, Washington University School of Medicine
    Washington University in St Louis)

  • Goo Jun

    (University of Michigan
    Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston)

  • Markus Hsi-Yang Fritz

    (European Molecular Biology Laboratory (EMBL), Genome Biology Unit)

  • Miriam K. Konkel

    (Louisiana State University)

  • Ankit Malhotra

    (The Jackson Laboratory for Genomic Medicine)

  • Adrian M. Stütz

    (European Molecular Biology Laboratory (EMBL), Genome Biology Unit)

  • Xinghua Shi

    (University of North Carolina at Charlotte)

  • Francesco Paolo Casale

    (European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus)

  • Jieming Chen

    (Program in Computational Biology and Bioinformatics, Yale University
    Integrated Graduate Program in Physical and Engineering Biology, Yale University)

  • Fereydoun Hormozdiari

    (University of Washington)

  • Gargi Dayama

    (University of Michigan)

  • Ken Chen

    (The University of Texas MD Anderson Cancer Center)

  • Maika Malig

    (University of Washington)

  • Mark J. P. Chaisson

    (University of Washington)

  • Klaudia Walter

    (The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus)

  • Sascha Meiers

    (European Molecular Biology Laboratory (EMBL), Genome Biology Unit)

  • Seva Kashin

    (Harvard Medical School
    Program in Medical and Population Genetics, Broad Institute of MIT and Harvard)

  • Erik Garrison

    (Boston College)

  • Adam Auton

    (Albert Einstein College of Medicine)

  • Hugo Y. K. Lam

    (Bina Technologies, Roche Sequencing)

  • Xinmeng Jasmine Mu

    (Program in Computational Biology and Bioinformatics, Yale University
    Cancer Program, Broad Institute of MIT and Harvard)

  • Can Alkan

    (Bilkent University)

  • Danny Antaki

    (University of California San Diego (UCSD))

  • Taejeong Bae

    (Center for Individualized Medicine, Mayo Clinic)

  • Eliza Cerveira

    (The Jackson Laboratory for Genomic Medicine)

  • Peter Chines

    (National Human Genome Research Institute, National Institutes of Health)

  • Zechen Chong

    (The University of Texas MD Anderson Cancer Center)

  • Laura Clarke

    (European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus)

  • Elif Dal

    (Bilkent University)

  • Li Ding

    (The Genome Institute, Washington University School of Medicine
    Washington University in St Louis
    Washington University in St Louis
    Siteman Cancer Center)

  • Sarah Emery

    (University of Michigan)

  • Xian Fan

    (The University of Texas MD Anderson Cancer Center)

  • Madhusudan Gujral

    (University of California San Diego (UCSD))

  • Fatma Kahveci

    (Bilkent University)

  • Jeffrey M. Kidd

    (University of Michigan
    University of Michigan)

  • Yu Kong

    (Albert Einstein College of Medicine)

  • Eric-Wubbo Lameijer

    (Molecular Epidemiology, Leiden University Medical Center)

  • Shane McCarthy

    (The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus)

  • Paul Flicek

    (European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus)

  • Richard A. Gibbs

    (Baylor College of Medicine)

  • Gabor Marth

    (Boston College)

  • Christopher E. Mason

    (The Department of Physiology and Biophysics and the HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine
    The Feil Family Brain and Mind Research Institute)

  • Androniki Menelaou

    (University of Oxford
    Center for Molecular Medicine, University Medical Center Utrecht)

  • Donna M. Muzny

    (Icahn School of Medicine, New York School of Natural Sciences)

  • Bradley J. Nelson

    (University of Washington)

  • Amina Noor

    (University of California San Diego (UCSD))

  • Nicholas F. Parrish

    (Institute for Virus Research, Kyoto University)

  • Matthew Pendleton

    (Icahn School of Medicine, New York School of Natural Sciences)

  • Andrew Quitadamo

    (University of North Carolina at Charlotte)

  • Benjamin Raeder

    (European Molecular Biology Laboratory (EMBL), Genome Biology Unit)

  • Eric E. Schadt

    (Icahn School of Medicine, New York School of Natural Sciences)

  • Mallory Romanovitch

    (The Jackson Laboratory for Genomic Medicine)

  • Andreas Schlattl

    (European Molecular Biology Laboratory (EMBL), Genome Biology Unit)

  • Robert Sebra

    (Icahn School of Medicine, New York School of Natural Sciences)

  • Andrey A. Shabalin

    (Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University)

  • Andreas Untergasser

    (European Molecular Biology Laboratory (EMBL), Genome Biology Unit
    Zentrum für Molekulare Biologie, University of Heidelberg)

  • Jerilyn A. Walker

    (Louisiana State University)

  • Min Wang

    (Baylor College of Medicine)

  • Fuli Yu

    (Baylor College of Medicine)

  • Chengsheng Zhang

    (The Jackson Laboratory for Genomic Medicine)

  • Jing Zhang

    (Program in Computational Biology and Bioinformatics, Yale University
    School of Medicine, Yale University)

  • Xiangqun Zheng-Bradley

    (European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus)

  • Wanding Zhou

    (The University of Texas MD Anderson Cancer Center)

  • Thomas Zichner

    (European Molecular Biology Laboratory (EMBL), Genome Biology Unit)

  • Jonathan Sebat

    (University of California San Diego (UCSD))

  • Mark A. Batzer

    (Louisiana State University)

  • Steven A. McCarroll

    (Harvard Medical School
    Program in Medical and Population Genetics, Broad Institute of MIT and Harvard)

  • Ryan E. Mills

    (University of Michigan
    University of Michigan)

  • Mark B. Gerstein

    (Program in Computational Biology and Bioinformatics, Yale University
    School of Medicine, Yale University
    Yale University)

  • Ali Bashir

    (Icahn School of Medicine, New York School of Natural Sciences)

  • Oliver Stegle

    (European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus)

  • Scott E. Devine

    (Institute for Genome Sciences, University of Maryland School of Medicine)

  • Charles Lee

    (The Jackson Laboratory for Genomic Medicine
    Ewha Womans University)

  • Evan E. Eichler

    (University of Washington
    Howard Hughes Medical Institute, University of Washington)

  • Jan O. Korbel

    (European Molecular Biology Laboratory (EMBL), Genome Biology Unit
    European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus)

Abstract

Structural variants are implicated in numerous diseases and make up the majority of varying nucleotides among human genomes. Here we describe an integrated set of eight structural variant classes comprising both balanced and unbalanced variants, which we constructed using short-read DNA sequencing data and statistically phased onto haplotype blocks in 26 human populations. Analysing this set, we identify numerous gene-intersecting structural variants exhibiting population stratification and describe naturally occurring homozygous gene knockouts that suggest the dispensability of a variety of human genes. We demonstrate that structural variants are enriched on haplotypes identified by genome-wide association studies and exhibit enrichment for expression quantitative trait loci. Additionally, we uncover appreciable levels of structural variant complexity at different scales, including genic loci subject to clusters of repeated rearrangement and complex structural variants with multiple breakpoints likely to have formed through individual mutational events. Our catalogue will enhance future studies into structural variant demography, functional impact and disease association.

Suggested Citation

  • Peter H. Sudmant & Tobias Rausch & Eugene J. Gardner & Robert E. Handsaker & Alexej Abyzov & John Huddleston & Yan Zhang & Kai Ye & Goo Jun & Markus Hsi-Yang Fritz & Miriam K. Konkel & Ankit Malhotra , 2015. "An integrated map of structural variation in 2,504 human genomes," Nature, Nature, vol. 526(7571), pages 75-81, October.
    • Handle: RePEc:nat:nature:v:526:y:2015:i:7571:d:10.1038_nature15394
    DOI: 10.1038/nature15394
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    Citations

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    Cited by:

    1. Yichen Henry Liu & Can Luo & Staunton G. Golding & Jacob B. Ioffe & Xin Maizie Zhou, 2024. "Tradeoffs in alignment and assembly-based methods for structural variant detection with long-read sequencing data," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    2. 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.
    3. Sudha Sunil Rajderkar & Kitt Paraiso & Maria Luisa Amaral & Michael Kosicki & Laura E. Cook & Fabrice Darbellay & Cailyn H. Spurrell & Marco Osterwalder & Yiwen Zhu & Han Wu & Sarah Yasmeen Afzal & Ma, 2024. "Dynamic enhancer landscapes in human craniofacial development," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    4. 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.
    5. Marsha M. Wheeler & Adrienne M. Stilp & Shuquan Rao & Bjarni V. Halldórsson & Doruk Beyter & Jia Wen & Anna V. Mihkaylova & Caitlin P. McHugh & John Lane & Min-Zhi Jiang & Laura M. Raffield & Goo Jun , 2022. "Whole genome sequencing identifies structural variants contributing to hematologic traits in the NHLBI TOPMed program," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    6. Junho Kim & August Yue Huang & Shelby L. Johnson & Jenny Lai & Laura Isacco & Ailsa M. Jeffries & Michael B. Miller & Michael A. Lodato & Christopher A. Walsh & Eunjung Alice Lee, 2022. "Prevalence and mechanisms of somatic deletions in single human neurons during normal aging and in DNA repair disorders," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    7. Can Luo & Yichen Henry Liu & Xin Maizie Zhou, 2024. "VolcanoSV enables accurate and robust structural variant calling in diploid genomes from single-molecule long read sequencing," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    8. 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.
    9. Qiliang Ding & Matthew M. Edwards & Ning Wang & Xiang Zhu & Alexa N. Bracci & Michelle L. Hulke & Ya Hu & Yao Tong & Joyce Hsiao & Christine J. Charvet & Sulagna Ghosh & Robert E. Handsaker & Kevin Eg, 2021. "The genetic architecture of DNA replication timing in human pluripotent stem cells," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    10. Xue Gao & Sheng Wang & Yan-Fen Wang & Shuang Li & Shi-Xin Wu & Rong-Ge Yan & Yi-Wen Zhang & Rui-Dong Wan & Zhen He & Ren-De Song & Xin-Quan Zhao & Dong-Dong Wu & Qi-En Yang, 2022. "Long read genome assemblies complemented by single cell RNA-sequencing reveal genetic and cellular mechanisms underlying the adaptive evolution of yak," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    11. Yu Chen & Amy Y. Wang & Courtney A. Barkley & Yixin Zhang & Xinyang Zhao & Min Gao & Mick D. Edmonds & Zechen Chong, 2023. "Deciphering the exact breakpoints of structural variations using long sequencing reads with DeBreak," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    12. 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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