title: An integrated map of structural variation in 2,504 human genomes.
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.
authors.affiliation: Department of Genome Sciences, University of Washington, 3720 15th Ave NE, Seattle, WA 98195-5065, USA.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Sudmant
authors.affiliation: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstr. 1, 69117 Heidelberg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Rausch
authors.affiliation: Institute for Genome Sciences, University of Maryland School of Medicine, 801 W Baltimore Street, Baltimore, MD 21201, USA.
authors.forename: Eugene J
authors.initials: EJ
authors.lastname: Gardner
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, 25 Shattuck Street, Boston, MA 02115, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Handsaker
authors.affiliation: Department of Health Sciences Research, Center for Individualized Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Alexej
authors.initials: A
authors.lastname: Abyzov
authors.affiliation: Department of Genome Sciences, University of Washington, 3720 15th Ave NE, Seattle, WA 98195-5065, USA.|Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA.
authors.forename: John
authors.initials: J
authors.lastname: Huddleston
authors.affiliation: Program in Computational Biology and Bioinformatics, Yale University, BASS 432&437, 266 Whitney Avenue, New Haven, CT 06520, USA.|Department of Molecular Biophysics and Biochemistry, School of Medicine, Yale University, 266 Whitney Ave, New Haven, CT 06520, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: The Genome Institute, Washington University School of Medicine, 4444 Forest Park Ave, St. Louis, MO 63108, USA.|Department of Genetics, Washington University in St. Louis, 4444 Forest Park Ave, St. Louis, MO 63108, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Ye
authors.affiliation: Department of Biostatistics and Center for Statistical Genetics, University of Michigan, 1415 Washington Heights, Ann Arbor, MI 48109, USA.|Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, 1200 Pressler St., Houston, TX 77030, USA.
authors.forename: Goo
authors.initials: G
authors.lastname: Jun
authors.affiliation: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstr. 1, 69117 Heidelberg, Germany.
authors.forename: Markus Hsi-Yang
authors.initials: MH
authors.lastname: Fritz
authors.affiliation: Department of Biological Sciences, Louisiana State University, 202 Life Sciences Building, Baton Rouge, LA 70803, USA.
authors.forename: Miriam K
authors.initials: MK
authors.lastname: Konkel
authors.affiliation: The Jackson Laboratory for Genomic Medicine, 10 Discovery 263 Farmington Ave, Farmington, CT 06030, USA.
authors.forename: Ankit
authors.initials: A
authors.lastname: Malhotra
authors.affiliation: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstr. 1, 69117 Heidelberg, Germany.
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Stütz
authors.affiliation: Department of Bioinformatics and Genomics, University of North Carolina at Charlotte, 9201 University City Blvd., Charlotte, NC 28223, USA.
authors.forename: Xinghua
authors.initials: X
authors.lastname: Shi
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD, United Kingdom.
authors.forename: Francesco Paolo
authors.initials: FP
authors.lastname: Casale
authors.affiliation: Program in Computational Biology and Bioinformatics, Yale University, BASS 432&437, 266 Whitney Avenue, New Haven, CT 06520, USA.|Integrated Graduate Program in Physical and Engineering Biology, Yale University, New Haven, CT 06520, USA.
authors.forename: Jieming
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Genome Sciences, University of Washington, 3720 15th Ave NE, Seattle, WA 98195-5065, USA.
authors.forename: Fereydoun
authors.initials: F
authors.lastname: Hormozdiari
authors.affiliation: Department of Computational Medicine & Bioinformatics, University of Michigan, 500 S. State Street, Ann Arbor, MI 48109, USA.
authors.forename: Gargi
authors.initials: G
authors.lastname: Dayama
authors.affiliation: The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Genome Sciences, University of Washington, 3720 15th Ave NE, Seattle, WA 98195-5065, USA.
authors.forename: Maika
authors.initials: M
authors.lastname: Malig
authors.affiliation: Department of Genome Sciences, University of Washington, 3720 15th Ave NE, Seattle, WA 98195-5065, USA.
authors.forename: Mark J P
authors.initials: MJP
authors.lastname: Chaisson
authors.affiliation: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.
authors.forename: Klaudia
authors.initials: K
authors.lastname: Walter
authors.affiliation: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstr. 1, 69117 Heidelberg, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Meiers
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, 25 Shattuck Street, Boston, MA 02115, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA.
authors.forename: Seva
authors.initials: S
authors.lastname: Kashin
authors.affiliation: Department of Biology, Boston College, 355 Higgins Hall, 140 Commonwealth Ave, Chestnut Hill, MA 02467, USA.
authors.forename: Erik
authors.initials: E
authors.lastname: Garrison
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, NY 10461, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Auton
authors.affiliation: Bina Technologies, Roche Sequencing, 555 Twin Dolphin Drive, Redwood City, CA 94065, USA.
authors.forename: Hugo Y K
authors.initials: HYK
authors.lastname: Lam
authors.affiliation: Program in Computational Biology and Bioinformatics, Yale University, BASS 432&437, 266 Whitney Avenue, New Haven, CT 06520, USA.|Cancer Program, Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA.
authors.forename: Xinmeng Jasmine
authors.initials: XJ
authors.lastname: Mu
authors.affiliation: Department of Computer Engineering, Bilkent University, 06800 Ankara, Turkey.
authors.forename: Can
authors.initials: C
authors.lastname: Alkan
authors.affiliation: University of California San Diego (UCSD), 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Danny
authors.initials: D
authors.lastname: Antaki
authors.affiliation: Department of Health Sciences Research, Center for Individualized Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Taejeong
authors.initials: T
authors.lastname: Bae
authors.affiliation: The Jackson Laboratory for Genomic Medicine, 10 Discovery 263 Farmington Ave, Farmington, CT 06030, USA.
authors.forename: Eliza
authors.initials: E
authors.lastname: Cerveira
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892 USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Chines
authors.affiliation: The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Zechen
authors.initials: Z
authors.lastname: Chong
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD, United Kingdom.
authors.forename: Laura
authors.initials: L
authors.lastname: Clarke
authors.affiliation: Department of Computer Engineering, Bilkent University, 06800 Ankara, Turkey.
authors.forename: Elif
authors.initials: E
authors.lastname: Dal
authors.affiliation: The Genome Institute, Washington University School of Medicine, 4444 Forest Park Ave, St. Louis, MO 63108, USA.|Department of Genetics, Washington University in St. Louis, 4444 Forest Park Ave, St. Louis, MO 63108, USA.|Department of Medicine, Washington University in St. Louis, 4444 Forest Park Ave, St. Louis, MO 63108, USA.|Siteman Cancer Center, 660 South Euclid Ave, St. Louis, MO 63110, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Ding
authors.affiliation: Department of Human Genetics, University of Michigan, 1241 Catherine Street, Ann Arbor, MI 48109, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Emery
authors.affiliation: The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Xian
authors.initials: X
authors.lastname: Fan
authors.affiliation: University of California San Diego (UCSD), 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Madhusudan
authors.initials: M
authors.lastname: Gujral
authors.affiliation: Department of Computer Engineering, Bilkent University, 06800 Ankara, Turkey.
authors.forename: Fatma
authors.initials: F
authors.lastname: Kahveci
authors.affiliation: Department of Biostatistics and Center for Statistical Genetics, University of Michigan, 1415 Washington Heights, Ann Arbor, MI 48109, USA.|Department of Human Genetics, University of Michigan, 1241 Catherine Street, Ann Arbor, MI 48109, USA.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Kidd
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, NY 10461, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Kong
authors.affiliation: Molecular Epidemiology, Leiden University Medical Center, Leiden 2300RA, The Netherlands.
authors.forename: Eric-Wubbo
authors.initials: EW
authors.lastname: Lameijer
authors.affiliation: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.
authors.forename: Shane
authors.initials: S
authors.lastname: McCarthy
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Flicek
authors.affiliation: Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.affiliation: Department of Biology, Boston College, 355 Higgins Hall, 140 Commonwealth Ave, Chestnut Hill, MA 02467, USA.
authors.forename: Gabor
authors.initials: G
authors.lastname: Marth
authors.affiliation: The Department of Physiology and Biophysics and the HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, 1305 York Avenue, Weill Cornell Medical College, New York, New York 10065, USA.|The Feil Family Brain and Mind Research Institute, 413 East 69th St, Weill Cornell Medical College, New York, New York 10065, USA.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Mason
authors.affiliation: University of Oxford, 1 South Parks Road, Oxford OX3 9DS, UK.|Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, 3584 CG, The Netherlands.
authors.forename: Androniki
authors.initials: A
authors.lastname: Menelaou
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine, Mount Sinai, NY School of Natural Sciences, 1428 Madison Ave, New York, NY 10029, USA.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Muzny
authors.affiliation: Department of Genome Sciences, University of Washington, 3720 15th Ave NE, Seattle, WA 98195-5065, USA.
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Nelson
authors.affiliation: University of California San Diego (UCSD), 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Amina
authors.initials: A
authors.lastname: Noor
authors.affiliation: Institute for Virus Research, Kyoto University, 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Nicholas F
authors.initials: NF
authors.lastname: Parrish
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine, Mount Sinai, NY School of Natural Sciences, 1428 Madison Ave, New York, NY 10029, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Pendleton
authors.affiliation: Department of Bioinformatics and Genomics, University of North Carolina at Charlotte, 9201 University City Blvd., Charlotte, NC 28223, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Quitadamo
authors.affiliation: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstr. 1, 69117 Heidelberg, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Raeder
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine, Mount Sinai, NY School of Natural Sciences, 1428 Madison Ave, New York, NY 10029, USA.
authors.forename: Eric E
authors.initials: EE
authors.lastname: Schadt
authors.affiliation: The Jackson Laboratory for Genomic Medicine, 10 Discovery 263 Farmington Ave, Farmington, CT 06030, USA.
authors.forename: Mallory
authors.initials: M
authors.lastname: Romanovitch
authors.affiliation: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstr. 1, 69117 Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schlattl
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine, Mount Sinai, NY School of Natural Sciences, 1428 Madison Ave, New York, NY 10029, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Sebra
authors.affiliation: Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University, 1112 East Clay Street, McGuire Hall, Richmond, VA 23298-0581, USA.
authors.forename: Andrey A
authors.initials: AA
authors.lastname: Shabalin
authors.affiliation: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstr. 1, 69117 Heidelberg, Germany.|Zentrum für Molekulare Biologie, University of Heidelberg, Im Neuenheimer Feld 282, 69120 Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Untergasser
authors.affiliation: Department of Biological Sciences, Louisiana State University, 202 Life Sciences Building, Baton Rouge, LA 70803, USA.
authors.forename: Jerilyn A
authors.initials: JA
authors.lastname: Walker
authors.affiliation: Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.affiliation: Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Fuli
authors.initials: F
authors.lastname: Yu
authors.affiliation: The Jackson Laboratory for Genomic Medicine, 10 Discovery 263 Farmington Ave, Farmington, CT 06030, USA.
authors.forename: Chengsheng
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Program in Computational Biology and Bioinformatics, Yale University, BASS 432&437, 266 Whitney Avenue, New Haven, CT 06520, USA.|Department of Molecular Biophysics and Biochemistry, School of Medicine, Yale University, 266 Whitney Ave, New Haven, CT 06520, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD, United Kingdom.
authors.forename: Xiangqun
authors.initials: X
authors.lastname: Zheng-Bradley
authors.affiliation: The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Wanding
authors.initials: W
authors.lastname: Zhou
authors.affiliation: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstr. 1, 69117 Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Zichner
authors.affiliation: University of California San Diego (UCSD), 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Sebat
authors.affiliation: Department of Biological Sciences, Louisiana State University, 202 Life Sciences Building, Baton Rouge, LA 70803, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Batzer
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, 25 Shattuck Street, Boston, MA 02115, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: McCarroll
authors.affiliation: Department of Computational Medicine & Bioinformatics, University of Michigan, 500 S. State Street, Ann Arbor, MI 48109, USA.|Department of Human Genetics, University of Michigan, 1241 Catherine Street, Ann Arbor, MI 48109, USA.
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Mills
authors.affiliation: Program in Computational Biology and Bioinformatics, Yale University, BASS 432&437, 266 Whitney Avenue, New Haven, CT 06520, USA.|Department of Molecular Biophysics and Biochemistry, School of Medicine, Yale University, 266 Whitney Ave, New Haven, CT 06520, USA.|Department of Computer Science, Yale University, 51 Prospect Street, New Haven, CT 06511, USA.
authors.forename: Mark B
authors.initials: MB
authors.lastname: Gerstein
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine, Mount Sinai, NY School of Natural Sciences, 1428 Madison Ave, New York, NY 10029, USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Bashir
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD, United Kingdom.
authors.forename: Oliver
authors.initials: O
authors.lastname: Stegle
authors.affiliation: Institute for Genome Sciences, University of Maryland School of Medicine, 801 W Baltimore Street, Baltimore, MD 21201, USA.
authors.forename: Scott E
authors.initials: SE
authors.lastname: Devine
authors.affiliation: The Jackson Laboratory for Genomic Medicine, 10 Discovery 263 Farmington Ave, Farmington, CT 06030, USA.|Department of Graduate Studies - Life Sciences, Ewha Womans University, Ewhayeodae-gil, Seodaemun-gu, Seoul, South Korea 120-750.
authors.forename: Charles
authors.initials: C
authors.lastname: Lee
authors.affiliation: Department of Genome Sciences, University of Washington, 3720 15th Ave NE, Seattle, WA 98195-5065, USA.|Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA.
authors.forename: Evan E
authors.initials: EE
authors.lastname: Eichler
authors.affiliation: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstr. 1, 69117 Heidelberg, Germany.|European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD, United Kingdom.
authors.forename: Jan O
authors.initials: JO
authors.lastname: Korbel
mesh_terms: D000595:Amino Acid Sequence; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation / Q000235:genetics*; D005826:Genetics, Medical; D005828:Genetics, Population; D015894:Genome, Human / Q000235:genetics*; D055106:Genome-Wide Association Study; D023281:Genomics; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006720:Homozygote; D006801:Humans; D008969:Molecular Sequence Data; D059645:Mutation Rate; D020161:Physical Chromosome Mapping; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion / Q000235:genetics