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Nature. 2015 Oct 1;526(7571):75-81. doi: 10.1038/nature15394.

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

Author information

1
Department of Genome Sciences, University of Washington, 3720 15th Ave NE, Seattle, WA 98195-5065, USA.
2
European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstr. 1, 69117 Heidelberg, Germany.
3
Institute for Genome Sciences, University of Maryland School of Medicine, 801 W Baltimore Street, Baltimore, MD 21201, USA.
4
Department of Genetics, Harvard Medical School, Boston, 25 Shattuck Street, Boston, MA 02115, USA.
5
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA.
6
Department of Health Sciences Research, Center for Individualized Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
7
Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA.
8
Program in Computational Biology and Bioinformatics, Yale University, BASS 432&437, 266 Whitney Avenue, New Haven, CT 06520, USA.
9
Department of Molecular Biophysics and Biochemistry, School of Medicine, Yale University, 266 Whitney Ave, New Haven, CT 06520, USA.
10
The Genome Institute, Washington University School of Medicine, 4444 Forest Park Ave, St. Louis, MO 63108, USA.
11
Department of Genetics, Washington University in St. Louis, 4444 Forest Park Ave, St. Louis, MO 63108, USA.
12
Department of Biostatistics and Center for Statistical Genetics, University of Michigan, 1415 Washington Heights, Ann Arbor, MI 48109, USA.
13
Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, 1200 Pressler St., Houston, TX 77030, USA.
14
Department of Biological Sciences, Louisiana State University, 202 Life Sciences Building, Baton Rouge, LA 70803, USA.
15
The Jackson Laboratory for Genomic Medicine, 10 Discovery 263 Farmington Ave, Farmington, CT 06030, USA.
16
Department of Bioinformatics and Genomics, University of North Carolina at Charlotte, 9201 University City Blvd., Charlotte, NC 28223, USA.
17
European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD, United Kingdom.
18
Integrated Graduate Program in Physical and Engineering Biology, Yale University, New Haven, CT 06520, USA.
19
Department of Computational Medicine & Bioinformatics, University of Michigan, 500 S. State Street, Ann Arbor, MI 48109, USA.
20
The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
21
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.
22
Department of Biology, Boston College, 355 Higgins Hall, 140 Commonwealth Ave, Chestnut Hill, MA 02467, USA.
23
Department of Genetics, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, NY 10461, USA.
24
Bina Technologies, Roche Sequencing, 555 Twin Dolphin Drive, Redwood City, CA 94065, USA.
25
Cancer Program, Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA.
26
Department of Computer Engineering, Bilkent University, 06800 Ankara, Turkey.
27
University of California San Diego (UCSD), 9500 Gilman Drive, La Jolla, CA 92093, USA.
28
National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892 USA.
29
Department of Medicine, Washington University in St. Louis, 4444 Forest Park Ave, St. Louis, MO 63108, USA.
30
Siteman Cancer Center, 660 South Euclid Ave, St. Louis, MO 63110, USA.
31
Department of Human Genetics, University of Michigan, 1241 Catherine Street, Ann Arbor, MI 48109, USA.
32
Molecular Epidemiology, Leiden University Medical Center, Leiden 2300RA, The Netherlands.
33
Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
34
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.
35
The Feil Family Brain and Mind Research Institute, 413 East 69th St, Weill Cornell Medical College, New York, New York 10065, USA.
36
University of Oxford, 1 South Parks Road, Oxford OX3 9DS, UK.
37
Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, 3584 CG, The Netherlands.
38
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.
39
Institute for Virus Research, Kyoto University, 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
40
Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University, 1112 East Clay Street, McGuire Hall, Richmond, VA 23298-0581, USA.
41
Zentrum für Molekulare Biologie, University of Heidelberg, Im Neuenheimer Feld 282, 69120 Heidelberg, Germany.
42
Department of Computer Science, Yale University, 51 Prospect Street, New Haven, CT 06511, USA.
43
Department of Graduate Studies - Life Sciences, Ewha Womans University, Ewhayeodae-gil, Seodaemun-gu, Seoul, South Korea 120-750.
#
Contributed equally

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.

PMID:
26432246
PMCID:
PMC4617611
DOI:
10.1038/nature15394
[Indexed for MEDLINE]
Free PMC Article

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