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

      1 , 2 , 3 , 4 , 5 , 6 , 1 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 2 , 14 , 15 , 2 , 16 , 17 , 8 , 18 , 1 , 19 , 20 , 1 , 1 , 21 , 2 , 4 , 5 , 22 , 23 , 24 , 8 , 25 , 26 , 27 , 6 , 15 , 28 , 20 , 17 , 26 , 10 , 11 , 29 , 30 , 31 , 20 , 27 , 26 , 12 , 31 , 23 , 32 , 21 , 17 , 33 , 22 , 34 , 35 , 36 , 37 , 38 , 1 , 27 , 39 , 38 , 16 , 2 , 38 , 15 , 2 , 38 , 40 , 2 , 41 , 14 , 33 , 33 , 15 , 8 , 9 , 17 , 20 , 2 , 27 , 14 , 4 , 5 , The 1000 Genomes Project Consortium, 19 , 31 , 8 , 9 , 42 , 38 , 17 , 3 , 15 , 43 , 1 , 7 , @ , 2 , 17 , @

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          Structural variants (SVs) are implicated in numerous diseases and make up the majority of varying nucleotides among human genomes. Here we describe an integrated set of eight SV 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. Analyzing this set, we identify numerous gene-intersecting SVs exhibiting population stratification and describe naturally occurring homozygous gene knockouts suggesting the dispensability of a variety of human genes. We demonstrate that SVs are enriched on haplotypes identified by genome-wide association studies and exhibit enrichment for expression quantitative trait loci. Additionally, we uncover appreciable levels of SV complexity at different scales, including genic loci subject to clusters of repeated rearrangement and complex SVs with multiple breakpoints likely formed through individual mutational events. Our catalog will enhance future studies into SV demography, functional impact and disease association.

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          Most cited references20

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          Global variation in copy number in the human genome.

          Copy number variation (CNV) of DNA sequences is functionally significant but has yet to be fully ascertained. We have constructed a first-generation CNV map of the human genome through the study of 270 individuals from four populations with ancestry in Europe, Africa or Asia (the HapMap collection). DNA from these individuals was screened for CNV using two complementary technologies: single-nucleotide polymorphism (SNP) genotyping arrays, and clone-based comparative genomic hybridization. A total of 1,447 copy number variable regions (CNVRs), which can encompass overlapping or adjacent gains or losses, covering 360 megabases (12% of the genome) were identified in these populations. These CNVRs contained hundreds of genes, disease loci, functional elements and segmental duplications. Notably, the CNVRs encompassed more nucleotide content per genome than SNPs, underscoring the importance of CNV in genetic diversity and evolution. The data obtained delineate linkage disequilibrium patterns for many CNVs, and reveal marked variation in copy number among populations. We also demonstrate the utility of this resource for genetic disease studies.
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            Mechanisms of change in gene copy number.

            Deletions and duplications of chromosomal segments (copy number variants, CNVs) are a major source of variation between individual humans and are an underlying factor in human evolution and in many diseases, including mental illness, developmental disorders and cancer. CNVs form at a faster rate than other types of mutation, and seem to do so by similar mechanisms in bacteria, yeast and humans. Here we review current models of the mechanisms that cause copy number variation. Non-homologous end-joining mechanisms are well known, but recent models focus on perturbation of DNA replication and replication of non-contiguous DNA segments. For example, cellular stress might induce repair of broken replication forks to switch from high-fidelity homologous recombination to non-homologous repair, thus promoting copy number change.
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              Paired-end mapping reveals extensive structural variation in the human genome.

              Structural variation of the genome involves kilobase- to megabase-sized deletions, duplications, insertions, inversions, and complex combinations of rearrangements. We introduce high-throughput and massive paired-end mapping (PEM), a large-scale genome-sequencing method to identify structural variants (SVs) approximately 3 kilobases (kb) or larger that combines the rescue and capture of paired ends of 3-kb fragments, massive 454 sequencing, and a computational approach to map DNA reads onto a reference genome. PEM was used to map SVs in an African and in a putatively European individual and identified shared and divergent SVs relative to the reference genome. Overall, we fine-mapped more than 1000 SVs and documented that the number of SVs among humans is much larger than initially hypothesized; many of the SVs potentially affect gene function. The breakpoint junction sequences of more than 200 SVs were determined with a novel pooling strategy and computational analysis. Our analysis provided insights into the mechanisms of SV formation in humans.

                Author and article information

                4 September 2015
                1 October 2015
                01 April 2016
                : 526
                : 7571
                : 75-81
                [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
                Author notes

                Joint senior authors


                A full list of participants and institutions is in the supplementary material.

                Author contributions

                SV discovery & genotyping: R.E.H., P.H.S., T.R., E.J.G., A.Ab., K.Y., F.H., K.C., G.D., K.W., M.H.-Y.F., S.K., C.A., S.A.M., R.E.M., M.B.G., S.E.D., E.E.E., J.O.K.; SV merging & haplotype-integration: T.R., R.E.H., M.H.-Y.F., E.G., A.Me., S.McC.; SV validation: R.E.H., A.Ab., G.J., M.H.-Y.F., A.M.S., M.K.K., A.Ma., S.K., M.M., M.J.P.C., S.M., P.C., S.E., J.M.K., B.R., J.A.W., F.Y., T.Z., M.A.B., R.E.M., A.B., C.L., E.E.E., J.O.K.; additional analyses: A.Au., C.M., E.C., E.D., E.-W.L., F.K., J.H., Y.Z., X.S., F.P.C., M.M., M.J.P.C., G.M., S.M., D.A., T.B., J.C., Z.C., L.D., X.F., M.G., J.M.K., H.Y.K.L., Y.K., X.J.M., B.J.N., A.N., R.A.G., M.P., M.R., R.S., D.M.M., M.W., N.F.P., A.Q., E.S., A.S., A.A.S., A.U., C.Z., J.Z., W.Z., J.S., O.S.; data management & archiving: L.C, X.Z-B, P.F.; display items: P.H.S., T.R., E.J.G., A.A., Y.Z., J.H., M.H.-Y.F., K.Y., M.B.G., A.B., O.S., R.E.M., S.E.D., E.E.E., J.O.K.; organization of Supplementary Material: G.D., J.O.K., P.H.S., R.E.M.; SV Analysis group co-chairs: C.L., E.E.E., J.O.K.; manuscript writing: P.H.S., T.R., E.J.G., J.H., R.E.M., M.B.G., O.S., S.E.D., E.E.E., J.O.K.

                [@ ]Correspondence and requests for materials should be addressed to eee@ 123456gs.washington.edu (EEE) and korbel@ 123456embl.de (JOK)

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