Mapping and sequencing of structural variation from eight human genomes

Jeffrey M. Kidd, Gregory M. Cooper, William F. Donahue, Hillary S. Hayden, Nick Sampas, Tina Graves, Nancy Hansen, Brian Teague, Can Alkan, Francesca Antonacci, Eric Haugen, Troy Zerr, N. Alice Yamada, Peter Tsang, Tera L. Newman, Eray Tüzün, Ze Cheng, Heather M. Ebling, Nadeem Tusneem, Robert David, Will Gillett, Karen A. Phelps, Molly Weaver, David Saranga, Adrianne Brand, Wei Tao, Erik Gustafson, Kevin McKernan, Lin Chen, Maika Malig, Joshua D. Smith, Joshua M. Korn, Steven A. McCarroll, David A. Altshuler, Daniel A. Peiffer, Michael Dorschner, John Stamatoyannopoulos, David Schwartz, Deborah A. Nickerson, James C. Mullikin, Richard K. Wilson, Laurakay Bruhn, Maynard V. Olson, Rajinder Kaul, Douglas R. Smith and Evan E. Eichler ()
Additional contact information
Jeffrey M. Kidd: University of Washington, Seattle, Washington 98195, USA
Gregory M. Cooper: University of Washington, Seattle, Washington 98195, USA
William F. Donahue: Agencourt Bioscience Corporation, Beverly, Massachusetts 01915, USA
Hillary S. Hayden: and University of Washington Genome Center, University of Washington, Seattle, Washington 98195, USA
Nick Sampas: Agilent Technologies, Santa Clara, California 95051, USA
Tina Graves: Washington University Genome Sequencing Center, School of Medicine, St Louis, Missouri 63108, USA
Nancy Hansen: Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
Brian Teague: Laboratory of Genetics, University of Wisconsin, Madison, Wisconsin 53706, USA
Can Alkan: University of Washington, Seattle, Washington 98195, USA
Francesca Antonacci: University of Washington, Seattle, Washington 98195, USA
Eric Haugen: and University of Washington Genome Center, University of Washington, Seattle, Washington 98195, USA
Troy Zerr: University of Washington, Seattle, Washington 98195, USA
N. Alice Yamada: Agilent Technologies, Santa Clara, California 95051, USA
Peter Tsang: Agilent Technologies, Santa Clara, California 95051, USA
Tera L. Newman: University of Washington, Seattle, Washington 98195, USA
Eray Tüzün: University of Washington, Seattle, Washington 98195, USA
Ze Cheng: University of Washington, Seattle, Washington 98195, USA
Heather M. Ebling: Agencourt Bioscience Corporation, Beverly, Massachusetts 01915, USA
Nadeem Tusneem: Agencourt Bioscience Corporation, Beverly, Massachusetts 01915, USA
Robert David: Agencourt Bioscience Corporation, Beverly, Massachusetts 01915, USA
Will Gillett: and University of Washington Genome Center, University of Washington, Seattle, Washington 98195, USA
Karen A. Phelps: and University of Washington Genome Center, University of Washington, Seattle, Washington 98195, USA
Molly Weaver: University of Washington, Seattle, Washington 98195, USA
David Saranga: Agencourt Bioscience Corporation, Beverly, Massachusetts 01915, USA
Adrianne Brand: Agencourt Bioscience Corporation, Beverly, Massachusetts 01915, USA
Wei Tao: Agencourt Bioscience Corporation, Beverly, Massachusetts 01915, USA
Erik Gustafson: Agencourt Bioscience Corporation, Beverly, Massachusetts 01915, USA
Kevin McKernan: Agencourt Bioscience Corporation, Beverly, Massachusetts 01915, USA
Lin Chen: University of Washington, Seattle, Washington 98195, USA
Maika Malig: University of Washington, Seattle, Washington 98195, USA
Joshua D. Smith: University of Washington, Seattle, Washington 98195, USA
Joshua M. Korn: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02114, USA
Steven A. McCarroll: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02114, USA
David A. Altshuler: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02114, USA
Daniel A. Peiffer: Illumina, Inc., 9885 Towne Centre Drive, San Diego, California 92121, USA
Michael Dorschner: University of Washington, Seattle, Washington 98195, USA
John Stamatoyannopoulos: University of Washington, Seattle, Washington 98195, USA
David Schwartz: Laboratory of Genetics, University of Wisconsin, Madison, Wisconsin 53706, USA
Deborah A. Nickerson: University of Washington, Seattle, Washington 98195, USA
James C. Mullikin: Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
Richard K. Wilson: Washington University Genome Sequencing Center, School of Medicine, St Louis, Missouri 63108, USA
Laurakay Bruhn: Agilent Technologies, Santa Clara, California 95051, USA
Maynard V. Olson: and University of Washington Genome Center, University of Washington, Seattle, Washington 98195, USA
Rajinder Kaul: and University of Washington Genome Center, University of Washington, Seattle, Washington 98195, USA
Douglas R. Smith: Agencourt Bioscience Corporation, Beverly, Massachusetts 01915, USA
Evan E. Eichler: University of Washington, Seattle, Washington 98195, USA

Nature, 2008, vol. 453, issue 7191, 56-64

Abstract: Abstract Genetic variation among individual humans occurs on many different scales, ranging from gross alterations in the human karyotype to single nucleotide changes. Here we explore variation on an intermediate scale—particularly insertions, deletions and inversions affecting from a few thousand to a few million base pairs. We employed a clone-based method to interrogate this intermediate structural variation in eight individuals of diverse geographic ancestry. Our analysis provides a comprehensive overview of the normal pattern of structural variation present in these genomes, refining the location of 1,695 structural variants. We find that 50% were seen in more than one individual and that nearly half lay outside regions of the genome previously described as structurally variant. We discover 525 new insertion sequences that are not present in the human reference genome and show that many of these are variable in copy number between individuals. Complete sequencing of 261 structural variants reveals considerable locus complexity and provides insights into the different mutational processes that have shaped the human genome. These data provide the first high-resolution sequence map of human structural variation—a standard for genotyping platforms and a prelude to future individual genome sequencing projects.

Date: 2008
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DOI: 10.1038/nature06862

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