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Originally published in Science Express on 27 September 2007
Science 19 October 2007:
Vol. 318. no. 5849, pp. 420 - 426
DOI: 10.1126/science.1149504
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Research Articles

Paired-End Mapping Reveals Extensive Structural Variation in the Human Genome

Jan O. Korbel,1,2* Alexander Eckehart Urban,3* Jason P. Affourtit,4* Brian Godwin,4 Fabian Grubert,5 Jan Fredrik Simons,4 Philip M. Kim,1 Dean Palejev,5 Nicholas J. Carriero,6 Lei Du,4 Bruce E. Taillon,4 Zhoutao Chen,4 Andrea Tanzer,7,8,9 A. C. Eugenia Saunders,3 Jianxiang Chi,10 Fengtang Yang,10 Nigel P. Carter,10 Matthew E. Hurles,10 Sherman M. Weissman,5 Timothy T. Harkins,11 Mark B. Gerstein,1,6,12 Michael Egholm,4{dagger} Michael Snyder1,3{dagger}

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) ~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.

1 Molecular Biophysics and Biochemistry Department, Yale University, New Haven, CT 06520, USA.
2 European Molecular Biology Laboratory, 69117 Heidelberg, Germany.
3 Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06520, USA.
4 454 Life Sciences, A Roche Company, Branford, CT 06405, USA.
5 Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.
6 Department of Computer Science, Yale University, New Haven, CT 06520, USA.
7 Department of Ecology and Evolutionary Biology, Yale University, New Haven, CT 06520, USA.
8 Department of Computer Science, University of Leipzig, 04107 Leipzig, Germany.
9 Institute for Theoretical Chemistry, University of Vienna, 1090 Vienna, Austria.
10 The Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK.
11 Roche Applied Science, Indianapolis, IN 46250, USA.
12 Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: megholm{at}454.com (M.E.); michael.snyder{at}yale.edu (M.S.)

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