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 Michael Snyder^1,3

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.

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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