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Nucleotide-resolution analysis of structural variants using BreakSeq and a breakpoint library

Nature Biotechnology volume 28, pages 47–55 (2010)Cite this article

Abstract

Structural variants (SVs) are a major source of human genomic variation; however, characterizing them at nucleotide resolution remains challenging. Here we assemble a library of breakpoints at nucleotide resolution from collating and standardizing ~2,000 published SVs. For each breakpoint, we infer its ancestral state (through comparison to primate genomes) and its mechanism of formation (e.g., nonallelic homologous recombination, NAHR). We characterize breakpoint sequences with respect to genomic landmarks, chromosomal location, sequence motifs and physical properties, finding that the occurrence of insertions and deletions is more balanced than previously reported and that NAHR-formed breakpoints are associated with relatively rigid, stable DNA helices. Finally, we demonstrate an approach, BreakSeq, for scanning the reads from short-read sequenced genomes against our breakpoint library to accurately identify previously overlooked SVs, which we then validate by PCR. As new data become available, we expect our BreakSeq approach will become more sensitive and facilitate rapid SV genotyping of personal genomes.

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Figure 1: Composition of the SV breakpoint library.
Figure 2: Mapping breakpoints using the library.
Figure 3: Ancestral state classification.
Figure 4: Inferring mechanisms of SV formation.
Figure 5: Analysis of breakpoint features.

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Acknowledgements

We acknowledge support from the National Institutes of Health, the A.L. Williams Professorship funds and the European Molecular Biology Laboratory. We thank R. Alexander and E. Khurana for proofreading the manuscript, and A. Abyzov, Z. Zhang, T. Rausch and J. Du for helpful discussions. Finally, we thank the 1000 Genomes Project for early data access.

Author information

Author notes

  1. Michael Snyder

    Present address: Present address: Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.,

  2. Hugo Y K Lam, Xinmeng Jasmine Mu and Jan O Korbel: These authors contributed equally to this work.

Authors and Affiliations

  1. Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut, USA

    Hugo Y K Lam, Xinmeng Jasmine Mu & Mark B Gerstein

  2. Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut, USA

    Xinmeng Jasmine Mu & Michael Snyder

  3. Genome Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany

    Adrian M Stütz & Jan O Korbel

  4. Institute for Theoretical Chemistry, University of Vienna, Vienna, Austria

    Andrea Tanzer

  5. Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, USA

    Philip D Cayting & Mark B Gerstein

  6. Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada

    Philip M Kim

  7. Banting and Best Department of Medical Research, University of Toronto, Toronto, Ontario, Canada

    Philip M Kim

  8. Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada

    Philip M Kim

  9. Department of Computer Science, University of Toronto, Toronto, Ontario, Canada

    Philip M Kim

  10. European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK

    Jan O Korbel

  11. Department of Computer Science, Yale University, New Haven, Connecticut, USA

    Mark B Gerstein

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Contributions

H.Y.K.L., X.J.M. and J.O.K. contributed equally to this work; M.B.G. and J.O.K. co-directed this work; M.B.G., J.O.K., H.Y.K.L. and X.J.M. designed the research; H.Y.K.L., X.J.M., A.M.S., A.T., P.D.C., M.S., P.M.K. and J.O.K. performed or provided direction for the analyses and/or experiments; M.B.G., J.O.K., H.Y.K.L., X.J.M., P.M.K. and A.T. wrote the manuscript.

Corresponding authors

Correspondence to Jan O Korbel or Mark B Gerstein.

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Lam, H., Mu, X., Stütz, A. et al. Nucleotide-resolution analysis of structural variants using BreakSeq and a breakpoint library. Nat Biotechnol 28, 47–55 (2010). https://doi.org/10.1038/nbt.1600

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