Discovery and genotyping of genome structural polymorphism by sequencing on a population scale (original) (raw)

Nature Genetics volume 43, pages 269–276 (2011)Cite this article

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Abstract

Accurate and complete analysis of genome variation in large populations will be required to understand the role of genome variation in complex disease. We present an analytical framework for characterizing genome deletion polymorphism in populations using sequence data that are distributed across hundreds or thousands of genomes. Our approach uses population-level concepts to reinterpret the technical features of sequence data that often reflect structural variation. In the 1000 Genomes Project pilot, this approach identified deletion polymorphism across 168 genomes (sequenced at 4× average coverage) with sensitivity and specificity unmatched by other algorithms. We also describe a way to determine the allelic state or genotype of each deletion polymorphism in each genome; the 1000 Genomes Project used this approach to type 13,826 deletion polymorphisms (48–995,664 bp) at high accuracy in populations. These methods offer a way to relate genome structural polymorphism to complex disease in populations.

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Acknowledgements

The authors wish to thank the 1000 Genomes Structural Variation Analysis Group for helpful conversations throughout this work and for collaborative work to evaluate the sensitivity and specificity of structural variation discovery algorithms. We would particularly like to acknowledge K. Chen for creation of a high-quality breakpoint library for the 1000 Genomes Project, on which Genome STRiP's genotyping algorithm drew, and R. Mills for managing the 1000 Genomes Project deletion discovery sets and validation data. We also thank C. Stewart, K. Walter, M. Hurles and N. Patterson for helpful conversations during the course of this work; D. Altshuler, M. DePristo and M. Daly for helpful comments on the manuscript and figures; and the anonymous reviewers of this manuscript, whose feedback improved it. This work was supported by the National Human Genome Research Institute (U01HG005208-01S1) and by startup funds from the Department of Genetics at Harvard Medical School.

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Authors and Affiliations

  1. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA
    Robert E Handsaker, Joshua M Korn, James Nemesh & Steven A McCarroll
  2. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
    Robert E Handsaker, Joshua M Korn, James Nemesh & Steven A McCarroll
  3. Stanley Center for Psychiatric Disease Research, Cambridge, Massachusetts, USA
    Steven A McCarroll

Authors

  1. Robert E Handsaker
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  2. Joshua M Korn
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  3. James Nemesh
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  4. Steven A McCarroll
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Contributions

R.E.H., J.M.K., J.N. and S.A.M. conceived the analytical approaches. R.E.H. implemented the algorithms and performed the data analysis. R.E.H. and S.A.M. wrote the manuscript.

Corresponding author

Correspondence toSteven A McCarroll.

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The authors declare no competing financial interests.

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Handsaker, R., Korn, J., Nemesh, J. et al. Discovery and genotyping of genome structural polymorphism by sequencing on a population scale.Nat Genet 43, 269–276 (2011). https://doi.org/10.1038/ng.768

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