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Accurate de novo and transmitted indel detection in exome-capture data using microassembly

Nature Methods volume 11, pages 1033–1036 (2014)Cite this article

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Abstract

We present an open-source algorithm, Scalpel (http://scalpel.sourceforge.net/), which combines mapping and assembly for sensitive and specific discovery of insertions and deletions (indels) in exome-capture data. A detailed repeat analysis coupled with a self-tuning k-mer strategy allows Scalpel to outperform other state-of-the-art approaches for indel discovery, particularly in regions containing near-perfect repeats. We analyzed 593 families from the Simons Simplex Collection and demonstrated Scalpel's power to detect long (≥30 bp) transmitted events and enrichment for de novo likely gene-disrupting indels in autistic children.

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Figure 1: Overview of the Scalpel algorithm workflow.
Figure 2: Concordance of indels between pipelines.
Figure 3: MiSeq validation.

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Sequence Read Archive

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Acknowledgements

The project was supported in part by the US National Institutes of Health (R01-HG006677) and US National Science Foundation (DBI-1350041) to M.C.S. and by the Cold Spring Harbor Laboratory (CSHL) Cancer Center Support Grant (5P30CA045508), the Stanley Institute for Cognitive Genomics and the Simons Foundation (SF51 and SF235988) to M.W. The DNA samples used in this work are included within SSC release 13. Approved researchers can obtain the SSC population data set described in this study by applying at https://base.sfari.org/. We thank S. Eskipehlivan for the technical assistance with the MiSeq validation experiments. We thank M. Bekritsky, S. Neuburgerand, M. Ronemus, D. Levy, B. Yamron and B. Mishra for helpful discussions and comments on the paper. We thank R. Aboukhalil for testing the software.

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Authors and Affiliations

  1. Simons Center for Quantitative Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA

    Giuseppe Narzisi, Ivan Iossifov, Yoon-ha Lee, Zihua Wang, Michael Wigler & Michael C Schatz

  2. New York Genome Center, New York, USA

    Giuseppe Narzisi

  3. Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA

    Jason A O'Rawe, Han Fang, Yiyang Wu & Gholson J Lyon

  4. Stony Brook University, Stony Brook, New York, USA

    Jason A O'Rawe, Han Fang, Yiyang Wu & Gholson J Lyon

Authors
  1. Giuseppe Narzisi
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  4. Han Fang
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  8. Gholson J Lyon
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  9. Michael Wigler
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Contributions

G.N. developed the software and conducted the computational experiments. G.N. and M.C.S. designed and analyzed the experiments. Y.W. assisted in designing the primers and performed the MiSeq validation experiments. J.A.O. designed the primers and analyzed the MiSeq data. H.F. and J.A.O. assisted with the computational experiments for the comparative analysis between different variant-detection pipelines. G.J.L. planned and supervised the experimental design for indel validation. Z.W. designed the primers and performed experiments for the validation of de novo and transmitted indels in the SSC. I.I., Y.-h.L. and M.W. assisted with the analysis of the SSC. G.N. and M.C.S. wrote the manuscript with input from all authors. All of the authors have read and approved the final manuscript.

Corresponding author

Correspondence to Giuseppe Narzisi.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–20, Supplementary Tables 1–11 and Supplementary Notes 1–6 (PDF 3587 kb)

Supplementary Data 1

Scripts and data used to generate Figure 3b (ZIP 225 kb)

Supplementary Data 2

List of 97 high-quality de novo indels in 593 SSC families (XLS 47 kb)

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Narzisi, G., O'Rawe, J., Iossifov, I. et al. Accurate de novo and transmitted indel detection in exome-capture data using microassembly. Nat Methods 11, 1033–1036 (2014). https://doi.org/10.1038/nmeth.3069

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