Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations (original) (raw)

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Data deposits

Access to the raw sequence reads can be found at the NCBI database of Genotypes and Phenotypes (dbGaP) and National Database for Autism Research under accession numbers phs000482.v1.p1 and NDARCOL0001878, respectively.

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Acknowledgements

We would like to thank and recognize the following ongoing studies that produced and provided exome variant calls for comparison: NHLBI Lung Cohort Sequencing Project (HL 1029230), NHLBI WHI Sequencing Project (HL 102924), NIEHS SNPs (HHSN273200800010C), NHLBI/NHGRI SeattleSeq (HL 094976), and the Northwest Genomics Center (HL 102926). We are grateful to all of the families at the participating Simons Simplex Collection (SSC) sites, as well as the principal investigators (A. Beaudet, R. Bernier, J. Constantino, E. Cook, E. Fombonne, D. Geschwind, E. Hanson, D. Grice, A. Klin, R. Kochel, D. Ledbetter, C. Lord, C. Martin, D. Martin, R. Maxim, J. Miles, O. Ousley, K. Pelphrey, B. Peterson, J. Piggot, C. Saulnier, M. State, W. Stone, J. Sutcliffe, C. Walsh, Z. Warren and E. Wijsman). We also acknowledge M. State and the Simons Simplex Collection Genetics Consortium for providing Illumina genotyping data, T. Lehner and the Autism Sequencing Consortium for providing an opportunity for pre-publication data exchange among the participating groups. We appreciate obtaining access to phenotypic data on SFARI Base. This work was supported by the Simons Foundation Autism Research Initiative (SFARI 137578 and 191889; E.E.E., J.S. and R.B.) and NIH HD065285 (E.E.E. and J.S.). E.B. is an Alfred P. Sloan Research Fellow. E.E.E. is an Investigator of the Howard Hughes Medical Institute.

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Authors and Affiliations

1. Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA,
   Brian J. O’Roak, Laura Vives, Santhosh Girirajan, Emre Karakoc, Niklas Krumm, Bradley P. Coe, Roie Levy, Arthur Ko, Choli Lee, Joshua D. Smith, Emily H. Turner, Ian B. Stanaway, Benjamin Vernot, Maika Malig, Carl Baker, Joshua M. Akey, Elhanan Borenstein, Mark J. Rieder, Deborah A. Nickerson, Jay Shendure & Evan E. Eichler
2. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington 98195, USA,
   Beau Reilly & Raphael Bernier
3. Department of Computer Science and Engineering, University of Washington, Seattle, Washington 98195, USA,
   Elhanan Borenstein
4. Santa Fe Institute, Santa Fe, New Mexico 87501, USA,
   Elhanan Borenstein
5. Howard Hughes Medical Institute, Seattle, Washington 98195, USA,
   Evan E. Eichler

Authors

1. Brian J. O’Roak
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2. Laura Vives
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3. Santhosh Girirajan
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4. Emre Karakoc
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5. Niklas Krumm
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6. Bradley P. Coe
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7. Roie Levy
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8. Arthur Ko
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9. Choli Lee
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10. Joshua D. Smith
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11. Emily H. Turner
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12. Ian B. Stanaway
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13. Benjamin Vernot
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14. Maika Malig
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15. Carl Baker
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16. Beau Reilly
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17. Joshua M. Akey
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18. Elhanan Borenstein
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19. Mark J. Rieder
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20. Deborah A. Nickerson
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21. Raphael Bernier
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22. Jay Shendure
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23. Evan E. Eichler
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Contributions

E.E.E., J.S. and B.J.O. designed the study and drafted the manuscript. E.E.E. and J.S. supervised the study. R.B., B.R. and B.J.O. analysed the clinical information. R.B., L.V., S.G., E.K., N.K. and B.P.C. contributed to the manuscript. S.G., N.K., B.P.C., A.K., C.B., M.M. and L.V. generated and analysed CNV data. B.J.O. and L.V. performed MIP resequencing and mutation validations. I.B.S., E.H.T., B.J.O. and J.S. developed MIP protocol and analysis. B.V. and J.M.A. generated loci-specific mutation rate estimates. R.L. and E.B. performed PPI network analysis and simulations. E.K. performed DADA analysis. C.L. performed Illumina sequencing. J.D.S., I.B.S., E.H.T. and C.L. analysed sequence data. B.P.C. performed IPA analysis. B.J.O., E.K. and N.K. developed the de novo analysis pipelines and analysed sequence data. D.A.N., M.J.R., J.D.S. and E.H.T. supervised exome sequencing and primary analysis.

Corresponding authors

Correspondence toJay Shendure or Evan E. Eichler.

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Competing interests

E.E.E. is on the scientific advisory boards for Pacific Biosciences, Inc and SynapDx Corp. J.S. is a member of the scientific advisory board or serves as a consultant for Aria Diagnostics, Stratos Genomics, Good Start Genetics, and Adaptive TCR. B.J.O. is an inventor on patent PCT/US2009/30620: mutations in contactin associated protein 2 are associated with increased risk for idiopathic autism.

Supplementary information

Supplementary Information

This file contains Supplementary Discussion; Supplementary Figures 1–13; Supplementary Tables 2, 4, 6-13; and Supplementary References. (PDF 2170 kb)

Supplementary Tables

This file contains Supplementary Tables 1, 3 and 5 which give detailed information on exome capture, sequence coverage, paternal age, de novo mutation sites, and functional annotations. (XLS 203 kb)

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O’Roak, B., Vives, L., Girirajan, S. et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.Nature 485, 246–250 (2012). https://doi.org/10.1038/nature10989

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• Received: 08 September 2011
• Accepted: 23 February 2012
• Published: 04 April 2012
• Issue Date: 10 May 2012
• DOI: https://doi.org/10.1038/nature10989