@article{337a0211b66644ca9e62477e15c1412f,
title = "Genomic Patterns of De Novo Mutation in Simplex Autism",
abstract = "To further our understanding of the genetic etiology of autism, we generated and analyzed genome sequence data from 516 idiopathic autism families (2,064 individuals). This resource includes >59 million single-nucleotide variants (SNVs) and 9,212 private copy number variants (CNVs), of which 133,992 and 88 are de novo mutations (DNMs), respectively. We estimate a mutation rate of ∼1.5 × 10−8 SNVs per site per generation with a significantly higher mutation rate in repetitive DNA. Comparing probands and unaffected siblings, we observe several DNM trends. Probands carry more gene-disruptive CNVs and SNVs, resulting in severe missense mutations and mapping to predicted fetal brain promoters and embryonic stem cell enhancers. These differences become more pronounced for autism genes (p = 1.8 × 10−3, OR = 2.2). Patients are more likely to carry multiple coding and noncoding DNMs in different genes, which are enriched for expression in striatal neurons (p = 3 × 10−3), suggesting a path forward for genetically characterizing more complex cases of autism. Genomic analysis of 516 families with an autistic child and an unaffected sibling suggests that simplex autism results from de novo mutation and is oligogenic.",
keywords = "attributable fraction, autism, de novo mutation, genome sequencing, mechanisms of disease, multifactorial genetics, noncoding, oligogenic, regulatory",
author = "Turner, {Tychele N.} and Coe, {Bradley P.} and Dickel, {Diane E.} and Kendra Hoekzema and Nelson, {Bradley J.} and Zody, {Michael C.} and Kronenberg, {Zev N.} and Fereydoun Hormozdiari and Archana Raja and Pennacchio, {Len A.} and Darnell, {Robert B.} and Eichler, {Evan E.}",
note = "Funding Information: We thank Tonia Brown for assistance in editing this manuscript. We are grateful to the NYGC sequencing production team for providing high-quality WGS data and Tom Maniatis, the scientific director of the NYGC, for his support and encouragement; Phil Green, Kelley Harris, and David Reich for helpful insights into the mutation rate analyses; Marta Benadetti and Stephan Sanders for working with us on initial family selection; and Natalia Volfovsky for assistance on general collection questions. We are thankful for discussions with Brian McNally and Skylar Thompson about IT optimizations during data production. Thanks also to Jason Underwood and Katy Munson for useful advice on the experimental design of the validation experiments. This work was supported by grants from the Simons Foundation Autism Research Initiative (SFARI 303241 and 385035) (to E.E.E.) and the NIH (R01MH101221 to E.E.E.; UM1 HG008901 to R.B.D.). The Centers for Common Disease Genomics are funded by the National Human Genome Research Institute and the National Heart, Lung, and Blood Institute and the GSP Coordinating Center (U24HG008956) contributed to cross-program scientific initiatives and provided logistical and general study coordination. Research conducted at the E.O. Lawrence Berkeley National Laboratory was additionally supported by NIH grants (R01HG003988 and U54HG006997) (to L.A.P.) and performed under a Department of Energy Contract (DE-AC02-05CH11231), University of California. This work was also supported by a postdoctoral fellowship grant from the Autism Science Foundation (#16-008) (to T.N.T.). We are grateful to all of the families at the participating SSC sites, as well as the principal investigators (A. Beaudet, R. Bernier, J. Constantino, E. Cook, E. Fombonne, D. Geschwind, R. Goin-Kochel, E. Hanson, D. Grice, A. Klin, 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 acknowledge obtaining access to phenotypic data on SFARI Base. E.E.E. and R.B.D. are investigators of the Howard Hughes Medical Institute. E.E.E. is on the scientific advisory board (SAB) of DNAnexus, Inc and was a consultant for Kunming University of Science and Technology (KUST) as part of the 1000 China Talent Program (2014?2016). Funding Information: We thank Tonia Brown for assistance in editing this manuscript. We are grateful to the NYGC sequencing production team for providing high-quality WGS data and Tom Maniatis, the scientific director of the NYGC, for his support and encouragement; Phil Green, Kelley Harris, and David Reich for helpful insights into the mutation rate analyses; Marta Benadetti and Stephan Sanders for working with us on initial family selection; and Natalia Volfovsky for assistance on general collection questions. We are thankful for discussions with Brian McNally and Skylar Thompson about IT optimizations during data production. Thanks also to Jason Underwood and Katy Munson for useful advice on the experimental design of the validation experiments. This work was supported by grants from the Simons Foundation Autism Research Initiative ( SFARI 303241 and 385035 ) (to E.E.E.) and the NIH ( R01MH101221 to E.E.E.; UM1 HG008901 to R.B.D.). The Centers for Common Disease Genomics are funded by the National Human Genome Research Institute and the National Heart, Lung, and Blood Institute and the GSP Coordinating Center ( U24HG008956 ) contributed to cross-program scientific initiatives and provided logistical and general study coordination. Research conducted at the E.O. Lawrence Berkeley National Laboratory was additionally supported by NIH grants ( R01HG003988 and U54HG006997 ) (to L.A.P.) and performed under a Department of Energy Contract ( DE-AC02-05CH11231 ), University of California. This work was also supported by a postdoctoral fellowship grant from the Autism Science Foundation (# 16-008 ) (to T.N.T.). We are grateful to all of the families at the participating SSC sites, as well as the principal investigators (A. Beaudet, R. Bernier, J. Constantino, E. Cook, E. Fombonne, D. Geschwind, R. Goin-Kochel, E. Hanson, D. Grice, A. Klin, 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 acknowledge obtaining access to phenotypic data on SFARI Base. E.E.E. and R.B.D. are investigators of the Howard Hughes Medical Institute. E.E.E. is on the scientific advisory board (SAB) of DNAnexus, Inc and was a consultant for Kunming University of Science and Technology (KUST) as part of the 1000 China Talent Program (2014–2016). Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",
year = "2017",
month = oct,
day = "19",
doi = "10.1016/j.cell.2017.08.047",
language = "English",
volume = "171",
pages = "710--722.e12",
journal = "Cell",
issn = "0092-8674",
number = "3",
}