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PMID: 27018473 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Frequency and Complexity of De Novo Structural Mutation in Autism.

American journal of human genetics ·Vol. 98 ·No. 4 ·2016-04-07 ·Pages 667-79

Brandler WM, Antaki D, Gujral M, Noor A, Rosanio G, Chapman TR, Barrera DJ, Lin GN, Malhotra D, Watts AC, Wong LC, Estabillo JA, Gadomski TE, Hong O, Fajardo KV, Bhandari A, Owen R, Baughn M, Yuan J, Solomon T, Moyzis AG, Maile MS, Sanders SJ, Reiner GE, Vaux KK, Strom CM, Zhang K, Muotri AR, Akshoomoff N, Leal SM, Pierce K, Courchesne E, Iakoucheva LM, Corsello C, Sebat J

Abstract

Genetic studies of autism spectrum disorder (ASD) have established that de novo duplications and deletions contribute to risk. However, ascertainment of structural variants (SVs) has been restricted by the coarse resolution of current approaches. By applying a custom pipeline for SV discovery, genotyping, and de novo assembly to genome sequencing of 235 subjects (71 affected individuals, 26 healthy siblings, and their parents), we compiled an atlas of 29,719 SV loci (5,213/genome), comprising 11 different classes. We found a high diversity of de novo mutations, the majority of which were undetectable by previous methods. In addition, we observed complex mutation clusters where combinations of de novo SVs, nucleotide substitutions, and indels occurred as a single event. We estimate a high rate of structural mutation in humans (20%) and propose that genetic risk for ASD is attributable to an elevated frequency of gene-disrupting de novo SVs, but not an elevated rate of genome rearrangement.

MeSH Terms
Alleles Amino Acid Sequence Autism Spectrum Disorder/genetics Base Sequence Case-Control Studies Child DNA Copy Number Variations Female Gene Deletion Gene Duplication Gene Frequency Gene Rearrangement Genetic Loci Genome, Human Genotyping Techniques Humans INDEL Mutation Male Microarray Analysis Molecular Sequence Data Pedigree Reproducibility of Results Sensitivity and Specificity
Authors & Affiliations
35 authors, click to expand affiliations / ORCID
Brandler William M
Beyster Center for Genomics of Psychiatric Diseases, University of California, San Diego, La Jolla, CA 92093, USA; Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Antaki Danny
Beyster Center for Genomics of Psychiatric Diseases, University of California, San Diego, La Jolla, CA 92093, USA; Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA.
Gujral Madhusudan
Beyster Center for Genomics of Psychiatric Diseases, University of California, San Diego, La Jolla, CA 92093, USA; Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Noor Amina
Beyster Center for Genomics of Psychiatric Diseases, University of California, San Diego, La Jolla, CA 92093, USA; Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Rosanio Gabriel
Beyster Center for Genomics of Psychiatric Diseases, University of California, San Diego, La Jolla, CA 92093, USA; Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Chapman Timothy R
Beyster Center for Genomics of Psychiatric Diseases, University of California, San Diego, La Jolla, CA 92093, USA; Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Barrera Daniel J
Beyster Center for Genomics of Psychiatric Diseases, University of California, San Diego, La Jolla, CA 92093, USA; Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Lin Guan Ning
Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA.
Malhotra Dheeraj
Beyster Center for Genomics of Psychiatric Diseases, University of California, San Diego, La Jolla, CA 92093, USA; Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Watts Amanda C
Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA.
Wong Lawrence C
Rady Children's Hospital, San Diego, CA 92123, USA.
Estabillo Jasper A
Rady Children's Hospital, San Diego, CA 92123, USA.
Gadomski Therese E
Beyster Center for Genomics of Psychiatric Diseases, University of California, San Diego, La Jolla, CA 92093, USA; Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Hong Oanh
Beyster Center for Genomics of Psychiatric Diseases, University of California, San Diego, La Jolla, CA 92093, USA; Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Fajardo Karin V Fuentes
Beyster Center for Genomics of Psychiatric Diseases, University of California, San Diego, La Jolla, CA 92093, USA; Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Bhandari Abhishek
Beyster Center for Genomics of Psychiatric Diseases, University of California, San Diego, La Jolla, CA 92093, USA; Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Owen Renius
Quest Diagnostics Nichols Institute, San Juan Capistrano, CA 92675, USA.
Baughn Michael
Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA.
Yuan Jeffrey
Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA.
Solomon Terry
Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA.
Moyzis Alexandra G
Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA.
Maile Michelle S
Beyster Center for Genomics of Psychiatric Diseases, University of California, San Diego, La Jolla, CA 92093, USA; Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Sanders Stephan J
Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA.
Reiner Gail E
Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Vaux Keith K
Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Strom Charles M
Quest Diagnostics Nichols Institute, San Juan Capistrano, CA 92675, USA.
Zhang Kang
Department of Ophthalmology, University of California, San Diego, La Jolla, CA 92093, USA.
Muotri Alysson R
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Akshoomoff Natacha
Rady Children's Hospital, San Diego, CA 92123, USA.
Leal Suzanne M
Center for Statistical Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Pierce Karen
Department of Neuroscience, University of California, San Diego, La Jolla, CA 92093, USA.
Courchesne Eric
Department of Neuroscience, University of California, San Diego, La Jolla, CA 92093, USA.
Iakoucheva Lilia M
Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA.
Corsello Christina
Rady Children's Hospital, San Diego, CA 92123, USA.
Sebat Jonathan
Beyster Center for Genomics of Psychiatric Diseases, University of California, San Diego, La Jolla, CA 92093, USA; Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: [email protected].
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Article Info
Journal
American journal of human genetics
Abbr.
Am J Hum Genet
ISSN
1537-6605
DOI
10.1016/j.ajhg.2016.02.018
Email
[email protected]
Published
2016-04-07
Epub
2016-00-24
Pages
667-79
Language
English
Region
United States
NLM ID
0370475
PMCID
PMC4833290
Subset
IM
Grants
NIMH NIH HHS · R01 MH076431 · United States
NHGRI NIH HHS · U41 HG007497 · United States
NHGRI NIH HHS · HG007497 · United States
NICHD NIH HHS · R01 HD065288 · United States
NICHD NIH HHS · HD065288 · United States
NIMH NIH HHS · MH105524 · United States
NIMH NIH HHS · R21 MH104766 · United States
NIMH NIH HHS · R01 MH109885 · United States
NIMH NIH HHS · R01 MH105524 · United States
NIMH NIH HHS · MH076431 · United States
NIGMS NIH HHS · T32 GM008666 · United States
NIMH NIH HHS · MH104766 · United States
External Links
PubMed source DOI: 10.1016/j.ajhg.2016.02.018 PMC Full Text View journal details
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