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Am J Hum Genet. 2016 Apr 7;98(4):667-79. doi: 10.1016/j.ajhg.2016.02.018. Epub 2016 Mar 24.

Frequency and Complexity of De Novo Structural Mutation in Autism.

Author information

1
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.
2
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.
3
Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA.
4
Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA.
5
Rady Children's Hospital, San Diego, CA 92123, USA.
6
Quest Diagnostics Nichols Institute, San Juan Capistrano, CA 92675, USA.
7
Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA.
8
Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
9
Department of Ophthalmology, University of California, San Diego, La Jolla, CA 92093, USA.
10
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
11
Center for Statistical Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
12
Department of Neuroscience, University of California, San Diego, La Jolla, CA 92093, USA.
13
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: jsebat@ucsd.edu.

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.

PMID:
27018473
PMCID:
PMC4833290
DOI:
10.1016/j.ajhg.2016.02.018
[Indexed for MEDLINE]
Free PMC Article

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