title: Frequency and Complexity of De Novo Structural Mutation in Autism.
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.
authors.affiliation: 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.
authors.forename: William M
authors.initials: WM
authors.lastname: Brandler
authors.affiliation: 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.
authors.forename: Danny
authors.initials: D
authors.lastname: Antaki
authors.affiliation: 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.
authors.forename: Madhusudan
authors.initials: M
authors.lastname: Gujral
authors.affiliation: 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.
authors.forename: Amina
authors.initials: A
authors.lastname: Noor
authors.affiliation: 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.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Rosanio
authors.affiliation: 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.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Chapman
authors.affiliation: 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.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Barrera
authors.affiliation: Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Guan Ning
authors.initials: GN
authors.lastname: Lin
authors.affiliation: 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.
authors.forename: Dheeraj
authors.initials: D
authors.lastname: Malhotra
authors.affiliation: Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Amanda C
authors.initials: AC
authors.lastname: Watts
authors.affiliation: Rady Children's Hospital, San Diego, CA 92123, USA.
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Wong
authors.affiliation: Rady Children's Hospital, San Diego, CA 92123, USA.
authors.forename: Jasper A
authors.initials: JA
authors.lastname: Estabillo
authors.affiliation: 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.
authors.forename: Therese E
authors.initials: TE
authors.lastname: Gadomski
authors.affiliation: 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.
authors.forename: Oanh
authors.initials: O
authors.lastname: Hong
authors.affiliation: 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.
authors.forename: Karin V Fuentes
authors.initials: KV
authors.lastname: Fajardo
authors.affiliation: 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.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Bhandari
authors.affiliation: Quest Diagnostics Nichols Institute, San Juan Capistrano, CA 92675, USA.
authors.forename: Renius
authors.initials: R
authors.lastname: Owen
authors.affiliation: Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Baughn
authors.affiliation: Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Terry
authors.initials: T
authors.lastname: Solomon
authors.affiliation: Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Alexandra G
authors.initials: AG
authors.lastname: Moyzis
authors.affiliation: 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.
authors.forename: Michelle S
authors.initials: MS
authors.lastname: Maile
authors.affiliation: Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Stephan J
authors.initials: SJ
authors.lastname: Sanders
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Gail E
authors.initials: GE
authors.lastname: Reiner
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Keith K
authors.initials: KK
authors.lastname: Vaux
authors.affiliation: Quest Diagnostics Nichols Institute, San Juan Capistrano, CA 92675, USA.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Strom
authors.affiliation: Department of Ophthalmology, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Kang
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Alysson R
authors.initials: AR
authors.lastname: Muotri
authors.affiliation: Rady Children's Hospital, San Diego, CA 92123, USA.
authors.forename: Natacha
authors.initials: N
authors.lastname: Akshoomoff
authors.affiliation: Center for Statistical Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Leal
authors.affiliation: Department of Neuroscience, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Pierce
authors.affiliation: Department of Neuroscience, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Courchesne
authors.affiliation: Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Lilia M
authors.initials: LM
authors.lastname: Iakoucheva
authors.affiliation: Rady Children's Hospital, San Diego, CA 92123, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Corsello
authors.affiliation: 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.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Sebat
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000067877:Autism Spectrum Disorder / Q000235:genetics*; D001483:Base Sequence; D016022:Case-Control Studies; D002648:Child; D056915:DNA Copy Number Variations; D005260:Female; D017353:Gene Deletion; D020440:Gene Duplication; D005787:Gene Frequency; D015321:Gene Rearrangement; D056426:Genetic Loci; D015894:Genome, Human; D060005:Genotyping Techniques; D006801:Humans; D054643:INDEL Mutation; D008297:Male; D046228:Microarray Analysis; D008969:Molecular Sequence Data; D010375:Pedigree; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity