Frequency and Complexity of De Novo Structural Mutation in Autism

William M Brandler; Danny Antaki; Madhusudan Gujral; Amina Noor; Gabriel Rosanio; Timothy R Chapman; Daniel J Barrera; Guan Ning Lin; Dheeraj Malhotra; Amanda C Watts; Lawrence C Wong; Jasper A Estabillo; Therese E Gadomski; Oanh Hong; Karin V Fuentes Fajardo; Abhishek Bhandari; Renius Owen; Michael Baughn; Jeffrey Yuan; Terry Solomon; Alexandra G Moyzis; Michelle S Maile; Stephan J Sanders; Gail E Reiner; Keith K Vaux; Charles M Strom; Kang Zhang; Alysson R Muotri; Natacha Akshoomoff; Suzanne M Leal; Karen Pierce; Eric Courchesne; Lilia M Iakoucheva; Christina Corsello; Jonathan Sebat

doi:10.1016/j.ajhg.2016.02.018

Frequency and Complexity of De Novo Structural Mutation in Autism

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

Authors

William M Brandler¹, Danny Antaki², Madhusudan Gujral¹, Amina Noor¹, Gabriel Rosanio¹, Timothy R Chapman¹, Daniel J Barrera¹, Guan Ning Lin³, Dheeraj Malhotra¹, Amanda C Watts⁴, Lawrence C Wong⁵, Jasper A Estabillo⁵, Therese E Gadomski¹, Oanh Hong¹, Karin V Fuentes Fajardo¹, Abhishek Bhandari¹, Renius Owen⁶, Michael Baughn⁴, Jeffrey Yuan⁴, Terry Solomon⁴, Alexandra G Moyzis⁴, Michelle S Maile¹, Stephan J Sanders⁷, Gail E Reiner⁸, Keith K Vaux⁸, Charles M Strom⁶, Kang Zhang⁹, Alysson R Muotri¹⁰, Natacha Akshoomoff⁵, Suzanne M Leal¹¹, Karen Pierce¹², Eric Courchesne¹², Lilia M Iakoucheva³, Christina Corsello⁵, Jonathan Sebat¹³

Affiliations

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: [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

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

Abstract

Publication types

MeSH terms

Grants and funding