1. Frequency and Complexity of De Novo Structural Mutation in Autism
- Author
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Danny Antaki, Daniel J. Barrera, Oanh Hong, Karin V. Fuentes Fajardo, Alysson R. Muotri, Natacha Akshoomoff, Charles M. Strom, Stephen Sanders, Eric Courchesne, Gail E. Reiner, Jasper A. Estabillo, Christina Corsello, Keith K. Vaux, Guan Ning Lin, Terry Solomon, Amina Noor, Lilia M. Iakoucheva, William M. Brandler, Jeffrey Yuan, Renius Owen, Amanda C. Watts, Madhusudan Gujral, Kang Zhang, Karen Pierce, Dheeraj Malhotra, Michael Baughn, Abhishek Bhandari, Suzanne M. Leal, Michelle S. Maile, Gabriel Rosanio, Alexandra G Moyzis, Timothy R. Chapman, Therese E. Gadomski, Jonathan Sebat, and Lawrence C. Wong
- Subjects
Male ,0301 basic medicine ,Genotyping Techniques ,Autism Spectrum Disorder ,Autism ,Sequence assembly ,Medical and Health Sciences ,Genome ,Gene Frequency ,INDEL Mutation ,Gene Duplication ,2.1 Biological and endogenous factors ,Genetics(clinical) ,Aetiology ,Child ,Genetics (clinical) ,Pediatric ,Genetics & Heredity ,Gene Rearrangement ,Genetics ,Biological Sciences ,Pedigree ,Mental Health ,Autism spectrum disorder ,Female ,Human ,DNA Copy Number Variations ,Intellectual and Developmental Disabilities (IDD) ,Molecular Sequence Data ,Biology ,Sensitivity and Specificity ,Article ,DNA sequencing ,03 medical and health sciences ,Behavioral and Social Science ,medicine ,Humans ,Amino Acid Sequence ,Indel ,Genotyping ,Gene ,Alleles ,Base Sequence ,Genome, Human ,Human Genome ,Reproducibility of Results ,Microarray Analysis ,medicine.disease ,Brain Disorders ,030104 developmental biology ,Genetic Loci ,Case-Control Studies ,Gene Deletion - 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.
- Published
- 2016
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