1. Frequency and complexity of de novo structural mutation in autism
- Author
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Stephen Sanders, William M. Brandler, Lilia M. Iakoucheva, Gail E. Reiner, Christina Corsello, Eric Courchesne, Amanda C. Watts, Dheeraj Malhotra, Lawrence C. Wong, Keith K. Vaux, Renius Owen, Terry Solomon, Amina Noor, Alexandra G Moyzis, Jasper A. Estabillo, Timothy R. Chapman, Gabriel Rosanio, Karen Pierce, Therese E. Gadomski, Jonathan Sebat, Daniel J. Barrera, Alysson R. Muotri, Natacha Akshoomoff, Charles M. Strom, Danny Antaki, Michael Baughn, Abhishek Bhandari, Guan Ning Lin, Suzanne M. Leal, Oanh Hong, Karin V. Fuentes Fajardo, Jeffrey Yuan, Madhusudan Gujral, and Kang Zhang
- Subjects
Genetics ,0303 health sciences ,Sequence assembly ,Genomics ,Biology ,medicine.disease ,Bioinformatics ,Genome ,DNA sequencing ,Structural variation ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Autism ,Indel ,Genotyping ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
Genetic studies of Autism Spectrum Disorder (ASD) have established that de novo duplications and deletions contribute to risk. However, ascertainment of structural variation (SV) 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 cases, 26 sibling controls and their parents, we present an atlas of 1.2 million SVs (5,213/genome), comprising 11 different classes. We demonstrate a high diversity of de novo mutations, a majority of which were undetectable by previous methods. In addition, we observe 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%). 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
- 2015
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