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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.

SUBMITTER: Brandler WM 

PROVIDER: S-EPMC4833290 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Frequency and Complexity of De Novo Structural Mutation in Autism.

Brandler William M WM   Antaki Danny D   Gujral Madhusudan M   Noor Amina A   Rosanio Gabriel G   Chapman Timothy R TR   Barrera Daniel J DJ   Lin Guan Ning GN   Malhotra Dheeraj D   Watts Amanda C AC   Wong Lawrence C LC   Estabillo Jasper A JA   Gadomski Therese E TE   Hong Oanh O   Fajardo Karin V Fuentes KV   Bhandari Abhishek A   Owen Renius R   Baughn Michael M   Yuan Jeffrey J   Solomon Terry T   Moyzis Alexandra G AG   Maile Michelle S MS   Sanders Stephan J SJ   Reiner Gail E GE   Vaux Keith K KK   Strom Charles M CM   Zhang Kang K   Muotri Alysson R AR   Akshoomoff Natacha N   Leal Suzanne M SM   Pierce Karen K   Courchesne Eric E   Iakoucheva Lilia M LM   Corsello Christina C   Sebat Jonathan J  

American journal of human genetics 20160324 4


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  ...[more]

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