Frequency and Complexity of De Novo Structural Mutation in Autism

Overview

Journal Am J Hum Genet

Publisher Cell Press

Specialty Genetics

Date 2016 Mar 29

PMID 27018473

Citations 57

Authors

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

Affiliations

Soon will be listed here.

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.

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