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Whole-Genome Sequencing in Autism Identifies Hot Spots for De Novo Germline Mutation
Jacob J. Michaelson ,
Yujian Shi ,
Madhusudan Gujral ,
Hancheng Zheng ,
Dheeraj Malhotra ,
Xin Jin ,
Minghan Jian ,
Guangming Liu ,
Douglas Greer ,
Abhishek Bhandari ,
Wenting Wu ,
Roser Corominas ,
Áine Peoples ,
Amnon Koren ,
Athurva Gore ,
Shuli Kang ,
Guan Ning Lin ,
Jasper Estabillo ,
Therese Gadomski ,
Balvindar Singh ,
Kun Zhang ,
Natacha Akshoomoff ,
Christina Corsello ,
Steven McCarroll ,
Lilia M. Iakoucheva ,
Yingrui Li ,
Jun Wang ,
Jonathan Sebat
December 2012
December 2012
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Abstract
De novo mutation plays an important role in autism spectrum disorders (ASDs). Notably,
pathogenic copy number variants (CNVs) are characterized by high mutation rates. We
hypothesize that hypermutability is a property of ASD genes and may also include nucleotide-substitution
hot spots. We investigated global patterns of germline mutation by whole-genome sequencing
of monozygotic twins concordant for ASD and their parents. Mutation rates varied widely
throughout the genome (by 100-fold) and could be explained by intrinsic characteristics
of DNA sequence and chromatin structure. Dense clusters of mutations within individual
genomes were attributable to compound mutation or gene conversion. Hypermutability
was a characteristic of genes involved in ASD and other diseases. In addition, genes
impacted by mutations in this study were associated with ASD in independent exome-sequencing
data sets. Our findings suggest that regional hypermutation is a significant factor
shaping patterns of genetic variation and disease risk in humans.
Copyright © 2012 Elsevier Inc. All rights reserved.