title: Whole-genome sequencing in autism identifies hot spots for de novo germline mutation.
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.
authors.affiliation: Beyster Center for Genomics of Psychiatric Diseases, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Jacob J
authors.initials: JJ
authors.lastname: Michaelson
authors.forename: Yujian
authors.initials: Y
authors.lastname: Shi
authors.forename: Madhusudan
authors.initials: M
authors.lastname: Gujral
authors.forename: Hancheng
authors.initials: H
authors.lastname: Zheng
authors.forename: Dheeraj
authors.initials: D
authors.lastname: Malhotra
authors.forename: Xin
authors.initials: X
authors.lastname: Jin
authors.forename: Minghan
authors.initials: M
authors.lastname: Jian
authors.forename: Guangming
authors.initials: G
authors.lastname: Liu
authors.forename: Douglas
authors.initials: D
authors.lastname: Greer
authors.forename: Abhishek
authors.initials: A
authors.lastname: Bhandari
authors.forename: Wenting
authors.initials: W
authors.lastname: Wu
authors.forename: Roser
authors.initials: R
authors.lastname: Corominas
authors.forename: Aine
authors.initials: A
authors.lastname: Peoples
authors.forename: Amnon
authors.initials: A
authors.lastname: Koren
authors.forename: Athurva
authors.initials: A
authors.lastname: Gore
authors.forename: Shuli
authors.initials: S
authors.lastname: Kang
authors.forename: Guan Ning
authors.initials: GN
authors.lastname: Lin
authors.forename: Jasper
authors.initials: J
authors.lastname: Estabillo
authors.forename: Therese
authors.initials: T
authors.lastname: Gadomski
authors.forename: Balvindar
authors.initials: B
authors.lastname: Singh
authors.forename: Kun
authors.initials: K
authors.lastname: Zhang
authors.forename: Natacha
authors.initials: N
authors.lastname: Akshoomoff
authors.forename: Christina
authors.initials: C
authors.lastname: Corsello
authors.forename: Steven
authors.initials: S
authors.lastname: McCarroll
authors.forename: Lilia M
authors.initials: LM
authors.lastname: Iakoucheva
authors.forename: Yingrui
authors.initials: Y
authors.lastname: Li
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Jonathan
authors.initials: J
authors.lastname: Sebat
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000235:genetics*; D002460:Cell Line; D005091:Exons; D005260:Female; D055106:Genome-Wide Association Study; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008423:Maternal Age; D059645:Mutation Rate; D002679:Pan troglodytes / Q000235:genetics; D010331:Paternal Age; D017422:Sequence Analysis, DNA; D014430:Twins, Monozygotic