Whole-Genome Sequencing in Autism Identifies Hot Spots for De Novo Germline Mutation | Zendy

Jacob J. Michaelson | Zendy; Yujian Shi | Zendy; Madhusudan Gujral | Zendy; Hancheng Zheng | Zendy; Dheeraj Malhotra | Zendy; Xin Jin | Zendy; Minghan Jian | Zendy; Guangming Liu | Zendy; Douglas S. Greer | Zendy; Abhishek Bhandari | Zendy; Wenting Wu | Zendy; Roser Corominas | Zendy; Áine Peoples | Zendy; Am Koren | Zendy; Athurva Gore | Zendy; Shuli Kang | Zendy; Guan Ning Lin | Zendy; Jasper A. Estabillo | Zendy; Therese Gadomski | Zendy; Balvindar Singh | Zendy; Kun Zhang | Zendy; Natacha Akshoomoff | Zendy; Christina Corsello | Zendy; Steven A. McCarroll | Zendy; Lilia M. Iakoucheva | Zendy; Yingrui Li | Zendy; Jun Wang | Zendy; Jonathan Sebat | Zendy

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Whole-Genome Sequencing in Autism Identifies Hot Spots for De Novo Germline Mutation

Author(s) -

Jacob J. Michaelson,

Yujian Shi,

Madhusudan Gujral,

Hancheng Zheng,

Dheeraj Malhotra,

Xin Jin,

Minghan Jian,

Guangming Liu,

Douglas S. Greer,

Abhishek Bhandari,

Wenting Wu,

Roser Corominas,

Áine Peoples,

Am Koren,

Athurva Gore,

Shuli Kang,

Guan Ning Lin,

Jasper A. Estabillo,

Therese Gadomski,

Balvindar Singh,

Kun Zhang,

Natacha Akshoomoff,

Christina Corsello,

Steven A. McCarroll,

Lilia M. Iakoucheva,

Yingrui Li,

Jun Wang,

Jonathan Sebat

Publication year - 2012

Publication title -

cell

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 26.304

H-Index - 776

eISSN - 1097-4172

pISSN - 0092-8674

DOI - 10.1016/j.cell.2012.11.019

Subject(s) - biology , genetics , mutation , genome , exome sequencing , germline mutation , gene , mutation rate , copy number variation , dna sequencing , somatic hypermutation , germline , b cell , antibody

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.

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