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Title: Genomic Patterns of De Novo Mutation in Simplex Autism

Abstract

In this study, to further our understanding of the genetic etiology of autism, we generated and analyzed genome sequence data from 516 idiopathic autism families (2,064 individuals). This resource includes > 59 million single-nucleotide variants (SNVs) and 9,212 private copy number variants (CNVs), of which 133,992 and 88 are de novo mutations (DNMs), respectively. We estimate a mutation rate of ~1.5 × 10-8 SNVs per site per generation with a significantly higher mutation rate in repetitive DNA. Comparing probands and unaffected siblings, we observe several DNM trends. Probands carry more gene-disruptive CNVs and SNVs, resulting in severe missense mutations and mapping to predicted fetal brain promoters and embryonic stem cell enhancers. These differences become more pronounced for autism genes (p = 1.8 × 10-3 , OR = 2.2). Patients are more likely to carry multiple coding and noncoding DNMs in different genes, which are enriched for expression in striatal neurons (p = 3 × 10-3 ), suggesting a path forward for genetically characterizing more complex cases of autism.

Authors:
; ; ; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1478260
Alternate Identifier(s):
OSTI ID: 1426741
Grant/Contract Number:  
AC02-05CH11231
Resource Type:
Published Article
Journal Name:
Cell
Additional Journal Information:
Journal Name: Cell Journal Volume: 171 Journal Issue: 3; Journal ID: ISSN 0092-8674
Publisher:
Elsevier
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; autism; de novo mutation; genome sequencing; mechanisms of disease; noncoding; regulatory; attributable fraction; multifactorial genetics; oligogenic

Citation Formats

Turner, Tychele N., Coe, Bradley P., Dickel, Diane E., Hoekzema, Kendra, Nelson, Bradley J., Zody, Michael C., Kronenberg, Zev N., Hormozdiari, Fereydoun, Raja, Archana, Pennacchio, Len A., Darnell, Robert B., and Eichler, Evan E. Genomic Patterns of De Novo Mutation in Simplex Autism. United States: N. p., 2017. Web. doi:10.1016/j.cell.2017.08.047.
Turner, Tychele N., Coe, Bradley P., Dickel, Diane E., Hoekzema, Kendra, Nelson, Bradley J., Zody, Michael C., Kronenberg, Zev N., Hormozdiari, Fereydoun, Raja, Archana, Pennacchio, Len A., Darnell, Robert B., & Eichler, Evan E. Genomic Patterns of De Novo Mutation in Simplex Autism. United States. https://doi.org/10.1016/j.cell.2017.08.047
Turner, Tychele N., Coe, Bradley P., Dickel, Diane E., Hoekzema, Kendra, Nelson, Bradley J., Zody, Michael C., Kronenberg, Zev N., Hormozdiari, Fereydoun, Raja, Archana, Pennacchio, Len A., Darnell, Robert B., and Eichler, Evan E. Sun . "Genomic Patterns of De Novo Mutation in Simplex Autism". United States. https://doi.org/10.1016/j.cell.2017.08.047.
@article{osti_1478260,
title = {Genomic Patterns of De Novo Mutation in Simplex Autism},
author = {Turner, Tychele N. and Coe, Bradley P. and Dickel, Diane E. and Hoekzema, Kendra and Nelson, Bradley J. and Zody, Michael C. and Kronenberg, Zev N. and Hormozdiari, Fereydoun and Raja, Archana and Pennacchio, Len A. and Darnell, Robert B. and Eichler, Evan E.},
abstractNote = {In this study, to further our understanding of the genetic etiology of autism, we generated and analyzed genome sequence data from 516 idiopathic autism families (2,064 individuals). This resource includes > 59 million single-nucleotide variants (SNVs) and 9,212 private copy number variants (CNVs), of which 133,992 and 88 are de novo mutations (DNMs), respectively. We estimate a mutation rate of ~1.5 × 10-8 SNVs per site per generation with a significantly higher mutation rate in repetitive DNA. Comparing probands and unaffected siblings, we observe several DNM trends. Probands carry more gene-disruptive CNVs and SNVs, resulting in severe missense mutations and mapping to predicted fetal brain promoters and embryonic stem cell enhancers. These differences become more pronounced for autism genes (p = 1.8 × 10-3 , OR = 2.2). Patients are more likely to carry multiple coding and noncoding DNMs in different genes, which are enriched for expression in striatal neurons (p = 3 × 10-3 ), suggesting a path forward for genetically characterizing more complex cases of autism.},
doi = {10.1016/j.cell.2017.08.047},
journal = {Cell},
number = 3,
volume = 171,
place = {United States},
year = {2017},
month = {10}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
https://doi.org/10.1016/j.cell.2017.08.047

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