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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:
 [1];  [1];  [2];  [1];  [1];  [3];  [1];  [4];  [5];  [6];  [7];  [8]
  1. University of Washington School of Medicine, Seattle, WA (United States). Department of Genome Sciences
  2. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Functional Genomics Department
  3. New York Genome Center, New York, NY (United States)
  4. Univ. of California, Davis, CA (United States). Department of Biochemistry and Molecular Medicine
  5. University of Washington School of Medicine, Seattle, WA (United States). Department of Genome Sciences ; Univ. of Washington, Seattle, WA (United States). Howard Hughes Medical Institute
  6. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Functional Genomics Department ; USDOE Joint Genome Institute (JGI), Walnut Creek, CA (United States)
  7. New York Genome Center, New York, NY (United States); Rockefeller Univ., New York, NY (United States). Laboratory of Molecular Neuro-Oncology and Howard Hughes Medical Institute
  8. University of Washington School of Medicine, Seattle, WA (United States). Department of Genome Sciences ; Univ. of Washington, Seattle, WA (United States). Howard Hughes Medical Institute
Publication Date:
Research Org.:
Lawrence Berkeley National Laboratory (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 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. Thu . "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 = {9}
}

Journal Article:
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https://doi.org/10.1016/j.cell.2017.08.047

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Whole-genome deep-learning analysis identifies contribution of noncoding mutations to autism risk
text, January 2019

  • Zhou, Jian; Park, Christopher Y.; Theesfeld, Chandra L.
  • Nature Publishing Group
  • DOI: 10.5167/uzh-180927

PsyMuKB: An Integrative De Novo Variant Knowledge Base for Developmental Disorders
journal, August 2019

  • Lin, Guan Ning; Guo, Sijia; Tan, Xian
  • Genomics, Proteomics & Bioinformatics, Vol. 17, Issue 4
  • DOI: 10.1016/j.gpb.2019.10.002

Kevlar: A Mapping-Free Framework for Accurate Discovery of De Novo Variants
journal, August 2019


Rare variants in the genetic background modulate cognitive and developmental phenotypes in individuals carrying disease-associated variants
journal, September 2018


A genome-wide scan statistic framework for whole-genome sequence data analysis
journal, July 2019


Pathogenic POGZ mutation causes impaired cortical development and reversible autism-like phenotypes
journal, February 2020


Nucleosome positioning stability is a modulator of germline mutation rate variation across the human genome
journal, March 2020


Resting-state abnormalities in Autism Spectrum Disorders: A meta-analysis
journal, March 2019


Characteristics of induced mutations in offspring derived from irradiated mouse spermatogonia and mature oocytes
journal, January 2020


De Novo Mutation Rate Estimation in Wolves of Known Pedigree
journal, July 2019

  • Koch, Evan M.; Schweizer, Rena M.; Schweizer, Teia M.
  • Molecular Biology and Evolution, Vol. 36, Issue 11
  • DOI: 10.1093/molbev/msz159

ATP1A3 mosaicism in families with alternating hemiplegia of childhood
journal, April 2019

  • Yang, Xiaoling; Yang, Xiaoxu; Chen, Jiaoyang
  • Clinical Genetics, Vol. 96, Issue 1
  • DOI: 10.1111/cge.13539

Disruptive variants of CSDE1 associate with autism and interfere with neuronal development and synaptic transmission
journal, September 2019


Anatomically and Physiologically Based Reference Level for Measurement of Intracardiac Pressures
journal, October 1995


Recurrent de novo mutations in neurodevelopmental disorders: properties and clinical implications
journal, November 2017


Dissecting the genetic basis of comorbid epilepsy phenotypes in neurodevelopmental disorders
journal, October 2019


An autism-causing calcium channel variant functions with selective autophagy to alter axon targeting and behavior
journal, December 2019


De novo Mutations (DNMs) in Autism Spectrum Disorder (ASD): Pathway and Network Analysis
journal, September 2018

  • Alonso-Gonzalez, Aitana; Rodriguez-Fontenla, Cristina; Carracedo, Angel
  • Frontiers in Genetics, Vol. 9
  • DOI: 10.3389/fgene.2018.00406

Genetic Causes and Modifiers of Autism Spectrum Disorder
journal, August 2019


Functional Genomics of Epilepsy and Associated Neurodevelopmental Disorders Using Simple Animal Models: From Genes, Molecules to Brain Networks
journal, December 2019

  • Rosch, Richard; Burrows, Dominic R. W.; Jones, Laura B.
  • Frontiers in Cellular Neuroscience, Vol. 13
  • DOI: 10.3389/fncel.2019.00556

Comparative Analysis for the Performance of Variant Calling Pipelines on Detecting the de novo Mutations in Humans
journal, April 2019


The Relevance of Variants With Unknown Significance for Autism Spectrum Disorder Considering the Genotype–Phenotype Interrelationship
journal, June 2019

  • Lovato, Diogo V.; Herai, Roberto R.; Pignatari, Graciela C.
  • Frontiers in Psychiatry, Vol. 10
  • DOI: 10.3389/fpsyt.2019.00409

Genetic Instability and Chromatin Remodeling in Spermatids
journal, January 2019

  • Cavé, Tiphanie; Desmarais, Rebecka; Lacombe-Burgoyne, Chloé
  • Genes, Vol. 10, Issue 1
  • DOI: 10.3390/genes10010040

The novel lncRNA lnc-NR2F1 is pro-neurogenic and mutated in human neurodevelopmental disorders
journal, January 2019


Large, three-generation human families reveal post-zygotic mosaicism and variability in germline mutation accumulation
journal, September 2019