title: Genome-wide characteristics ofde novomutations in autism.
abstract: De novomutations (DNMs) are important in Autism Spectrum Disorder (ASD), but so far analyses have mainly been on the ~1.5% of the genome encoding genes. Here, we performed whole genome sequencing (WGS) of 200 ASD parent-child trios and characterized germline and somatic DNMs. We confirmed that the majority of germline DNMs (75.6%) originated from the father, and these increased significantly with paternal age only (p=4.2×10-10). However, when clustered DNMs (those within 20kb) were found in ASD, not only did they mostly originate from the mother (p=7.7×10-13), but they could also be found adjacent tode novocopy number variations (CNVs) where the mutation rate was significantly elevated (p=2.4×10-24). By comparing DNMs detected in controls, we found a significant enrichment of predicted damaging DNMs in ASD cases (p=8.0×10-9; OR=1.84), of which 15.6% (p=4.3×10-3) and 22.5% (p=7.0×10-5) were in the non-coding or genic non-coding, respectively. The non-coding elements most enriched for DNM were untranslated regions of genes, boundaries involved in exon-skipping and DNase I hypersensitive regions. Using microarrays and a novel outlier detection test, we also found aberrant methylation profiles in 2/185 (1.1%) of ASD cases. These same individuals carried independently identified DNMs in the ASD risk- and epigenetic- genesDNMT3AandADNP.Our data begins to characterize different genome-wide DNMs, and highlight the contribution of non-coding variants, to the etiology of ASD.
authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
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authors.initials: RK
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authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
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authors.affiliation: BGI-Shenzhen, Yantian, Shenzhen, China.
authors.forename: Hongzhi
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authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
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authors.affiliation: Department of Electrical and Computer Engineering, University of Toronto, Toronto, Ontario, Canada.
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authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Bhooma
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authors.affiliation: BGI-Shenzhen, Yantian, Shenzhen, China.
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authors.affiliation: BGI-Shenzhen, Yantian, Shenzhen, China.
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authors.affiliation: BGI-Shenzhen, Yantian, Shenzhen, China.
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authors.affiliation: BGI-Shenzhen, Yantian, Shenzhen, China.
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authors.affiliation: BGI-Shenzhen, Yantian, Shenzhen, China.
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authors.affiliation: BGI-Shenzhen, Yantian, Shenzhen, China.
authors.forename: Xin
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authors.affiliation: BGI-Shenzhen, Yantian, Shenzhen, China.
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authors.affiliation: BGI-Shenzhen, Yantian, Shenzhen, China.
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authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
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authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
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authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
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authors.initials: JL
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authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
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authors.lastname: Wang
authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
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authors.initials: JR
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authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
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authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
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authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
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authors.lastname: Deneault
authors.affiliation: Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
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authors.initials: MT
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authors.affiliation: Center of Neurodevelopmental Disorders (KIND), Pediatric Neuropsychiatry Unit, Karolinska Institutet, Stockholm, Sweden.
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authors.initials: K
authors.lastname: Tammimies
authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
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authors.lastname: Uddin
authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Mehdi
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authors.lastname: Zarrei
authors.affiliation: BGI-Shenzhen, Yantian, Shenzhen, China.
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authors.lastname: Wang
authors.affiliation: BGI-Shenzhen, Yantian, Shenzhen, China.
authors.forename: Yingrui
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authors.affiliation: BGI-Shenzhen, Yantian, Shenzhen, China.
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authors.affiliation: BGI-Shenzhen, Yantian, Shenzhen, China.
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authors.lastname: Wang
authors.affiliation: BGI-Shenzhen, Yantian, Shenzhen, China.
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authors.affiliation: Google, Mountain View, California, USA.
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authors.affiliation: Google, Mountain View, California, USA.
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authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Molecular Genetics, Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
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authors.initials: CR
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authors.affiliation: Bloorview Research Institute, University of Toronto, Toronto, Ontario, Canada.
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authors.affiliation: Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada.
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authors.lastname: Zwaigenbaum
authors.affiliation: Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
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authors.initials: BA
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authors.affiliation: Autism Research Unit, The Hospital for Sick Children, Toronto, Ontario, Canada.
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authors.affiliation: Autism Research Unit, The Hospital for Sick Children, Toronto, Ontario, Canada; Child Youth and Family Services, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
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authors.affiliation: Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
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authors.affiliation: Department of Electrical and Computer Engineering, University of Toronto, Toronto, Ontario, Canada; Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada.
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authors.initials: BJ
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authors.affiliation: BGI-Shenzhen, Yantian, Shenzhen, China.
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authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada; McLaughlin Centre, University of Toronto, Toronto, Ontario, Canada.
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