title: Direct measure of the de novo mutation rate in autism and schizophrenia cohorts.
abstract: The role of de novo mutations (DNMs) in common diseases remains largely unknown. Nonetheless, the rate of de novo deleterious mutations and the strength of selection against de novo mutations are critical to understanding the genetic architecture of a disease. Discovery of high-impact DNMs requires substantial high-resolution interrogation of partial or complete genomes of families via resequencing. We hypothesized that deleterious DNMs may play a role in cases of autism spectrum disorders (ASD) and schizophrenia (SCZ), two etiologically heterogeneous disorders with significantly reduced reproductive fitness. We present a direct measure of the de novo mutation rate (μ) and selective constraints from DNMs estimated from a deep resequencing data set generated from a large cohort of ASD and SCZ cases (n = 285) and population control individuals (n = 285) with available parental DNA. A survey of ∼430 Mb of DNA from 401 synapse-expressed genes across all cases and 25 Mb of DNA in controls found 28 candidate DNMs, 13 of which were cell line artifacts. Our calculated direct neutral mutation rate (1.36 × 10(-8)) is similar to previous indirect estimates, but we observed a significant excess of potentially deleterious DNMs in ASD and SCZ individuals. Our results emphasize the importance of DNMs as genetic mechanisms in ASD and SCZ and the limitations of using DNA from archived cell lines to identify functional variants.
authors.affiliation: Department of Pediatrics, Université de Montréal, Quebec, Canada. philip.awadalla@umontreal.ca
authors.forename: Philip
authors.initials: P
authors.lastname: Awadalla
authors.forename: Julie
authors.initials: J
authors.lastname: Gauthier
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Myers
authors.forename: Ferran
authors.initials: F
authors.lastname: Casals
authors.forename: Fadi F
authors.initials: FF
authors.lastname: Hamdan
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Griffing
authors.forename: Mélanie
authors.initials: M
authors.lastname: Côté
authors.forename: Edouard
authors.initials: E
authors.lastname: Henrion
authors.forename: Dan
authors.initials: D
authors.lastname: Spiegelman
authors.forename: Julien
authors.initials: J
authors.lastname: Tarabeux
authors.forename: Amélie
authors.initials: A
authors.lastname: Piton
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.forename: Adam
authors.initials: A
authors.lastname: Boyko
authors.forename: Carlos
authors.initials: C
authors.lastname: Bustamante
authors.forename: Lan
authors.initials: L
authors.lastname: Xiong
authors.forename: Judith L
authors.initials: JL
authors.lastname: Rapoport
authors.forename: Anjené M
authors.initials: AM
authors.lastname: Addington
authors.forename: J Lynn E
authors.initials: JL
authors.lastname: DeLisi
authors.forename: Marie-Odile
authors.initials: MO
authors.lastname: Krebs
authors.forename: Ridha
authors.initials: R
authors.lastname: Joober
authors.forename: Bruno
authors.initials: B
authors.lastname: Millet
authors.forename: Eric
authors.initials: E
authors.lastname: Fombonne
authors.forename: Laurent
authors.initials: L
authors.lastname: Mottron
authors.forename: Martine
authors.initials: M
authors.lastname: Zilversmit
authors.forename: Jon
authors.initials: J
authors.lastname: Keebler
authors.forename: Hussein
authors.initials: H
authors.lastname: Daoud
authors.forename: Claude
authors.initials: C
authors.lastname: Marineau
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Roy-Gagnon
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Dubé
authors.forename: Adam
authors.initials: A
authors.lastname: Eyre-Walker
authors.forename: Pierre
authors.initials: P
authors.lastname: Drapeau
authors.forename: Eric A
authors.initials: EA
authors.lastname: Stone
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Lafrenière
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
mesh_terms: D001321:Autistic Disorder / Q000235:genetics*; D020029:Base Pairing / Q000235:genetics; D002460:Cell Line; D020090:Chromosome Segregation / Q000235:genetics; D015331:Cohort Studies; D004252:DNA Mutational Analysis / Q000379:methods*; D005190:Family; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D016296:Mutagenesis / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics*
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