Direct measure of the de novo mutation rate in autism and schizophrenia cohorts.
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.
Awadalla
Philip
P
Department of Pediatrics, Université de Montréal, Quebec, Canada. philip.awadalla@umontreal.ca
Gauthier
Julie
J
Myers
Rachel A
RA
Casals
Ferran
F
Hamdan
Fadi F
FF
Griffing
Alexander R
AR
Côté
Mélanie
M
Henrion
Edouard
E
Spiegelman
Dan
D
Tarabeux
Julien
J
Piton
Amélie
A
Yang
Yan
Y
Boyko
Adam
A
Bustamante
Carlos
C
Xiong
Lan
L
Rapoport
Judith L
JL
Addington
Anjené M
AM
DeLisi
J Lynn E
JL
Krebs
Marie-Odile
MO
Joober
Ridha
R
Millet
Bruno
B
Fombonne
Eric
E
Mottron
Laurent
L
Zilversmit
Martine
M
Keebler
Jon
J
Daoud
Hussein
H
Marineau
Claude
C
Roy-Gagnon
Marie-Hélène
MH
Dubé
Marie-Pierre
MP
Eyre-Walker
Adam
A
Drapeau
Pierre
P
Stone
Eric A
EA
Lafrenière
Ronald G
RG
Rouleau
Guy A
GA
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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