NDLI: Direct Measure of the De Novo Mutation Rate in Autism and Schizophrenia Cohorts

Content Provider	PubMed Central
Author	Awadalla, Philip Gauthier, Julie Myers, Rachel A. Casals, Ferran Hamdan, Fadi F. Griffing, Alexander R. Côté, Mélanie Henrion, Edouard Spiegelman, Dan Julien, Tarabeux Piton, Amélie Yang, Yan Boyko, Adam Bustamante, Carlos Xiong, Lan Rapoport, Judith L. Addington, Anjené M. Delisi, J. Lynn E. Krebs, Marie-odile Ridha, Joober Millet, Bruno Fombonne, Éric Mottron, Laurent Zilversmit, Martine Keebler, Jon Daoud, Hussein Marineau, Claude Roy-gagnon, Marie-hélène Dubé, Marie-pierre Adam, Eyre-walker Drapeau, Pierre Stone, Eric A. Lafrenière, Ronald G. Rouleau, Guy A.
Copyright Year	2010
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.
Related Links	http://dx.doi.org/10.1016/j.ajhg.2010.07.019
Ending Page	324
Page Count	9
Starting Page	316
File Format	PDF
ISSN	00029297
e-ISSN	15376605
Journal	American Journal of Human Genetics
Issue Number	3
Volume Number	87
Language	English
Publisher	Elsevier
Publisher Date	2010-09-01
Access Restriction	Open
Rights Holder	Elsevier
Subject Keyword	Genetics(clinical) Genetics Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Genetics Genetics (clinical)

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