Direct measure of the de novo mutation rate in autism and schizophrenia cohorts

Philip Awadalla; Julie Gauthier; Rachel A. Myers; Ferran Casals; Fadi F. Hamdan; Alexander R. Griffing; Mélanie Côté; Edouard Henrion; Dan Spiegelman; Julien Tarabeux; Amélie Piton; Yan Yang; Adam Boyko; Carlos Bustamante; Lan Xiong; Judith L. Rapoport; Anjené M. Addington; J. Lynn E. Delisi; Marie Odile Krebs; Ridha Joober; Bruno Millet; Éric Fombonne; Laurent Mottron; Martine Zilversmit; Jon Keebler; Hussein Daoud; Claude Marineau; Marie Hélne Roy-Gagnon; Marie Pierre Dubé; Adam Eyre-Walker; Pierre Drapeau; Eric A. Stone; Ronald G. Lafrenire; Guy A. Rouleau

doi:10.1016/j.ajhg.2010.07.019

Direct measure of the de novo mutation rate in autism and schizophrenia cohorts

Philip Awadalla, Julie Gauthier, Rachel A. Myers, Ferran Casals, Fadi F. Hamdan, Alexander R. Griffing, Mélanie Côté, Edouard Henrion, Dan Spiegelman, Julien Tarabeux, Amélie Piton, Yan Yang, Adam Boyko, Carlos Bustamante, Lan Xiong, Judith L. Rapoport, Anjené M. Addington, J. Lynn E. Delisi, Marie Odile Krebs, Ridha JooberBruno Millet, Éric Fombonne, Laurent Mottron, Martine Zilversmit, Jon Keebler, Hussein Daoud, Claude Marineau, Marie Hélne Roy-Gagnon, Marie Pierre Dubé, Adam Eyre-Walker, Pierre Drapeau, Eric A. Stone, Ronald G. Lafrenire, Guy A. Rouleau

Research output: Contribution to journal › Article › peer-review

182 Scopus citations

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.

Original language	English (US)
Pages (from-to)	316-324
Number of pages	9
Journal	American Journal of Human Genetics
Volume	87
Issue number	3
DOIs	https://doi.org/10.1016/j.ajhg.2010.07.019
State	Published - Sep 10 2010
Externally published	Yes

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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Awadalla, P., Gauthier, J., Myers, R. A., Casals, F., Hamdan, F. F., Griffing, A. R., Côté, M., Henrion, E., Spiegelman, D., Tarabeux, J., Piton, A., Yang, Y., Boyko, A., Bustamante, C., Xiong, L., Rapoport, J. L., Addington, A. M., Delisi, J. L. E., Krebs, M. O., ... Rouleau, G. A. (2010). Direct measure of the de novo mutation rate in autism and schizophrenia cohorts. American Journal of Human Genetics, 87(3), 316-324. https://doi.org/10.1016/j.ajhg.2010.07.019

Awadalla, P, Gauthier, J, Myers, RA, Casals, F, Hamdan, FF, Griffing, AR, Côté, M, Henrion, E, Spiegelman, D, Tarabeux, J, Piton, A, Yang, Y, Boyko, A, Bustamante, C, Xiong, L, Rapoport, JL, Addington, AM, Delisi, JLE, Krebs, MO, Joober, R, Millet, B, Fombonne, É, Mottron, L, Zilversmit, M, Keebler, J, Daoud, H, Marineau, C, Roy-Gagnon, MH, Dubé, MP, Eyre-Walker, A, Drapeau, P, Stone, EA, Lafrenire, RG & Rouleau, GA 2010, 'Direct measure of the de novo mutation rate in autism and schizophrenia cohorts', American Journal of Human Genetics, vol. 87, no. 3, pp. 316-324. https://doi.org/10.1016/j.ajhg.2010.07.019

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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.",

author = "Philip Awadalla and Julie Gauthier and Myers, {Rachel A.} and Ferran Casals and Hamdan, {Fadi F.} and Griffing, {Alexander R.} and M{\'e}lanie C{\^o}t{\'e} and Edouard Henrion and Dan Spiegelman and Julien Tarabeux and Am{\'e}lie Piton and Yan Yang and Adam Boyko and Carlos Bustamante and Lan Xiong and Rapoport, {Judith L.} and Addington, {Anjen{\'e} M.} and Delisi, {J. Lynn E.} and Krebs, {Marie Odile} and Ridha Joober and Bruno Millet and {\'E}ric Fombonne and Laurent Mottron and Martine Zilversmit and Jon Keebler and Hussein Daoud and Claude Marineau and Roy-Gagnon, {Marie H{\'e}lne} and Dub{\'e}, {Marie Pierre} and Adam Eyre-Walker and Pierre Drapeau and Stone, {Eric A.} and Lafrenire, {Ronald G.} and Rouleau, {Guy A.}",

note = "Funding Information: We would like to thank all the families and individuals who participated in this study. We are thankful for the efforts of the members of the Genome Qu{\'e}bec Innovation Centre Sequencing and Bioinformatic groups. This work was supported by Genome Canada and G{\'e}nome Qu{\'e}bec and received cofunding from Universit{\'e} de Montr{\'e}al for the Synapse-to-Disease (S2D) Project, funding from the Canadian Foundation for Innovation to both G.A.R and P.A., and cofunding from the Ministr{\'e} de Exploration, Innovation et Economique of Qu{\'e}bec. G.A.R. holds the Canada Research Chair in Genetics of the Nervous System; P.A. holds career awards from the Fonds de Recherche Sant{\'e} Qu{\'e}bec and G{\'e}nome Qu{\'e}bec. ",

year = "2010",

month = sep,

day = "10",

doi = "10.1016/j.ajhg.2010.07.019",

language = "English (US)",

volume = "87",

pages = "316--324",

journal = "American Journal of Human Genetics",

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T1 - Direct measure of the de novo mutation rate in autism and schizophrenia cohorts

AU - Awadalla, Philip

AU - Gauthier, Julie

AU - Myers, Rachel A.

AU - Casals, Ferran

AU - Hamdan, Fadi F.

AU - Griffing, Alexander R.

AU - Côté, Mélanie

AU - Henrion, Edouard

AU - Spiegelman, Dan

AU - Tarabeux, Julien

AU - Piton, Amélie

AU - Yang, Yan

AU - Boyko, Adam

AU - Bustamante, Carlos

AU - Xiong, Lan

AU - Rapoport, Judith L.

AU - Addington, Anjené M.

AU - Delisi, J. Lynn E.

AU - Krebs, Marie Odile

AU - Joober, Ridha

AU - Millet, Bruno

AU - Fombonne, Éric

AU - Mottron, Laurent

AU - Zilversmit, Martine

AU - Keebler, Jon

AU - Daoud, Hussein

AU - Marineau, Claude

AU - Roy-Gagnon, Marie Hélne

AU - Dubé, Marie Pierre

AU - Eyre-Walker, Adam

AU - Drapeau, Pierre

AU - Stone, Eric A.

AU - Lafrenire, Ronald G.

AU - Rouleau, Guy A.

N1 - Funding Information: We would like to thank all the families and individuals who participated in this study. We are thankful for the efforts of the members of the Genome Québec Innovation Centre Sequencing and Bioinformatic groups. This work was supported by Genome Canada and Génome Québec and received cofunding from Université de Montréal for the Synapse-to-Disease (S2D) Project, funding from the Canadian Foundation for Innovation to both G.A.R and P.A., and cofunding from the Ministré de Exploration, Innovation et Economique of Québec. G.A.R. holds the Canada Research Chair in Genetics of the Nervous System; P.A. holds career awards from the Fonds de Recherche Santé Québec and Génome Québec.

PY - 2010/9/10

Y1 - 2010/9/10

N2 - 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.

AB - 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.

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U2 - 10.1016/j.ajhg.2010.07.019

DO - 10.1016/j.ajhg.2010.07.019

M3 - Article

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SN - 0002-9297

VL - 87

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EP - 324

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 3

ER -

Direct measure of the de novo mutation rate in autism and schizophrenia cohorts

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