Analysis of mammalian gene function through broad-based phenotypic screens across a consortium of mouse clinics

Martin Hrabě De Angelis; George Nicholson; Mohammed Selloum; Jacqueline K. White; Hugh Morgan; Ramiro Ramirez-Solis; Tania Sorg; Sara Wells; Helmut Fuchs; Martin Fray; David J. Adams; Niels C. Adams; Thure Adler; Antonio Aguilar-Pimentel; Dalila Ali-Hadji; Gregory Amann; Philippe André; Sarah Atkins; Aurelie Auburtin; Abdel Ayadi; Julien Becker; Lore Becker; Elodie Bedu; Raffi Bekeredjian; Marie Christine Birling; Andrew Blake; Joanna Bottomley; Michael R. Bowl; Véronique Brault; Dirk H. Busch; James N. Bussell; Julia Calzada-Wack; Heather Cater; Marie France Champy; Philippe Charles; Claire Chevalier; Francesco Chiani; Gemma F. Codner; Roy Combe; Roger Cox; Emilie Dalloneau; André Dierich; Armida Di Fenza; Brendan Doe; Arnaud Duchon; Oliver Eickelberg; Chris T. Esapa; Lahcen El Fertak; Tanja Feigel; Markus Ollert; EUMODIC Consortium

doi:10.1038/ng.3360

Analysis of mammalian gene function through broad-based phenotypic screens across a consortium of mouse clinics

Martin Hrabě De Angelis, George Nicholson, Mohammed Selloum, Jacqueline K. White, Hugh Morgan, Ramiro Ramirez-Solis, Tania Sorg, Sara Wells, Helmut Fuchs, Martin Fray, David J. Adams, Niels C. Adams, Thure Adler, Antonio Aguilar-Pimentel, Dalila Ali-Hadji, Gregory Amann, Philippe André, Sarah Atkins, Aurelie Auburtin, Abdel AyadiJulien Becker, Lore Becker, Elodie Bedu, Raffi Bekeredjian, Marie Christine Birling, Andrew Blake, Joanna Bottomley, Michael R. Bowl, Véronique Brault, Dirk H. Busch, James N. Bussell, Julia Calzada-Wack, Heather Cater, Marie France Champy, Philippe Charles, Claire Chevalier, Francesco Chiani, Gemma F. Codner, Roy Combe, Roger Cox, Emilie Dalloneau, André Dierich, Armida Di Fenza, Brendan Doe, Arnaud Duchon, Oliver Eickelberg, Chris T. Esapa, Lahcen El Fertak, Tanja Feigel, Markus Ollert, EUMODIC Consortium

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Abstract

The function of the majority of genes in the mouse and human genomes remains unknown. The mouse embryonic stem cell knockout resource provides a basis for the characterization of relationships between genes and phenotypes. The EUMODIC consortium developed and validated robust methodologies for the broad-based phenotyping of knockouts through a pipeline comprising 20 disease-oriented platforms. We developed new statistical methods for pipeline design and data analysis aimed at detecting reproducible phenotypes with high power. We acquired phenotype data from 449 mutant alleles, representing 320 unique genes, of which half had no previous functional annotation. We captured data from over 27,000 mice, finding that 83% of the mutant lines are phenodeviant, with 65% demonstrating pleiotropy. Surprisingly, we found significant differences in phenotype annotation according to zygosity. New phenotypes were uncovered for many genes with previously unknown function, providing a powerful basis for hypothesis generation and further investigation in diverse systems.

Original language	English
Pages (from-to)	969-978
Number of pages	10
Journal	Nature Genetics
Volume	47
Issue number	9
DOIs	https://doi.org/10.1038/ng.3360
Publication status	Published - 27 Aug 2015
Externally published	Yes

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De Angelis, M. H., Nicholson, G., Selloum, M., White, J. K., Morgan, H., Ramirez-Solis, R., Sorg, T., Wells, S., Fuchs, H., Fray, M., Adams, D. J., Adams, N. C., Adler, T., Aguilar-Pimentel, A., Ali-Hadji, D., Amann, G., André, P., Atkins, S., Auburtin, A., ... EUMODIC Consortium (2015). Analysis of mammalian gene function through broad-based phenotypic screens across a consortium of mouse clinics. Nature Genetics, 47(9), 969-978. https://doi.org/10.1038/ng.3360

@article{87e4ea6346d64b58bf6fb82621d82e34,

title = "Analysis of mammalian gene function through broad-based phenotypic screens across a consortium of mouse clinics",

abstract = "The function of the majority of genes in the mouse and human genomes remains unknown. The mouse embryonic stem cell knockout resource provides a basis for the characterization of relationships between genes and phenotypes. The EUMODIC consortium developed and validated robust methodologies for the broad-based phenotyping of knockouts through a pipeline comprising 20 disease-oriented platforms. We developed new statistical methods for pipeline design and data analysis aimed at detecting reproducible phenotypes with high power. We acquired phenotype data from 449 mutant alleles, representing 320 unique genes, of which half had no previous functional annotation. We captured data from over 27,000 mice, finding that 83% of the mutant lines are phenodeviant, with 65% demonstrating pleiotropy. Surprisingly, we found significant differences in phenotype annotation according to zygosity. New phenotypes were uncovered for many genes with previously unknown function, providing a powerful basis for hypothesis generation and further investigation in diverse systems.",

author = "{De Angelis}, {Martin Hrab{\v e}} and George Nicholson and Mohammed Selloum and White, {Jacqueline K.} and Hugh Morgan and Ramiro Ramirez-Solis and Tania Sorg and Sara Wells and Helmut Fuchs and Martin Fray and Adams, {David J.} and Adams, {Niels C.} and Thure Adler and Antonio Aguilar-Pimentel and Dalila Ali-Hadji and Gregory Amann and Philippe Andr{\'e} and Sarah Atkins and Aurelie Auburtin and Abdel Ayadi and Julien Becker and Lore Becker and Elodie Bedu and Raffi Bekeredjian and Birling, {Marie Christine} and Andrew Blake and Joanna Bottomley and Bowl, {Michael R.} and V{\'e}ronique Brault and Busch, {Dirk H.} and Bussell, {James N.} and Julia Calzada-Wack and Heather Cater and Champy, {Marie France} and Philippe Charles and Claire Chevalier and Francesco Chiani and Codner, {Gemma F.} and Roy Combe and Roger Cox and Emilie Dalloneau and Andr{\'e} Dierich and {Di Fenza}, Armida and Brendan Doe and Arnaud Duchon and Oliver Eickelberg and Esapa, {Chris T.} and Fertak, {Lahcen El} and Tanja Feigel and Markus Ollert and {EUMODIC Consortium}",

note = "Funding Information: In the version of this article initially published online, the authors neglected to acknowledge one of the funding sources for their study. The acknowledgements should have recognized support from the Medical Research Council under project number MC_U142684172. The error has been corrected for the print, PDF and HTML versions of this article. Funding Information: The EUMODIC project was funded by European Commission contract number LSHG-CT-2006-037188. The work at MRC-Harwell was funded by the Medical Research Council under project MC_U142684172. The work at the Toronto Centre for Phenogenomics (TCP) was funded under the NorCOMM project by the government of Canada through Genome Canada and Genome Prairie. The Institut Clinique de la Souris (ICS) has been supported by French state funds through the Agence Nationale de la Recherche under the framework program Investissements d{\textquoteright}Avenir by ANR-10-IDEX-0002-02, ANR-10-LABX-0030-INRT and ANR-10-INBS-07 PHENOMIN. A full list of members of the EUMODIC consortium who contributed to the goals of the project is available in the Supplementary Note, and a list of partners is available at http://www.eumodic.org/partners.html. Publisher Copyright: {\textcopyright} 2015 Nature America, Inc. All rights reserved.",

year = "2015",

month = aug,

day = "27",

doi = "10.1038/ng.3360",

language = "English",

volume = "47",

pages = "969--978",

journal = "Nature Genetics",

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De Angelis, MH, Nicholson, G, Selloum, M, White, JK, Morgan, H, Ramirez-Solis, R, Sorg, T, Wells, S, Fuchs, H, Fray, M, Adams, DJ, Adams, NC, Adler, T, Aguilar-Pimentel, A, Ali-Hadji, D, Amann, G, André, P, Atkins, S, Auburtin, A, Ayadi, A, Becker, J, Becker, L, Bedu, E, Bekeredjian, R, Birling, MC, Blake, A, Bottomley, J, Bowl, MR, Brault, V, Busch, DH, Bussell, JN, Calzada-Wack, J, Cater, H, Champy, MF, Charles, P, Chevalier, C, Chiani, F, Codner, GF, Combe, R, Cox, R, Dalloneau, E, Dierich, A, Di Fenza, A, Doe, B, Duchon, A, Eickelberg, O, Esapa, CT, Fertak, LE, Feigel, T, Ollert, M & EUMODIC Consortium 2015, 'Analysis of mammalian gene function through broad-based phenotypic screens across a consortium of mouse clinics', Nature Genetics, vol. 47, no. 9, pp. 969-978. https://doi.org/10.1038/ng.3360

TY - JOUR

T1 - Analysis of mammalian gene function through broad-based phenotypic screens across a consortium of mouse clinics

AU - De Angelis, Martin Hrabě

AU - Nicholson, George

AU - Selloum, Mohammed

AU - White, Jacqueline K.

AU - Morgan, Hugh

AU - Ramirez-Solis, Ramiro

AU - Sorg, Tania

AU - Wells, Sara

AU - Fuchs, Helmut

AU - Fray, Martin

AU - Adams, David J.

AU - Adams, Niels C.

AU - Adler, Thure

AU - Aguilar-Pimentel, Antonio

AU - Ali-Hadji, Dalila

AU - Amann, Gregory

AU - André, Philippe

AU - Atkins, Sarah

AU - Auburtin, Aurelie

AU - Ayadi, Abdel

AU - Becker, Julien

AU - Becker, Lore

AU - Bedu, Elodie

AU - Bekeredjian, Raffi

AU - Birling, Marie Christine

AU - Blake, Andrew

AU - Bottomley, Joanna

AU - Bowl, Michael R.

AU - Brault, Véronique

AU - Busch, Dirk H.

AU - Bussell, James N.

AU - Calzada-Wack, Julia

AU - Cater, Heather

AU - Champy, Marie France

AU - Charles, Philippe

AU - Chevalier, Claire

AU - Chiani, Francesco

AU - Codner, Gemma F.

AU - Combe, Roy

AU - Cox, Roger

AU - Dalloneau, Emilie

AU - Dierich, André

AU - Di Fenza, Armida

AU - Doe, Brendan

AU - Duchon, Arnaud

AU - Eickelberg, Oliver

AU - Esapa, Chris T.

AU - Fertak, Lahcen El

AU - Feigel, Tanja

AU - Ollert, Markus

AU - EUMODIC Consortium

N1 - Funding Information: In the version of this article initially published online, the authors neglected to acknowledge one of the funding sources for their study. The acknowledgements should have recognized support from the Medical Research Council under project number MC_U142684172. The error has been corrected for the print, PDF and HTML versions of this article. Funding Information: The EUMODIC project was funded by European Commission contract number LSHG-CT-2006-037188. The work at MRC-Harwell was funded by the Medical Research Council under project MC_U142684172. The work at the Toronto Centre for Phenogenomics (TCP) was funded under the NorCOMM project by the government of Canada through Genome Canada and Genome Prairie. The Institut Clinique de la Souris (ICS) has been supported by French state funds through the Agence Nationale de la Recherche under the framework program Investissements d’Avenir by ANR-10-IDEX-0002-02, ANR-10-LABX-0030-INRT and ANR-10-INBS-07 PHENOMIN. A full list of members of the EUMODIC consortium who contributed to the goals of the project is available in the Supplementary Note, and a list of partners is available at http://www.eumodic.org/partners.html. Publisher Copyright: © 2015 Nature America, Inc. All rights reserved.

PY - 2015/8/27

Y1 - 2015/8/27

N2 - The function of the majority of genes in the mouse and human genomes remains unknown. The mouse embryonic stem cell knockout resource provides a basis for the characterization of relationships between genes and phenotypes. The EUMODIC consortium developed and validated robust methodologies for the broad-based phenotyping of knockouts through a pipeline comprising 20 disease-oriented platforms. We developed new statistical methods for pipeline design and data analysis aimed at detecting reproducible phenotypes with high power. We acquired phenotype data from 449 mutant alleles, representing 320 unique genes, of which half had no previous functional annotation. We captured data from over 27,000 mice, finding that 83% of the mutant lines are phenodeviant, with 65% demonstrating pleiotropy. Surprisingly, we found significant differences in phenotype annotation according to zygosity. New phenotypes were uncovered for many genes with previously unknown function, providing a powerful basis for hypothesis generation and further investigation in diverse systems.

AB - The function of the majority of genes in the mouse and human genomes remains unknown. The mouse embryonic stem cell knockout resource provides a basis for the characterization of relationships between genes and phenotypes. The EUMODIC consortium developed and validated robust methodologies for the broad-based phenotyping of knockouts through a pipeline comprising 20 disease-oriented platforms. We developed new statistical methods for pipeline design and data analysis aimed at detecting reproducible phenotypes with high power. We acquired phenotype data from 449 mutant alleles, representing 320 unique genes, of which half had no previous functional annotation. We captured data from over 27,000 mice, finding that 83% of the mutant lines are phenodeviant, with 65% demonstrating pleiotropy. Surprisingly, we found significant differences in phenotype annotation according to zygosity. New phenotypes were uncovered for many genes with previously unknown function, providing a powerful basis for hypothesis generation and further investigation in diverse systems.

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JO - Nature Genetics

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ER -

Analysis of mammalian gene function through broad-based phenotypic screens across a consortium of mouse clinics

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