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

M. H. de Angelis; G. Nicholson; M. Selloum; J. K. White; H. Morgan; R. Ramirez-Solis; T. Sorg; S. Wells; H. Fuchs; M. Fray; D. J. Adams; N. C. Adams; T. Adler; A. Aguilar-Pimentel; D. Ali-Hadji; G. Amann; P. Andre; S. Atkins; A. Auburtin; A. Ayadi; J. Becker; L. Becker; E. Bedu; R. Bekeredjian; M. C. Birling; A. Blake; J. Bottomley; M. R. Bowl; V. Brault; D. H. Busch; J. N. Bussell; J. Calzada-Wack; H. Cater; M. F. Champy; P. Charles; C. Chevalier; F. Chiani; G. F. Codner; R. Combe; R. Cox; E. Dalloneau; A. Dierich; A. Di Fenza; B. Doe; A. Duchon; O. Eickelberg; C. T. Esapa; L. E. Fertak; T. Feigel; I. Emelyanova; J. Estabel; J. Favor; A. Flenniken; A. Gambadoro; L. Garrett; H. Gates; A. K. Gerdin; G. Gkoutos; S. Greenaway; L. Glasl; P. Goetz; I. G. Da Cruz; A. Gotz; J. Graw; A. Guimond; W. Hans; G. Hicks; S. M. Holter; H. Hofler; J. M. Hancock; R. Hoehndorf; T. Hough; R. Houghton; A. Hurt; B. Ivandic; H. Jacobs; S. Jacquot; N. Jones; N. A. Karp; H. A. Katus; S. Kitchen; T. Klein-Rodewald; M. Klingenspor; T. Klopstock; V. Lalanne; S. Leblanc; C. Lengger; E. le Marchand; T. Ludwig; A. Lux; C. McKerlie; H. Maier; J. L. Mandel; S. Marschall; M. Mark; D. G. Melvin; H. Meziane; K. Micklich; C. Mittelhauser; L. Monassier; D. Moulaert; S. Muller; B. Naton; F. Neff; P. M. Nolan; L. M. Nutter; M. Ollert; G. Pavlovic; N. S. Pellegata; E. Peter; B. Petit-Demouliere; A. Pickard; C. Podrini; P. Potter; L. Pouilly; O. Puk; D. Richardson; S. Rousseau; L. Quintanilla-Fend; M. M. Quwailid; I. Racz; B. Rathkolb; F. Riet; J. Rossant; M. Roux; J. Rozman; E. Ryder; J. Salisbury; L. Santos; K. H. Schable; E. Schiller; A. Schrewe; H. Schulz; R. Steinkamp; M. Simon; M. Stewart; C. Stoger; T. Stoger; M. Sun; D. Sunter; L. Teboul; I. Tilly; G. P. Tocchini-Valentini; M. Tost; I. Treise; L. Vasseur; E. Velot; D. Vogt-Weisenhorn; C. Wagner; A. Walling; M. Wattenhofer-Donze; B. Weber; O. Wendling; H. Westerberg; M. Willershauser; E. Wolf; A. Wolter; J. Wood; W. Wurst; A. O. Yildirim; R. Zeh; A. Zimmer; A. Zimprich; C. Holmes; K. P. Steel; Y. Herault; V. Gailus-Durner; A. M. Mallon; S. D. Brown

doi:10.1038/ng.3360

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

M. H. de Angelis, G. Nicholson, M. Selloum, J. K. White, H. Morgan, R. Ramirez-Solis, T. Sorg, S. Wells, H. Fuchs, M. Fray, D. J. Adams, N. C. Adams, T. Adler, A. Aguilar-Pimentel, D. Ali-Hadji, G. Amann, P. Andre, S. Atkins, A. Auburtin, A. AyadiJ. Becker, L. Becker, E. Bedu, R. Bekeredjian, M. C. Birling, A. Blake, J. Bottomley, M. R. Bowl, V. Brault, D. H. Busch, J. N. Bussell, J. Calzada-Wack, H. Cater, M. F. Champy, P. Charles, C. Chevalier, F. Chiani, G. F. Codner, R. Combe, R. Cox, E. Dalloneau, A. Dierich, A. Di Fenza, B. Doe, A. Duchon, O. Eickelberg, C. T. Esapa, L. E. Fertak, T. Feigel, I. Emelyanova, J. Estabel, J. Favor, A. Flenniken, A. Gambadoro, L. Garrett, H. Gates, A. K. Gerdin, G. Gkoutos, S. Greenaway, L. Glasl, P. Goetz, I. G. Da Cruz, A. Gotz, J. Graw, A. Guimond, W. Hans, G. Hicks, S. M. Holter, H. Hofler, J. M. Hancock, R. Hoehndorf, T. Hough, R. Houghton, A. Hurt, B. Ivandic, H. Jacobs, S. Jacquot, N. Jones, N. A. Karp, H. A. Katus, S. Kitchen, T. Klein-Rodewald, M. Klingenspor, T. Klopstock, V. Lalanne, S. Leblanc, C. Lengger, E. le Marchand, T. Ludwig, A. Lux, C. McKerlie, H. Maier, J. L. Mandel, S. Marschall, M. Mark, D. G. Melvin, H. Meziane, K. Micklich, C. Mittelhauser, L. Monassier, D. Moulaert, S. Muller, B. Naton, F. Neff, P. M. Nolan, L. M. Nutter, M. Ollert, G. Pavlovic, N. S. Pellegata, E. Peter, B. Petit-Demouliere, A. Pickard, C. Podrini, P. Potter, L. Pouilly, O. Puk, D. Richardson, S. Rousseau, L. Quintanilla-Fend, M. M. Quwailid, I. Racz, B. Rathkolb, F. Riet, J. Rossant, M. Roux, J. Rozman, E. Ryder, J. Salisbury, L. Santos, K. H. Schable, E. Schiller, A. Schrewe, H. Schulz, R. Steinkamp, M. Simon, M. Stewart, C. Stoger, T. Stoger, M. Sun, D. Sunter, L. Teboul, I. Tilly, G. P. Tocchini-Valentini, M. Tost, I. Treise, L. Vasseur, E. Velot, D. Vogt-Weisenhorn, C. Wagner, A. Walling, M. Wattenhofer-Donze, B. Weber, O. Wendling, H. Westerberg, M. Willershauser, E. Wolf, A. Wolter, J. Wood, W. Wurst, A. O. Yildirim, R. Zeh, A. Zimmer, A. Zimprich, C. Holmes, K. P. Steel, Y. Herault, V. Gailus-Durner, A. M. Mallon, S. D. Brown

Cancer and Genomic Sciences

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

90 Citations (Scopus)

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 - 1 Sept 2015

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10.1038/ng.3360

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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., Andre, P., Atkins, S., Auburtin, A., ... Brown, S. D. (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{47203f6c3f564e3fb3dbafb841317459,

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}, {M. H.} and G. Nicholson and M. Selloum and White, {J. K.} and H. Morgan and R. Ramirez-Solis and T. Sorg and S. Wells and H. Fuchs and M. Fray and Adams, {D. J.} and Adams, {N. C.} and T. Adler and A. Aguilar-Pimentel and D. Ali-Hadji and G. Amann and P. Andre and S. Atkins and A. Auburtin and A. Ayadi and J. Becker and L. Becker and E. Bedu and R. Bekeredjian and Birling, {M. C.} and A. Blake and J. Bottomley and Bowl, {M. R.} and V. Brault and Busch, {D. H.} and Bussell, {J. N.} and J. Calzada-Wack and H. Cater and Champy, {M. F.} and P. Charles and C. Chevalier and F. Chiani and Codner, {G. F.} and R. Combe and R. Cox and E. Dalloneau and A. Dierich and {Di Fenza}, A. and B. Doe and A. Duchon and O. Eickelberg and Esapa, {C. T.} and Fertak, {L. E.} and T. Feigel and I. Emelyanova and J. Estabel and J. Favor and A. Flenniken and A. Gambadoro and L. Garrett and H. Gates and Gerdin, {A. K.} and G. Gkoutos and S. Greenaway and L. Glasl and P. Goetz and {Da Cruz}, {I. G.} and A. Gotz and J. Graw and A. Guimond and W. Hans and G. Hicks and Holter, {S. M.} and H. Hofler and Hancock, {J. M.} and R. Hoehndorf and T. Hough and R. Houghton and A. Hurt and B. Ivandic and H. Jacobs and S. Jacquot and N. Jones and Karp, {N. A.} and Katus, {H. A.} and S. Kitchen and T. Klein-Rodewald and M. Klingenspor and T. Klopstock and V. Lalanne and S. Leblanc and C. Lengger and {le Marchand}, E. and T. Ludwig and A. Lux and C. McKerlie and H. Maier and Mandel, {J. L.} and S. Marschall and M. Mark and Melvin, {D. G.} and H. Meziane and K. Micklich and C. Mittelhauser and L. Monassier and D. Moulaert and S. Muller and B. Naton and F. Neff and Nolan, {P. M.} and Nutter, {L. M.} and M. Ollert and G. Pavlovic and Pellegata, {N. S.} and E. Peter and B. Petit-Demouliere and A. Pickard and C. Podrini and P. Potter and L. Pouilly and O. Puk and D. Richardson and S. Rousseau and L. Quintanilla-Fend and Quwailid, {M. M.} and I. Racz and B. Rathkolb and F. Riet and J. Rossant and M. Roux and J. Rozman and E. Ryder and J. Salisbury and L. Santos and Schable, {K. H.} and E. Schiller and A. Schrewe and H. Schulz and R. Steinkamp and M. Simon and M. Stewart and C. Stoger and T. Stoger and M. Sun and D. Sunter and L. Teboul and I. Tilly and Tocchini-Valentini, {G. P.} and M. Tost and I. Treise and L. Vasseur and E. Velot and D. Vogt-Weisenhorn and C. Wagner and A. Walling and M. Wattenhofer-Donze and B. Weber and O. Wendling and H. Westerberg and M. Willershauser and E. Wolf and A. Wolter and J. Wood and W. Wurst and Yildirim, {A. O.} and R. Zeh and A. Zimmer and A. Zimprich and C. Holmes and Steel, {K. P.} and Y. Herault and V. Gailus-Durner and Mallon, {A. M.} and Brown, {S. D.}",

year = "2015",

month = sep,

day = "1",

doi = "10.1038/ng.3360",

language = "English",

volume = "47",

pages = "969--978",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "9",

}

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, Andre, 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, Emelyanova, I, Estabel, J, Favor, J, Flenniken, A, Gambadoro, A, Garrett, L, Gates, H, Gerdin, AK, Gkoutos, G, Greenaway, S, Glasl, L, Goetz, P, Da Cruz, IG, Gotz, A, Graw, J, Guimond, A, Hans, W, Hicks, G, Holter, SM, Hofler, H, Hancock, JM, Hoehndorf, R, Hough, T, Houghton, R, Hurt, A, Ivandic, B, Jacobs, H, Jacquot, S, Jones, N, Karp, NA, Katus, HA, Kitchen, S, Klein-Rodewald, T, Klingenspor, M, Klopstock, T, Lalanne, V, Leblanc, S, Lengger, C, le Marchand, E, Ludwig, T, Lux, A, McKerlie, C, Maier, H, Mandel, JL, Marschall, S, Mark, M, Melvin, DG, Meziane, H, Micklich, K, Mittelhauser, C, Monassier, L, Moulaert, D, Muller, S, Naton, B, Neff, F, Nolan, PM, Nutter, LM, Ollert, M, Pavlovic, G, Pellegata, NS, Peter, E, Petit-Demouliere, B, Pickard, A, Podrini, C, Potter, P, Pouilly, L, Puk, O, Richardson, D, Rousseau, S, Quintanilla-Fend, L, Quwailid, MM, Racz, I, Rathkolb, B, Riet, F, Rossant, J, Roux, M, Rozman, J, Ryder, E, Salisbury, J, Santos, L, Schable, KH, Schiller, E, Schrewe, A, Schulz, H, Steinkamp, R, Simon, M, Stewart, M, Stoger, C, Stoger, T, Sun, M, Sunter, D, Teboul, L, Tilly, I, Tocchini-Valentini, GP, Tost, M, Treise, I, Vasseur, L, Velot, E, Vogt-Weisenhorn, D, Wagner, C, Walling, A, Wattenhofer-Donze, M, Weber, B, Wendling, O, Westerberg, H, Willershauser, M, Wolf, E, Wolter, A, Wood, J, Wurst, W, Yildirim, AO, Zeh, R, Zimmer, A, Zimprich, A, Holmes, C, Steel, KP, Herault, Y, Gailus-Durner, V, Mallon, AM & Brown, SD 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, M. H.

AU - Nicholson, G.

AU - Selloum, M.

AU - White, J. K.

AU - Morgan, H.

AU - Ramirez-Solis, R.

AU - Sorg, T.

AU - Wells, S.

AU - Fuchs, H.

AU - Fray, M.

AU - Adams, D. J.

AU - Adams, N. C.

AU - Adler, T.

AU - Aguilar-Pimentel, A.

AU - Ali-Hadji, D.

AU - Amann, G.

AU - Andre, P.

AU - Atkins, S.

AU - Auburtin, A.

AU - Ayadi, A.

AU - Becker, J.

AU - Becker, L.

AU - Bedu, E.

AU - Bekeredjian, R.

AU - Birling, M. C.

AU - Blake, A.

AU - Bottomley, J.

AU - Bowl, M. R.

AU - Brault, V.

AU - Busch, D. H.

AU - Bussell, J. N.

AU - Calzada-Wack, J.

AU - Cater, H.

AU - Champy, M. F.

AU - Charles, P.

AU - Chevalier, C.

AU - Chiani, F.

AU - Codner, G. F.

AU - Combe, R.

AU - Cox, R.

AU - Dalloneau, E.

AU - Dierich, A.

AU - Di Fenza, A.

AU - Doe, B.

AU - Duchon, A.

AU - Eickelberg, O.

AU - Esapa, C. T.

AU - Fertak, L. E.

AU - Feigel, T.

AU - Emelyanova, I.

AU - Estabel, J.

AU - Favor, J.

AU - Flenniken, A.

AU - Gambadoro, A.

AU - Garrett, L.

AU - Gates, H.

AU - Gerdin, A. K.

AU - Gkoutos, G.

AU - Greenaway, S.

AU - Glasl, L.

AU - Goetz, P.

AU - Da Cruz, I. G.

AU - Gotz, A.

AU - Graw, J.

AU - Guimond, A.

AU - Hans, W.

AU - Hicks, G.

AU - Holter, S. M.

AU - Hofler, H.

AU - Hancock, J. M.

AU - Hoehndorf, R.

AU - Hough, T.

AU - Houghton, R.

AU - Hurt, A.

AU - Ivandic, B.

AU - Jacobs, H.

AU - Jacquot, S.

AU - Jones, N.

AU - Karp, N. A.

AU - Katus, H. A.

AU - Kitchen, S.

AU - Klein-Rodewald, T.

AU - Klingenspor, M.

AU - Klopstock, T.

AU - Lalanne, V.

AU - Leblanc, S.

AU - Lengger, C.

AU - le Marchand, E.

AU - Ludwig, T.

AU - Lux, A.

AU - McKerlie, C.

AU - Maier, H.

AU - Mandel, J. L.

AU - Marschall, S.

AU - Mark, M.

AU - Melvin, D. G.

AU - Meziane, H.

AU - Micklich, K.

AU - Mittelhauser, C.

AU - Monassier, L.

AU - Moulaert, D.

AU - Muller, S.

AU - Naton, B.

AU - Neff, F.

AU - Nolan, P. M.

AU - Nutter, L. M.

AU - Ollert, M.

AU - Pavlovic, G.

AU - Pellegata, N. S.

AU - Peter, E.

AU - Petit-Demouliere, B.

AU - Pickard, A.

AU - Podrini, C.

AU - Potter, P.

AU - Pouilly, L.

AU - Puk, O.

AU - Richardson, D.

AU - Rousseau, S.

AU - Quintanilla-Fend, L.

AU - Quwailid, M. M.

AU - Racz, I.

AU - Rathkolb, B.

AU - Riet, F.

AU - Rossant, J.

AU - Roux, M.

AU - Rozman, J.

AU - Ryder, E.

AU - Salisbury, J.

AU - Santos, L.

AU - Schable, K. H.

AU - Schiller, E.

AU - Schrewe, A.

AU - Schulz, H.

AU - Steinkamp, R.

AU - Simon, M.

AU - Stewart, M.

AU - Stoger, C.

AU - Stoger, T.

AU - Sun, M.

AU - Sunter, D.

AU - Teboul, L.

AU - Tilly, I.

AU - Tocchini-Valentini, G. P.

AU - Tost, M.

AU - Treise, I.

AU - Vasseur, L.

AU - Velot, E.

AU - Vogt-Weisenhorn, D.

AU - Wagner, C.

AU - Walling, A.

AU - Wattenhofer-Donze, M.

AU - Weber, B.

AU - Wendling, O.

AU - Westerberg, H.

AU - Willershauser, M.

AU - Wolf, E.

AU - Wolter, A.

AU - Wood, J.

AU - Wurst, W.

AU - Yildirim, A. O.

AU - Zeh, R.

AU - Zimmer, A.

AU - Zimprich, A.

AU - Holmes, C.

AU - Steel, K. P.

AU - Herault, Y.

AU - Gailus-Durner, V.

AU - Mallon, A. M.

AU - Brown, S. D.

PY - 2015/9/1

Y1 - 2015/9/1

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.

U2 - 10.1038/ng.3360

DO - 10.1038/ng.3360

M3 - Article

SN - 1061-4036

VL - 47

SP - 969

EP - 978

JO - Nature Genetics

JF - Nature Genetics

IS - 9

ER -

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

Abstract

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