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

Author

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

Subjects
Genetics, Male, Mice, Knockout, Heterozygote, Mutant, Homozygote, Aucun, Molecular Sequence Annotation, Biology, Phenotype, Mice, Inbred C57BL, Pleiotropy, ddc:570, Mutation, Animals, Humans, Human genome, Female, Allele, Gene, Gene knockout, Genetic Association Studies
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. Comment in : Genetic differential calculus. [Nat Genet. 2015] Comment in : Scaling up phenotyping studies. [Nat Biotechnol. 2015]

Published
2015
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5. Synthesis and Photoisomerization of Divinyltetramethyldisiloxane and Divinyltetramethyldisilazane Complexes of (η<SUP>5</SUP>-C<INF>5</INF>R<INF>5</INF>)Rh (R = H, Me). Crystal and Molecular Structure of (η<SUP>5</SUP>-C<INF>5</INF>Me<INF>5</INF>)Rh[η<SUP>4</SUP>-(CH<INF>2</INF>&dbd;CH)Me<INF>2</INF>SiOSiMe<INF>2</INF>(CH&dbd;CH<INF>2</INF>)]

Author

Brown, S. S. D., Heaton, S. N., Moore, M. H., Perutz, R. N., and Wilson, G.

Abstract

The synthesis and photochemistry of a series of new rhodium complexes of 1,3-divinyl-1,1,3,3-tetramethyldisiloxane, (CH2&dbd;CHSiMe2)2O, and its disilazane analogue (CH2&dbd;CHSiMe2)2NH are reported. The divinyldisiloxane or divinyldisilazane ligands in (η5-C5R5)Rh[η4-(CH2&dbd;CHSiMe2)2X] (R = H, Me; X = O, NH; type 1 complexes) are coordinated through the vinyl groups as for a diene. The structure of (η5-C5Me5)Rh[η4-(CH2&dbd;CHSiMe2)2O] was established crystallographically. The two coordinated double bonds are arranged with their Si substitutents in a cis orientation with respect to the metal. The strain in the structure is suggested by the scissor geometry of the vinyl C&dbd;C bonds relative to the C5 plane of the ring, combined with unequal Rh-C and C&dbd;C bond lengths. Photolysis of (η5-C5R5)Rh(C2H4)2 (R = H, Me) in the presence of (CH2&dbd;CHSiMe2)2X (X = O, NH) results in the formation of the complexes of type 1, together with an isomer in which the substituents on the coordinated C&dbd;C bonds are oriented trans at rhodium (2) and species containing two dangling divinyldisiloxane ligands, (η5-C5R5)Rh[η2-(CH2&dbd;CHSiMe2)2X]2, in both cis and trans configurations. Direct irradiation of species of type 1 converts them to the photoisomer 2. The 16-electron intermediate with one η2-divinyldisiloxane ligand may be trapped by addition of CH2&dbd;CHSiMe3 or excess (CH2&dbd;CHSiMe2)2X (X = O, NH). The isomerization of type 2 species to type 1 species proceeds by first-order kinetics. For trans-(η5-C5H5)Rh[η4-(CH2&dbd;CHSiMe2)2O] (2a) the values of ΔH&thermod; and ΔS&thermod; are 114 ± 1 kJ mol-1 and 41 ± 4 J mol-1 K-1, consistent with rate-determining dissociation of one double bond. Replacement of C5H5 by C5Me5 increases H&thermod; by 9 ± 2 kJ mol-1. The assignment of the photoisomers 2 as the trans species is supported by further observations that (i) a mixture of 1 and 2 can be synthesized by hydrolysis of chlorovinylsilane precursors (η5-C5H5)Rh(η2-CH2&dbd;CHSiMe2Cl)2, a method which generates the Si−O−Si linkage in situ, (ii) the conformationally locked species with a cyclic trivinyltrimethyltrisiloxane ligand, (η5-C5H5)Rh[η4-(CH2&dbd;CHSi(Me)O)3], does not undergo photoisomerization, and (iii) the species with the Si−O−Si linkage replaced by a C−O−Si linkage (η5-C5H5)Rh[η4-(CH2&dbd;CMe)CH2OSiMe2(CH&dbd;CH2)] also fails to undergo photoisomerization. These complexes represent the first examples of adoption of a trans configuration at a metal by η4-divinyldisiloxane ligands and the first examples of this type of isomerization.

Published
1996

11. ChemInform Abstract: The Heteronuclear Cluster Chemistry of the Group 1B Metals. Part 10. Synthesis, Structures, and Dynamic Behavior of the Bimetallic Hexanuclear Group 1B Metal Cluster Compounds (M2Ru4(μ3-H)2(μ-Ph2As(CH2)nEPh2)(CO)12) (M: Cu or Ag; E: A

Author

BROWN, S. S. D., primary, MCCARTHY, P. J., additional, SALTER, I. D., additional, BATES, P. A., additional, HURSTHOUSE, M. B., additional, COLQUHOUN, I. J., additional, MCFARLANE, W., additional, and MURRAY, M., additional

Published
1989
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12. ChemInform Abstract: Heteronuclear Cluster Chemistry of the Group 1B Metals. Part 11. Effect of the Nature of the Bidentate Diphosphine Ligand on the Metal Framework Structures of the Gold Heteronuclear Cluster Compounds (Au2Ru4(μ3‐H)(μ‐H)(μ‐Ph2P(CH2)nPPh2)(CO)12) (n = 1‐6). X‐Ray Crystal Structures of (Au2Ru4(μ3‐H)(μ‐H)(μ‐Ph2P(CH2)nPPh2)(CO)12) (n = 1 or 2).

Author

BROWN, S. S. D., primary, SALTER, I. D., additional, DENT, A. J., additional, KITCHEN, G. F. M., additional, ORPEN, A. G., additional, BATES, P. A., additional, and HURSTHOUSE, M. B., additional

Published
1989
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14. ChemInform Abstract: The Heteronuclear Cluster Chemistry of the Group 1B Metals. Part 9. Stereochemical Non‐Rigidity of the Metal Skeletons of Cluster Compounds in Solution. 109Ag‐(1H) INEPT NMR Studies on (Ag2Ru4(μ3‐H)2(μ‐Ph2P(CH2)nPPh2)(CO)12) (n = 1, 2, or 4) and X‐Ray Crystal Structure of (Ag2Ru4(μ3‐H)2(μ‐Ph2PCH2PPh2)(CO)12).

Author

BROWN, S. S. D., primary, SALTER, I. D., additional, SIK, V., additional, COLQUHOUN, I. J., additional, MCFARLANE, W., additional, BATES, P. A., additional, HURSTHOUSE, M. B., additional, and MURRAY, M., additional

Published
1988
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