Genome-wide Generation and Systematic Phenotyping of Knockout Mice Reveals New Roles for Many Genes

Mutations in whole organisms are powerful ways of interrogating gene function in a realistic context. We describe a program, the Sanger Institute Mouse Genetics Project, that provides a step toward the aim of knocking out all genes and screening each line for a broad range of traits. We found that h...

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Bibliographic Details
Published in:	Cell Vol. 154; no. 2; pp. 452 - 464
Main Authors:	White, Jacqueline K., Gerdin, Anna-Karin, Karp, Natasha A., Ryder, Ed, Bussell, James N., Salisbury, Jennifer, Clare, Simon, Ingham, Neil J., Podrini, Christine, Houghton, Richard, Estabel, Jeanne, Bottomley, Joanna R., Melvin, David G., Sunter, David, Barnes, Caroline, Cambridge, Emma, Carragher, Damian, Chana, Prabhjoat, Clarke, Kay, Igosheva, Natalia, Ismail, Ozama, Jackson, Hannah, Kane, Leanne, Lacey, Rosalind, Lucas, Mark, McGill, Katherine, McIntyre, Rebecca E., Messager, Sophie, Mottram, Lynda, Mulderrig, Lee, Pearson, Selina, Roberson, Laura-Anne, Salsbury, Grace, Sanger, Daniel, Shannon, Carl, Thompson, Paul C., Tuck, Elizabeth, Bushell, Wendy, Cook, Ross, Dalvi, Priya, Gleeson, Diane, Habib, Bishoy, Hardy, Matt, Miklejewska, Evelina, Price, Stacey, Sethi, Debarati, von Schiller, Dominique, Vyas, Sapna, West, Anthony P., Evans, Arthur, Holroyd, Simon, Iyer, Vivek, Lewis, Morag, Oakley, Darren, Richardson, David, Smedley, Damian, Agu, Chukwuma, Bryant, Jackie, Delaney, Liz, Gueorguieva, Nadia I., Tharagonnet, Helen, Townsend, Anne J., Biggs, Daniel, Collinson, Adam, Dumeau, Charles-Etienne, Grau, Evelyn, Harrison, Sarah, Ingle, Catherine E., Kundi, Helen, Madich, Alla, Mayhew, Danielle, Metcalf, Tom, Pass, Johanna, Reynolds, Helen, Sinclair, Caroline, Wardle-Jones, Hannah, Woods, Michael, Alexander, Liam, Brown, Terry, Flack, Francesca, Griggs, Nicola, McDermott, Jordan, Rogerson, Claire, White, Gemma, Zielezinski, Pawel, DiTommaso, Tia, Edwards, Andrew, Mahajan, Mary Ann, Yalcin, Binnaz, Tannahill, David, Logan, Darren W., MacArthur, Daniel G., Flint, Jonathan, Mahajan, Vinit B., Smyth, Ian, Watt, Fiona M., Skarnes, William C., Dougan, Gordon, Adams, David J., Bradley, Allan
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 18-07-2013 Elsevier Cell Press
Subjects:	Animals Disease - genetics Disease Models, Animal essential genes Female Genes, Essential Genetic Techniques Genome-Wide Association Study knockout mutants Life Sciences Male Mice Mice, Knockout mutation Phenotype pleiotropy Resource screening viability
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Summary:	Mutations in whole organisms are powerful ways of interrogating gene function in a realistic context. We describe a program, the Sanger Institute Mouse Genetics Project, that provides a step toward the aim of knocking out all genes and screening each line for a broad range of traits. We found that hitherto unpublished genes were as likely to reveal phenotypes as known genes, suggesting that novel genes represent a rich resource for investigating the molecular basis of disease. We found many unexpected phenotypes detected only because we screened for them, emphasizing the value of screening all mutants for a wide range of traits. Haploinsufficiency and pleiotropy were both surprisingly common. Forty-two percent of genes were essential for viability, and these were less likely to have a paralog and more likely to contribute to a protein complex than other genes. Phenotypic data and more than 900 mutants are openly available for further analysis. [Display omitted] [Display omitted] •Large openly available resource of targeted mouse mutants and phenotypic data•Screen for broad range of disease features and traits•Many novel phenotypes suggest functions for both studied and unstudied genes•Haploinsufficiency and pleiotropy are common More than 900 new mutant mice lines and a multifaceted phenotypic screening platform reveal unanticipated pleiotropies, widespread effects of haploinsufficiency, potential disease models, and functions for unstudied genes.
Bibliography:	http://dx.doi.org/10.1016/j.cell.2013.06.022 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 PMCID: PMC3717207 A full list of The Sanger Institute Mouse Genetics Project contributors may be found in the Supplemental Information
ISSN:	0092-8674 1097-4172
DOI:	10.1016/j.cell.2013.06.022