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1. Genome-wide in vivo screen identifies novel host regulators of metastatic colonization

Author

Kim Wong, Nicola Griggs, Elizabeth Tuck, Sarah Spiegel, Emma L. Cambridge, Antonella Galli, Sanger Mouse Genetics, Hannah Wardle-Jones, Louise van der Weyden, Anneliese O. Speak, Natasha A. Karp, Andrew D. Campbell, Martin Del Castillo Velasco-Herrera, Owen J. Sansom, Thierry Voet, Thomas Tüting, Edward Ryder, Diane Gleeson, David J. Adams, Mark J. Arends, Iain C. Macaulay, Simon Clare, and Tobias Bald

Subjects
Male, 0301 basic medicine, Lung Neoplasms, Stromal cell, T-Lymphocytes, Lymphocyte, Anion Transport Proteins, Cell, Biology, Article, Metastasis, Mice, 03 medical and health sciences, Immune system, Cell Movement, Sphingosine, Cell Line, Tumor, Lymphopenia, Tumor Microenvironment, medicine, Animals, Neoplasm Metastasis, Tumor microenvironment, Genome, Multidisciplinary, Genomics, medicine.disease, Killer Cells, Natural, Disease Models, Animal, 030104 developmental biology, Lymphatic system, medicine.anatomical_structure, Cell killing, Immunology, Cancer research, Female, Lysophospholipids
Abstract

Metastasis is the leading cause of death for cancer patients. This multi-stage process requires tumour cells to survive in the circulation, extravasate at distant sites, then proliferate; it involves contributions from both the tumour cell and tumour microenvironment (‘host’, which includes stromal cells and the immune system1). Studies suggest the early steps of the metastatic process are relatively efficient, with the post-extravasation regulation of tumour growth (‘colonization’) being critical in determining metastatic outcome2. Here we show the results of screening 810 mutant mouse lines using an in vivo assay to identify microenvironmental regulators of metastatic colonization. We identify 23 genes that, when disrupted in mouse, modify the ability of tumour cells to establish metastatic foci, with 19 of these genes not previously demonstrated to play a role in host control of metastasis. The largest reduction in pulmonary metastasis was observed in sphingosine-1-phosphate (S1P) transporter spinster homologue 2 (Spns2)-deficient mice. We demonstrate a novel outcome of S1P-mediated regulation of lymphocyte trafficking, whereby deletion of Spns2, either globally or in a lymphatic endothelial-specific manner, creates a circulating lymphopenia and a higher percentage of effector T cells and natural killer (NK) cells present in the lung. This allows for potent tumour cell killing, and an overall decreased metastatic burden.

Published
2017
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2. Genome-wide Generation and Systematic Phenotyping of Knockout Mice Reveals New Roles for Many Genes

Author

Jacqueline K. White, Anna-Karin Gerdin, Natasha A. Karp, Ed Ryder, Marija Buljan, James N. Bussell, Jennifer Salisbury, Simon Clare, Neil J. Ingham, Christine Podrini, Richard Houghton, Jeanne Estabel, Joanna R. Bottomley, David G. Melvin, David Sunter, Niels C. Adams, David Tannahill, Darren W. Logan, Daniel G. MacArthur, Jonathan Flint, Vinit B. Mahajan, Stephen H. Tsang, Ian Smyth, Fiona M. Watt, William C. Skarnes, Gordon Dougan, David J. Adams, Ramiro Ramirez-Solis, Allan Bradley, Karen P. Steel, Lauren Baker, Caroline Barnes, Ryan Beveridge, Emma Cambridge, Damian Carragher, Prabhjoat Chana, Kay Clarke, Yvette Hooks, Natalia Igosheva, Ozama Ismail, Hannah Jackson, Leanne Kane, Rosalind Lacey, David Tino Lafont, Mark Lucas, Simon Maguire, Katherine McGill, Rebecca E. McIntyre, Sophie Messager, Lynda Mottram, Lee Mulderrig, Selina Pearson, Hayley J. Protheroe, Laura-Anne Roberson, Grace Salsbury, Mark Sanderson, Daniel Sanger, Carl Shannon, Paul C. Thompson, Elizabeth Tuck, Valerie E. Vancollie, Lisa Brackenbury, Wendy Bushell, Ross Cook, Priya Dalvi, Diane Gleeson, Bishoy Habib, Matt Hardy, Kifayathullah Liakath-Ali, Evelina Miklejewska, Stacey Price, Debarati Sethi, Elizabeth Trenchard, Dominique von Schiller, Sapna Vyas, Anthony P. West, John Woodward, Elizabeth Wynn, Arthur Evans, David Gannon, Mark Griffiths, Simon Holroyd, Vivek Iyer, Christian Kipp, Morag Lewis, Wei Li, Darren Oakley, David Richardson, Damian Smedley, Chukwuma Agu, Jackie Bryant, Liz Delaney, Nadia I. Gueorguieva, Helen Tharagonnet, Anne J. Townsend, Daniel Biggs, Ellen Brown, Adam Collinson, Charles-Etienne Dumeau, Evelyn Grau, Sarah Harrison, James Harrison, Catherine E. Ingle, Helen Kundi, Alla Madich, Danielle Mayhew, Tom Metcalf, Stuart Newman, Johanna Pass, Laila Pearson, Helen Reynolds, Caroline Sinclair, Hannah Wardle-Jones, Michael Woods, Liam Alexander, Terry Brown, Francesca Flack, Carole Frost, Nicola Griggs, Silvia Hrnciarova, Andrea Kirton, Jordan McDermott, Claire Rogerson, Gemma White, Pawel Zielezinski, Tia DiTommaso, Andrew Edwards, Emma Heath, Mary Ann Mahajan, Binnaz Yalcin, The Wellcome Trust Sanger Institute [Cambridge], The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford, University of Iowa [Iowa City], Monash University [Melbourne], Wellcome Trust - MRC Cambridge, Columbia University [New York], University of Cambridge [UK] (CAM), Wolfson Centre for Age-Related Diseases [Londres, Royaume-Uni], Guy's Campus [Londres, Royaume-Uni], King‘s College London-King‘s College London, Sanger Institute Mouse Genetics Project: Lauren Baker, Caroline Barnes, Ryan Beveridge, Emma Cambridge, Damian Carragher, Prabhjoat Chana, Kay Clarke, Yvette Hooks, Natalia Igosheva, Ozama Ismail, Hannah Jackson, Leanne Kane, Rosalind Lacey, David Tino Lafont, Mark Lucas, Simon Maguire, Katherine McGill, Rebecca E McIntyre, Sophie Messager, Lynda Mottram, Lee Mulderrig, Selina Pearson, Hayley J Protheroe, Laura-Anne Roberson, Grace Salsbury, Mark Sanderson, Daniel Sanger, Carl Shannon, Paul C Thompson, Elizabeth Tuck, Valerie E Vancollie, Lisa Brackenbury, Wendy Bushell, Ross Cook, Priya Dalvi, Diane Gleeson, Bishoy Habib, Matt Hardy, Kifayathullah Liakath-Ali, Evelina Miklejewska, Stacey Price, Debarati Sethi, Elizabeth Trenchard, Dominique von Schiller, Sapna Vyas, Anthony P West, John Woodward, Elizabeth Wynn, Arthur Evans, David Gannon, Mark Griffiths, Simon Holroyd, Vivek Iyer, Christian Kipp, Morag Lewis, Wei Li, Darren Oakley, David Richardson, Damian Smedley, Chukwuma Agu, Jackie Bryant, Liz Delaney, Nadia I Gueorguieva, Helen Tharagonnet, Anne J Townsend, Daniel Biggs, Ellen Brown, Adam Collinson, Charles-Etienne Dumeau, Evelyn Grau, Sarah Harrison, James Harrison, Catherine E Ingle, Helen Kundi, Alla Madich, Danielle Mayhew, Tom Metcalf, Stuart Newman, Johanna Pass, Laila Pearson, Helen Reynolds, Caroline Sinclair, Hannah Wardle-Jones, Michael Woods, Liam Alexander, Terry Brown, Francesca Flack, Carole Frost, Nicola Griggs, Silvia Hrnciarova, Andrea Kirton, Jordan McDermott, Claire Rogerson, Gemma White, Pawel Zielezinski, Tia Ditommaso, Andrew Edwards, Emma Heath, Mary Ann Mahajan, Binnaz Yalcin., Dupuis, Christine, Estabel, Jeanne [0000-0002-4472-3820], Tannahill, David [0000-0002-3811-6864], Dougan, Gordon [0000-0003-0022-965X], Bradley, Allan [0000-0002-2349-8839], and Apollo - University of Cambridge Repository

Subjects
Resource, Male, [SDV]Life Sciences [q-bio], Mutant, Genome-wide association study, Biology, Genome, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Mice, 0302 clinical medicine, Animals, Disease, Gene, 030304 developmental biology, Genetics, Mice, Knockout, 0303 health sciences, Genes, Essential, Biochemistry, Genetics and Molecular Biology(all), Robustness (evolution), Phenotype, [SDV] Life Sciences [q-bio], Disease Models, Animal, Genetic Techniques, Knockout mouse, Female, Haploinsufficiency, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

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. PaperClip, Graphical Abstract, Highlights • 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.

Published
2013
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3. Prevalence of sexual dimorphism in mammalian phenotypic traits

Author

Damian Smedley, Colin McKerlie, Xiang Gao, Henrik Westerberg, Simon Greenaway, Monica J. Justice, Hiroshi Masuya, Elissa J. Chesler, Robert E. Braun, Mary E. Dickinson, Shay Yaacoby, Stephen A. Murray, Karen L. Svenson, Jeremy Mason, Martin Hrabé de Angelis, Luis Santos, Tania Sorg, Christopher J. Lelliott, Sara Wells, Ann M. Flenniken, Ruth Heller, Ann-Marie Mallon, Lynette Bower, Karen P. Steel, Helen Parkinson, Judith E. Mank, Arthur L. Beaudet, Kevin C K Lloyd, Richard Mott, Yann Herault, Yoav Benjamini, Jacqueline K. White, Steve D.M. Brown, Shiying Guo, John R. Seavitt, Helmut Fuchs, Natalja Kurbatova, Anneliese O. Speak, Natasha A. Karp, Ramiro Ramirez-Solis, Terrence F. Meehan, David B. West, Shigeharu Wakana, The Wellcome Trust Sanger Institute [Cambridge], AstraZeneca [Cambridge, UK], European Bioinformatics Institute [Hinxton] (EMBL-EBI), EMBL Heidelberg, Baylor College of Medicine (BCM), Baylor University, Tel Aviv University (TAU), University of California [Davis] (UC Davis), University of California (UC), The Jackson Laboratory [Bar Harbor] (JAX), MRC Harwell Institute [UK], Helmholtz Zentrum München = German Research Center for Environmental Health, Technische Universität München = Technical University of Munich (TUM), German Center for Diabetes Research - Deutsches Zentrum für Diabetesforschung [Neuherberg] (DZD), Nanjing University (NJU), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), French National Infrastructure for Mouse Phenogenomics (PHENOMIN), Institut Clinique de la Souris (ICS), The Hospital for sick children [Toronto] (SickKids), University College of London [London] (UCL), RIKEN BioResource Research Center [Tsukuba, Japan] (RIKEN BRC), Queen Mary University of London (QMUL), King‘s College London, Children's Hospital Oakland Research Institute (CHORI), International Mouse Phenotyping Consortium: Yuichi Obata, Tomohiro Suzuki, Masaru Tamura, Hideki Kaneda, Tamio Furuse, Kimio Kobayashi, Ikuo Miura, Ikuko Yamada, Nobuhiko Tanaka, Atsushi Yoshiki, Shinya Ayabe, David A Clary, Heather A Tolentino, Michael A Schuchbauer, Todd Tolentino, Joseph Anthony Aprile, Sheryl M Pedroia, Lois Kelsey, Igor Vukobradovic, Zorana Berberovic, Celeste Owen, Dawei Qu, Ruolin Guo, Susan Newbigging, Lily Morikawa, Napoleon Law, Xueyuan Shang, Patricia Feugas, Yanchun Wang, Mohammad Eskandarian, Yingchun Zhu, Lauryl M J Nutter, Patricia Penton, Valerie Laurin, Shannon Clarke, Qing Lan, Khondoker Sohel, David Miller, Greg Clark, Jane Hunter, Jorge Cabezas, Mohammed Bubshait, Tracy Carroll, Sandra Tondat, Suzanne MacMaster, Monica Pereira, Marina Gertsenstein, Ozge Danisment, Elsa Jacob, Amie Creighton, Gillian Sleep, James Clark, Lydia Teboul, Martin Fray, Adam Caulder, Jorik Loeffler, Gemma Codner, James Cleak, Sara Johnson, Zsombor Szoke-Kovacs, Adam Radage, Marina Maritati, Joffrey Mianne, Wendy Gardiner, Susan Allen, Heather Cater, Michelle Stewart, Piia Keskivali-Bond, Caroline Sinclair, Ellen Brown, Brendan Doe, Hannah Wardle-Jones, Evelyn Grau, Nicola Griggs, Mike Woods, Helen Kundi, Mark N D Griffiths, Christian Kipp, David G Melvin, Navis P S Raj, Simon A Holroyd, David J Gannon, Rafael Alcantara, Antonella Galli, Yvette E Hooks, Catherine L Tudor, Angela L Green, Fiona L Kussy, Elizabeth J Tuck, Emma J Siragher, Simon A Maguire, David T Lafont, Valerie E Vancollie, Selina A Pearson, Amy S Gates, Mark Sanderson, Carl Shannon, Lauren F E Anthony, Maksymilian T Sumowski, Robbie S B McLaren, Agnieszka Swiatkowska, Christopher M Isherwood, Emma L Cambridge, Heather M Wilson, Susana S Caetano, Cecilia Icoresi Mazzeo, Monika H Dabrowska, Charlotte Lillistone, Jeanne Estabel, Anna Karin B Maguire, Laura-Anne Roberson, Guillaume Pavlovic, Marie-Christine Birling, Wattenhofer-Donze Marie, Sylvie Jacquot, Abdel Ayadi, Dalila Ali-Hadji, Philippe Charles, Philippe André, Elise Le Marchand, Amal El Amri, Laurent Vasseur, Antonio Aguilar-Pimentel, Lore Becker, Irina Treise, Kristin Moreth, Tobias Stoeger, Oana V Amarie, Frauke Neff, Wolfgang Wurst, Raffi Bekeredjian, Markus Ollert, Thomas Klopstock, Julia Calzada-Wack, Susan Marschall, Robert Brommage, Ralph Steinkamp, Christoph Lengger, Manuela A Östereicher, Holger Maier, Claudia Stoeger, Stefanie Leuchtenberger, AliÖ Yildrim, Lillian Garrett, Sabine M Hölter, Annemarie Zimprich, Claudia Seisenberger, Antje Bürger, Jochen Graw, Oliver Eickelberg, Andreas Zimmer, Eckhard Wolf, Dirk H Busch, Martin Klingenspor, Carsten Schmidt-Weber, Valérie Gailus-Durner, Johannes Beckers, Birgit Rathkolb, Jan Rozman, univOAK, Archive ouverte, Mason, Jeremy [0000-0002-2796-5123], Chesler, Elissa J [0000-0002-5642-5062], Angelis, Martin Hrabe de [0000-0002-7898-2353], Herault, Yann [0000-0001-7049-6900], Lelliott, Christopher J [0000-0001-8087-4530], McKerlie, Colin [0000-0002-2232-0967], Wakana, Shigeharu [0000-0001-8532-0924], Yaacoby, Shay [0000-0002-2583-4170], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Genotype, Science, Mutant, General Physics and Astronomy, [SDV.GEN] Life Sciences [q-bio]/Genetics, Quantitative trait locus, Biology, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Mice, Quantitative Trait, Quantitative Trait, Heritable, Genetics, Animals, Modifier, Gene, Heritable, Mammals, Sex Characteristics, [SDV.GEN]Life Sciences [q-bio]/Genetics, Multidisciplinary, Genes, Modifier, Body Weight, General Chemistry, Phenotypic trait, Phenotype, Sexual dimorphism, 030104 developmental biology, Genes, Evolutionary biology, Female, International Mouse Phenotyping Consortium, Sex characteristics
Abstract

The role of sex in biomedical studies has often been overlooked, despite evidence of sexually dimorphic effects in some biological studies. Here, we used high-throughput phenotype data from 14,250 wildtype and 40,192 mutant mice (representing 2,186 knockout lines), analysed for up to 234 traits, and found a large proportion of mammalian traits both in wildtype and mutants are influenced by sex. This result has implications for interpreting disease phenotypes in animal models and humans., Systemic dissection of sexually dimorphic phenotypes in mice is lacking. Here, Karp and the International Mouse Phenotype Consortium show that approximately 10% of qualitative traits and 56% of quantitative traits in mice as measured in laboratory setting are sexually dimorphic.

Published
2017
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