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1. Impact of essential genes on the success of genome editing experiments generating 3313 new genetically engineered mouse lines

Author: Elrick, Hillary, Peterson, Kevin A., Willis, Brandon J., Lanza, Denise G., Acar, Elif F., Ryder, Edward J., Teboul, Lydia, Kasparek, Petr, Birling, Marie-Christine, Adams, David J., Bradley, Allan, Braun, Robert E., Brown, Steve D., Caulder, Adam, Codner, Gemma F., DeMayo, Francesco J., Dickinson, Mary E., Doe, Brendan, Duddy, Graham, Gertsenstein, Marina, Goodwin, Leslie O., Hérault, Yann, Lintott, Lauri G., Lloyd, K. C. Kent, Lorenzo, Isabel, Mackenzie, Matthew, Mallon, Ann-Marie, McKerlie, Colin, Parkinson, Helen, Ramirez-Solis, Ramiro, Seavitt, John R., Sedlacek, Radislav, Skarnes, William C., Smedley, Damien, Wells, Sara, White, Jacqueline K., Wood, Joshua A., Murray, Stephen A., Heaney, Jason D., and Nutter, Lauryl M. J.
Published: 2024
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2. Multiple reaction monitoring assays for large-scale quantitation of proteins from 20 mouse organs and tissues

Author: Michaud, Sarah A., Pětrošová, Helena, Sinclair, Nicholas J., Kinnear, Andrea L., Jackson, Angela M., McGuire, Jamie C., Hardie, Darryl B., Bhowmick, Pallab, Ganguly, Milan, Flenniken, Ann M., Nutter, Lauryl M. J., McKerlie, Colin, Smith, Derek, Mohammed, Yassene, Schibli, David, Sickmann, Albert, and Borchers, Christoph H.
Published: 2024
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3. Sexual Dimorphism of the Mouse Plasma Metabolome Is Associated with Phenotypes of 30 Gene Knockout Lines

Author: Zhang, Ying, Barupal, Dinesh K, Fan, Sili, Gao, Bei, Zhu, Chao, Flenniken, Ann M, McKerlie, Colin, Nutter, Lauryl MJ, Lloyd, Kevin C Kent, and Fiehn, Oliver
Subjects: Medical Biochemistry and Metabolomics, Analytical Chemistry, Biomedical and Clinical Sciences, Chemical Sciences, Genetics, 2.1 Biological and endogenous factors, Aetiology, animal models, lipidomics, mass spectrometry, physiology, complex diseases, Biochemistry and Cell Biology, Clinical Sciences, Biochemistry and cell biology, Medical biochemistry and metabolomics, Analytical chemistry
Abstract: Although metabolic alterations are observed in many monogenic and complex genetic disorders, the impact of most mammalian genes on cellular metabolism remains unknown. Understanding the effect of mouse gene dysfunction on metabolism can inform the functions of their human orthologues. We investigated the effect of loss-of-function mutations in 30 unique gene knockout (KO) lines on plasma metabolites, including genes coding for structural proteins (11 of 30), metabolic pathway enzymes (12 of 30) and protein kinases (7 of 30). Steroids, bile acids, oxylipins, primary metabolites, biogenic amines and complex lipids were analyzed with dedicated mass spectrometry platforms, yielding 827 identified metabolites in male and female KO mice and wildtype (WT) controls. Twenty-two percent of 23,698 KO versus WT comparison tests showed significant genotype effects on plasma metabolites. Fifty-six percent of identified metabolites were significantly different between the sexes in WT mice. Many of these metabolites were also found to have sexually dimorphic changes in KO lines. We used plasma metabolites to complement phenotype information exemplified for Dhfr, Idh1, Mfap4, Nek2, Npc2, Phyh and Sra1. The association of plasma metabolites with IMPC phenotypes showed dramatic sexual dimorphism in wildtype mice. We demonstrate how to link metabolomics to genotypes and (disease) phenotypes. Sex must be considered as critical factor in the biological interpretation of gene functions.
Published: 2023

4. Genome-wide screening reveals the genetic basis of mammalian embryonic eye development

Author: Chee, Justine M, Lanoue, Louise, Clary, Dave, Higgins, Kendall, Bower, Lynette, Flenniken, Ann, Guo, Ruolin, Adams, David J, Bosch, Fatima, Braun, Robert E, Brown, Steve DM, Chin, H-J Genie, Dickinson, Mary E, Hsu, Chih-Wei, Dobbie, Michael, Gao, Xiang, Galande, Sanjeev, Grobler, Anne, Heaney, Jason D, Herault, Yann, de Angelis, Martin Hrabe, Mammano, Fabio, Nutter, Lauryl MJ, Parkinson, Helen, Qin, Chuan, Shiroishi, Toshi, Sedlacek, Radislav, Seong, J-K, Xu, Ying, Brooks, Brian, McKerlie, Colin, Lloyd, KC Kent, Westerberg, Henrik, and Moshiri, Ala
Subjects: Biological Sciences, Genetics, Congenital Structural Anomalies, Rare Diseases, Human Genome, Eye Disease and Disorders of Vision, Pediatric, 2.1 Biological and endogenous factors, Eye, Humans, Mice, Animals, Eye Abnormalities, Anophthalmos, Microphthalmos, Coloboma, Mice, Knockout, Embryonic Development, Phenotype, Mammals, MAC spectrum, Eye development, Mouse, IMPC, Serine-glycine biosynthesis, CPLANE, International Mouse Phenotyping Consortium, Developmental Biology
Abstract: BackgroundMicrophthalmia, anophthalmia, and coloboma (MAC) spectrum disease encompasses a group of eye malformations which play a role in childhood visual impairment. Although the predominant cause of eye malformations is known to be heritable in nature, with 80% of cases displaying loss-of-function mutations in the ocular developmental genes OTX2 or SOX2, the genetic abnormalities underlying the remaining cases of MAC are incompletely understood. This study intended to identify the novel genes and pathways required for early eye development. Additionally, pathways involved in eye formation during embryogenesis are also incompletely understood. This study aims to identify the novel genes and pathways required for early eye development through systematic forward screening of the mammalian genome.ResultsQuery of the International Mouse Phenotyping Consortium (IMPC) database (data release 17.0, August 01, 2022) identified 74 unique knockout lines (genes) with genetically associated eye defects in mouse embryos. The vast majority of eye abnormalities were small or absent eyes, findings most relevant to MAC spectrum disease in humans. A literature search showed that 27 of the 74 lines had previously published knockout mouse models, of which only 15 had ocular defects identified in the original publications. These 12 previously published gene knockouts with no reported ocular abnormalities and the 47 unpublished knockouts with ocular abnormalities identified by the IMPC represent 59 genes not previously associated with early eye development in mice. Of these 59, we identified 19 genes with a reported human eye phenotype. Overall, mining of the IMPC data yielded 40 previously unimplicated genes linked to mammalian eye development. Bioinformatic analysis showed that several of the IMPC genes colocalized to several protein anabolic and pluripotency pathways in early eye development. Of note, our analysis suggests that the serine-glycine pathway producing glycine, a mitochondrial one-carbon donator to folate one-carbon metabolism (FOCM), is essential for eye formation.ConclusionsUsing genome-wide phenotype screening of single-gene knockout mouse lines, STRING analysis, and bioinformatic methods, this study identified genes heretofore unassociated with MAC phenotypes providing models to research novel molecular and cellular mechanisms involved in eye development. These findings have the potential to hasten the diagnosis and treatment of this congenital blinding disease.
Published: 2023

5. Bridging mouse and human anatomies; a knowledge-based approach to comparative anatomy for disease model phenotyping

Author: Ruberte, Jesús, Schofield, Paul N., Sundberg, John P., Rodriguez-Baeza, Alfonso, Carretero, Ana, and McKerlie, Colin
Published: 2023
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6. Large-scale genomic investigation of pediatric cholestasis reveals a novel hepatorenal ciliopathy caused by PSKH1 mutations

Author: Maddirevula, Sateesh, Shagrani, Mohammad, Ji, Ae-Ri, Horne, Christopher R., Young, Samuel N., Mather, Lucy J., Alqahtani, Mashael, McKerlie, Colin, Wood, Geoffrey, Potter, Paul K., Abdulwahab, Firdous, AlSheddi, Tarfa, van der Woerd, Wendy L., van Gassen, Koen L.I., AlBogami, Dalal, Kumar, Kishwer, Muhammad Akhtar, Ali Syed, Binomar, Hiba, Almanea, Hadeel, Faqeih, Eissa, Fuchs, Sabine A., Scott, John W., Murphy, James M., and Alkuraya, Fowzan S.
Published: 2024
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7. Identifying genetic determinants of inflammatory pain in mice using a large-scale gene-targeted screen

Author: Wotton, Janine M, Peterson, Emma, Flenniken, Ann M, Bains, Rasneer S, Veeraragavan, Surabi, Bower, Lynette R, Bubier, Jason A, Parisien, Marc, Bezginov, Alexandr, Haselimashhadi, Hamed, Mason, Jeremy, Moore, Michayla A, Stewart, Michelle E, Clary, Dave A, Delbarre, Daniel J, Anderson, Laura C, D'Souza, Abigail, Goodwin, Leslie O, Harrison, Mark E, Huang, Ziyue, Mckay, Matthew, Qu, Dawei, Santos, Luis, Srinivasan, Subhiksha, Urban, Rachel, Vukobradovic, Igor, Ward, Christopher S, Willett, Amelia M, Consortium, The International Mouse Phenotyping, Braun, Robert E, Brown, Steve DM, Dickinson, Mary E, Heaney, Jason D, Kumar, Vivek, Lloyd, KC Kent, Mallon, Ann-Marie, McKerlie, Colin, Murray, Stephen A, Nutter, Lauryl MJ, Parkinson, Helen, Seavitt, John R, Wells, Sara, Samaco, Rodney C, Chesler, Elissa J, Smedley, Damian, Diatchenko, Luda, Baumbauer, Kyle M, Young, Erin E, Bonin, Robert P, Mandillo, Silvia, and White, Jacqueline K
Subjects: Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Basic Behavioral and Social Science, Genetics, Pain Research, Chronic Pain, Behavioral and Social Science, Biotechnology, Aetiology, 2.1 Biological and endogenous factors, Animals, Freund's Adjuvant, Mice, Mice, Knockout, Nociception, Pain, Pain Measurement, Nocifensive behavior, Sensitization, Formalin, Hargreaves, von Frey, Complete Freund's adjuvant, Single-gene knockout mouse, Screen, IMPC, Comorbidity, Autism, International Mouse Phenotyping Consortium, Medical and Health Sciences, Psychology and Cognitive Sciences, Anesthesiology, Biomedical and clinical sciences, Health sciences, Psychology
Abstract: AbstractIdentifying the genetic determinants of pain is a scientific imperative given the magnitude of the global health burden that pain causes. Here, we report a genetic screen for nociception, performed under the auspices of the International Mouse Phenotyping Consortium. A biased set of 110 single-gene knockout mouse strains was screened for 1 or more nociception and hypersensitivity assays, including chemical nociception (formalin) and mechanical and thermal nociception (von Frey filaments and Hargreaves tests, respectively), with or without an inflammatory agent (complete Freund's adjuvant). We identified 13 single-gene knockout strains with altered nocifensive behavior in 1 or more assays. All these novel mouse models are openly available to the scientific community to study gene function. Two of the 13 genes (Gria1 and Htr3a) have been previously reported with nociception-related phenotypes in genetically engineered mouse strains and represent useful benchmarking standards. One of the 13 genes (Cnrip1) is known from human studies to play a role in pain modulation and the knockout mouse reported herein can be used to explore this function further. The remaining 10 genes (Abhd13, Alg6, BC048562, Cgnl1, Cp, Mmp16, Oxa1l, Tecpr2, Trim14, and Trim2) reveal novel pathways involved in nociception and may provide new knowledge to better understand genetic mechanisms of inflammatory pain and to serve as models for therapeutic target validation and drug development.
Published: 2022

8. Comprehensive ECG reference intervals in C57BL/6N substrains provide a generalizable guide for cardiac electrophysiology studies in mice

Author: Oestereicher, Manuela A., Wotton, Janine M., Ayabe, Shinya, Bou About, Ghina, Cheng, Tsz Kwan, Choi, Jae-Hoon, Clary, Dave, Dew, Emily M., Elfertak, Lahcen, Guimond, Alain, Haseli Mashhadi, Hamed, Heaney, Jason D., Kelsey, Lois, Keskivali-Bond, Piia, Lopez Gomez, Federico, Marschall, Susan, McFarland, Michael, Meziane , Hamid, Munoz Fuentes, Violeta, Nam , Ki-Hoan, Nichtová, Zuzana, Pimm, Dale, Bower, Lynette, Prochazka, Jan, Rozman, Jan, Santos, Luis, Stewart, Michelle, Tanaka, Nobuhiko, Ward, Christopher S., Willett, Amelia M. E., Wilson, Robert, Braun, Robert E., Dickinson, Mary E., Flenniken, Ann M., Herault, Yann, Lloyd, K. C. Kent, Mallon, Ann-Marie, McKerlie, Colin, Murray, Stephen A., Nutter, Lauryl M. J., Sedlacek, Radislav, Seong, Je Kyung, Sorg, Tania, Tamura, Masaru, Wells, Sara, Schneltzer, Elida, Fuchs, Helmut, Gailus-Durner, Valerie, Hrabe de Angelis, Martin, White, Jacqueline K., and Spielmann, Nadine
Published: 2023
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9. Mendelian gene identification through mouse embryo viability screening

Author: Cacheiro, Pilar, Westerberg, Carl Henrik, Mager, Jesse, Dickinson, Mary E, Nutter, Lauryl MJ, Muñoz-Fuentes, Violeta, Hsu, Chih-Wei, Van den Veyver, Ignatia B, Flenniken, Ann M, McKerlie, Colin, Murray, Stephen A, Teboul, Lydia, Heaney, Jason D, Lloyd, KC Kent, Lanoue, Louise, Braun, Robert E, White, Jacqueline K, Creighton, Amie K, Laurin, Valerie, Guo, Ruolin, Qu, Dawei, Wells, Sara, Cleak, James, Bunton-Stasyshyn, Rosie, Stewart, Michelle, Harrisson, Jackie, Mason, Jeremy, Haseli Mashhadi, Hamed, Parkinson, Helen, Mallon, Ann-Marie, and Smedley, Damian
Subjects: Biological Sciences, Bioinformatics and Computational Biology, Biotechnology, Human Genome, Rare Diseases, Genetics, 2.1 Biological and endogenous factors, Animals, Embryo, Mammalian, Female, Genes, Lethal, Homozygote, Humans, Mice, Mice, Knockout, Phenotype, Pregnancy, International Mouse Phenotyping Consortium, Genomics England Research Consortium, Clinical Sciences
Abstract: BackgroundThe diagnostic rate of Mendelian disorders in sequencing studies continues to increase, along with the pace of novel disease gene discovery. However, variant interpretation in novel genes not currently associated with disease is particularly challenging and strategies combining gene functional evidence with approaches that evaluate the phenotypic similarities between patients and model organisms have proven successful. A full spectrum of intolerance to loss-of-function variation has been previously described, providing evidence that gene essentiality should not be considered as a simple and fixed binary property.MethodsHere we further dissected this spectrum by assessing the embryonic stage at which homozygous loss-of-function results in lethality in mice from the International Mouse Phenotyping Consortium, classifying the set of lethal genes into one of three windows of lethality: early, mid, or late gestation lethal. We studied the correlation between these windows of lethality and various gene features including expression across development, paralogy and constraint metrics together with human disease phenotypes. We explored a gene similarity approach for novel gene discovery and investigated unsolved cases from the 100,000 Genomes Project.ResultsWe found that genes in the early gestation lethal category have distinct characteristics and are enriched for genes linked with recessive forms of inherited metabolic disease. We identified several genes sharing multiple features with known biallelic forms of inborn errors of the metabolism and found signs of enrichment of biallelic predicted pathogenic variants among early gestation lethal genes in patients recruited under this disease category. We highlight two novel gene candidates with phenotypic overlap between the patients and the mouse knockouts.ConclusionsInformation on the developmental period at which embryonic lethality occurs in the knockout mouse may be used for novel disease gene discovery that helps to prioritise variants in unsolved rare disease cases.
Published: 2022

10. Analysis of genome-wide knockout mouse database identifies candidate ciliopathy genes

Author: Higgins, Kendall, Moore, Bret A, Berberovic, Zorana, Adissu, Hibret A, Eskandarian, Mohammad, Flenniken, Ann M, Shao, Andy, Imai, Denise M, Clary, Dave, Lanoue, Louise, Newbigging, Susan, Nutter, Lauryl MJ, Adams, David J, Bosch, Fatima, Braun, Robert E, Brown, Steve DM, Dickinson, Mary E, Dobbie, Michael, Flicek, Paul, Gao, Xiang, Galande, Sanjeev, Grobler, Anne, Heaney, Jason D, Herault, Yann, de Angelis, Martin Hrabe, Chin, Hsian-Jean Genie, Mammano, Fabio, Qin, Chuan, Shiroishi, Toshihiko, Sedlacek, Radislav, Seong, J-K, Xu, Ying, Lloyd, KC Kent, McKerlie, Colin, and Moshiri, Ala
Subjects: Biological Sciences, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Genetics, Biotechnology, Rare Diseases, 2.1 Biological and endogenous factors, Mice, Animals, Mice, Knockout, Ciliopathies, Gene Knockout Techniques, Cilia, Databases, Factual, Nerve Tissue Proteins, Cell Cycle Proteins, IMPC Consortium
Abstract: We searched a database of single-gene knockout (KO) mice produced by the International Mouse Phenotyping Consortium (IMPC) to identify candidate ciliopathy genes. We first screened for phenotypes in mouse lines with both ocular and renal or reproductive trait abnormalities. The STRING protein interaction tool was used to identify interactions between known cilia gene products and those encoded by the genes in individual knockout mouse strains in order to generate a list of "candidate ciliopathy genes." From this list, 32 genes encoded proteins predicted to interact with known ciliopathy proteins. Of these, 25 had no previously described roles in ciliary pathobiology. Histological and morphological evidence of phenotypes found in ciliopathies in knockout mouse lines are presented as examples (genes Abi2, Wdr62, Ap4e1, Dync1li1, and Prkab1). Phenotyping data and descriptions generated on IMPC mouse line are useful for mechanistic studies, target discovery, rare disease diagnosis, and preclinical therapeutic development trials. Here we demonstrate the effective use of the IMPC phenotype data to uncover genes with no previous role in ciliary biology, which may be clinically relevant for identification of novel disease genes implicated in ciliopathies.
Published: 2022

11. Co-expression of prepulse inhibition and Schizophrenia genes in the mouse and human brain

Author: Aguilar-Pimental, Juan A., Amarie, Oana V., Becker, Lore, Calzada-Wack, Julia, Da Silva-Buttkus, Patricia, Dragano, Nathalia, Kraiger, Markus, Lengger, Christoph, Leuchtenberger, Stefanie, Marschall, Susan, Oestereicher, Manuela A., Rathkolb, Birgit, Sanz-Moreno, Adrián, Seisenberger, Claudia, Spielmann, Nadine, Stoeger, Claudia, Kumar, Vivek, Keskivali, Piia, King, Ruairidh, Haselimashhadi, Hamed, Bezginov, Alexandr, Norris, Clare, Taylor, Sarah, Pimm, Dale, Kelsey, Lois, Berberovic, Zorana, Qu, Dawei, D'Souza, Abigail, Bradaschia, Vivian, Eskandarian, Mohammed, Shang, Xueyuan, Duffin, Kyle, Roberton, Kyle, Xu, Catherine, Baguinat, Gloria, Laurin, Valerie, Lan, Qing, Sleep, Gillian, Lintott, Lauri, Gertsenstein, Marina, Tondat, Sandra, Cruz, Maribelle, Miller, David, Sorg, Tania, Riet, Fabrice, Tolentino, Heather, Tolentino, Todd, Schuchbauer, Mike, Hockenbury, Nichole, Beeman, Karrie, Pedroia, Sheryl, Salazar, Jason, Heffner, Mollie, Hsu, Joanne, Fletcher, Colin, Vanzanten, Maya, Golini, Elisabetta, Seavitt, John R., Lanza, Denise G., Lorenzo, Isabel, Gaspero, Angelina, Rios, Amanda, Garrett, Lillian, Trümbach, Dietrich, Lee, Donghyung, Mandillo, Silvia, Samaco, Rodney, Flenniken, Ann M., Stewart, Michelle, White, Jacqueline K., McKerlie, Colin, Nutter, Lauryl M.J., Vukobradovic, Igor, Veeraragavan, Surabi, Yuva, Lisa, Heaney, Jason D., Dickinson, Mary E., Meziane, Hamid, Hérault, Yann, Wells, Sara, Lloyd, K.C. Kent, Bower, Lynette, Lanoue, Louise, Clary, Dave, Zimprich, Annemarie, Gailus-Durner, Valerie, Fuchs, Helmut, Brown, Steve D.M., Chesler, Elissa J., Wurst, Wolfgang, Hrabě de Angelis, Martin, and Hölter, Sabine M.
Published: 2024
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12. A resource of targeted mutant mouse lines for 5,061 genes

Author: Birling, Marie-Christine, Yoshiki, Atsushi, Adams, David J, Ayabe, Shinya, Beaudet, Arthur L, Bottomley, Joanna, Bradley, Allan, Brown, Steve DM, Bürger, Antje, Bushell, Wendy, Chiani, Francesco, Chin, Hsian-Jean Genie, Christou, Skevoulla, Codner, Gemma F, DeMayo, Francesco J, Dickinson, Mary E, Doe, Brendan, Donahue, Leah Rae, Fray, Martin D, Gambadoro, Alessia, Gao, Xiang, Gertsenstein, Marina, Gomez-Segura, Alba, Goodwin, Leslie O, Heaney, Jason D, Hérault, Yann, de Angelis, Martin Hrabe, Jiang, Si-Tse, Justice, Monica J, Kasparek, Petr, King, Ruairidh E, Kühn, Ralf, Lee, Ho, Lee, Young Jae, Liu, Zhiwei, Lloyd, KC Kent, Lorenzo, Isabel, Mallon, Ann-Marie, McKerlie, Colin, Meehan, Terrence F, Fuentes, Violeta Munoz, Newman, Stuart, Nutter, Lauryl MJ, Oh, Goo Taeg, Pavlovic, Guillaume, Ramirez-Solis, Ramiro, Rosen, Barry, Ryder, Edward J, Santos, Luis A, Schick, Joel, Seavitt, John R, Sedlacek, Radislav, Seisenberger, Claudia, Seong, Je Kyung, Skarnes, William C, Sorg, Tania, Steel, Karen P, Tamura, Masaru, Tocchini-Valentini, Glauco P, Wang, Chi-Kuang Leo, Wardle-Jones, Hannah, Wattenhofer-Donzé, Marie, Wells, Sara, Wiles, Michael V, Willis, Brandon J, Wood, Joshua A, Wurst, Wolfgang, Xu, Ying, Teboul, Lydia, and Murray, Stephen A
Subjects: Biological Sciences, Genetics, Animals, Gene Deletion, Genetic Association Studies, Genome, Genotype, Information Dissemination, International Cooperation, Internet, Mice, Mice, Knockout, Mouse Embryonic Stem Cells, Mutagenesis, Phenotype, International Mouse Phenotyping Consortium, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract: The International Mouse Phenotyping Consortium reports the generation of new mouse mutant strains for over 5,000 genes, including 2,850 novel null, 2,987 novel conditional- ready, and 4,433 novel reporter alleles.
Published: 2021

13. Proteotyping of knockout mouse strains reveals sex- and strain-specific signatures in blood plasma

Author: Mohammed, Yassene, Michaud, Sarah A, Pětrošová, Helena, Yang, Juncong, Ganguly, Milan, Schibli, David, Flenniken, Ann M, Nutter, Lauryl MJ, Adissu, Hibret A, Lloyd, KC Kent, McKerlie, Colin, and Borchers, Christoph H
Subjects: Biochemistry and Cell Biology, Biological Sciences, Rare Diseases, Aging, Biotechnology, Cancer, Genetics, Aetiology, 2.2 Factors relating to the physical environment, Animals, Female, Male, Mice, Mice, Knockout, Plasma, Proteome, Proteomics, Bioinformatics and computational biology
Abstract: We proteotyped blood plasma from 30 mouse knockout strains and corresponding wild-type mice from the International Mouse Phenotyping Consortium. We used targeted proteomics with internal standards to quantify 375 proteins in 218 samples. Our results provide insights into the manifested effects of each gene knockout at the plasma proteome level. We first investigated possible contamination by erythrocytes during sample preparation and labeled, in one case, up to 11 differential proteins as erythrocyte originated. Second, we showed that differences in baseline protein abundance between female and male mice were evident in all mice, emphasizing the necessity to include both sexes in basic research, target discovery, and preclinical effect and safety studies. Next, we identified the protein signature of each gene knockout and performed functional analyses for all knockout strains. Further, to demonstrate how proteome analysis identifies the effect of gene deficiency beyond traditional phenotyping tests, we provide in-depth analysis of two strains, C8a-/- and Npc2+/-. The proteins encoded by these genes are well-characterized providing good validation of our method in homozygous and heterozygous knockout mice. Ig alpha chain C region, a poorly characterized protein, was among the differentiating proteins in C8a-/-. In Npc2+/- mice, where histopathology and traditional tests failed to differentiate heterozygous from wild-type mice, our data showed significant difference in various lysosomal storage disease-related proteins. Our results demonstrate how to combine absolute quantitative proteomics with mouse gene knockout strategies to systematically study the effect of protein absence. The approach used here for blood plasma is applicable to all tissue protein extracts.
Published: 2021

14. The Deep Genome Project

Author: Lloyd, KC Kent, Adams, David J, Baynam, Gareth, Beaudet, Arthur L, Bosch, Fatima, Boycott, Kym M, Braun, Robert E, Caulfield, Mark, Cohn, Ronald, Dickinson, Mary E, Dobbie, Michael S, Flenniken, Ann M, Flicek, Paul, Galande, Sanjeev, Gao, Xiang, Grobler, Anne, Heaney, Jason D, Herault, Yann, de Angelis, Martin Hrabě, Lupski, James R, Lyonnet, Stanislas, Mallon, Ann-Marie, Mammano, Fabio, MacRae, Calum A, McInnes, Roderick, McKerlie, Colin, Meehan, Terrence F, Murray, Stephen A, Nutter, Lauryl MJ, Obata, Yuichi, Parkinson, Helen, Pepper, Michael S, Sedlacek, Radislav, Seong, Je Kyung, Shiroishi, Toshihiko, Smedley, Damian, Tocchini-Valentini, Glauco, Valle, David, Wang, Chi-Kuang Leo, Wells, Sara, White, Jacqueline, Wurst, Wolfgang, Xu, Ying, and Brown, Steve DM
Subjects: Animals, Genes, Genome, Humans, Mice, Mutation, Phenotype, Proteins, Environmental Sciences, Biological Sciences, Information and Computing Sciences, Bioinformatics
Published: 2020

15. Soft windowing application to improve analysis of high-throughput phenotyping data

Author: Haselimashhadi, Hamed, Mason, Jeremy C, Munoz-Fuentes, Violeta, López-Gómez, Federico, Babalola, Kolawole, Acar, Elif F, Kumar, Vivek, White, Jacqui, Flenniken, Ann M, King, Ruairidh, Straiton, Ewan, Seavitt, John Richard, Gaspero, Angelina, Garza, Arturo, Christianson, Audrey E, Hsu, Chih-Wei, Reynolds, Corey L, Lanza, Denise G, Lorenzo, Isabel, Green, Jennie R, Gallegos, Juan J, Bohat, Ritu, Samaco, Rodney C, Veeraragavan, Surabi, Kim, Jong Kyoung, Miller, Gregor, Fuchs, Helmult, Garrett, Lillian, Becker, Lore, Kang, Yeon Kyung, Clary, David, Cho, Soo Young, Tamura, Masaru, Tanaka, Nobuhiko, Soo, Kyung Dong, Bezginov, Alexandr, About, Ghina Bou, Champy, Marie-France, Vasseur, Laurent, Leblanc, Sophie, Meziane, Hamid, Selloum, Mohammed, Reilly, Patrick T, Spielmann, Nadine, Maier, Holger, Gailus-Durner, Valerie, Sorg, Tania, Hiroshi, Masuya, Yuichi, Obata, Heaney, Jason D, Dickinson, Mary E, Wolfgang, Wurst, Tocchini-Valentini, Glauco P, Lloyd, Kevin C Kent, McKerlie, Colin, Seong, Je Kyung, Yann, Herault, de Angelis, Martin Hrabé, Brown, Steve DM, Smedley, Damian, Flicek, Paul, Mallon, Ann-Marie, Parkinson, Helen, and Meehan, Terrence F
Subjects: Biological Sciences, Genetics, Animals, Genetic Association Studies, Humans, Mice, Phenotype, Population Health, Software, Mathematical Sciences, Information and Computing Sciences, Bioinformatics, Biological sciences, Information and computing sciences, Mathematical sciences
Abstract: MotivationHigh-throughput phenomic projects generate complex data from small treatment and large control groups that increase the power of the analyses but introduce variation over time. A method is needed to utlize a set of temporally local controls that maximizes analytic power while minimizing noise from unspecified environmental factors.ResultsHere we introduce 'soft windowing', a methodological approach that selects a window of time that includes the most appropriate controls for analysis. Using phenotype data from the International Mouse Phenotyping Consortium (IMPC), adaptive windows were applied such that control data collected proximally to mutants were assigned the maximal weight, while data collected earlier or later had less weight. We applied this method to IMPC data and compared the results with those obtained from a standard non-windowed approach. Validation was performed using a resampling approach in which we demonstrate a 10% reduction of false positives from 2.5 million analyses. We applied the method to our production analysis pipeline that establishes genotype-phenotype associations by comparing mutant versus control data. We report an increase of 30% in significant P-values, as well as linkage to 106 versus 99 disease models via phenotype overlap with the soft-windowed and non-windowed approaches, respectively, from a set of 2082 mutant mouse lines. Our method is generalizable and can benefit large-scale human phenomic projects such as the UK Biobank and the All of Us resources.Availability and implementationThe method is freely available in the R package SmoothWin, available on CRAN http://CRAN.R-project.org/package=SmoothWin.Supplementary informationSupplementary data are available at Bioinformatics online.
Published: 2020

16. High-throughput discovery of genetic determinants of circadian misalignment

Author: Zhang, Tao, Xie, Pancheng, Dong, Yingying, Liu, Zhiwei, Zhou, Fei, Pan, Dejing, Huang, Zhengyun, Zhai, Qiaocheng, Gu, Yue, Wu, Qingyu, Tanaka, Nobuhiko, Obata, Yuichi, Bradley, Allan, Lelliott, Christopher J, Nutter, Lauryl MJ, McKerlie, Colin, Flenniken, Ann M, Champy, Marie-France, Sorg, Tania, Herault, Yann, De Angelis, Martin Hrabe, Durner, Valerie Gailus, Mallon, Ann-Marie, Brown, Steve DM, Meehan, Terry, Parkinson, Helen E, Smedley, Damian, Lloyd, KC Kent, Yan, Jun, Gao, Xiang, Seong, Je Kyung, Wang, Chi-Kuang Leo, Sedlacek, Radislav, Liu, Yi, Rozman, Jan, Yang, Ling, and Xu, Ying
Subjects: Biochemistry and Cell Biology, Biological Sciences, Sleep Research, Genetics, Neurosciences, Amino Acid Transport System y+, Animals, Circadian Rhythm, Machine Learning, Male, Mice, Mice, Inbred C57BL, Mutation, Receptors, Oxytocin, Repressor Proteins, Serine Endopeptidases, Telomere-Binding Proteins, Ubiquitin-Protein Ligase Complexes, Sanger Institute Mouse Genetics Project, Developmental Biology
Abstract: Circadian systems provide a fitness advantage to organisms by allowing them to adapt to daily changes of environmental cues, such as light/dark cycles. The molecular mechanism underlying the circadian clock has been well characterized. However, how internal circadian clocks are entrained with regular daily light/dark cycles remains unclear. By collecting and analyzing indirect calorimetry (IC) data from more than 2000 wild-type mice available from the International Mouse Phenotyping Consortium (IMPC), we show that the onset time and peak phase of activity and food intake rhythms are reliable parameters for screening defects of circadian misalignment. We developed a machine learning algorithm to quantify these two parameters in our misalignment screen (SyncScreener) with existing datasets and used it to screen 750 mutant mouse lines from five IMPC phenotyping centres. Mutants of five genes (Slc7a11, Rhbdl1, Spop, Ctc1 and Oxtr) were found to be associated with altered patterns of activity or food intake. By further studying the Slc7a11tm1a/tm1a mice, we confirmed its advanced activity phase phenotype in response to a simulated jetlag and skeleton photoperiod stimuli. Disruption of Slc7a11 affected the intercellular communication in the suprachiasmatic nucleus, suggesting a defect in synchronization of clock neurons. Our study has established a systematic phenotype analysis approach that can be used to uncover the mechanism of circadian entrainment in mice.
Published: 2020

17. Human and mouse essentiality screens as a resource for disease gene discovery

Author: Cacheiro, Pilar, Muñoz-Fuentes, Violeta, Murray, Stephen A, Dickinson, Mary E, Bucan, Maja, Nutter, Lauryl MJ, Peterson, Kevin A, Haselimashhadi, Hamed, Flenniken, Ann M, Morgan, Hugh, Westerberg, Henrik, Konopka, Tomasz, Hsu, Chih-Wei, Christiansen, Audrey, Lanza, Denise G, Beaudet, Arthur L, Heaney, Jason D, Fuchs, Helmut, Gailus-Durner, Valerie, Sorg, Tania, Prochazka, Jan, Novosadova, Vendula, Lelliott, Christopher J, Wardle-Jones, Hannah, Wells, Sara, Teboul, Lydia, Cater, Heather, Stewart, Michelle, Hough, Tertius, Wurst, Wolfgang, Sedlacek, Radislav, Adams, David J, Seavitt, John R, Tocchini-Valentini, Glauco, Mammano, Fabio, Braun, Robert E, McKerlie, Colin, Herault, Yann, de Angelis, Martin Hrabě, Mallon, Ann-Marie, Lloyd, KC Kent, Brown, Steve DM, Parkinson, Helen, Meehan, Terrence F, and Smedley, Damian
Subjects: Biological Sciences, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Genetics, Biotechnology, Human Genome, Prevention, 2.1 Biological and endogenous factors, Aetiology, Generic health relevance, Good Health and Well Being, Animals, Disease, Genes, Essential, Genetic Association Studies, Genomics, Humans, Mice, Mice, Knockout, Genomics England Research Consortium, International Mouse Phenotyping Consortium
Abstract: The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and essentiality screens carried out on human cell lines. We propose a cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing biological properties. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented among genes non-essential for cell survival but required for organism development. After screening developmental disorder cases from three independent disease sequencing consortia, we identify potentially pathogenic variants in genes not previously associated with rare diseases. We therefore propose FUSIL as an efficient approach for disease gene discovery.
Published: 2020

18. Mouse mutant phenotyping at scale reveals novel genes controlling bone mineral density

Author: Swan, Anna L, Schütt, Christine, Rozman, Jan, del Mar Muñiz Moreno, Maria, Brandmaier, Stefan, Simon, Michelle, Leuchtenberger, Stefanie, Griffiths, Mark, Brommage, Robert, Keskivali-Bond, Piia, Grallert, Harald, Werner, Thomas, Teperino, Raffaele, Becker, Lore, Miller, Gregor, Moshiri, Ala, Seavitt, John R, Cissell, Derek D, Meehan, Terrence F, Acar, Elif F, Lelliott, Christopher J, Flenniken, Ann M, Champy, Marie-France, Sorg, Tania, Ayadi, Abdel, Braun, Robert E, Cater, Heather, Dickinson, Mary E, Flicek, Paul, Gallegos, Juan, Ghirardello, Elena J, Heaney, Jason D, Jacquot, Sylvie, Lally, Connor, Logan, John G, Teboul, Lydia, Mason, Jeremy, Spielmann, Nadine, McKerlie, Colin, Murray, Stephen A, Nutter, Lauryl MJ, Odfalk, Kristian F, Parkinson, Helen, Prochazka, Jan, Reynolds, Corey L, Selloum, Mohammed, Spoutil, Frantisek, Svenson, Karen L, Vales, Taylor S, Wells, Sara E, White, Jacqueline K, Sedlacek, Radislav, Wurst, Wolfgang, Lloyd, KC Kent, Croucher, Peter I, Fuchs, Helmut, Williams, Graham R, Bassett, JH Duncan, Gailus-Durner, Valerie, Herault, Yann, Mallon, Ann-Marie, Brown, Steve DM, Mayer-Kuckuk, Philipp, and Hrabe de Angelis, Martin
Subjects: Biological Sciences, Genetics, Osteoporosis, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Aetiology, Underpinning research, Musculoskeletal, Animals, Bone Density, Female, Gene Expression Regulation, Gene Ontology, Genetic Pleiotropy, Genome-Wide Association Study, Genotype, Male, Mice, Mice, Transgenic, Mutation, Osteoblasts, Osteoclasts, Phenotype, Promoter Regions, Genetic, Protein Interaction Maps, Sex Characteristics, Transcriptome, IMPC Consortium, Developmental Biology
Abstract: The genetic landscape of diseases associated with changes in bone mineral density (BMD), such as osteoporosis, is only partially understood. Here, we explored data from 3,823 mutant mouse strains for BMD, a measure that is frequently altered in a range of bone pathologies, including osteoporosis. A total of 200 genes were found to significantly affect BMD. This pool of BMD genes comprised 141 genes with previously unknown functions in bone biology and was complementary to pools derived from recent human studies. Nineteen of the 141 genes also caused skeletal abnormalities. Examination of the BMD genes in osteoclasts and osteoblasts underscored BMD pathways, including vesicle transport, in these cells and together with in silico bone turnover studies resulted in the prioritization of candidate genes for further investigation. Overall, the results add novel pathophysiological and molecular insight into bone health and disease.
Published: 2020

19. Co-expression of prepulse inhibition and schizophrenia genes in the mouse and human brain

Author: Garrett, Lillian, primary, Trümbach, Dietrich, additional, Lee, Dongyhung, additional, Mandillo, Silvia, additional, Samaco, Rodney, additional, Flenniken, Ann M., additional, Stewart, Michelle, additional, Aguilar-Pimental, Juan A., additional, Amarie, Oana V., additional, Becker, Lore, additional, Calzada-Wack, Julia, additional, Da Silva-Buttkus, Patricia, additional, Dragano, Nathalia, additional, Kraiger, Markus, additional, Lengger, Christoph, additional, Leuchtenberger, Stefanie, additional, Marschall, Susan, additional, Oestereicher, Manuela A., additional, Rathkolb, Birgit, additional, Sanz-Moreno, Adrián, additional, Seisenberger, Claudia, additional, Spielmann, Nadine, additional, Stoeger, Claudia, additional, Kumar, Vivek, additional, Keskivali, Piia, additional, King, Ruairidh, additional, Haselimashhadi, Hamed, additional, Bezginov, Alexandr, additional, Norris, Clare, additional, Taylor, Sarah, additional, Pimm, Dale, additional, Kelsey, Lois, additional, Berberovic, Zorana, additional, Qu, Dawei, additional, D'Souza, Abigail, additional, Bradaschia, Vivian, additional, Eskandarian, Mohammed, additional, Shang, Xueyuan, additional, Duffin, Kyle, additional, Roberton, Kyle, additional, Xu, Catherine, additional, Baguinat, Gloria, additional, Laurin, Valerie, additional, Lan, Qing, additional, Sleep, Gillian, additional, Lintott, Lauri, additional, Gertsenstein, Marina, additional, Tondat, Sandra, additional, Cruz, Maribelle, additional, Miller, David, additional, Sorg, Tania, additional, Riet, Fabrice, additional, Tolentino, Heather, additional, Tolentino, Todd, additional, Schuchbauer, Mike, additional, Hockenbury, Nichole, additional, Beeman, Karrie, additional, Pedroia, Sheryl, additional, Salazar, Jason, additional, Heffner, Mollie, additional, Hsu, Joanne, additional, Fletcher, Colin, additional, Vanzanten, Maya, additional, Golini, Elisabetta, additional, Seavitt, John R., additional, Lanza, Denise G., additional, Lorenzo, Isabel, additional, Gaspero, Angelina, additional, Rios, Amanda, additional, White, Jacqueline K., additional, McKerlie, Colin, additional, Nutter, Lauryl M.J., additional, Vukobradovic, Igor, additional, Veeraragavan, Surabi, additional, Yuva, Lisa, additional, Heaney, Jason D., additional, Dickinson, Mary E., additional, Meziane, Hamid, additional, Hérault, Yann, additional, Wells, Sara, additional, Lloyd, K.C.Kent, additional, Bower, Lynette, additional, Lanoue, Louise, additional, Clary, Dave, additional, Zimprich, Annemarie, additional, Gailus-Durner, Valerie, additional, Fuchs, Helmut, additional, Brown, Steve D.M., additional, Chesler, Elissa J., additional, Wurst, Wolfgang, additional, Hrabě de Angelis, Martin, additional, and Hölter, Sabine M., additional
Published: 2024
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20. Genome-wide screening of mouse knockouts reveals novel genes required for normal integumentary and oculocutaneous structure and function.

Author: Moore, Bret A, Flenniken, Ann M, Clary, Dave, Moshiri, Ata S, Nutter, Lauryl MJ, Berberovic, Zorana, Owen, Celeste, Newbigging, Susan, Adissu, Hibret, Eskandarian, Mohammad, McKerlie, Colin, International Mouse Phenotyping Consortium, Thomasy, Sara M, Lloyd, KC Kent, Murphy, Christopher J, and Moshiri, Ala
Subjects: International Mouse Phenotyping Consortium
Abstract: Oculocutaneous syndromes are often due to mutations in single genes. In some cases, mouse models for these diseases exist in spontaneously occurring mutations, or in mice resulting from forward mutatagenesis screens. Here we present novel genes that may be causative for oculocutaneous disease in humans, discovered as part of a genome-wide screen of knockout-mice in a targeted single-gene deletion project. The International Mouse Phenotyping Consortium (IMPC) database (data release 10.0) was interrogated for all mouse strains with integument abnormalities, which were then cross-referenced individually to identify knockouts with concomitant ocular abnormalities attributed to the same targeted gene deletion. The search yielded 307 knockout strains from unique genes with integument abnormalities, 226 of which have not been previously associated with oculocutaneous conditions. Of the 307 knockout strains with integument abnormalities, 52 were determined to have ocular changes attributed to the targeted deletion, 35 of which represent novel oculocutaneous genes. Some examples of various integument abnormalities are shown, as well as two examples of knockout strains with oculocutaneous phenotypes. Each of the novel genes provided here are potentially relevant to the pathophysiology of human integumentary, or oculocutaneous conditions, such as albinism, phakomatoses, or other multi-system syndromes. The novel genes reported here may implicate molecular pathways relevant to these human diseases and may contribute to the discovery of novel therapeutic targets.
Published: 2019

21. A Comprehensive Plasma Metabolomics Dataset for a Cohort of Mouse Knockouts within the International Mouse Phenotyping Consortium.

Author: Barupal, Dinesh K, Zhang, Ying, Shen, Tong, Fan, Sili, Roberts, Bryan S, Fitzgerald, Patrick, Wancewicz, Benjamin, Valdiviez, Luis, Wohlgemuth, Gert, Byram, Gregory, Choy, Ying Yng, Haffner, Bennett, Showalter, Megan R, Vaniya, Arpana, Bloszies, Clayton S, Folz, Jacob S, Kind, Tobias, Flenniken, Ann M, McKerlie, Colin, Nutter, Lauryl MJ, Lloyd, Kent C, and Fiehn, Oliver
Subjects: GC-MS, IMPC, LC-MS, Metabolic phenotyping, functional genomics, lipidomics, metabolomics, mouse knockouts, Analytical Chemistry, Biochemistry and Cell Biology, Clinical Sciences
Abstract: Mouse knockouts facilitate the study ofgene functions. Often, multiple abnormal phenotypes are induced when a gene is inactivated. The International Mouse Phenotyping Consortium (IMPC) has generated thousands of mouse knockouts and catalogued their phenotype data. We have acquired metabolomics data from 220 plasma samples from 30 unique mouse gene knockouts and corresponding wildtype mice from the IMPC. To acquire comprehensive metabolomics data, we have used liquid chromatography (LC) combined with mass spectrometry (MS) for detecting polar and lipophilic compounds in an untargeted approach. We have also used targeted methods to measure bile acids, steroids and oxylipins. In addition, we have used gas chromatography GC-TOFMS for measuring primary metabolites. The metabolomics dataset reports 832 unique structurally identified metabolites from 124 chemical classes as determined by ChemRICH software. The GCMS and LCMS raw data files, intermediate and finalized data matrices, R-Scripts, annotation databases, and extracted ion chromatograms are provided in this data descriptor. The dataset can be used for subsequent studies to link genetic variants with molecular mechanisms and phenotypes.
Published: 2019

22. Author Correction: Identification of genes required for eye development by high-throughput screening of mouse knockouts

Author: Moore, Bret A, Leonard, Brian C, Sebbag, Lionel, Edwards, Sydney G, Cooper, Ann, Imai, Denise M, Straiton, Ewan, Santos, Luis, Reilly, Christopher, Griffey, Stephen M, Bower, Lynette, Clary, David, Mason, Jeremy, Roux, Michel J, Meziane, Hamid, Herault, Yann, McKerlie, Colin, Flenniken, Ann M, Nutter, Lauryl MJ, Berberovic, Zorana, Owen, Celeste, Newbigging, Susan, Adissu, Hibret, Eskandarian, Mohammed, Hsu, Chih-Wei, Kalaga, Sowmya, Udensi, Uchechukwu, Asomugha, Chinwe, Bohat, Ritu, Gallegos, Juan J, Seavitt, John R, Heaney, Jason D, Beaudet, Arthur L, Dickinson, Mary E, Justice, Monica J, Philip, Vivek, Kumar, Vivek, Svenson, Karen L, Braun, Robert E, Wells, Sara, Cater, Heather, Stewart, Michelle, Clementson-Mobbs, Sharon, Joynson, Russell, Gao, Xiang, Suzuki, Tomohiro, Wakana, Shigeharu, Smedley, Damian, Seong, JK, Tocchini-Valentini, Glauco, Moore, Mark, Fletcher, Colin, Karp, Natasha, Ramirez-Solis, Ramiro, White, Jacqueline K, de Angelis, Martin Hrabe, Wurst, Wolfgang, Thomasy, Sara M, Flicek, Paul, Parkinson, Helen, Brown, Steve DM, Meehan, Terrence F, Nishina, Patsy M, Murray, Stephen A, Krebs, Mark P, Mallon, Ann-Marie, Kent Lloyd, KC, Murphy, Christopher J, and Moshiri, Ala
Subjects: Biomedical and Clinical Sciences, Genetics, International Mouse Phenotyping Consortium, Biological sciences, Biomedical and clinical sciences
Abstract: [This corrects the article DOI: 10.1038/s42003-018-0226-0.].
Published: 2019

23. Erratum: Author Correction: Identification of genes required for eye development by high-throughput screening of mouse knockouts.

Author: Moore, Bret A, Leonard, Brian C, Sebbag, Lionel, Edwards, Sydney G, Cooper, Ann, Imai, Denise M, Straiton, Ewan, Santos, Luis, Reilly, Christopher, Griffey, Stephen M, Bower, Lynette, Clary, David, Mason, Jeremy, Roux, Michel J, Meziane, Hamid, Herault, Yann, International Mouse Phenotyping Consortium, McKerlie, Colin, Flenniken, Ann M, Nutter, Lauryl MJ, Berberovic, Zorana, Owen, Celeste, Newbigging, Susan, Adissu, Hibret, Eskandarian, Mohammed, Hsu, Chih-Wei, Kalaga, Sowmya, Udensi, Uchechukwu, Asomugha, Chinwe, Bohat, Ritu, Gallegos, Juan J, Seavitt, John R, Heaney, Jason D, Beaudet, Arthur L, Dickinson, Mary E, Justice, Monica J, Philip, Vivek, Kumar, Vivek, Svenson, Karen L, Braun, Robert E, Wells, Sara, Cater, Heather, Stewart, Michelle, Clementson-Mobbs, Sharon, Joynson, Russell, Gao, Xiang, Suzuki, Tomohiro, Wakana, Shigeharu, Smedley, Damian, Seong, JK, Tocchini-Valentini, Glauco, Moore, Mark, Fletcher, Colin, Karp, Natasha, Ramirez-Solis, Ramiro, White, Jacqueline K, de Angelis, Martin Hrabe, Wurst, Wolfgang, Thomasy, Sara M, Flicek, Paul, Parkinson, Helen, Brown, Steve DM, Meehan, Terrence F, Nishina, Patsy M, Murray, Stephen A, Krebs, Mark P, Mallon, Ann-Marie, Kent Lloyd, KC, Murphy, Christopher J, and Moshiri, Ala
Subjects: International Mouse Phenotyping Consortium, Genetics
Abstract: [This corrects the article DOI: 10.1038/s42003-018-0226-0.].
Published: 2019

24. Extensive identification of genes involved in congenital and structural heart disorders and cardiomyopathy

Author: Spielmann, Nadine, Miller, Gregor, Oprea, Tudor I., Hsu, Chih-Wei, Fobo, Gisela, Frishman, Goar, Montrone, Corinna, Haseli Mashhadi, Hamed, Mason, Jeremy, Munoz Fuentes, Violeta, Leuchtenberger, Stefanie, Ruepp, Andreas, Wagner, Matias, Westphal, Dominik S., Wolf, Cordula, Görlach, Agnes, Sanz-Moreno, Adrián, Cho, Yi-Li, Teperino, Raffaele, Brandmaier, Stefan, Sharma, Sapna, Galter, Isabella Rikarda, Östereicher, Manuela A., Zapf, Lilly, Mayer-Kuckuk, Philipp, Rozman, Jan, Teboul, Lydia, Bunton-Stasyshyn, Rosie K. A., Cater, Heather, Stewart, Michelle, Christou, Skevoulla, Westerberg, Henrik, Willett, Amelia M., Wotton, Janine M., Roper, Willson B., Christiansen, Audrey E., Ward, Christopher S., Heaney, Jason D., Reynolds, Corey L., Prochazka, Jan, Bower, Lynette, Clary, David, Selloum, Mohammed, Bou About, Ghina, Wendling, Olivia, Jacobs, Hugues, Leblanc, Sophie, Meziane, Hamid, Sorg, Tania, Audain, Enrique, Gilly, Arthur, Rayner, Nigel W., Hitz, Marc-Phillip, Zeggini, Eleftheria, Wolf, Eckhard, Sedlacek, Radislav, Murray, Steven A., Svenson, Karen L., Braun, Robert E., White, Jaqueline K., Kelsey, Lois, Gao, Xiang, Shiroishi, Toshihiko, Xu, Ying, Seong, Je Kyung, Mammano, Fabio, Tocchini-Valentini, Glauco P., Beaudet, Arthur L., Meehan, Terrence F., Parkinson, Helen, Smedley, Damian, Mallon, Ann-Marie, Wells, Sara E., Grallert, Harald, Wurst, Wolfgang, Marschall, Susan, Fuchs, Helmut, Brown, Steve D. M., Flenniken, Ann M., Nutter, Lauryl M. J., McKerlie, Colin, Herault, Yann, Lloyd, K. C. Kent, Dickinson, Mary E., Gailus-Durner, Valerie, and Hrabe de Angelis, Martin
Published: 2022
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25. Publisher Correction: Extensive identification of genes involved in congenital and structural heart disorders and cardiomyopathy

Author: Spielmann, Nadine, Miller, Gregor, Oprea, Tudor I., Hsu, Chih-Wei, Fobo, Gisela, Frishman, Goar, Montrone, Corinna, Haseli Mashhadi, Hamed, Mason, Jeremy, Munoz Fuentes, Violeta, Leuchtenberger, Stefanie, Ruepp, Andreas, Wagner, Matias, Westphal, Dominik S., Wolf, Cordula, Görlach, Agnes, Sanz-Moreno, Adrián, Cho, Yi-Li, Teperino, Raffaele, Brandmaier, Stefan, Sharma, Sapna, Galter, Isabella Rikarda, Östereicher, Manuela A., Zapf, Lilly, Mayer-Kuckuk, Philipp, Rozman, Jan, Teboul, Lydia, Bunton-Stasyshyn, Rosie K. A., Cater, Heather, Stewart, Michelle, Christou, Skevoulla, Westerberg, Henrik, Willett, Amelia M., Wotton, Janine M., Roper, Willson B., Christiansen, Audrey E., Ward, Christopher S., Heaney, Jason D., Reynolds, Corey L., Prochazka, Jan, Bower, Lynette, Clary, David, Selloum, Mohammed, Bou About, Ghina, Wendling, Olivia, Jacobs, Hugues, Leblanc, Sophie, Meziane, Hamid, Sorg, Tania, Audain, Enrique, Gilly, Arthur, Rayner, Nigel W., Hitz, Marc-Phillip, Zeggini, Eleftheria, Wolf, Eckhard, Sedlacek, Radislav, Murray, Steven A., Svenson, Karen L., Braun, Robert E., White, Jaqueline K., Kelsey, Lois, Gao, Xiang, Shiroishi, Toshihiko, Xu, Ying, Seong, Je Kyung, Mammano, Fabio, Tocchini-Valentini, Glauco P., Beaudet, Arthur L., Meehan, Terrence F., Parkinson, Helen, Smedley, Damian, Mallon, Ann-Marie, Wells, Sara E., Grallert, Harald, Wurst, Wolfgang, Marschall, Susan, Fuchs, Helmut, Brown, Steve D. M., Flenniken, Ann M., Nutter, Lauryl M. J., McKerlie, Colin, Herault, Yann, Lloyd, K. C. Kent, Dickinson, Mary E., Gailus-Durner, Valerie, and Hrabe de Angelis, Martin
Published: 2022
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26. The International Mouse Phenotyping Consortium (IMPC): a functional catalogue of the mammalian genome that informs conservation

Author: Muñoz-Fuentes, Violeta, Cacheiro, Pilar, Meehan, Terrence F, Aguilar-Pimentel, Juan Antonio, Brown, Steve DM, Flenniken, Ann M, Flicek, Paul, Galli, Antonella, Mashhadi, Hamed Haseli, Hrabě de Angelis, Martin, Kim, Jong Kyoung, Lloyd, KC Kent, McKerlie, Colin, Morgan, Hugh, Murray, Stephen A, Nutter, Lauryl MJ, Reilly, Patrick T, Seavitt, John R, Seong, Je Kyung, Simon, Michelle, Wardle-Jones, Hannah, Mallon, Ann-Marie, Smedley, Damian, Parkinson, Helen E, and the IMPC consortium
Subjects: Biological Sciences, Bioinformatics and Computational Biology, Genetics, Human Genome, Underpinning research, 1.1 Normal biological development and functioning, Aetiology, 2.1 Biological and endogenous factors, Generic health relevance, Life on Land, Cheetah, Endangered species, Loss-of-function, Non-model species, Panda, Polar bear, Phenotype, Wolf, Essential genes, IMPC, Knockout, Mouse, IMPC consortium, Environmental Sciences, Evolutionary Biology, Biological sciences, Environmental sciences
Abstract: The International Mouse Phenotyping Consortium (IMPC) is building a catalogue of mammalian gene function by producing and phenotyping a knockout mouse line for every protein-coding gene. To date, the IMPC has generated and characterised 5186 mutant lines. One-third of the lines have been found to be non-viable and over 300 new mouse models of human disease have been identified thus far. While current bioinformatics efforts are focused on translating results to better understand human disease processes, IMPC data also aids understanding genetic function and processes in other species. Here we show, using gorilla genomic data, how genes essential to development in mice can be used to help assess the potentially deleterious impact of gene variants in other species. This type of analyses could be used to select optimal breeders in endangered species to maintain or increase fitness and avoid variants associated to impaired-health phenotypes or loss-of-function mutations in genes of critical importance. We also show, using selected examples from various mammal species, how IMPC data can aid in the identification of candidate genes for studying a condition of interest, deliver information about the mechanisms involved, or support predictions for the function of genes that may play a role in adaptation. With genotyping costs decreasing and the continued improvements of bioinformatics tools, the analyses we demonstrate can be routinely applied.
Published: 2018

27. Identification of genetic elements in metabolism by high-throughput mouse phenotyping

Author: Rozman, Jan, Rathkolb, Birgit, Oestereicher, Manuela A, Schütt, Christine, Ravindranath, Aakash Chavan, Leuchtenberger, Stefanie, Sharma, Sapna, Kistler, Martin, Willershäuser, Monja, Brommage, Robert, Meehan, Terrence F, Mason, Jeremy, Haselimashhadi, Hamed, IMPC Consortium, Hough, Tertius, Mallon, Ann-Marie, Wells, Sara, Santos, Luis, Lelliott, Christopher J, White, Jacqueline K, Sorg, Tania, Champy, Marie-France, Bower, Lynette R, Reynolds, Corey L, Flenniken, Ann M, Murray, Stephen A, Nutter, Lauryl MJ, Svenson, Karen L, West, David, Tocchini-Valentini, Glauco P, Beaudet, Arthur L, Bosch, Fatima, Braun, Robert B, Dobbie, Michael S, Gao, Xiang, Herault, Yann, Moshiri, Ala, Moore, Bret A, Kent Lloyd, KC, McKerlie, Colin, Masuya, Hiroshi, Tanaka, Nobuhiko, Flicek, Paul, Parkinson, Helen E, Sedlacek, Radislav, Seong, Je Kyung, Wang, Chi-Kuang Leo, Moore, Mark, Brown, Steve D, Tschöp, Matthias H, Wurst, Wolfgang, Klingenspor, Martin, Wolf, Eckhard, Beckers, Johannes, Machicao, Fausto, Peter, Andreas, Staiger, Harald, Häring, Hans-Ulrich, Grallert, Harald, Campillos, Monica, Maier, Holger, Fuchs, Helmut, Gailus-Durner, Valerie, Werner, Thomas, and Hrabe de Angelis, Martin
Subjects: Biochemistry and Cell Biology, Bioinformatics and Computational Biology, Genetics, Biological Sciences, Human Genome, Nutrition, 2.1 Biological and endogenous factors, Generic health relevance, Animals, Area Under Curve, Basal Metabolism, Blood Glucose, Body Weight, Diabetes Mellitus, Type 2, Gene Regulatory Networks, Genome-Wide Association Study, High-Throughput Screening Assays, Humans, Metabolic Diseases, Mice, Mice, Knockout, Obesity, Oxygen Consumption, Phenotype, Triglycerides, IMPC Consortium
Abstract: Metabolic diseases are a worldwide problem but the underlying genetic factors and their relevance to metabolic disease remain incompletely understood. Genome-wide research is needed to characterize so-far unannotated mammalian metabolic genes. Here, we generate and analyze metabolic phenotypic data of 2016 knockout mouse strains under the aegis of the International Mouse Phenotyping Consortium (IMPC) and find 974 gene knockouts with strong metabolic phenotypes. 429 of those had no previous link to metabolism and 51 genes remain functionally completely unannotated. We compared human orthologues of these uncharacterized genes in five GWAS consortia and indeed 23 candidate genes are associated with metabolic disease. We further identify common regulatory elements in promoters of candidate genes. As each regulatory element is composed of several transcription factor binding sites, our data reveal an extensive metabolic phenotype-associated network of co-regulated genes. Our systematic mouse phenotype analysis thus paves the way for full functional annotation of the genome.
Published: 2018

28. Identification of genes required for eye development by high-throughput screening of mouse knockouts

Author: Moore, Bret A, Leonard, Brian C, Sebbag, Lionel, Edwards, Sydney G, Cooper, Ann, Imai, Denise M, Straiton, Ewan, Santos, Luis, Reilly, Christopher, Griffey, Stephen M, Bower, Lynette, Clary, David, Mason, Jeremy, Roux, Michel J, Meziane, Hamid, Herault, Yann, McKerlie, Colin, Flenniken, Ann M, Nutter, Lauryl MJ, Berberovic, Zorana, Owen, Celeste, Newbigging, Susan, Adissu, Hibret, Eskandarian, Mohammed, Hsu, Chih-Wei, Kalaga, Sowmya, Udensi, Uchechukwu, Asomugha, Chinwe, Bohat, Ritu, Gallegos, Juan J, Seavitt, John R, Heaney, Jason D, Beaudet, Arthur L, Dickinson, Mary E, Justice, Monica J, Philip, Vivek, Kumar, Vivek, Svenson, Karen L, Braun, Robert E, Wells, Sara, Cater, Heather, Stewart, Michelle, Clementson-Mobbs, Sharon, Joynson, Russell, Gao, Xiang, Suzuki, Tomohiro, Wakana, Shigeharu, Smedley, Damian, Seong, JK, Tocchini-Valentini, Glauco, Moore, Mark, Fletcher, Colin, Karp, Natasha, Ramirez-Solis, Ramiro, White, Jacqueline K, de Angelis, Martin Hrabe, Wurst, Wolfgang, Thomasy, Sara M, Flicek, Paul, Parkinson, Helen, Brown, Steve DM, Meehan, Terrence F, Nishina, Patsy M, Murray, Stephen A, Krebs, Mark P, Mallon, Ann-Marie, Lloyd, KC Kent, Murphy, Christopher J, and Moshiri, Ala
Subjects: Biological Sciences, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Genetics, Ophthalmology and Optometry, Human Genome, Biotechnology, Eye Disease and Disorders of Vision, Aetiology, 2.1 Biological and endogenous factors, Eye, International Mouse Phenotyping Consortium, Biological sciences, Biomedical and clinical sciences
Abstract: Despite advances in next generation sequencing technologies, determining the genetic basis of ocular disease remains a major challenge due to the limited access and prohibitive cost of human forward genetics. Thus, less than 4,000 genes currently have available phenotype information for any organ system. Here we report the ophthalmic findings from the International Mouse Phenotyping Consortium, a large-scale functional genetic screen with the goal of generating and phenotyping a null mutant for every mouse gene. Of 4364 genes evaluated, 347 were identified to influence ocular phenotypes, 75% of which are entirely novel in ocular pathology. This discovery greatly increases the current number of genes known to contribute to ophthalmic disease, and it is likely that many of the genes will subsequently prove to be important in human ocular development and disease.
Published: 2018

29. Correction: Corrigendum: High-throughput discovery of novel developmental phenotypes

Author: Dickinson, Mary E, Flenniken, Ann M, Ji, Xiao, Teboul, Lydia, Wong, Michael D, White, Jacqueline K, Meehan, Terrence F, Weninger, Wolfgang J, Westerberg, Henrik, Adissu, Hibret, Baker, Candice N, Bower, Lynette, Brown, James M, Caddle, L Brianna, Chiani, Francesco, Clary, Dave, Cleak, James, Daly, Mark J, Denegre, James M, Doe, Brendan, Dolan, Mary E, Edie Helmut Fuchs, Sarah M, Gailus-Durner, Valerie, Galli, Antonella, Gambadoro, Alessia, Gallegos, Juan, Guo, Shiying, Horner, Neil R, Hsu, Chih-Wei, Johnson, Sara J, Kalaga, Sowmya, Keith, Lance C, Lanoue, Louise, Lawson, Thomas N, Lek, Monkol, Mark, Manuel, Marschall, Susan, Mason, Jeremy, McElwee, Melissa L, Nutter, Susan Newbigging Lauryl MJ, Peterson, Kevin A, Ramirez-Solis, Ramiro, Rowland, Douglas J, Ryder, Edward, Samocha, Kaitlin E, Seavitt, John R, Selloum, Mohammed, Szoke-Kovacs, Zsombor, Tamura, Masaru, Trainor, Amanda G, Tudose, Ilinca, Wakana, Shigeharu, Warren, Jonathan, Wendling, Olivia, West, David B, Wong, Leeyean, Yoshiki, Atsushi, Wurst, Wolfgang, MacArthur, Daniel G, Tocchini-Valentini, Glauco P, Gao, Xiang, Flicek, Paul, Bradley, Allan, Skarnes, William C, Justice, Monica J, Parkinson, Helen E, Moore, Mark, Wells, Sara, Braun, Robert E, Svenson, Karen L, de Angelis, Martin Hrabe, Herault, Yann, Mohun, Tim, Mallon, Ann-Marie, Henkelman, R Mark, Brown, Steve DM, Adams, David J, Lloyd, KC Kent, McKerlie, Colin, Beaudet, Arthur L, and Murray, Maja Bućan Stephen A
Subjects: International Mouse Phenotyping Consortium, General Science & Technology
Abstract: This corrects the article DOI: 10.1038/nature19356.
Published: 2017

30. INFRAFRONTIER quality principles in systemic phenotyping

Author: Ehlich, Hilke, Cater, Heather L., Flenniken, Ann M., Goncalves Da Cruz, Isabelle, Mura, Anne-Marie, Ntafis, Vasileios, Raess, Michael, Selloum, Mohammed, Stoeger, Claudia, Suchanova, Sarka, Vuolteenaho, Reetta, Brown, Steve D. M., Hérault, Yann, Hinttala, Reetta, Hrabě de Angelis, Martin, Kollias, George, Kontoyiannis, Dimitris L., Malissen, Bernard, McKerlie, Colin, Sedláček, Radislav, Wells, Sara E., Zarubica, Ana, Rozman, Jan, and Sorg, Tania
Published: 2022
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31. Disease model discovery from 3,328 gene knockouts by The International Mouse Phenotyping Consortium.

Author: Meehan, Terrence F, Conte, Nathalie, West, David B, Jacobsen, Julius O, Mason, Jeremy, Warren, Jonathan, Chen, Chao-Kung, Tudose, Ilinca, Relac, Mike, Matthews, Peter, Karp, Natasha, Santos, Luis, Fiegel, Tanja, Ring, Natalie, Westerberg, Henrik, Greenaway, Simon, Sneddon, Duncan, Morgan, Hugh, Codner, Gemma F, Stewart, Michelle E, Brown, James, Horner, Neil, International Mouse Phenotyping Consortium, Haendel, Melissa, Washington, Nicole, Mungall, Christopher J, Reynolds, Corey L, Gallegos, Juan, Gailus-Durner, Valerie, Sorg, Tania, Pavlovic, Guillaume, Bower, Lynette R, Moore, Mark, Morse, Iva, Gao, Xiang, Tocchini-Valentini, Glauco P, Obata, Yuichi, Cho, Soo Young, Seong, Je Kyung, Seavitt, John, Beaudet, Arthur L, Dickinson, Mary E, Herault, Yann, Wurst, Wolfgang, de Angelis, Martin Hrabe, Lloyd, KC Kent, Flenniken, Ann M, Nutter, Lauryl MJ, Newbigging, Susan, McKerlie, Colin, Justice, Monica J, Murray, Stephen A, Svenson, Karen L, Braun, Robert E, White, Jacqueline K, Bradley, Allan, Flicek, Paul, Wells, Sara, Skarnes, William C, Adams, David J, Parkinson, Helen, Mallon, Ann-Marie, Brown, Steve DM, and Smedley, Damian
Subjects: International Mouse Phenotyping Consortium, Animals, Mice, Knockout, Humans, Mice, Genetic Diseases, Inborn, Disease Models, Animal, Genetic Predisposition to Disease, Phenotype, Female, Male, Gene Knockout Techniques, Knockout, Genetic Diseases, Inborn, Disease Models, Animal, Developmental Biology, Biological Sciences, Medical and Health Sciences
Abstract: Although next-generation sequencing has revolutionized the ability to associate variants with human diseases, diagnostic rates and development of new therapies are still limited by a lack of knowledge of the functions and pathobiological mechanisms of most genes. To address this challenge, the International Mouse Phenotyping Consortium is creating a genome- and phenome-wide catalog of gene function by characterizing new knockout-mouse strains across diverse biological systems through a broad set of standardized phenotyping tests. All mice will be readily available to the biomedical community. Analyzing the first 3,328 genes identified models for 360 diseases, including the first models, to our knowledge, for type C Bernard-Soulier, Bardet-Biedl-5 and Gordon Holmes syndromes. 90% of our phenotype annotations were novel, providing functional evidence for 1,092 genes and candidates in genetically uncharacterized diseases including arrhythmogenic right ventricular dysplasia 3. Finally, we describe our role in variant functional validation with The 100,000 Genomes Project and others.
Published: 2017

32. A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction

Author: Bowl, Michael R, Simon, Michelle M, Ingham, Neil J, Greenaway, Simon, Santos, Luis, Cater, Heather, Taylor, Sarah, Mason, Jeremy, Kurbatova, Natalja, Pearson, Selina, Bower, Lynette R, Clary, Dave A, Meziane, Hamid, Reilly, Patrick, Minowa, Osamu, Kelsey, Lois, The International Mouse Phenotyping Consortium, Tocchini-Valentini, Glauco P, Gao, Xiang, Bradley, Allan, Skarnes, William C, Moore, Mark, Beaudet, Arthur L, Justice, Monica J, Seavitt, John, Dickinson, Mary E, Wurst, Wolfgang, de Angelis, Martin Hrabe, Herault, Yann, Wakana, Shigeharu, Nutter, Lauryl MJ, Flenniken, Ann M, McKerlie, Colin, Murray, Stephen A, Svenson, Karen L, Braun, Robert E, West, David B, Lloyd, KC Kent, Adams, David J, White, Jacqui, Karp, Natasha, Flicek, Paul, Smedley, Damian, Meehan, Terrence F, Parkinson, Helen E, Teboul, Lydia M, Wells, Sara, Steel, Karen P, Mallon, Ann-Marie, and Brown, Steve DM
Subjects: Biological Sciences, Biomedical and Clinical Sciences, Genetics, Allied Health and Rehabilitation Science, Clinical Sciences, Health Sciences, Clinical Research, Hearing Loss, Human Genome, Neurosciences, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Neurological, Ear, Animals, Datasets as Topic, Genetic Testing, Hearing Tests, Mice, Mice, Knockout, Phenotype, Protein Interaction Maps, International Mouse Phenotyping Consortium
Abstract: The developmental and physiological complexity of the auditory system is likely reflected in the underlying set of genes involved in auditory function. In humans, over 150 non-syndromic loci have been identified, and there are more than 400 human genetic syndromes with a hearing loss component. Over 100 non-syndromic hearing loss genes have been identified in mouse and human, but we remain ignorant of the full extent of the genetic landscape involved in auditory dysfunction. As part of the International Mouse Phenotyping Consortium, we undertook a hearing loss screen in a cohort of 3006 mouse knockout strains. In total, we identify 67 candidate hearing loss genes. We detect known hearing loss genes, but the vast majority, 52, of the candidate genes were novel. Our analysis reveals a large and unexplored genetic landscape involved with auditory function.The full extent of the genetic basis for hearing impairment is unknown. Here, as part of the International Mouse Phenotyping Consortium, the authors perform a hearing loss screen in 3006 mouse knockout strains and identify 52 new candidate genes for genetic hearing loss.
Published: 2017

33. Prevalence of sexual dimorphism in mammalian phenotypic traits

Author: Karp, Natasha A, Mason, Jeremy, Beaudet, Arthur L, Benjamini, Yoav, Bower, Lynette, Braun, Robert E, Brown, Steve DM, Chesler, Elissa J, Dickinson, Mary E, Flenniken, Ann M, Fuchs, Helmut, Angelis, Martin Hrabe de, Gao, Xiang, Guo, Shiying, Greenaway, Simon, Heller, Ruth, Herault, Yann, Justice, Monica J, Kurbatova, Natalja, Lelliott, Christopher J, Lloyd, KC Kent, Mallon, Ann-Marie, Mank, Judith E, Masuya, Hiroshi, McKerlie, Colin, Meehan, Terrence F, Mott, Richard F, Murray, Stephen A, Parkinson, Helen, Ramirez-Solis, Ramiro, Santos, Luis, Seavitt, John R, Smedley, Damian, Sorg, Tania, Speak, Anneliese O, Steel, Karen P, Svenson, Karen L, Wakana, Shigeharu, West, David, Wells, Sara, Westerberg, Henrik, Yaacoby, Shay, and White, Jacqueline K
Subjects: Biological Psychology, Biological Sciences, Biomedical and Clinical Sciences, Psychology, Genetics, Animals, Body Weight, Female, Genes, Modifier, Genotype, Mammals, Mice, Phenotype, Quantitative Trait, Heritable, Sex Characteristics, International Mouse Phenotyping Consortium
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.
Published: 2017

34. High-throughput discovery of novel developmental phenotypes.

Author: Dickinson, Mary E, Flenniken, Ann M, Ji, Xiao, Teboul, Lydia, Wong, Michael D, White, Jacqueline K, Meehan, Terrence F, Weninger, Wolfgang J, Westerberg, Henrik, Adissu, Hibret, Baker, Candice N, Bower, Lynette, Brown, James M, Caddle, L Brianna, Chiani, Francesco, Clary, Dave, Cleak, James, Daly, Mark J, Denegre, James M, Doe, Brendan, Dolan, Mary E, Edie, Sarah M, Fuchs, Helmut, Gailus-Durner, Valerie, Galli, Antonella, Gambadoro, Alessia, Gallegos, Juan, Guo, Shiying, Horner, Neil R, Hsu, Chih-Wei, Johnson, Sara J, Kalaga, Sowmya, Keith, Lance C, Lanoue, Louise, Lawson, Thomas N, Lek, Monkol, Mark, Manuel, Marschall, Susan, Mason, Jeremy, McElwee, Melissa L, Newbigging, Susan, Nutter, Lauryl MJ, Peterson, Kevin A, Ramirez-Solis, Ramiro, Rowland, Douglas J, Ryder, Edward, Samocha, Kaitlin E, Seavitt, John R, Selloum, Mohammed, Szoke-Kovacs, Zsombor, Tamura, Masaru, Trainor, Amanda G, Tudose, Ilinca, Wakana, Shigeharu, Warren, Jonathan, Wendling, Olivia, West, David B, Wong, Leeyean, Yoshiki, Atsushi, International Mouse Phenotyping Consortium, Jackson Laboratory, Infrastructure Nationale PHENOMIN, Institut Clinique de la Souris (ICS), Charles River Laboratories, MRC Harwell, Toronto Centre for Phenogenomics, Wellcome Trust Sanger Institute, RIKEN BioResource Center, MacArthur, Daniel G, Tocchini-Valentini, Glauco P, Gao, Xiang, Flicek, Paul, Bradley, Allan, Skarnes, William C, Justice, Monica J, Parkinson, Helen E, Moore, Mark, Wells, Sara, Braun, Robert E, Svenson, Karen L, de Angelis, Martin Hrabe, Herault, Yann, Mohun, Tim, Mallon, Ann-Marie, Henkelman, R Mark, Brown, Steve DM, Adams, David J, Lloyd, KC Kent, McKerlie, Colin, Beaudet, Arthur L, Bućan, Maja, and Murray, Stephen A
Subjects: International Mouse Phenotyping Consortium, Jackson Laboratory, Infrastructure Nationale PHENOMIN, Institut Clinique de la Souris, Charles River Laboratories, MRC Harwell, Toronto Centre for Phenogenomics, Wellcome Trust Sanger Institute, RIKEN BioResource Center, Animals, Mice, Inbred C57BL, Mice, Knockout, Humans, Mice, Disease, Imaging, Three-Dimensional, Conserved Sequence, Sequence Homology, Phenotype, Penetrance, Mutation, Polymorphism, Single Nucleotide, Genes, Essential, Genes, Lethal, Embryo, Mammalian, Genome-Wide Association Study, High-Throughput Screening Assays, Biotechnology, Human Genome, Pediatric, Congenital Structural Anomalies, Genetics, 2.1 Biological and endogenous factors, General Science & Technology
Abstract: Approximately one-third of all mammalian genes are essential for life. Phenotypes resulting from knockouts of these genes in mice have provided tremendous insight into gene function and congenital disorders. As part of the International Mouse Phenotyping Consortium effort to generate and phenotypically characterize 5,000 knockout mouse lines, here we identify 410 lethal genes during the production of the first 1,751 unique gene knockouts. Using a standardized phenotyping platform that incorporates high-resolution 3D imaging, we identify phenotypes at multiple time points for previously uncharacterized genes and additional phenotypes for genes with previously reported mutant phenotypes. Unexpectedly, our analysis reveals that incomplete penetrance and variable expressivity are common even on a defined genetic background. In addition, we show that human disease genes are enriched for essential genes, thus providing a dataset that facilitates the prioritization and validation of mutations identified in clinical sequencing efforts.
Published: 2016

35. PATHBIO: an international training program for precision mouse phenotyping

Author: Ruberte, Jesus, Schofield, Paul N., Brakebusch, Cord, Vogel, Peter, Herault, Yann, Gracia, Guillem, McKerlie, Colin, Hrabĕ de Angelis, Martin, Hagn, Michael, and Sundberg, John P.
Published: 2020
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36. The mammalian gene function resource: the International Knockout Mouse Consortium.

Author: Bradley, Allan, Anastassiadis, Konstantinos, Ayadi, Abdelkader, Battey, James F, Bell, Cindy, Birling, Marie-Christine, Bottomley, Joanna, Brown, Steve D, Bürger, Antje, Bult, Carol J, Bushell, Wendy, Collins, Francis S, Desaintes, Christian, Doe, Brendan, Economides, Aris, Eppig, Janan T, Finnell, Richard H, Fletcher, Colin, Fray, Martin, Frendewey, David, Friedel, Roland H, Grosveld, Frank G, Hansen, Jens, Hérault, Yann, Hicks, Geoffrey, Hörlein, Andreas, Houghton, Richard, Hrabé de Angelis, Martin, Huylebroeck, Danny, Iyer, Vivek, de Jong, Pieter J, Kadin, James A, Kaloff, Cornelia, Kennedy, Karen, Koutsourakis, Manousos, Lloyd, KC Kent, Marschall, Susan, Mason, Jeremy, McKerlie, Colin, McLeod, Michael P, von Melchner, Harald, Moore, Mark, Mujica, Alejandro O, Nagy, Andras, Nefedov, Mikhail, Nutter, Lauryl M, Pavlovic, Guillaume, Peterson, Jane L, Pollock, Jonathan, Ramirez-Solis, Ramiro, Rancourt, Derrick E, Raspa, Marcello, Remacle, Jacques E, Ringwald, Martin, Rosen, Barry, Rosenthal, Nadia, Rossant, Janet, Ruiz Noppinger, Patricia, Ryder, Ed, Schick, Joel Zupicich, Schnütgen, Frank, Schofield, Paul, Seisenberger, Claudia, Selloum, Mohammed, Simpson, Elizabeth M, Skarnes, William C, Smedley, Damian, Stanford, William L, Stewart, A Francis, Stone, Kevin, Swan, Kate, Tadepally, Hamsa, Teboul, Lydia, Tocchini-Valentini, Glauco P, Valenzuela, David, West, Anthony P, Yamamura, Ken-ichi, Yoshinaga, Yuko, and Wurst, Wolfgang
Subjects: Animals, Mice, Knockout, Mice, Internationality, Internet, Knockout, Genetics, Genetics & Heredity
Abstract: In 2007, the International Knockout Mouse Consortium (IKMC) made the ambitious promise to generate mutations in virtually every protein-coding gene of the mouse genome in a concerted worldwide action. Now, 5 years later, the IKMC members have developed high-throughput gene trapping and, in particular, gene-targeting pipelines and generated more than 17,400 mutant murine embryonic stem (ES) cell clones and more than 1,700 mutant mouse strains, most of them conditional. A common IKMC web portal (www.knockoutmouse.org) has been established, allowing easy access to this unparalleled biological resource. The IKMC materials considerably enhance functional gene annotation of the mammalian genome and will have a major impact on future biomedical research.
Published: 2012

37. Variant in NHLRC2 leads to increased hnRNP C2 in developing neurons and the hippocampus of a mouse model of FINCA disease

Author: Hiltunen, Anniina E., Kangas, Salla M., Ohlmeier, Steffen, Pietilä, Ilkka, Hiltunen, Jori, Tanila, Heikki, McKerlie, Colin, Govindan, Subashika, Tuominen, Hannu, Kaarteenaho, Riitta, Hallman, Mikko, Uusimaa, Johanna, and Hinttala, Reetta
Published: 2020
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38. Control of Late Off-Center Cone Bipolar Cell Differentiation and Visual Signaling by the Homeobox Gene Vsx1

Author: Chow, Robert L., Volgyi, Bela, Szilard, Rachel K., Ng, David, McKerlie, Colin, Bloomfield, Stewart A., Birch, David G., McInnes, Roderick R., and Nathans, Jeremy
Published: 2004

39. Protection of Cftr Knockout Mice from Acute Lung Infection by a Helper-Dependent Adenoviral Vector Expressing Cftr in Airway Epithelia

Author: Koehler, David R., Sajjan, Umadevi, Chow, Yu-Hua, Martin, Bernard, Kent, Geraldine, Tanswell, A. Keith, McKerlie, Colin, Forstner, Janet F., and Hu, Jim
Published: 2003

40. N-Glycan Processing Deficiency Promotes Spontaneous Inflammatory Demyelination and Neurodegeneration*

Author: Lee, Sung-Uk, Grigorian, Ani, Pawling, Judy, Chen, I-Ju, Gao, Guoyan, Mozaffar, Tahseen, McKerlie, Colin, and Demetriou, Michael
Subjects: Rare Diseases, Neurodegenerative, Brain Disorders, Neurosciences, Multiple Sclerosis, Autoimmune Disease, 1.1 Normal biological development and functioning, Aetiology, Underpinning research, 2.1 Biological and endogenous factors, Neurological, Animals, Apoptosis, Axons, Cell Separation, Demyelinating Diseases, Flow Cytometry, Inflammation, Mice, Mice, Inbred C57BL, Mice, Transgenic, Models, Biological, Neurodegenerative Diseases, Neurons, Polysaccharides, T-Lymphocytes, Chemical Sciences, Biological Sciences, Medical and Health Sciences, Biochemistry & Molecular Biology
Abstract: Multiple sclerosis (MS) is characterized by inflammatory demyelination of axons and neurodegeneration, the latter inadequately modeled in experimental autoimmune encephalomyelitis (EAE). Susceptibility of inbred mouse strains to EAE is in part determined by major histocompatibility complex haplotype; however, other molecular mechanisms remain elusive. Galectins bind GlcNAc-branched N-glycans attached to surface glycoproteins, forming a molecular lattice that restricts lateral movement and endocytosis of glycoproteins. GlcNAc branching negatively regulates T cell activity and autoimmunity, and when absent in neurons, induces apoptosis in vivo in young adult mice. We find that EAE susceptible mouse strains PL/J, SJL, and NOD have reduced GlcNAc branching. PL/J mice display the lowest levels, partial deficiencies in N-acetylglucosaminyltransferase I, II, and V (i.e. Mgat1, -2, and -5), T cell hyperactivity and spontaneous late onset inflammatory demyelination and neurodegeneration; phenotypes markedly enhanced by Mgat5(+/-) and Mgat5(-/-) backgrounds in a gene dose-dependent manner. Spontaneous disease is transferable and characterized by progressive paralysis, tremor, dystonia, neuronophagia, and axonal damage in both demyelinated lesions and normal white matter, phenocopying progressive MS. Our data identify hypomorphic Golgi processing as an inherited trait that determines susceptibility to EAE, provides a unique spontaneous model of MS, and suggests GlcNAc-branching deficiency may promote T cell-mediated demyelination and neurodegeneration in MS.
Published: 2007

41. Glypican-3-Deficient Mice Exhibit Developmental Overgrowth and Some of the Abnormalities Typical of Simpson-Golabi-Behmel Syndrome

Author: Cano-Gauci, Danielle F., Song, Howard H., Yang, Huiling, McKerlie, Colin, Choo, Barbara, Shi, Wen, Pullano, Rose, Piscione, Tino D., Grisaru, Silviu, Soon, Shawn, Sedlackova, Larisa, Tanswell, A. Keith, Mak, Tak W., Yeger, Herman, Lockwood, Gina A., Rosenblum, Norman D., and Filmus, Jorge
Published: 1999

42. Precision medicine: Look to the mice

Author: Lloyd, K. C. Kent, Meehan, Terry, Beaudet, Arthur, Murray, Steve, Svenson, Karen, McKerlie, Colin, West, David, Morse, Iva, Parkinson, Helen, Brown, Steve, Mallon, Ann-Marie, and Moore, Mark
Published: 2015

43. (NZW × BXSB) F1 male mice: An unusual, severe and fatal mouse model of lupus erythematosus

Author: Almizraq, Ruqayyah J., primary, Frias Boligan, Kayluz, additional, Loriamini, Melika, additional, McKerlie, Colin, additional, and Branch, Donald R., additional
Published: 2022
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44. TAp73 is required for spermatogenesis and the maintenance of male fertility

Author: Inoue, Satoshi, Tomasini, Richard, Rufini, Alessandro, Elia, Andrew J., Agostini, Massimiliano, Amelio, Ivano, Cescon, Dave, Dinsdale, David, Zhou, Lily, Harris, Isaac S., Lac, Sophie, Silvester, Jennifer, Li, Wanda Y., Sasaki, Masato, Haight, Jillian, Brüstle, Anne, Wakeham, Andrew, Mckerlie, Colin, Jurisicova, Andrea, Melino, Gerry, and Mak, Tak W.
Published: 2014

45. Corrigendum: High-throughput discovery of novel developmental phenotypes

Author: Dickinson, Mary E., Flenniken, Ann M., Ji, Xiao, Teboul, Lydia, Wong, Michael D., White, Jacqueline K., Meehan, Terrence F., Weninger, Wolfgang J., Westerberg, Henrik, Adissu, Hibret, Baker, Candice N., Bower, Lynette, Brown, James M., Caddle, Brianna L., Chiani, Francesco, Clary, Dave, Cleak, James, Daly, Mark J., Denegre, James M., Doe, Brendan, Dolan, Mary E., Helmut Fuchs, Sarah M. Edie, Gailus-Durner, Valerie, Galli, Antonella, Gambadoro, Alessia, Gallegos, Juan, Guo, Shiying, Horner, Neil R., Hsu, Chih-Wei, Johnson, Sara J., Kalaga, Sowmya, Keith, Lance C., Lanoue, Louise, Lawson, Thomas N., Lek, Monkol, Mark, Manuel, Marschall, Susan, Mason, Jeremy, McElwee, Melissa L., Nutter, Susan Newbigging Lauryl M. J., Peterson, Kevin A., Ramirez-Solis, Ramiro, Rowland, Douglas J., Ryder, Edward, Samocha, Kaitlin E., Seavitt, John R., Selloum, Mohammed, Szoke-Kovacs, Zsombor, Tamura, Masaru, Trainor, Amanda G., Tudose, Ilinca, Wakana, Shigeharu, Warren, Jonathan, Wendling, Olivia, West, David B., Wong, Leeyean, Yoshiki, Atsushi, Wurst, Wolfgang, MacArthur, Daniel G., Tocchini-Valentini, Glauco P., Gao, Xiang, Flicek, Paul, Bradley, Allan, Skarnes, William C., Justice, Monica J., Parkinson, Helen E., Moore, Mark, Wells, Sara, Braun, Robert E., Svenson, Karen L., de Angelis, Martin Hrabe, Herault, Yann, Mohun, Tim, Mallon, Ann-Marie, Henkelman, Mark R., Brown, Steve D. M., Adams, David J., Lloyd, Kent K.C., McKerlie, Colin, Beaudet, Arthur L., and Murray, Maja Bućan Stephen A.
Published: 2017
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46. Effect of different cryoprotectant agents on spermatogenesis efficiency in cryopreserved and grafted neonatal mouse testicular tissue

Author: Yildiz, Cengiz, Mullen, Brendan, Jarvi, Keith, McKerlie, Colin, and Lo, Kirk C.
Published: 2013
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47. Analysis of mammalian gene function through broad-based phenotypic screens across a consortium of mouse clinics

Author: Hrabě de Angelis, Martin, Nicholson, George, Selloum, Mohammed, White, Jacqueline K, Morgan, Hugh, Ramirez-Solis, Ramiro, Sorg, Tania, Wells, Sara, Fuchs, Helmut, Fray, Martin, Adams, David J, Adams, Niels C, Adler, Thure, Aguilar-Pimentel, Antonio, Ali-Hadji, Dalila, Amann, Gregory, André, Philippe, Atkins, Sarah, Auburtin, Aurelie, Ayadi, Abdel, Becker, Julien, Becker, Lore, Bedu, Elodie, Bekeredjian, Raffi, Birling, Marie-Christine, Blake, Andrew, Bottomley, Joanna, Bowl, Michael R, Brault, Véronique, Busch, Dirk H, Bussell, James N, Calzada-Wack, Julia, Cater, Heather, Champy, Marie-France, Charles, Philippe, Chevalier, Claire, Chiani, Francesco, Codner, Gemma F, Combe, Roy, Cox, Roger, Dalloneau, Emilie, Dierich, André, Di Fenza, Armida, Doe, Brendan, Duchon, Arnaud, Eickelberg, Oliver, Esapa, Chris T, Fertak, Lahcen El, Feigel, Tanja, Emelyanova, Irina, Estabel, Jeanne, Favor, Jack, Flenniken, Ann, Gambadoro, Alessia, Garrett, Lilian, Gates, Hilary, Gerdin, Anna-Karin, Gkoutos, George, Greenaway, Simon, Glasl, Lisa, Goetz, Patrice, Da Cruz, Isabelle Goncalves, Götz, Alexander, Graw, Jochen, Guimond, Alain, Hans, Wolfgang, Hicks, Geoff, Hölter, Sabine M, Höfler, Heinz, Hancock, John M, Hoehndorf, Robert, Hough, Tertius, Houghton, Richard, Hurt, Anja, Ivandic, Boris, Jacobs, Hughes, Jacquot, Sylvie, Jones, Nora, Karp, Natasha A, Katus, Hugo A, Kitchen, Sharon, Klein-Rodewald, Tanja, Klingenspor, Martin, Klopstock, Thomas, Lalanne, Valerie, Leblanc, Sophie, Lengger, Christoph, le Marchand, Elise, Ludwig, Tonia, Lux, Aline, McKerlie, Colin, Maier, Holger, Mandel, Jean-Louis, Marschall, Susan, Mark, Manuel, Melvin, David G, Meziane, Hamid, Micklich, Kateryna, Mittelhauser, Christophe, Monassier, Laurent, Moulaert, David, Muller, Stéphanie, Naton, Beatrix, Neff, Frauke, Nolan, Patrick M, Nutter, Lauryl M J, Ollert, Markus, Pavlovic, Guillaume, Pellegata, Natalia S, Peter, Emilie, Petit-Demoulière, Benoit, Pickard, Amanda, Podrini, Christine, Potter, Paul, Pouilly, Laurent, Puk, Oliver, Richardson, David, Rousseau, Stephane, Quintanilla-Fend, Leticia, Quwailid, Mohamed M, Racz, Ildiko, Rathkolb, Birgit, Riet, Fabrice, Rossant, Janet, Roux, Michel, Rozman, Jan, Ryder, Edward, Salisbury, Jennifer, Santos, Luis, Schäble, Karl-Heinz, Schiller, Evelyn, Schrewe, Anja, Schulz, Holger, Steinkamp, Ralf, Simon, Michelle, Stewart, Michelle, Stöger, Claudia, Stöger, Tobias, Sun, Minxuan, Sunter, David, Teboul, Lydia, Tilly, Isabelle, Tocchini-Valentini, Glauco P, Tost, Monica, Treise, Irina, Vasseur, Laurent, Velot, Emilie, Vogt-Weisenhorn, Daniela, Wagner, Christelle, Walling, Alison, Wattenhofer-Donze, Marie, Weber, Bruno, Wendling, Olivia, Westerberg, Henrik, Willershäuser, Monja, Wolf, Eckhard, Wolter, Anne, Wood, Joe, Wurst, Wolfgang, Yildirim, Ali Önder, Zeh, Ramona, Zimmer, Andreas, Zimprich, Annemarie, Holmes, Chris, Steel, Karen P, Herault, Yann, Gailus-Durner, Valérie, Mallon, Ann-Marie, and Brown, Steve D M
Published: 2015
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48. Additional file 2 of Mendelian gene identification through mouse embryo viability screening

Author: Cacheiro, Pilar, Westerberg, Carl Henrik, Mager, Jesse, Dickinson, Mary E., Nutter, Lauryl M. J., Muñoz-Fuentes, Violeta, Hsu, Chih-Wei, Van den Veyver, Ignatia B., Flenniken, Ann M., McKerlie, Colin, Murray, Stephen A., Teboul, Lydia, Heaney, Jason D., Lloyd, K. C. Kent, Lanoue, Louise, Braun, Robert E., White, Jacqueline K., Creighton, Amie K., Laurin, Valerie, Guo, Ruolin, Qu, Dawei, Wells, Sara, Cleak, James, Bunton-Stasyshyn, Rosie, Stewart, Michelle, Harrisson, Jackie, Mason, Jeremy, Haseli Mashhadi, Hamed, Parkinson, Helen, Mallon, Ann-Marie, and Smedley, Damian
Abstract: Additional file 2: Fig. S1. WoL and cell essentiality scores. Fig. S2. WoL and cell essentiality categorisation. Fig. S3. WoL and additional gene features. Fig. S4. WoL and paralogues features. Fig. S5. WoL and additional disease features. Fig. S6. Prediction of early lethal genes. Fig. S7. Enrichment analysis of genes sharing attributes with a BIEM gene among the EL category.
Published: 2022
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49. Additional file 1 of Mendelian gene identification through mouse embryo viability screening

Author: Cacheiro, Pilar, Westerberg, Carl Henrik, Mager, Jesse, Dickinson, Mary E., Nutter, Lauryl M. J., Muñoz-Fuentes, Violeta, Hsu, Chih-Wei, Van den Veyver, Ignatia B., Flenniken, Ann M., McKerlie, Colin, Murray, Stephen A., Teboul, Lydia, Heaney, Jason D., Lloyd, K. C. Kent, Lanoue, Louise, Braun, Robert E., White, Jacqueline K., Creighton, Amie K., Laurin, Valerie, Guo, Ruolin, Qu, Dawei, Wells, Sara, Cleak, James, Bunton-Stasyshyn, Rosie, Stewart, Michelle, Harrisson, Jackie, Mason, Jeremy, Haseli Mashhadi, Hamed, Parkinson, Helen, Mallon, Ann-Marie, and Smedley, Damian
Abstract: Additional file 1: Table S1. Gene features: Human cellular essential genes. Table S2. Gene features: Gene expression in human brain. Table S3. Gene features: Intolerance to variation metrics and paralogues. Table S4. Disease features. Table S5. HPO phenotypes Odds Ratios. Table S6. Comparison of our approach based on EL genes with other strategies based on standard scores thresholds: F-score. Table S7. Odds Ratios and 95% CI from multiple logistic regression analysis.
Published: 2022
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50. Male Reproductive System

Author: Knoblaugh, Sue E., primary, Adissu, Hibret A., additional, McKerlie, Colin, additional, and Cardiff, Robert D., additional
Published: 2021
Full Text: View/download PDF

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