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Mouse large-scale phenotyping initiatives: overview of the European Mouse Disease Clinic (EUMODIC) and of the Wellcome Trust Sanger Institute Mouse Genetics Project.

Two large-scale phenotyping efforts, the European Mouse Disease Clinic (EUMODIC) and the Wellcome Trust Sanger Institute Mouse Genetics Project (SANGER-MGP), started during the late 2000s with the aim to deliver a comprehensive assessment of phenotypes or to screen for robust indicators of diseases in mouse mutants. They both took advantage of available mouse mutant lines but predominantly of the embryonic stem (ES) cells resources derived from the European Conditional Mouse Mutagenesis programme (EUCOMM) and the Knockout Mouse Project (KOMP) to produce and study 799 mouse models that were systematically analysed with a comprehensive set of physiological and behavioural paradigms. They captured more than 400 variables and an additional panel of metadata describing the conditions of the tests. All the data are now available through EuroPhenome database (www.europhenome.org) and the WTSI mouse portal (http://www.sanger.ac.uk/mouseportal/), and the corresponding mouse lines are available through the European Mouse Mutant Archive (EMMA), the International Knockout Mouse Consortium (IKMC), or the Knockout Mouse Project (KOMP) Repository. Overall conclusions from both studies converged, with at least one phenotype scored in at least 80% of the mutant lines. In addition, 57% of the lines were viable, 13% subviable, 30% embryonic lethal, and 7% displayed fertility impairments. These efforts provide an important underpinning for a future global programme that will undertake the complete functional annotation of the mammalian genome in the mouse model.

Pubmed ID: 22961258 RIS Download

Mesh terms: Animals | Europe | Genome | Germ Cells | Mice | Mutation | Phenotype

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This is a list of tools and resources that we have found mentioned in this publication.


Understanding Human Disease Through Mouse Genetics

A portal documenting a project for the development of novel approaches in phenotyping, mutagenesis and informatics to improve the characterization of mouse models for understanding human molecular physiology and pathology. EUMORPHIA has developed a new robust primary screening platform for determining the phenotype of mice: EMPReSS - European Mouse Phenotyping Resource for Standardised Screens. The project is also focused on training new young scientists by funding them to work in a variety of laboratories to gain a broader swathe of techniques. The project has also identified the need for more trained mouse pathologists. To address this, they are setting up training courses in pathology and working at a European level to establish more training.

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European Conditional Mouse Mutagenesis Program

Generate, archive, and distribute world-wide up to 12.000 conditional mutations across the mouse genome in mouse embryonic stem (ES) cells and Establish a limited number of mouse mutants from this resource. EUCOMM contributes the largest fraction of conditionally trapped and targeted genes in mouse C57BL/6N embryonic stem (ES) cells to the IKMC. EUCOMM vectors, mutant ES cells and mutant mice are distributed worldwide, enabling functional genomics research in a standardized and cost-effective manner by a much wider biomedical research community than has been possible previously. EUCOMM mutant ES cells and vectors can be obtained from the European Mouse Mutant Cell Repository (EuMMCR). EUCOMM mutant mice are archived and distributed by the European Mouse Mutant Archive (EMMA). Mutagenesis Strategies * Conditional gene trapping - random approach for expressed genes * Conditional targeted trapping - directed approach, used for expressed genes * Conditional gene targeting - directed approach, used for non-expressed genes

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International Knockout Mouse Consortium

Database of the international consortium working together to mutate all protein-coding genes in the mouse using a combination of gene trapping and gene targeting in C57BL/6 mouse embryonic stem (ES) cells. Detailed information on targeted genes is available. The IKMC includes the following programs: * Knockout Mouse Project (KOMP) (USA) ** CSD, a collaborative team at the Children''''s Hospital Oakland Research Institute (CHORI), the Wellcome Trust Sanger Institute and the University of California at Davis School of Veterinary Medicine , led by Pieter deJong, Ph.D., CHORI, along with K. C. Kent Lloyd, D.V.M., Ph.D., UC Davis; and Allan Bradley, Ph.D. FRS, and William Skarnes, Ph.D., at the Wellcome Trust Sanger Institute. ** Regeneron, a team at the VelociGene division of Regeneron Pharmaceuticals, Inc., led by David Valenzuela, Ph.D. and George D. Yancopoulos, M.D., Ph.D. * European Conditional Mouse Mutagenesis Program (EUCOMM) (Europe) * North American Conditional Mouse Mutagenesis Project (NorCOMM) (Canada) * Texas A&M Institute for Genomic Medicine (TIGM) (USA) Products (vectors, mice, ES cell lines) may be ordered from the above programs.

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EMMA

Non-profit repository for the collection, archiving (via cryopreservation) and distribution of relevant mutant strains essential for basic biomedical research. Users may browse by strain, gene, phenotype, or human disease. EMMA''''s primary objective is to establish and manage a unified repository for maintaining medically relevant mouse mutants and making them available to the scientific community. Therefore, EMMA archives mutant strains and distributes them to requesting researchers. EMMA also hosts courses in cryopreservation, to promote the use and dissemination of frozen embryos and spermatozoa. Dissemination of knowledge is further fostered by a dedicated resource database. Anybody who wants their mutant mouse strains cryopreserved may deposit strains with EMMA. However depositors must be aware that these strains become freely available to other researchers after being deposited.

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IMPC

Produce knockout mice and carry out high-throughput phenotyping of each line in order to determine the function of every gene in the mouse genome. These mice will be preserved in repositories and made available to the scientific community representing a valuable resource for basic scientific research as well as generating new models for human diseases. The approaches that are being developed build on the efforts of a number of pilot programs around the world such as the EUMODIC programme and the MGP programme. The European EUMODIC consortium generated and phenotyped 500 mouse strains in a high-throughput fashion. This was completed early in 2012. From 2011/12 onwards the IMPC is continuing the task to generate knockout mice and phenotype the remainder of the 20,000 plus genes in a worldwide coordinated program. IMPC Goals: * Establish a world-wide consortium of mouse centers with capacity and expertise for large-scale primary phenotyping * Establish a world-wide consortium of mouse production centers to generate germ line transmission of targeted knockout mutations in embryonic stem cells for all known and predicted mouse genes * Test each mutant mouse line (4,000 mouse lines in the first 5 years, and ultimately up to 20,000) through a broad based primary phenotyping pipeline in all the major adult organ systems and most areas of major human disease * Through this activity and employing data annotation tools, systematically aim to discover and ascribe biological function to each gene, driving new ideas and underpinning future research into biological systems * Establish collaborative networks with specialist phenotyping consortia or laboratories, providing standardized secondary phenotyping that enriches the primary dataset, and end-user, project specific tertiary level phenotyping that adds value to the mammalian gene functional annotation and fosters hypothesis driven research * Provide a centralized data center and portal for free, unrestricted access to primary and secondary data by the scientific community, promoting sharing of data, genotype-phenotype annotation, and the development of open source data analysis tools

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Sanger Mouse Resources Portal

Database of mouse research resources at Sanger: BACs, targeting vectors, targeted ES cells, mutant mouse lines, and phenotypic data generated from the Institute''''s primary screen. The Wellcome Trust Sanger Institute generates, characterizes, and uses a variety of reagents for mouse genetics research. It also aims to facilitate the distribution of these resources to the external scientific community. Here, you will find unified access to the different resources available from the Institute or its collaborators. The resources include: 129S7 and C57BL6/J bacterial artificial chromosomes (BACs), MICER gene targeting vectors, knock-out first conditional-ready gene targeting vectors, embryonic stem (ES) cells with gene targeted mutations or with retroviral gene trap insertions, mutant mouse lines, and phenotypic data generated from the Institute''''s primary screen.

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Europhenome Mouse Phenotyping Resource

Open source software system for capturing, storing and analyzing raw phenotyping data from SOPs contained in EMPReSS, it provides access to raw and annotated mouse phenotyping data generated from primary pipelines such as EMPReSSlim and secondary procedures from specialist centers. Mutants of interest can be identified by searching the gene or the predicted phenotype. You can also access phenotype data from the EMPReSSlim Pipeline for inbred mouse strains. Initially EuroPhenome was developed within the EUMORPHIA programme to capture and store pilot phenotyping data obtained on four background strains (C57BL/6J, C3H/HeBFeJ, BALB/cByJ and 129/SvPas). EUMORPHIA (European Union Mouse Research for Public Health and Industrial Applications) was a large project comprising of 18 research centers in 8 European countries, with the main focus of the project being the development of novel approaches in phenotyping, mutagenesis and informatics to improve the characterization of mouse models for understanding human molecular physiology and pathology. The current version of EuroPhenome is capturing data from the EUMODIC project as well as the WTSI MGP, HMGU GMC pipeline and the CMHD. EUMODIC is undertaking a primary phenotype assessment of up to 500 mouse mutant lines derived from ES cells developed in the EUCOMM project as well as other lines. Lines showing an interesting phenotype will be subject to a more in depth assessment. EUMODIC is building upon the comprehensive database of standardized phenotyping protocols, called EMPReSS, developed by the EUMORPHIA project. EUMODIC has developed a selection of these screens, called EMPReSSslim, to enable comprehensive, high throughput, primary phenotyping of large numbers of mice. Phenovariants are annotated using a automated pipeline, which assigns a MP term if the mutant data is statistically different to the baseline data. This data is shown in the Phenomap and the mine for a mutant tool. Please note that a statistically significant result and the subsequent MP annotation does not necessarily mean a true phenovariant. There are other factors that could cause this result that have not been accounted for in the analysis. It is the responsibility of the user to download the data and use their expert knowledge or further analysis to decide whether they agree or not. EuroPhenome is primarily based in the bioinformatics group at MRC Harwell. The development of EuroPhenome is in collaboration with the Helmholtz Zentrum Munchen, Germany, the Wellcome Trust Sanger Institute, UK and the Institut Clinique de la Souris, France.

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Knockout Mouse Project Repository

Repository of mouse vectors, ES cells, mice, embryos, and sperm generated by the NIH KOMP Mutagenesis Project. In addition, the KOMP Repository offers services in support of the KOMP products, including ES cell microinjection, vector cloning, post-insertional modification of cloned ES cells, cryopreservation, assisted reproduction techniques (IVF, ICSI) and mouse breeding, pathology (clinical and anatomical) pathology services, phenotyping services, etc. The KOMP Repository is the final component of a more than $50 million trans-NIH initiative to increase the availability of genetically altered mice and related materials. The University of California, Davis (UC Davis) and Children''s Hospital Oakland Research Institute (CHORI) in Oakland, Calif., are collaborating to preserve, protect, and make available about 8,500 types of knockout mice and related products available to the research community. The products are generated by two KOMP mutagenesis teams (the CSD consortium and Regeneron Inc). All KOMP products generated by the CSD consortium and Regeneron are available through the KOMP Repository.

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MGD

An integrated data resource for mouse genetic, genomic, and biological information. MGD includes a variety of data, ranging from gene characterization and genomic structures, to orthologous relationships between mouse genes and those of other mammalian species, to maps (genetic, cytogenetic, physical), to descriptions of mutant phenotypes, to characteristics of inbred strains, to information about biological reagents such as clones and primers. Data are accessed via search/retrieval Web forms and displayed as tables, text, and graphical maps, with supporting primary data. A rich set of hypertext links is provided, such as those from gene and clone information to DNA and protein sequence databases (GenBank, EMBL, DDBJ, SWISS-PROT), from bibliographic data to PubMed, from phenotypes to OMIM (Online Mendelian Inheritance in Man), and from gene homology records to the genomic databases of other species. MGD's data integration process places disparate data in contextual relationship, bringing together information from electronic downloads, the mouse Chromosome Committees, submissions from individual researchers, and actively curated data from the published literature. MGD encourages community participation via contributions of data and the development of consensus representations of the mouse genome. The resource's electronic bulletin boards are maintained to facilitate communication and collaboration among interested scientists. These Bulletin Boards provide a forum for community discussions and an excellent communication vehicle for MGD news. For more on the Mouse Genome Database follow the link, http://www.informatics.jax.org/mgihome/projects/overview.shtml.

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