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The mammalian gene function resource: the International Knockout Mouse Consortium.

Bradley A | Anastassiadis K | Ayadi A | Battey JF | Bell C | Birling MC | Bottomley J | Brown SD | Bürger A | Bult CJ | Bushell W | Collins FS | Desaintes C | Doe B | Economides A | Eppig JT | Finnell RH | Fletcher C | Fray M | Frendewey D | Friedel RH | Grosveld FG | Hansen J | Hérault Y | Hicks G | Hörlein A | Houghton R | Hrabé de Angelis M | Huylebroeck D | Iyer V | de Jong PJ | Kadin JA | Kaloff C | Kennedy K | Koutsourakis M | Lloyd KC | Marschall S | Mason J | McKerlie C | McLeod MP | von Melchner H | Moore M | Mujica AO | Nagy A | Nefedov M | Nutter LM | Pavlovic G | Peterson JL | Pollock J | Ramirez-Solis R | Rancourt DE | Raspa M | Remacle JE | Ringwald M | Rosen B | Rosenthal N | Rossant J | Ruiz Noppinger P | Ryder E | Schick JZ | Schnütgen F | Schofield P | Seisenberger C | Selloum M | Simpson EM | Skarnes WC | Smedley D | Stanford WL | Stewart AF | Stone K | Swan K | Tadepally H | Teboul L | Tocchini-Valentini GP | Valenzuela D | West AP | Yamamura K | Yoshinaga Y | Wurst W

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.

Pubmed ID: 22968824 RIS Download

Mesh terms: Animals | Internationality | Internet | Mice | Mice, Knockout

Research resources used in this publication

None found

Data used in this publication

None found

Associated grants

  • Agency: NCRR NIH HHS, Id: U42 RR024244
  • Agency: NCI NIH HHS, Id: P30 CA093373
  • Agency: NHGRI NIH HHS, Id: U41 HG000330
  • Agency: NHGRI NIH HHS, Id: U54 HG006364
  • Agency: NIH HHS, Id: U42 OD012210
  • Agency: Medical Research Council, Id: MC_U142684172
  • Agency: NIH HHS, Id: U42 OD011175

Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.

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


EUCOMMTOOLS

Functional Annotation of the Mouse Genome, it will complete the International Knockout Mouse Consortium (IKMC) resource of mutations for all protein coding genes. Furthermore, it will maximize the utility of the conditional IKMC resource by generating up to 250 different, mostly inducible Cre driver mouse lines. In addition, EUCOMMTOOLS will develop novel tools to enhance the versatility of the IKMC resource. EUCOMMTOOLS vectors, mutant ES cells and mutant mice are distributed worldwide: EUCOMMTOOLS mutant ES cells and vectors can be obtained from the European Mouse Mutant Cell Repository (EuMMCR). EUCOMMTOOLS mutant mice are archived and distributed by the European Mouse Mutant Archive (EMMA). Knockout-first Mutant Alleles: EUCOMMTOOLS will create 3500 C57Bl/6 conditional mutant alleles for single-exon (or otherwise previously conditionally untargeted) protein-coding mouse genes. These alleles will be made predominantly by introducing an "artificial intron", containing a standard EUCOMM promoter-driven targeting cassette, into the coding sequence of the single-exon gene. Cre Resources: EUCOMMTOOLS will engineer 500 new Cre C57Bl/6 ES cell lines by Cre knock-ins into genes with useful expression patterns. The resource will be made with inducible forms of Cre recombinase such as CreERT2. Up to 250 lines of Cre driver mice on a pure C57Bl/6N background will be generated and the Cre expression patterns documented and annotated in day P14 and P56. These mice will form a matched Cre driver resource for C57Bl/6N mice produced from conditional IKMC resources. Research, Technology and Complementary Reagents: EUCOMMTOOLS will develop novel technologies to add value, depth and flexibility to existing IKMC ES cell and mouse resources. Key areas include: * Development of novel recombinase based regulatory switches * Exploration of zinc-finger nuclease stimulated homologous recombination strategies in fertilized oocytes * Development and validation of complementary modular vector reagents which enable the construction of new useful knock-in alleles such as fluorescent and other reporters, site specific recombinases, and mutant cDNAs. These novel alleles can be constructed either by re-utilizing existing IKMC modular vector resources or directly modifying existing targeted IKMC ES cell lines by RMCE.

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EuMMCR

An embryonic stem (ES) cell distribution unit that distributes material arising within the European Conditional Mouse Mutagenesis Program (EUCOMM) consortium, currently targeting vectors and ES cells. Targeting vectors: Upon user request EUCOMM grow targeting vectors from glycerol stocks and prepare vector DNA. The identity of the vector is then verified by restriction mapping. DNA of vectors that passed this EuMMCR quality control are then sent to the requestor. ES cells: Upon user request EUCOMM thaw, expand and re-freeze several aliquots of a desired ES cell clone. Their standard controls include a PCR based assay to ensure that ES cells are mycoplasma free and a genotype verification using a short PCR strategy. ES cells, which have passed both EuMMCR quality controls will be sent to the requestor. Upon additional request the EuMMCR unit also develops a genotyping PCR, which can be used to genotype the chimeric mice that may be generated using those ES cell clones.

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Texas A and M Institute for Genomic Medicine

World's largest library of mouse knockout embryonic stem cells and provides both ES cells and mice to academic and commercial institutions around the world. Transgenic and phenotyping services are also available. The TIGM mouse knockout database currently includes links identifying embryonic stem cell clones from the C57BL/6 and 129S5/SvEvBrd gene trap libraries, as well as more than 2,500 established mouse knockout lines from the 129 line. Together, these resources cover more than 13,000 mouse genes and can be searched by gene or protein sequence, accession number, chromosome, gene ID or keyword. TIGM also offers more than 200 established cryopreserved lines in their mouse repository. C57BL/6 Mice and ES Cell Clones: TIGM operates a gene trap library a premier knockout mouse ES cell resource that contains over 350,000 cell lines in the C57BL/6 mouse background. This library contains mutated ES cell clones representing more than 10,000 genes. 129S5/SvEvBrd Mice and ES Cell Clones: TIGM has access to a privately held 129S5/SvEvBrd gene trap library. This gene trap library contains more than 270,000 sequence-tagged embryonic stem cell clones in the 129/SvEvBrd mouse strain representing mutations in over 10,000 genes. The National Institutes of Health (NIH) and Wellcome Trust Sanger Institute have obtained rights to a subset of these lines (NIH Lines and Wellcome Trust Lines), allowing TIGM to make them available for distribution to the academic research community on a subsidized basis. Please note that some of the 129S5/SvEvBrd lines in the database are not available to the public as they are reserved due to commercial proprietary research.

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Mutant Mouse Regional Resource Centers

Repository of spontaneous and induced mutant mouse and cell lines. It includes breeding/distribution facilities and an information coordinating center. Mice strains are cryopreserved, unless a live colony must be established. Live mice are supplied from a production colony, from a colony recovered from cryopreservation, or via micro-injection of a cell line into host blastocysts. MMRRC member facilities also develop technologies to improve the handling of mutant mice, including advances in assisted reproductive techniques, cryobiology, genetic analysis, phenotyping and infectious disease diagnostics.

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CanEuCre

Cre expressing mice under the control of promoters with a design focus on the brain. Each promoter is derived from human sequence, but the resulting expression is assessed in the mouse for the activation of a LacZ reporter gene by the Cre activity. Promoters tested as large MaxiPromoters (BACs inserted into the mouse genome) and MiniPromoters (plasmid-based sequences inserted either into the mouse genome or introduced within AAV viruses). The Cre-related project continues from the Pleiades Promoter Project. Here is the list of genes for which icre/ERT2 mice are currently in development: AGTR1, CARTPT, CLDN5, CLVS2, CRH, GABRA6, HTR1A, HTR1B, KCNA4, KDM5C, MKI67, NEUROD6, NKX6-1, NOV, NPY2R, NR2E1, OLIG2, POU4F2, SLITRK6, SOX1, SOX3, SOX9,, SPRY1, VSX2

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Jackson Laboratory

An independent, nonprofit organization focused on mammalian genetics research to advance human health. Their mission is to discover the genetic basis for preventing, treating, and curing human disease, and to enable research for the global biomedical community. Jackson Laboratory breeds and manages colonies of mice as resources for other research institutions and laboratories, along with providing software and techniques. Jackson Lab also conducts genetic research and provides educational material for various educational levels.

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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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CREATE

The CREATE consortium represents a core of major European and international mouse database holders and research groups involved in conditional mutagenesis, primarily to develop a strategy for the integration and dissemination of Cre driver strains for modelling aspects of complex human diseases in the mouse. Collectively the participants have amassed a significant number of these strains in their respective databases. Therefore one of the goals of CREATE is to provide a unified portal for worldwide access to these critical resources. The portal can either be searched through an advanced BioMart interface, by driver name, or by anatomical site of expression using Embryonic Mouse Anatomy Project (EMAP) and Mouse Anatomy (MA) ontology terms. Search results link back to the original source of the data for more detailed information and to IMSR to order mice if available. The ontology browser is particularly useful as it enables the CREATE consortium to identify cell and tissues that are not currently covered by existing lines. CREATE also aims to coordinate the production of suitable lines by the Cre generation projects described above. Through the CREATE portal, the CREATE consortium aims to develop a strategy for the production, integration and dissemination of new Cre driver strains for modelling aspects of complex human diseases in the mouse. CREATE is also developing a roadmap for harnessing emerging technologies and methods for improving Cre-mediated recombination in vivo through targeted, intensive workshops and discussion forums on the portal. This will entail review of construct design options for classical transgenic constructs (promoter/enhancer used, small size <2025 Kb) vs large transgenic constructs (BAC, P1, YAC etc.); methods used for Cre transgenic lines including random vs targeted integration, position independent expression loci, or replacement of endogenous coding sequences with Cre recombinase under the control of the endogenous locus. CREATE provides a platform for discussion of additional issues specific to inducible Cre strategies including background activity before induction, inducibility (kinetics), efficiency, and protocols used for induction of Cre recombinase activity. Additional components of the technology roadmap will be the cataloguing of other existing methodologies (rtTA, FLP, Dre) of mouse genome modification, sharing information on validated Cre mutant lines as well as identification and assessment of new methods of mutagenesis such as RNAi and other emerging technologies. Other discussion topics addressed through surveys on the CREATE portal include the characterization of Cre lines (specificity of expression/deletion; efficiency of expression/ deletion; reproducibility of deletion from animal to animal for the same floxed allele; reproducibility with different floxed alleles; timing of expression/deletion, etc.), the extent to which Cre expression changes upon backcrossing to specific genetic backgrounds through variegation and silencing; potential phenotypes caused by either integration- mediated mutagenesis or Cre ''toxicity''; and other factors affecting the specificity of Cre-mediated expression/deletion. CREATE regularly integrates common fields from the Cre-X, CreZOO and the MGI recombinase portal resources described below. The data in common consists of: * Transgene or Knock-in name. * MGI ID of allele. * Driver. * Anatomical site of expression. * Pubmed ID. * IMSR strain name and link. * Inducibility (YES/NO).

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European Mouse Mutant Archive

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. Its 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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Toronto Centre for Phenogenomics

The Toronto Centre for Phenogenomics (TCP) is an innovative, scientific collaboration between four research hospitals to operate a centralized, state-of-the-art research-enabling mouse facility. We conduct and support genetic research involving generation of mutant mice, physiological phenotyping, behavioural analysis, imaging, pathology and cryopreservation for storage and distribution. This joint project involving Mount Sinai Hospital, The Hospital for Sick Children, University Health Network and St. Michael''s Hospital pools resources and expertise to achieve excellence and economies of scale. The TCP opened for operations in October 2007. The centre functions as a regional, national and international resource for mouse models of human disease. This 120,000 square foot facility is located at 25 Orde Street, Toronto, and occupies four floors two below ground and two above. It houses specialized laboratories for mouse generation and analysis and, when fully occupied, it will contain approximately 36,000 cages (180,000 mice). The world-renowned scientific staff studies mammalian gene function, identifies genetic components of complex human disease, produces new mouse models of human disease, develops and tests new cell-based and gene-based therapies, and develops technologies for genome manipulation and phenotypic analysis. The TCP offers state-of-the-art mouse holding and facility support services to academic stakeholders and strategic private sector partners. It houses the Centre for Modeling Human Disease (CMHD), the Canadian Mouse Mutant Repository (CMMR), and the Mouse Imaging Centre (MICe) to provide an array of pre-clinical research services to clients. TCP Services * Phenotyping * Genetic Mapping * Pathology * Cryopreservation * Imaging * Genetically Engineered Mouse Models * Mouse Holding and Technical Services

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CMMR - Canadian Mouse Mutant Repository

Central repository for the physical archive and distribution of cryopreserved ES cells, spermatozoa, ova, embryos, and non-germ cell tissue DNA generated by Canada''''s mouse genome effort. The CMMR acts in coordination with other repositories worldwide and is establishing a nation-wide network of repository nodes to house sub-sets of the resources generated across Canada. The CMMR is the repository and distribution center for the North American Conditional Mouse Mutagenesis project (NorCOMM). The CMMR also collects and stores somatic tissue from mouse models in a variety of formats (fixed, embedded, and glass-slide mounted) enabling world wide access to specimens from established mouse models. Services include: * Embryo cryopreservation and recovery * Ovary cryopreservation and recovery * Ovary transplant * Sperm cryopreservation and recovery * Strain services, including rederivation by IVF, speed expansion and strain rescue * NorCOMM ES cell withdrawal * Non-NorCOMM ES cell expansion

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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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Recombinase (cre) Activity

Curated data about all recombinase-containing transgenes and knock-ins developed in mice providing a comprehensive resource delineating known activity patterns and allows users to find relevant mouse resources for their studies.

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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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