The mammalian gene function resource: The International Knockout Mouse Consortium

The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1HH, UK, .
Mammalian Genome (Impact Factor: 3.07). 09/2012; 23(9-10):580-6. DOI: 10.1007/s00335-012-9422-2
Source: PubMed


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 ( ) 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.

Download full-text


Available from: Richard H Finnell
    • "Model organisms are required to dissect the biological consequences of a particular mutation and to provide proof of concept for therapeutic intervention. The mouse is the most widely used model organism in mammalian genetics, and powerful platforms/networks for large-scale systematic mutagenesis and standardized phenotyping have been established (Bradley et al. 2012;Infrafrontier Consortium 2015). However, mutant mouse models do not always reflect the phenotypes of the corresponding human genetic diseases. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Despite enormous advances in translational biomedical research, there remains a growing demand for improved animal models of human disease. This is particularly true for diseases where rodent models do not reflect the human disease phenotype. Compared to rodents, pig anatomy and physiology are more similar to humans in cardiovascular, immune, respiratory, skeletal muscle, and metabolic systems. Importantly, efficient and precise techniques for genetic engineering of pigs are now available, facilitating the creation of tailored large animal models that mimic human disease mechanisms at the molecular level. In this article, the benefits of genetically engineered pigs for basic and translational research are exemplified by a novel pig model of Duchenne muscular dystrophy and by porcine models of cystic fibrosis. Particular emphasis is given to potential advantages of using these models for efficacy and safety testing of targeted therapies, such as exon skipping and gene editing, for example, using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated system. In general, genetically tailored pig models have the potential to bridge the gap between proof-of-concept studies in rodents and clinical trials in patients, thus supporting translational medicine.
    No preview · Article · Oct 2015 · Toxicologic Pathology
  • Source
    • "A tremendous progress in mouse genetics has been enabled by site-specific recombinase technology. Conditional control of gene deletion in vivo is accomplished with Cre, Flp, Dre or UC31 recombinases acting on their specific recognition sites (Birling et al. 2009). The best-characterized and most popular gene deletion strategy relies on the Cre-loxP system, which involves the insertion of two loxP recognition sites in the same directional orientation around a critical region of the gene of interest. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Temporal control of site-specific recombination is commonly achieved by using a tamoxifen-inducible form of Cre or Flp recombinases. Although powerful protocols of induction have been developed for gene inactivation at adult stages or during embryonic development, induction of recombination at late gestational or early postnatal stages is still difficult to achieve. In this context, using the ubiquitous CMV-CreER(T2) transgenic mice, we have tested and validated two procedures to achieve recombination just before and just after birth. The efficiency of recombination was evaluated in the brain, which is known to be more problematic to target. For the late gestation treatment with tamoxifen, different protocols of complementary administration of progesterone and estrogen were tested. However, delayed delivery and/or mortality of pups due to difficult delivery were always observed. To circumvent this problem, pups were collected from tamoxifen-treated pregnant dams by caesarian section at E18.5 and given to foster mothers. For postnatal treatment, different dosages of tamoxifen were administered by intragastric injection to the pups during 3 or 4 days after birth. The efficiency of these treatments was analyzed at P7 using a transgenic reporter line. They were also validated with the Hoxa5 conditional allele. In conclusion, we have developed efficient procedures that allow achieving efficient recombination of floxed alleles at perinatal stages. These protocols will allow investigating the late/adult functions of many developmental genes, whose characterization has been so far restricted to embryonic development.
    Full-text · Article · Sep 2015 · Transgenic Research
  • Source
    • "Systematically defining the function of genes remains one of the most challenging endeavors in biological sciences. Several large forward and reverse genetic efforts have been initiated in mice to address this issue (Justice et al. 1999; Clark et al. 2004; Bradley et al. 2012; White et al. 2013). However, Caenorhabditis elegans and Drosophila melanogaster are still the most coveted systems to perform systematic functional annotation of genes required for development , nervous system function, organogenesis, metabolism, etc. (Venken et al. 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Forward genetic screens using chemical mutagens have been successful in defining the function of thousands of genes in eukaryotic model organisms. The main drawback of this strategy is the time-consuming identification of the molecular lesions causative of the phenotypes of interest. With whole-genome sequencing (WGS), it is now possible to sequence hundreds of strains, but determining which mutations are causative among thousands of polymorphisms remains challenging. We have sequenced 394 mutant strains, generated in a chemical mutagenesis screen, for essential genes on the Drosophila X chromosome and describe strategies to reduce the number of candidate mutations from an average of ∼3500 to 35 single-nucleotide variants per chromosome. By combining WGS with a rough mapping method based on large duplications, we were able to map 274 (∼70%) mutations. We show that these mutations are causative, using small 80-kb duplications that rescue lethality. Hence, our findings demonstrate that combining rough mapping with WGS dramatically expands the toolkit necessary for assigning function to genes
    Full-text · Article · Sep 2014 · Genome Research
Show more