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.

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    • "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. "
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    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.
    Transgenic Research 09/2015; 24(6). DOI:10.1007/s11248-015-9905-5 · 2.32 Impact Factor
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    • "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). "
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    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
    Genome Research 09/2014; 24(10). DOI:10.1101/gr.174615.114 · 14.63 Impact Factor
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    • "The mouse research community enjoys the availability of an extensive palette of standardized inbred strains, as well as strains with targeted inactivation/mutation of specific genes, and many of these are commercially available from established sources (The Jackson Laboratory, Charles River, Harlan, Taconic Farms, to name a few). An ambitious project aimed at inactivation of all predicted mouse genes is in progress [10]. Even though mouse models of disease are not limited to targeted gene mutation or inactivation, the results of studies of the strains produced by gene targeting technology have made an undisputable impact on biology and medicine. "
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    ABSTRACT: Creation of lethal and synthetic lethal mutations in an experimental organism is a cornerstone of genetic dissection of gene function, and is related to the concept of an essential gene. Common inbred mouse strains carry background mutations, which can act as genetic modifiers, interfering with the assignment of gene essentiality. The inbred strain C57BL/6J, commonly known as “Black Six”, stands out, as it carries a spontaneous homozygous deletion in the nicotinamide nucleotide transhydrogenase (Nnt) gene [GenBank: AH009385.2], resulting in impairment of steroidogenic mitochondria of the adrenal gland, and a multitude of indirect modifier effects, coming from alteration of glucocorticoid-regulated processes. Over time, the popular strain has been used, by means of gene targeting technology, to assign “essential” and “redundant” qualifiers to numerous genes, thus creating an internally consistent “parallel universe” of knowledge. It is unrealistic to suggest phasing-out of this strain, given the scope of shared resources built around it, however, continuing on the road of “strain-unawareness” will result in profound waste of effort, particularly where translational research is concerned. The review analyzes the historical roots of this phenomenon and proposes that building of “parallel universes” should be urgently made visible to a critical reader by obligatory use of unambiguous and persistent tags in publications and databases, such as hypertext links, pointing to a vendor’s strain description web page, or to a digital object identifier (d.o.i.) of the original publication, so that any research done exclusively in C57BL/6J, could be easily identified. Reviewers This article was reviewed by Dr. Neil Smalheiser and Dr. Miguel Andrade-Navarro.
    Biology Direct 07/2014; 9(1):18. DOI:10.1186/1745-6150-9-18 · 4.66 Impact Factor
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