Consortium for large-scale production and phenotyping of knockout mice (UM1) ABSTRACT: The long-term goal of the International Knockout Mouse Consortium (IKMC) is to develop a resource of targeted mutations in mice for every protein-coding gene in the mammalian genome that the research community can use to elucidate gene function in human biology and disease. We have formed a consortium of two Institutes (Baylor College of Medicine and MRC Harwell). This application describes our plan to generate null alleles for 1500 mouse genes using CRISPR/RGN genome editing technology and validate each line using established QC procedures. We will cryopreserve all mutant strains and deliver germplasm to the MMRRC repositories. These mutant alleles represent a gold standard resource of mutant alleles for the wider community, and an important foundation for future research and translational studies using the mouse models created. We will perform broad-based adult phenotyping on all mutant lines, and for the first time incorporate an ageing component for a significant fraction of mutants, the latter involving an additional testing component from 12 months onwards. We will also assess homozygous lethal and subviable lines in an embryonic phenotyping pipeline, It is apparent that there is a relationship of mouse lethal (essential) and subviable genes with human disease loci. All allele and phenotype data will be submitted in real time to the Data Coordination Center, ensuring that all of the BasH data is disseminated to the wider biomedical scientific community. We will continue our R&D program to introduce appropriate methodological and technological developments from production to phenotyping. BasH will continue to pilot improvements in Cas9 RGN for the production of more sophisticated alleles, and in parallel ensure that developments in cryopreservation approaches at Baylor and Harwell are integrated into the production pipeline. We will also continue our major projects in improving and enriching the adult and embryo phenotyping pipelines, focusing on areas such as metabolomics, behavioral phenotyping and home cage monitoring, with the aim of providing more complex and longitudinal data. Baylor College of Medicine and MRC Harwell have the established expertise, experience, and resources to efficiently and cost-effectively meet this goal.
Consortium for large-scale production and phenotyping of knockout mice (UM1) NARRATIVE: The human genome has been completely sequenced, but a large proportion of the genome encodes genes with no known function. Expanding our knowledge of gene function will help identify the genes underlying disease. We propose to continue our efforts as part of a consortium for large-scale production and phenotyping of knockout mice. The generation of mutant alleles and broad-based, systematic phenotyping will identify new human disease models and will define new functions and pathways underlying the mechanisms of disease. All mouse lines and their phenotyping will be publicly released as they become available.
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