Disease Model Discovery

We remain ignorant of the function of the majority of genes in both the human and mouse genomes, and the roles they play in development, physiology and disease. Given the similarities between mouse and human and their respective genomes, one approach to understanding gene function in humans is to mutate the gene in the mouse and comprehensively study the characteristics (or phenotypes) that result from the mutation. A major focus of research at the MRC Harwell Institute is to undertake large-scale mutagenesis and phenotyping programmes to generate a comprehensive catalogue of mammalian gene function. MRC Harwell is a key participant in the International Mouse Phenotyping Consortium (IMPC) whose goals are to generate and characterise a mutant for every gene in the mouse genome. IMPC by the end of 2017 will have mutated and analysed around one-third of all the genes in the mouse genome. A particular focus at MRC Harwell and across other centres in the IMPC is to better identify and characterise genes that result in age-related disease. The burden on society from such diseases is increasing year on year and it is important that we address our limited understanding to develop new therapies and treatments. Many of the mutant lines studied by IMPC are being aged in order to find genes that when mutated cause age-related disease. MRC Harwell is studying a broad spectrum of diseases affecting quality of life in the aged, including deafness, diabetes and neurodegenerative diseases.

The aim of the Disease Model Discovery programme is to generate novel mouse models of disease providing a key resource for the elucidation and characterisation of new genes and pathways involved with diverse disease systems. The programme delivers a critical underpinning to our intramural research programmes at MRC Harwell, as well as furnishing a wider platform for gene and pathway discovery for the biomedical sciences community within the UK and abroad. Currently, large-scale mutagenesis and phenotyping platforms at MRC Harwell focus on the International Mouse Phenotyping Consortium (IMPC) pipeline for the generation and identification of mouse models.
The IMPC mutagenesis and phenotyping pipeline is a key ongoing programme for the discovery of novel genes associated with both early-onset and late-onset disease phenotypes. However, there is an increasing focus on the delivery of late-onset phenotypes. Diseases associated with ageing pose an increasing social and financial burden on society and represent a vital imperative for research in the biomedical sciences. There have been considerable advances, for example through GWAS studies, in identifying putative loci and pathways involved in diseases of ageing. Nevertheless, our knowledge of the genes and pathways involved with late-onset disease is neither comprehensive nor complete. As part of MRC funding to Programme 1 over the next five years we plan to introduce over 100 genes into the IMPC pipeline encompassing both early-onset and late-onset phenotyping platforms. This effort will be supplemented by additional funding from the NIH which will enable us to feed a further ~200 genes into the IMPC pipeline for the determination of both early and late-onset phenotypes. Proposals for genes to enter late-onset phenotyping will be sought via the regular calls to the UK community for gene nominations as part of the wider IMPC effort at MRC Harwell. In line with the wider IMPC programme, all data is freely available and deposited in the IMPC database – see www.mousephenotype.org.
For the future the bulk of null mutations that enter the IMPC pipeline will be generated by CRISPR/Cas9. In addition, with funding from Strategy Board, the MRC has established the new GEMM (Genome Editing Mice for Medicine) programme at MRC Harwell, utilising the CRISPR/Cas9 route to introduce additional types of alleles, such as point mutations, enabling for example investigators to introduce and analyse human point mutations. This programme underpins the high demand across the human and clinical genetics communities for access to models of rare and Mendelian disorders. Moreover, it is an important pillar in the Genomics England and Precision Medicine Initiative in the US. MRC Harwell has established a collaboration with Genomics England and it is expected that many of the mutants generated in the GEMM programme will be pivotal in the validation and analysis of loci identified through the 100,000 genomes project.
In summary, Programme 1 at MGU Harwell is at the forefront of delivering mutants, disease models and data that are a critical pillar for functional genomics studies across the biomedical sciences spectrum and provide key resources for understanding the genetic bases for disease and an important tool for the development of novel therapeutic strategies.