International Mammalian Genome Society


The 13th International Mouse Genome Conference
October 31-November 3, 1999

Table of Contents * Structure * Bioinformatics * Sequence * Mapping * New Tools * Gene Discovery * Developmental * Mutagenesis * Functional Genomics

H6 A Large Scale Mutagenesis Programme in the Mouse

Jackie Hunter1, Jo Peters+, Lucie Vizor+, Claire Thornton+, Pete Glenister+, Simon Greenaway+, Rachael Selley+, Mark Strivens+, Pat Nolan+, Jo Martin2, Elizabeth Fisher3, Derek Rogers1, Jim Hagan1, Nigel Spurr1, Sohaila Rastan1, Mick Browne1 and Steve Brown4. 1SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Harlow, UK; 2 MRC Mammalian Genetics Unit and UK Mouse Genome Centre, Harwell, UK; 3 Department of Morbid Anatomy, Queen Mary and Westfield College, London, UK; 4 Neurogenetics Unit, Imperial College, London, UK

Systematic approaches to mouse mutagenesis will be vital for future studies of gene function. Mouse mutants are available for only a small percentage of the total number of mammalian genes - there is a 'phenotype gap' (Brown and Peters, TIGS 12: 433) and we need to increase both the breadth and depth of the mouse mutation resource. We have begun a major ENU mutagenesis programme incorporating a large genome-wide screen for dominant mutations. Over 20,000 mice have been produced to date and the majority screened employing a systematic and semi-quantitative screening protocol - SHIRPA (Rogers et al. Mammalian Genome 8: 711-713). SHIRPA is a hierarchical screening protocol employing a rapid and efficient primary screen for deficits in muscle and lower motor neurone function, spinocerebellar function, sensory function, neuropsychiatric function and autonomic function. Moreover, in the primary screen, blood is collected from all mice and subjected to a comprehensive clinical chemistry analysis. Subsequently, secondary and tertiary screens of increasing complexity can be employed on animals demonstrating deficits in the primary screen. Frozen sperm is archived from all the male mice passing through the screen. In addition, tail tips are stored for DNA.

Progeny testing of mice carrying abnormal phenotypes indicates that around 1-1.5% of mice from the screen carry a new heritable dominant phenotype. Over 100 mutants have been confirmed and heritable and will be, or have been, added to the mouse mutant catalogue. For further information on the project and details of data derived from the screening, see: http://www.har.mrc.ac.uk/

Overall, the programme will provide an extensive new resource of mutant and phenotype data to the mouse and human genetics communities at large. We are currently using frozen sperm and IVF for the rapid generation of small backcrosses in order to map many of the newly catalogued mutations to the mouse genome. This mutant resource will contribute to the analysis of the function and the analysis and identification of novel pathways involved in human disease.

 


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