International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)


H8. Genetic and Functional Studies of Mutations Identified in a Large-Scale ENU-Mutagenesis Screen

Patrick M. Nolan1, Jo Peters1, Lucie Vizor1, Mark Strivens1, Rebecca Washbourne1, Tertius Hough1, Peter Glenister1, Claire Thornton1, Simon Greenaway1, Mazda Hewitt1, Xinhong Liu1, Stefan McCormack1, Rachael Selley1, Christine Wells1, Zuzanna Tymowska-Lalanne1, Phil Roby1, Jo Martin2, Elizabeth Fisher3, Derek Rogers4, Jim Hagan4, Charlie Reavill4, Ian Gray4, John Wood4, Nigel Spurr4, Mick Browne4, Sohaila Rastan4, Jackie Hunter4 and Steve D.M. Brown1
1MRC Mammalian Genetics Unit and UK Mouse Genome Centre, Harwell, UK
2Department of Morbid Anatomy, Queen Mary and Westfield College, London, UK
3Neurogenetics Department, Imperial College, London, UK
4SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Harlow, UK

We have undertaken a major ENU-mutagenesis programme to generate large numbers of new mouse mutations. Male mice are treated with ENU and F1 progeny screened for dominant mutations (Nolan et al., Nature Genetics , in press). Over the past 3 years, approximately 27,000 F1 mice have been generated and screened using hierarchical protocols including dysmorphlogy screens at birth and weaning, the SHIRPA phenotypic assessment, and behavioural and biochemical screens. Over 1000 abnormal phenotypes have been identified to date. We have already confirmed that over 130 mutant phenotypes are inherited and expect to have recovered over 500 mutants in total. For further information on the project and details of data derived from the screening see: http://www.mut.har.mrc.ac.uk/

New mutations in several phenotypic classes have been identified including examples of neurological, behavioural, hearing, vision and biochemical mutants. The range of mutants identified indicates the breadth and depth of phenotypes that can be recovered in large-scale mutagenesis programmes. To expedite rapid genetic and functional analysis of mutants generated, we are using frozen sperm and IVF for the generation of backcrosses. We have mapped over 30 mutants to date and confirmed that many of the novel phenotypes represent mutations at previously unidentified loci in the mouse genome. An important aspect of this screen has been to assign gene function to known and to novel gene sequences. For this purpose, large groups backcross mice generated using IVF can be screened simultaneously. We are currently undertaking a battery of secondary phenotypic screens, including neurochemical and histological analysis, to characterise the mutations further.


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