International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)

Table of Contents * Genes, Physical Mapping and Sequencing * Gene Identification * Bioinformatics * Common Resources * RIKEN Session * Functional Genomics * Complex Traits * Mutagenesis * Developmental Genetics and Differentiation * Verne Chapman Memorial Lecture I and II

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. Brown^1
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.