A systematic, genome-wide, phenotype-driven mutagenesis programme for gene function studies in the mouse

Patrick M. Nolan, Jo Peters, Mark Strivens, Derek Rogers, Jim Hagan, Nigel Spurr, Ian C. Gray, Lucie Vizor, Debra Brooker, Elaine Whitehill, Rebecca Washbourne, Tertius Hough, Simon Greenaway, Mazda Hewitt, Xinhong Liu, Stefan McCormack, Karen Pickford, Rachael Selley, Christine Wells, Zuzanna Tymowska-Lalanne, Phil Roby, Peter Glenister, Claire Thornton, Caroline Thaung, Julie-Anne Stevenson, Ruth Arkell, Philomena Mburu, Rachel Hardisty, Amy Kiernan, Alexandra Erven, Karen P. Steel, Stephanie Voegeling, Jean-Louis Guenet, Carole Nickols, Ramin Sadri, Mahmood Naase, Adrian Isaacs, Kay Davies, Mick Browne, Elizabeth M.C. Fisher, Jo Martin, Sohaila Rastan, Steve D.M. Brown, Jackie Hunter

As the human genome project approaches completion, the challenge for mammalian geneticists is to develop approaches for the systematic determination of mammalian gene function. Mouse mutagenesis will be a key element of studies of gene function. Phenotype-driven approaches using the chemical mutagen ethylnitrosourea (ENU) represent a potentially efficient route for the generation of large numbers of mutant mice that can be screened for novel phenotypes. The advantage of this approach is that, in assessing gene function, no a priori assumptions are made about the genes involved in any pathway. Phenotype-driven mutagenesis is thus an effective method for the identification of novel genes and pathways. We have undertaken a genome-wide, phenotype-driven screen for dominant mutations in the mouse. We generated and screened over 26,000 mice, and recovered some 500 new mouse mutants. Our work, along with the programme reported in the accompanying paper, has led to a substantial increase in the mouse mutant resource and represents a first step towards systematic studies of gene function in mammalian genetics.