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

As the human genome project approaches completion, the challenge for mammal ian geneticists is to develop approaches for the systematic determination o f mammalian gene function. Mouse mutagenesis will be a key element of studi es of gene function(1-3). Phenotype-driven approaches using the chemical mu tagen ethylnitrosourea(4-6) (ENU) represent a potentially efficient route f or 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(1,2). We have undertaken a genom e-wide, phenotype-driven screen for dominant mutations in the mouse. We gen erated and screened over 26,000 mice, and recovered some 500 new mouse muta nts. Our work along with the programme reported in the accompanying paper(7 ), has led to a substantial increase in the mouse mutant resource and repre sents a first step towards systematic studies of gene function in mammalian genetics.