Mouse models of genetic disease: new approaches, new paradigms.
The mouse mutant resource is a valuable tool for gene function studies in the post-genomics era. However, despite a seemingly large catalogue of mouse mutants, it is recognized that we have access to mutations at only a small fraction of the total number of mouse genes. There is a phenotype gap that needs to be narrowed by the implementation of large-scale, systematic mutagenesis programmes in the mouse. Both genotype-driven and phenotype-driven approaches can be employed to recover new mouse mutations. Genotype-driven approaches include large-scale genome-wide mutagenesis by gene trapping in embryonic stem cells. For genotype-driven approaches, the initial focus is on the characterization of the mutational change to the genome. Identification of the mutated gene is relatively trivial, but the genotype-driven route provides little indication of the likely phenotypic outcome of the mutation. In contrast, phenotype-driven approaches employ mutagenesis procedures that emphasize the recovery of novel phenotypes without prior assumptions about the underlying gene or pathway that has been disrupted--although identifying the underlying gene may not be trivial. One phenotype-driven approach includes chemical mutagenesis using N-ethyl-N-nitrosourea (ENU). ENU mutagenesis programmes are increasingly being brought to bear on increasing the breadth and depth of the mouse mutant resource, and in so doing narrowing the phenotype gap.
Brown
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SD
MRC Mammalian Genetics Unit, Harwell, UK.
D000818:Animals; D004195:Disease Models, Animal; D005038:Ethylnitrosourea / Q000633:toxicity; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains / Q000235:genetics*; D016296:Mutagenesis; D009153:Mutagens / Q000633:toxicity; D010641:Phenotype
D009153:Mutagens; D005038:Ethylnitrosourea