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.