ENU has been well documented as an extremely efficient agent for the introduction of mutations in the mouse genome. This mutagenesis approach, coupled with the rapid development of mapping strategies and genomic reagents, are facilitating the mapping and cloning of mutations in the mouse and provide a powerful means for the development of a new repertoire of mouse mutations. In this proposal the applicant plans to use ENU mutagenesis to generate novel recessive mutations which effect the structure of the mouse brain, heart and kidney. Since mice carrying these mutations will frequently not be viable after birth, the investigator is proposing to screen for mutations in late embryonic development [day 18 of gestation] from a cross predicted to produce animals homozygous for the mutant allele. By using different defined inbred strains in the crosses, a mapping step is built into the screen which facilitates the localization of mutations as they are phenotypically identified. The combination of mutagenesis, anatomical analysis, and genetic mapping represents a novel and powerful means to study mammalian development and organogenesis. In addition, limiting the analysis to mutants that survive to late gestation maximizes the likelihood that the mutations which are found will be relevant to models of human congenital defects. In parallel to these analyses the applicant proposes to use a sequence-based assay of mutation frequencies as a means to monitor and optimize mutagenesis protocols.
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