The long term goal of this proposal is to develop a scheme for identifying and characterizing mammalian genes which cause developmental abnormalities. In the course of studying chlorambucil-induced mutagenesis in the mouse, we have found that chlorambucil (CHL) is a very efficient inducer of recessive visible mutations. Because CHL induces gross chromosomal abnormalities (deletions, translocations, etc.) instead of point mutations, the mutations caused by this drug can be easily mapped and characterized. We would like to use these mutations to positionally clone and characterize mammalian genes which cause developmental abnormalities. In this grant proposal, we would like to establish the parameters of the CHL mutagenesis system as well as produce a new series of recessive visible and developmental mutations in the mouse.
Our specific aims are: (1) to determine the most efficient system for producing CHL mutations in mice, (2) to produce dominant and recessive visible mutations affecting development, (3) to map new CHL-induced mutations to specific chromosomal regions, and (4) to further characterize the usefulness of CHL as an inducer of specific mutations.
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