The long term objective of these studies is to decode the genetic information contained within a relatively small chromosomal region in the central portion of mouse chromosome 5. Classical genetic studies have resulted in the identification of several developmental mutations (W, Ph, Rw, rs, l, pi) within this region. Recent studies have shown that two of these mutations (Ph and W) are caused by alterations in genes encoding receptor tyrosine kinases. The extensive information about the genetic structure of this region, and its involvement in key developmental processes, provide a rationale for the establishment of a more comprehensive functional map. The experiments proposed here will provide both a structural map consisting of cloned and characterized mutation breakpoints associated with chromosomal rearrangement and a transcription map consisting of an array of partially characterized physically mapped exons/genes. To define the functional role of the genes in this region, a hemizygous screen for novel visible / lethal / behavioral mutations among the progeny of chemically mutagenized mice will also be performed. Complementation analysis and phenotypic characterization of new and several preexisting mutations in this region will result in significant progress toward the long term goal of these studies - to determine the relationship between genes defined by mutations, molecularly defined transcription units and gene sequences identified by large scale genomic sequencing. Molecular genetic information about the function of genes within the central portion of mouse chromosome 5 will be directly applicable to the genetic dissection of the homologous region on human chromosome 4. Moreover, the results of this project will facilitate a global study of the mammalian genome and provide insight into genome alterations that lead to abnormal function / disease.
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