The nucleotide sequence of an estimated 80,000 to 100,000 human genes is available in data bases, yet only a small fraction of these genes have a known role. Nucleotide sequence alone is insufficient to predict gene function, functional genomic studies are required. One of the most powerful ways of revealing gene function is to generate mutations and characterize them phenotypically. Given the physiological and anatomical parallels between mice and humans, it is widely accepted that genotype phenotype relationships established in mice can be extrapolated to human syndromes. The overall goal of this program is to provide functional information for genes which map to human chromosome 17, a linkage group which is conserved on mouse chromosome 11. Our hypothesis is that among the 2000 genes which will be investigated in this study, many will be casually involved in human disease. In this project, functional information will be derived by employing phenotype-driven screens in mice or cell lines which have been manipulated by loxP/Cre chromosomal engineering techniques to contain regions of segmental haploidy. Mice with deficiencies will be generated by the Deletion Core and utilized directly by the different projects. In Project I, the Smith-Magenis micro- deletion syndrome will be modeled and sub-deletions will be made to begin to define where in the interval the causal gene(s) are located. In Project II, cell lines derived from mice with deletions will be screened in vitro to identify tumor suppressor loci. In Project III ENUS mutagenesis will be used with the deficiency chromosomes to uncover recessive alleles. These mice will be screened for variety of phenotypes including physiological, reproductive, neurological and skeletal abnormalities. In Project IV a physical map covering the entire distal half of mouse chromosome will be assembled BAC and PAC clones. This will facilitate the cloning of the mutant genes identified in Projects II and III and serve as a starting point for the eventual sequencing of this chromosomal region. This project is the most ambitious recessive genetic screen ever attempted in the mouse. The knowledge of gene function on mouse chromosome 11 provided by these studies is predicted to be substantial, highly significant and relevant to human syndromes which map to human chromosome 17.
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