Now that the mouse and human genome sequences are complete, biologists need systematic approaches to determine the function of each gene. Nucleotide sequence alone does not predict gene function, so functional genomic studies are required. One of the most powerful ways to reveal gene function is to generate mutations and determine their consequence in the living organism. Here, our goal is to provide functional information for genes that map to human chromosome 17, a linkage group that is conserved on mouse chromosome 11, through mouse mutagenesis. Among the nearly 700 genes that will be investigated in this study, many will be causally associated with human disease. Genetic resources for functional genetic studies of this targeted region were generated previously. The purpose of this R01 is to use these genetic resources to ask 1) how many genes are essential, 2) what proportion of genes are likely to mutate to a readily detectable phenotype, 3) what phenotypes are most commonly observed after mutation, and 4) what diverse functions can mammalian genes perform? Our underlying hypothesis is that forward genetics using N-ethyl-N-nitrosourea (ENU) mutagenesis is an efficient way of asking questions about gene function in mammals.
Our specific aims are to 1) query genetic function on mouse Chromosome 11 using high- efficiency ENU mutagenesis, 2) identify the molecular lesions in mutations, 3) determine the molecular and cellular basis for the defects in mutants with blood cell and/or cardiovascular defects, and 4) extend the depth of an established sperm/DNA archive for future gene-based screens. The mutations we generate have been shared, and will continue to be shared with the scientific community, through a public website www.mouse-genome.bcm.tmc.edu. Our previous work has made a difference in the way we can approach mouse genetics, and our proposed work will influence the way we understand what genes do and how they work in mammals.
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