The mouse has an estimated 80,000 to 100,000 genes. While the sequences of the vast majority of these will become available over the next few years through EST sequencing projects, primary sequence alone will not reveal the function of these genes. The need for functional genetic studies is very pressing. Generating mutations in a gene coupled with detailed phenotypic analysis will provide a wealth of information on gene function. The goal of the Deletion Core is to establish as mouse strains, a series of deletions which in sum cover the distal 35 cM of mouse chromosome 11. This region of the mouse genome is gene rich and probably contains in excess of 2,000 genes. Almost every gene which has been localized on human chromosome 17 has been mapped to mouse chromosome 11. Fifty three human genetic diseases have along been linked to human chromosome 17 and although the genes for many of these have yet to be identified, the mouse homologies for these disease genes are predicted to be on mouse chromosome 11. The strains of mice with deletions developed by this Core will constitute the essential experimental material for Projects I, II and III in phenotype driven genetic screens for recessive or haplo-insufficient mutations in genes which have clinical relevance. Once relevant mutations have been identified the deletion core will assist in defining a critical interval for gene identification by generating vested deletions and performing complementation analysis of mutations with BACs. To achieve the goal of generating this deficiencies, a novel technology based on Cre-loxP recombination developed the principal investigator will be utilized. This technology enables large regions of the mouse genome to be deleted and each deletion will be tagged with coat color markers which will facilitate all of the genetic screens. Each primary deletion will be about cM and the endpoints will principally be based on D11Mit microsattelite markers. It is estimated that a minimum of ten strains will be required to fully represent this region of the genome with deficiencies. Sub-deficiencies will be generated by random insertion of retroviral vectors carrying the loxP-Hprt cassettes and screening for deletions of the appropriate size. The core will also generate a series of tagged chromosomes for tracking the mutations once they are identified.
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