Unraveling the genetic control of diseases has important impact in disease prevention, diagnosis and therapy. Positional cloning is the main strategy for disease gene mapping. Despite advances in technology and increasing resources such as semi-automated genotyping instruments and dense maps of genetic markers, gene mapping remains a difficult task. Recently, we have developed an alternative gene mapping method that does not require genotyping. Instead gene regions are isolated by genome screens for shared genomic segments between individuals affected with the disease of interest. The isolated DNA fragments are then mapped by hybridization onto a genomic microarray. We call this method direct identical by descent (IBD) mapping. It is a combination of two techniques: genomic mismatch scanning and DNA microarrays. We have shown that direct IBD mapping is feasible on one chromosome by mapping the gene for congenital hyperinsulinism. The goal of this proposal is to expand this result by accomplishing the following aims. 1. To generate a whole genome DNA microarray for gene mapping, a """"""""genome on a chip"""""""". 2. To test genome wide IBD mapping in CEPH grandparent-grandchild pairs. 3. To develop statistical methods for the analysis of data derived from direct IBD mapping. Development of direct IBD mapping should provide a gene mapping method that is less labor-intensive and more efficient than the current methods. We expect that it can be applied as a tool for genome wide linkage disequilibrium analysis and affected relative pair mapping.
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