The completion of the genome sequence brings us several major advantages that we can use in positional cloning. First of all, all of the coding sequences of a chromosomal region of interest can be identified. Secondly, information on the introns, 5' and 3' region of the sequences will be available, making it possible for the gene to be analyzed thoroughly throughout the coding region and the regulatory region. Thirdly, with the availability of all the sequences of a chromosomal region, nucleotide organization, gene ordering, gene expression patterns, and chromosomal structure can be analyzed. At the same time, high throughput technologies for mutation analysis and gene profiling have also developed rapidly to meet the new needs. All of these developments will greatly improve our search for candidate genes in positional cloning. By using a new strategy which combines genetic mapping, genome resources, and high throughput technology, we have identified mutated genes from two spontaneous mutation models in the last ten months. Our work suggests that positional cloning is no longer years of team effort of several laboratories for identifying one gene, but it is a work of one laboratory in one year for several genes. In this extraordinary study, we propose the massive screening of the targeted spontaneous mutants in JAX. In the four years of this project, we will focus on mouse models for skeletal diseases and expect to identify mutated genes from more than 10 spontaneous mutations.
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