The principal investigator, Cassandra Smith (along with the co-principal investigator, Charles Cantor) pioneered some of the physical methods that are used in conventional positional cloning of disease genes. These physical methods will be applied to Projects I (the human gene search) and Project II (the mouse gene search) once genetic studies narrow the search region. It is quite clear that conventional positional cloning methods will work for essential any disease gene provided that the appropriate samples and resources are available. However, it is also clear that the conventional methods are so inefficient (and expensive) that they cannot be used to uncover all human disease genes. Hence, this group has focused on developing and applying a number of novel physical methods and approaches that should considerably increase the efficiency of gene searches. Specifically, these methods focus on parallel processing and coincident detection schemes that allow the analysis of large numbers of samples en masse such as genetic markers and cDNAs, and the generation of useful candidate sequences from selected genomic regions.