Positional Cloning Works!: Identification of Genes That Cause IDDM

The strategy of positional cloning has been highly successful in identifying a number of single gene disorders that exhibit clear Mendelian patterns of inheritance. Positional cloning of insulin-dependent diabetes mellitus (IDDM) has been assisted by the expansion of molecular genetic tools and highly informative markers, so that new IDDM susceptibility genes are being uncovered. The ultimate characterization of IDDM susceptibility, including the manner in which the individual genes interact to determine the genetic component of susceptibility, may be hindered by the complexity of the disease itself. Recent developments in analytic and experimental genetics have renewed enthusiasm in the use of identity by descent (state) methods that use affected relatives (sib pairs) rather than pedigrees as a fundamental tool of gene mapping. Given the relative position of IDDM susceptibility genes, major hurdles in understanding the roles of the identified genes in defining genetic susceptibility as well as their function lie ahead.