The Evolving Genome Project: current and future impact.

The National Institutes of Health/Department of Energy Human Genome Project has been funding directed research for only 5 years, and it is understandably difficult to cite important research advances directly attributable to the project. However, the project has been constructive in fostering multidisciplinary group research and an inspiring and synergistic "just do it" attitude in both political and scientific circles, domestically and abroad. This collaborative spirit has spawned large-scale genetic and physical mapping projects, with the most impressive and useful results to date being the dense genetic maps produced by the Généthon, a French organization largely supported by the French muscular dystrophy association. With the genetic and physical map reagents now becoming available, disease-gene cloning is proceeding at an increasingly rapid pace. More important than the predictable acceleration of disease-gene mapping are the unpredictable benefits: Will a dense PCR-based dinucleotide-repeat genetic map open novel alternative approaches to disease-gene isolation? Will it become possible to localize disease genes by simply analyzing unrelated, isolated probands rather than the rarer "extended family"? Proband-based "linkage-disequilibrium cloning" may become possible if adequate density, informativeness, and stability of polymorphic loci are obtained. In addition, "genome exclusion cloning" will be added to the established positional, candidate-gene, and functional-disease-gene-cloning experimental approaches. The anticipated exponential expansion of human genetic disease information over the remainder of the 10-year tenure of the Human Genome Project unveils critical yet unresolved issues for medical education and the practice of medicine.(ABSTRACT TRUNCATED AT 250 WORDS)