||The First Five Years The goals established for the first five years of the genome project were designed to set the stage for the culminating achievement of obtaining the complete sequences. They included defining chromosomal sites and developing better DNA sequencing technology. First, markers, or signposts, were to be mapped onto chromosomes both to provide a resource for genetic studies and to establish the framework, or starting points, for sequencing. Markers are very short stretches of DNA sequence, usually not associated with genes, that are variable in the human population. By following the inheritance of each of these polymorphic sites in pedigrees, their relative order on chromosomes can be calculated, to produce a "genetic map". Some 10,000 markers have been established on human chromosomes through the efforts of a number of groups, with a major contribution coming from a Utah group led by Dr. Ray White. In fact this mapping technology was a strategy first outlined by Ray White, David Botstein, Ron Davis and Mark Skolnik, and it enabled the whole mapping effort. White, who had the conviction to commit his career to establishing the new DNA-based human genetics, together with a group in Paris that included Jean Marc Lalouel, established an international archive to compile and coordinate mapping information from a set of reference families, 37 from Utah and 13 from France, whose DNA was immortalized and made available to the scientific community world-wide. This allowed many groups to contribute to construction of maps and the job is now essentially complete. The fruits of this work are the discoveries of genes involved in specific clinical syndromes. Many of these successes resulted directly from the fact that maps of DNA markers can be applied to any family. Identification of which version of a marker is inherited along with a particular trait localizes the suspect gene for the trait to the known chromosomal position of its "linked" marker. From this initial localization, often a region containing a million bases and perhaps 50-100 genes, a painstaking hunt can eventually reveal the defective gene by the fact that its sequence is different from normal. The expanding data base of gene sequences is making the difficult process easier. Of the 6500 known heritable diseases in humans, the genes involved in half have now been indentified and more complex diseases involving multiple genes, such as cancer and heart disease, are being attacked. These successes along the way are obviously significant and the power of this information is pervading many branches of medicine, leading already to changes in diagnosis and treatment of human disease.