Understanding Gene Testing - How are disease genes identified?

Tracking down every chemical base in each of the estimated 50,000 to 100,000 genes as well as the spaces between them - mapping the human genome - is the task of an international 15-year collaboration known as the Human Genome Project. (The United States effort is shared by the National Center for Human Genome Research at the National Institutes of Health and the Office of Health and Environmental Research of the Department of Energy.) Scientists expect that having a detailed map of the entire set of human genes will revolutionize medical practice and biomedical research.

The Human Genome Project is focusing on the creation of genome maps, both genetic linkage maps and physical maps. Genome maps depict the order in which genes, genetic markers, and other landmarks are found along the chromosomes.

Genes and markers that are physically close to one another on the chromosome are said to be tightly linked; they are much less likely to be separated by recombination than are gene markers that are located far apart. In 1994, international collaborators published a comprehensive linkage map charting more than 5,000 markers and more than 400 genes.

After scientists use genetic linkage maps to assign a gene to a relatively small area on a chromosome, they next examine the region up close to learn the gene's precise location. To do this, scientists turn to physical maps.

To construct a physical map, a chromosome (or in some cases, the whole genome) is first broken into smaller pieces of DNA. Scientists then copy or clone the pieces in the laboratory, obtaining millions of identical copies of specific DNA segments. They next line up the clones to reflect the order that existed on the original chromosome. Information about the location and known genetic content of these unique and ordered DNA fragments (called contigs) is stored in a computer, while clones of the ordered pieces themselves are stored in laboratory freezers.

When genetic linkage maps indicate that a gene lies in a particular region, scientists can go to the freezer and retrieve clones of interest; they then use the clones as the raw material for DNA sequencing - actually identifying the order of each and every chemical base in the gene.

Benefiting from the increasingly detailed maps and sophisticated DNA sequencing techniques and tools, scientists are mapping and isolating new disease genes at the rate of several per month. By the year 2005, scientists hope to pinpoint the location of each of the 50,000 to 100,000 genes and to identify the exact sequence of their chemical bases.