dentified) was probably "linked" to that polymorphism. Different families might have polymorphisms on the same chromosome and very close to the marker, or might have different forms of the same polymorphism, but if each of them had an inherited disease that originated from the same gene, they would be "linked" to that same marker. Since the chromosome location of the marker was known (or could be easily determined), the chromosome location of the disease gene was immediately evident. Then the search for the gene itself could begin. There can be a very long gap between gene localization—finding the general location of the gene on the chromosome—and gene identification and isolation. The Huntington disease gene was the first autosomal gene to be localized using new DNA marker techniques (Gusella et al., 1983). Ten years later, it was found (Huntington's Disease Research Collaborative Group, 1993). Many marker genes including those responsible for cystic fibrosis (CF) (Rommens et al., 1989; Collins, 1992), neurofibromatosis (Collins et al., 1989), and a form of colon cancer (Fearon and Vogelstein, 1990) have been isolated using this approach.

The international effort to map the human genome is accelerating the development of new markers and the construction of detailed linkage maps of the human genome. Disease-causing genes are also being discovered at an accelerating pace (NIH-CEPH Collaborative Mapping Group, 1992; Weissenbach et al., 1992). New technological innovation in mapping and sequencing will lead to the cloning of disease-causing genes and the discovery of alterations in those genes (mutations) that lead to the occurrence of specific disease. As of July 15, 1992, 3,836 polymorphic markers had been localized on specific regions of chromosomes, and 611 disease-related genes had been mapped (Donis-Keller et al., 1987, 1992; see Figure 1-1).

As a result of these discoveries, it is still a very difficult but technically more straightforward matter to localize and identify disease-causing genes for singlegene diseases—those that follow the rules of inheritance established by Gregor Mendel in 1865—provided that families in which the disease occurs are willing to participate in linkage studies and are of sufficient size to study. As the Human Genome Project progresses, genes will be found by means other than their association with a specific disease in such families. Theoretically, there could be as many diseases as there are genes (50,000 to 100,000 human genes by current estimates), although some genes are so essential to embryonic and fetal development that defects in them will result in spontaneous abortion rather than postnatal disease. It is possible that some functioning genes are so nonessential that defects in them will not result in any impairment. As is the case with most single-gene diseases, many of those waiting to be discovered will be rare. There is considerable conservation of gene sequences across species. This allows scientists to find homologous genes in mice, fruit flies, or primates, and to create artificial manifestations in the DNA to mimic the mutation in the human gene. Animal models carrying the actual human gene will permit the study of the normal and abnormal function of the gene in the development of new therapies.



The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement