Whitehead Scientists Complete Major Goal of the Human Genome Project

CAMBRIDGE, Mass. — Scientists at the Whitehead Institute for Biomedical Research have achieved a major goal of the international Human Genome Project with the completion of the world's first comprehensive genetic map of the mouse genome. The mouse map appears in the March 14 issue of Nature along with a comprehensive genetic map of the human genome created by researchers at Genethon in France.

"These two achievements signify the completion of the genetic mapping phase of the Human Genome Project," says Dr. Francis S. Collins, director of the National Center for Human Genome Research of the National Institutes of Health. "Now, the once-daunting task of mapping a disorder can be accomplished in a modest-size lab in a few months."

Dr. Eric S. Lander, director of the Whitehead/MIT Center for Genome Research, explains that it is crucial to map both the mouse and the human genomes, because much of human disease research is done in laboratory models and the mouse is the best available model. Even before it was finished, the mouse genetic map has enabled the analysis of previously intractable genetic traits, providing new insights into the genetic origins of asthma, hypertension, colon cancer, diabetes, and epilepsy.

"Genetic maps provide very powerful tools for exploring the origins of polygenic diseases, that is, diseases resulting from the interaction of multiple genes," Dr. Lander says. "Understanding how different genes work together to affect the timing, severity, and outcome of diseases such as cancer and diabetes will lead to important new strategies for disease prevention and therapy."

The mouse genome contains essentially the same complement of 100,000 genes found in the human, with typical mouse genes being about 75 percent identical to their human counterparts. There is a high probability that any disease-related genes identified in mice will play a role in the same biological process in human disease.

The Whitehead mouse map consists of 7,377 markers and provides dense coverage of all 20 chromosomes of the mouse genome. "You can think of these markers as bookmarks spaced throughout the mouse genome," Dr. Lander says. "When we're searching for a new disease gene in mice, we look for markers that tend to be inherited along with the disease. Once we discover that the disease gene occurs, say, in the final pages of chapter 10 (because the disease is always inherited along with a bookmark lodged in chapter 10, or a marker residing on chromosome 10), then it becomes much easier to search through nearby pages and find the gene."

The vast majority (6,580) of markers on the Whitehead map consist of highly variable regions called simple sequence length polymorphisms (SSLPs). These regions consist of a simple alternating two-letter DNA pattern: CACACA. Such SSLPs have formed the backbone for the genetic maps of both mouse and man.

"These CA repeats are especially useful because they are highly variable in length," explains Dr. William F. Dietrich, the first author of the Nature paper.

"Genetic experiments in mice often consist of mating two different strains of mice, one with known susceptibility to the disease of interest and one resistant to the disease. We can follow inheritance patterns in the offspring of these mice by tracking the lengths of the CA repeats. Differences between the two parental strains allow us to zero in on the disease gene. The same phenomenon makes it easy to use CA repeats to trace inheritance in human families."

Dr. Lander adds, "With the completion of dense maps of mouse and man, it is now possible to dissect virtually any genetic trait. Although it would be possible to extend these maps further, they are more than adequate for genetic studies and it is now time to turn to the determination of the complete 3 billion letter DNA sequence of these two mammals." The co-leaders of the mouse genome mapping group at the Whitehead Institute are Dr. Dietrich and Dr. Joyce Miller. Among their collaborators on the Nature paper are Drs. Neal G. Copeland and Nancy A. Jenkins of the Mammalian Genetics Laboratory, NCI-Frederick Cancer Research and Development Center in Frederick, Maryland. This work was supported by the National Center for Human Genome Research, NIH.



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