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June 15, 2001
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wild-type fruit fly with normal bristles (arrow) and mutant fly, with extra
bristles (arrow) due to misexpression of a "presenilin" gene, which
causes Alzheimer's in humans when mutated.
IDENTIFY 548 GENES IN THE FRUIT FLY
Biologists at the University of California, San Diego have identified genes in the common fruit fly, Drosophila melanogaster, that appear to be counterparts of genes responsible for more than 700 different genetic diseases in humans.
Their discovery, detailed in the June issue of the journal Genome Research, provides medical geneticists with a powerful new tool to identify the many genes that may be responsible for a particular human genetic disease and to understand its underlying biochemical mechanisms so that effective treatments can be developed.
"Scientists have long known that humans share many similar genes with fruit flies," says Ethan Bier, a professor of biology at UCSD who headed the research. "The surprise is how deep these similarities really are. Basically, every category of human genetic disease is well represented with a counterpart in the fly."
The UCSD scientists screened the genes involved in 929 human genetic diseases in their database against the fruit-fly genes in the complete Drosophila genome, published last March in Science. Their comparison of the amino acid sequences identified 548 fruit-fly genes that are so similar to genes involved in 714 human genetic disorders that the similarity could have statistically occurred by chance only one time out of 10 billion.
"If the probability was less than one out of 10 billion, we considered it a hit," says Bier. "That means that the proteins these genes code for are so similar that all of them or part of them most likely came from an ancestral protein."
Knowing which genes in fruit flies are the ancestral counterparts to genes that cause genetic diseases in humans is important to medical researchers for a variety of reasons.
"The fly offers an ideal model system in which these genes can be studied," explains Lawrence T. Reiter, a UCSD researcher and the lead author of the paper. "It's a simple genetic system that's well understood, and flies are inexpensive to rear and have a short generation time, enabling us to screen through thousands of individuals to identify mutations in new candidate genes that may have human counterparts that cause disease. All of these things make Drosophila a superior model genetic organism compared to the laboratory mouse."
The study began two years ago when Reiter, a human geneticist, came to Bier's Drosophila genetics laboratory with the idea of working on human disease genes that had counterparts in fruit flies. With Michael Gribskov, a computational biologist at UCSD's San Diego Supercomputer Center, they created a database of human genes, fly genes and human genetic diseases called Homophila (http://homophila.sdsc.edu/) that went online last fall.
Based on this dataset, Lorraine Potocki, a clinical geneticist at Baylor College of Medicine, categorized the human genetic disorders that might be studied in Drosophila. These diseases fell into essentially every major category, including neurological, immunological, cardiovascular, auditory, visual, developmental and metabolic disorders, as well as many forms of cancer.
Another striking feature of the study is that a significant number of the fly genes-more than 200 genes-are so similar to their human-disease counterparts that they are very likely to carry out equivalent functions. Whether these particular Drosophila genes and their human-disease counterparts are, in fact, related or share similar functions must be determined by additional experimental studies. But the identification of the 548 fruit-fly genes has given medical researchers a head start in searching for human counterparts for a wide variety of human genetic disorders from Alzheimer's disease to deafness to cancer, as well as a new way in which to investigate the function of those genes.
"Most people don't think of studying blindness, hearing or cancer in Drosophila," says Reiter. "But human genetics has hit a wall with regards to function. And the fly turns out to be an ideal model genetic system for analyzing genes and placing them in the context of known genetic pathways."
The UCSD scientists note that by working with fly geneticists, human geneticists could narrow down the large number of candidate genes for a particular genetic disorder to a handful that have counterparts in the fly. These genes could be identified in flies based on the fact that they function together in a common process, or "pathway." Since genes causing human disease are also likely to function in similar pathways, the fly studies should provide invaluable clues to narrow down the search for genes causing similar disease conditions such as the many inherited forms of Alzheimer's disease.
How many human diseases could be studied in fruit flies? Of the 548 genes identified in the analysis, Bier suspects that 200 to 300 will probably turn out to be functionally equivalent to their human counterparts. Because those 200 to 300 genes were culled from a database of more than 900 human genetic disorders, he believes fly genes could ultimately play an important role in the investigation of at least 1,000 of the 5,000 known human genetic diseases.
"The fly will be a useful tool for understanding and treating human disease," says Bier, noting that the Homophila database is an important link for promoting collaboration between human and fruit-fly geneticists. "You can't easily use mice to perform a genetic screen for new genes that may play a role in disease. The fly offers a compelling advantage that doesn't exist in the mouse."
The UCSD study was
supported by grants from the National Institutes of Health, National Science
Foundation, the Glaucoma Foundation, the Angelman Syndrome Foundation and the
National Biomedical Computation Resource.
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