By Mark D. Uehling
August 13, 2002 | Unraveling the relationship between genes and behavior could be crucial to understanding many diseases: heart disease and alcoholism, obesity and cancer. But establishing any connection between complexes of genes in a living organism, on the one hand, and its behavior, on the other, has proved supremely challenging. Now a team lead by Ralph Greenspan at The Neurosciences Institute in La Jolla, Calif., has published the first faint glimmers of success.
In work just published this month in Nature Genetics, Greenspan and his colleagues at Yale University and the University of Illinois studied two established lines of fruit flies (the venerable Drosophila melanogaster). Both groups of flies have odd behavior. Unlike normal flies, which go directly through a vertically oriented maze, one group of flies consistently drifts up toward the top of the maze; the other gravitates down to the bottom. No single gene is responsible for either tendency, known as geotaxis.
Greenspan and his colleagues wanted to know which genes cause geotaxis. They also wanted to combine traditional breeding techniques and the best IT tools they could find. Starting with a third of all the genes in D. melanogaster, they used cDNA microarrays to find 250 genes that are expressed twice as much in the flies with gravity-related behavioral quirks. Using existing strains of fruit flies and breeding new ones, the scientists soon detected three well-known genes that collectively contribute to the gravity-related behavior: cry, Pdf, and Pen.
Greenspan says his work would not have been possible without the online FlyBase database, a repository of the collective wisdom of the biologists and geneticists devoted to the insect. That Web site (flybase.bio.indiana.edu:82) even helps scientists find mutant strains of flies for research, and obtain them through the mail in vials.
Another key tool was GenePix, software from a Union City, Calif., company called Axon Instruments Inc. that sells $32,000 and $49,000 benchtop instruments (also called GenePix) for the reading of spotted, two-color microarrays. The software that comes with those machines has become so popular, especially in academia, that the company sells it as a stand-alone package (list price: $3,000).
Recently released in version 4.1, GenePix has a popular file format for microarrays and a relatively easy-to-use interface. All of the company's tech support staff have either doctoral degrees or extensive life science experience as postdocs. Says Shawn Handran, Axon's product line manager for functional genomics, "They understand not only the instrument and the software but the biology as well."
Other Genes, Other Behaviors?
In the lab, meanwhile, Greenspan and his colleagues still need to figure out the respective roles of the three geotaxis genes. There may also be other genes, as yet unknown, influencing the behavior.
But Greenspan and his colleagues have already sidestepped one of the central problems in using genetic markers -- namely, that such markers are not confined to the genes responsible for a behavioral trait of scientific interest. "Getting from that marker to what the real gene is has proven to be a very difficult process," says Greenspan. "The number of successes relative to the number of attempts has been very, very small."
The ramifications for human medicine are not immediate, but they are intriguing. Greenspan notes that after scientists found the genes for circadian rhythms in fruit flies, they searched for the same genes in human beings -- and found them. A rare human sleep disorder turns out to be almost identical to a disruption in the daily rhythms of fruit flies. In theory, using the techniques published in Nature Genetics, it may be possible to identify genes linked to other behaviors in fruit flies and identify the same genes -- and similar behaviors -- in people.
Greenspan says one of the directions of his future research will be to use the microarrays and his 28-year knowledge of D. melanogaster genetics to tease apart how genes work together. "We're trying to get beyond looking at genes one at a time and understand how they function as a set and how they function really as a network," says Greenspan. "These network relationships between genes are flexible and malleable. They're not rigid. When you introduce one genetic change in the animal, a lot of other things change in concert with that."
And some things, at least with D. melanogaster, don't change: The ancestors of the geotaxis fruit flies in Greenspan's research were bred 40 and even 50 years ago in Jerry Hirsch's lab at the University of Illinois. After Hirsch went into semi-retirement and lost his lab, he kept his gravitationally skewed flies alive in his office anyway, just in case. Says Greenspan of his coauthor: "He's delighted with all this."