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College Profile: If you live to be 100, you may be thanking a fruit fly-- and Dr. Trudy Mackay's research of its 'beautiful genetics.'--- by Art Latham.
Photo of Dr. Trudy Mackay by Becky Kirkland.

Ornate letter "H"
er research subjects are fruit flies, but Dr. Trudy Mackay is no fly-by-night researcher.

Mackay, William Neal Reynolds professor of genetics in the College of Agriculture and Life Sciences, keeps accumulating awards for her decades of research. The latest is the prestigious 2004 Genetics Society of America Medal, awarded at the March GSA-sponsored 45th annual Drosophila Research Conference in Washington, D.C. Previous recipients have included five Nobel laureates.

“I was surprised and greatly honored to be awarded the 2004 GSA medal,” Mackay says with her usual modesty. Yet since she received her Ph.D. from the University of Edinburgh in 1979, Mackay’s research findings — including evidence that two central nervous system neurotransmitters, dopamine and serotonin, link to lifespan regulation — have been pushing the frontiers of medicine.

Her relatively recent discovery that both gender and environment can affect gene expression lent medical researchers new insight into the genetic mechanisms responsible for complex traits, which result when several genes interact. Unraveling gene combinations affecting the expression of complex traits such as milk production, disease resistance, high blood pressure, heart disease, even longevity, has long challenged researchers.

She credits much of her research success to her experiences at Edinburgh. “Scotland is so beautiful and it was a fantastic time to be there in my field,” she says. “All the great quantitative geneticists were there.”

She mentions genetics research superstars such as William Hill, professor emeritus at Edinburgh and one of the world’s foremost statistical geneticists. Also present were internationally renowned geneticists Douglas Falconer, known for his classic textbook, Introduction to Quantitative Genetics, of which Mackay is fourth edition co-author, and her Ph.D. mentor Alan Robertson. Both men are Fellows of the Royal Society, and Robertson was a Foreign National Academy of Science, USA, member.

In those years, however, genome maps weren’t available for a farthing or a fortune.

“Robertson was frustrated, thinking he couldn’t progress unless he knew what genes were doing what,” Mackay says. “He knew how to map these genes, but he could not do so because molecular marker technology wasn’t yet available.”

The field of quantitative genetics “used to be totally statistical,” says Mackay. “We knew the genes were doing something and how in principle to discover them, but our efforts were stymied by the lack of molecular marker technology.

“But just as I was starting my lab, the technology started to became available and that was kind of good luck. Then it was possible to determine what genes affected complex traits, using fruit flies as a model system. We can now put names to these genes affecting several quantitative traits in flies, from numbers of sensory bristles, to longevity, olfactory behavior, aggression and alcohol tolerance.”

And figuring out what those genes were, says Mackay, “has been my goal since starting at Edinburgh.”

Dr. Trudy Mackay received the Genetics Society of America Medal in March. (Photo by Becky Kirkland)

Ornate letter "B"
orn in Moncton, New Brunswick, Canada, Mackay moved frequently with her family, as her dad, who was in the Royal Canadian Air Force, took on various assignments in far-off places: Calgary, Alberta; Clinton and North Bay, Ontario; and finally, back to the Atlantic Seaboard to Halifax, Nova Scotia.

Of her adolescent years in North Bay, she recalls two things: “A lot of cold,” Mackay says, “and swarms of things that bred in Lake Nippissing that we called ‘mayflies,’ millions of them. If your car stopped, they’d cover it all over like in a horror movie.” You can still hear the shudder in her voice.

But mayfly swarms didn’t spark her later interest in fruit fly genes and longevity. Nova Scotia’s rugged coastal environment indirectly did that, and “a marine creature called Spirorbis borealis. They’re beautiful little things that live in a small shell, and their larvae have two tiny red eye spots,” she says.

She studied the tiny worm’s behavior as her honors baccalaureate project and master’s degree research at Dalhousie University in Nova Scotia.

“That was my first introduction to behavioral biology,” Mackay says. “The creatures choose what type of seaweed they want to settle on. We needed better insights into the genetic mechanisms that drove those choices. There were no genes we could name that might be responsible for those effects. That stimulated me to go to the University of Edinburgh to learn about quantitative genetics in flies and the effects of different environments in maintaining genetic variation.”

Why flies? Well, for one, the elegance of “their beautiful genetics,” she says.

“The fruit fly is a handy model organism for studying the genetics of longevity and other complex traits in animals,” Mackay says. “We can make designer genotypes in fruit flies and test the effects of mutations. And part of the attraction for looking at complex traits in flies is the possible application to human health. We know there are parallels between the genetics of complex traits in fruit flies and in humans; so much so that if we find something to be true in fruit flies, it also is likely true in humans.”

For instance, her longevity project is motivated by the fact that “if we could learn what genes affect life span and why, it would perhaps open the door for pharmacological interventions in the aging process.”

In other words, someday you might be able to thank a bunch of fruit flies and Mackay for your anti-aging pills.

Her work also is critical to agricultural research, especially livestock and crop breeding. “To successfully breed these complex traits into a line, scientists need to better understand the underlying mechanisms that regulate them,” Mackay says.

She thinks Edinburgh was the right place for cutting-edge quantitative genetics research, and she was there at the right time. While Mackay was pursuing her doctorate and teaching at Edinburgh, genetic researchers needed a “handle” with which to manipulate genetic structures. That handle turned out to be something called “P elements”:
genomic “parasites” that move around a genome, efficiently inserting themselves into new locations, where they can cause mutations.

Today, a major goal of the current Berkeley Drosophila Gene Disruption project is to insert a P element into every Drosophila gene so researchers can study the gene’s function.

Also while Mackay was at Edinburgh, two N.C. State University geneticists were there on sabbaticals: Dr. Bruce Weir, William Neal Reynolds Professor of Statistics and Genetics and N.C. State’s Bioinformatics Research Center director, and Dr. Gene Eisen, William Neal Reynolds Professor Emeritus and graduate programs director in the College’s Animal Science Department. Weir met Mackay and encouraged her to apply for a faculty position in the College’s Genetics Department when it became available.

Now at N.C. State, Mackay and her team of geneticists continue to study what genes and mutations affect traits, how genes interact with other genes and with the environment and the molecular basis of the interactions.

“Also along those quantitative lines,” she says, “we’re looking at aggression and alcohol tolerance in flies. In evolutionary genetics, we’re following the stress resistance theme, subjecting the flies to cold, heat, starvation and looking at stress adaptation.”

Mackay’s research is published in many of the world’s most prestigious peer-reviewed journals, including Science and The Proceedings of the National Academy of Sciences, and most recently in 2003 in Nature Genetics.

The National Institutes of Health, the National Science Foundation and the W. M. Keck Center for Behavioral Biology fund Mackay’s research. Her NIH grants help educate the next generation of scientists, who’ll continue to expand those frontiers.

“To date,” Mackay notes, “we have mapped and studied one gene at a time. Now, with quantitative genetics, we can look at whole networks. That’s the Holy Grail, so to speak, what we’d like to understand. And we’re making good progress.”

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