Genetic Variations are Keys to Diversity

We’re no longer limited by the amount of genomic information we can easily obtain.

Fruit flies. Mice. Butterflies. Ongoing research on all three species helped NC State’s Department of Genetics land Recovery Act grants to study drug toxicity and complex traits such as sleep and wake cycles, as well as to purchase tools to decode genetic variations in those and other organisms.

Dr. Trudy Mackay, William Neal Reynolds and Distinguished University Professor of Genetics, has studied Drosophila melanongaster, or fruit flies, for years to determine variants of genes that produce differences in physiological traits, from alcohol sensitivity to aggressive tendencies. She has inbred scores of strains of the insects she captured at the State Farmers Market to produce genetically identical lines that she uses to determine what causes variations in traits. “You have to build a chain of gene expressions to get that trait,” Mackay says. “Once you have that network, you can usually determine what each gene’s role is.” Because humans have similar genetic pathways, she says, pinpointing the genetic source of a trait in fruit flies gives researchers a target when studying human diseases and behavior.

A pair of two-year grants from the National Institutes of Health — totaling more than $1.1 million — helps Mackay and genetics colleagues Drs. Robert Anholt and Eric Stone expand such studies. One study focuses on circadian rhythms to determine which strains of Drosophila scan best reset their internal clocks in the dark. It builds on earlier work on genetic variations in the insects’ sleep patterns. The second could help in the treatment of Parkinson’s disease. Exposure to some chemicals is linked to the degenerative neurological disorder in humans, so the NC State researchers are exposing the Drosophila strains to low levels of insecticides to measure genetic impact and resulting effects on locomotion. “We want to map the genetic variants to find the mechanisms that may protect the flies and what may make the condition worse,” Mackay says.

Similarly, Dr. David Threadgill is determining genetic mechanisms that make mice more susceptible to adverse drug reactions, with an eye toward applying that knowledge to human drug trials. “Right now, you usually find out drug toxicity in humans because someone is sensitive to a drug,” says Threadgill, who heads the Department of Genetics. “We want to identify genetic markers that would show in advance whether an individual could tolerate a drug or whether it could cause problems for them.” A two-year, $1 million grant from the National Institute of Diabetes and Digestive and Kidney Diseases funds two technicians.

Pharmaceutical companies have provided Threadgill’s team with several drugs no longer on the market, or that the firms are no longer pursuing. Threadgill has several strains of mice bred to be genetically identical so that he can see how each strain reacts to different doses. His team collects blood and tissue samples from the mice to check for enzymes suggesting liver damage and have found sensitivity with some strains. “We’re matching genetic variations to the damage to determine which genes are driving it,” he says, adding that he hopes future research also will identify markers for people who might develop heart issues due to an adverse drug reaction.

Understanding genetic variations is a data-intensive process. Researchers now compile reams of information more quickly and cheaply because of a DNA sequencer purchased with a $450,000 grant from the National Science Foundation and matching funds from NC State. The new tool produces about 40 times the data at about a tenth of the cost of the old sequencer. “We can parlay this equipment into game-changing research,” says Dr. Owen McMillan, an adjunct associate professor of genetics. “It really opens things up to asking new questions.” McMillan, now at the Smithsonian Tropical Research Institute in Panama, studies adaptive variations in butterflies that use wing colors to ward off predators. Different species living in the same area often display identical or similar color patterns, he notes. Meanwhile, there can be as many as 25 distinct pattern variations within a single species. “Some of these species are, in effect, sharing the cost of advertising,” he says. “Advertising is expensive in the wild. You send the wrong message, and you’re dead.”

To study which genes are turned on and off, McMillan breeds several butterfly species to determine genes responsible for altering the pattern of bold stripes and patches of red, yellow and black on the wings. He also identifies how gene expression changes through stages of metamorphosis. The new sequencer is critical. “We’re no longer limited by the amount of genomic information we can easily obtain,” McMillan says. “This allows us to rapidly get at the nature of differences in organisms and provides great insight into the extraordinary diversity on our planet.”

 

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Genetic studies of insects and mice can provide groundwork to solve human problems.

Dr. David Threadgill wants to identify genetic markers that would indicate if an individual could tolerate a drug.