My pace slows as I enter the atrium of my laboratory building. The decision is always the same: elevator or stairs?
“We’re taking the stairs,” my wife says as she accelerates. I lumber behind her up to the fifth floor.
People have always differed in how much they like to move. Mark Twain leaned toward the sedentary: “I am pushing sixty, that’s enough exercise for me.” My wife would have had an ally in Marcus Tullius Cicero, Roman orator and philosopher: “It is exercise alone that supports the spirits, and keeps the mind in vigor.”
I don’t have a natural love of exercise, but as a physiologist I’m fully aware of the benefits of physical activity. People who engage in regular physical activity have lower rates of coronary heart disease, high blood pressure, stroke, type 2 diabetes, metabolic syndrome, colon cancer, breast cancer, and depression. Yet many Americans don’t exercise regularly. What predisposes some people to exercise while others don’t?
It sounds like a busy playground — the shuffling of a thousand little feet. The air feels sterile, a constant 72˚F, accented by fluorescent lights. This is the animal-research facility of Theodore Garland Jr. at the University of California, Riverside. Next door, in a room lined floor-to-ceiling with cages, hundreds of exercise wheels spin as fast as mice can turn them.
Given a wheel, rodents will run. Laboratory mice are no exception, and as with humans, the amount of running that a mouse does is a trait that can be passed down from one generation to the next. For more than ten years, Garland has been giving mice access to wheels, monitoring how much they voluntarily run and breeding the mice that run the farthest. Some of Garland’s mice now run more than twelve miles a night, every night — three times more than a typical laboratory mouse. These mice are quite literally born to run.
The mice achieve their increased distances mostly by running faster, not for more minutes each night. But these mice aren’t sprinters; they’re built more like marathon runners — lighter and leaner. And there are other differences between a runner and a typical mouse: larger hearts, more symmetrical hind limb bones (a trait often seen in the most successful race horses), and less body fat. These changes, called correlated responses, evolved in conjunction with the increased activity and are thought, in most cases, to aid the wheel running. Correlated responses are a common feature of selective breeding and, as Charles Darwin noted in On the Origin of Species: “If man goes on selecting, and thus augmenting, any peculiarity, he will almost certainly modify unintentionally other parts of the structure, owing to the mysterious laws of correlation.”
For five years questions about these correlated responses dominated my focus. But as I completed my PhD, this research only heightened my interest in the question of why some mice and people run, while others run.
From sunny Southern California to Chapel Hill. In UNC’s School of Medicine, Daniel Pomp, renowned for research on animal and obesity genetics, investigates exercise, a powerful trait potentially capable of controlling and preventing obesity.
A trait is any property or characteristic of an organism. Exercise behavior, body composition, and blood type are all traits — some simple and others complex. Simple traits such as blood type are controlled by differences in single genes. Variation in complex traits, such as body composition and the predisposition to exercise, are controlled by many factors, genetic and environmental. Individual variation in complex traits can be extreme: think Homer Simpson versus Lance Armstrong. Scientists have studied complex traits in organisms ranging from humans to fruit flies, but Pomp’s experience and expertise has led him to Garland’s exercise-fiend mice.
Are these mice healthier? Do they live longer? Are they disease-resistant?
These questions dominated my conversations after arriving at UNC. Of course, there are no easy answers for questions related to health, longevity, or disease resistance, especially when comparing mice and humans. But the mice run voluntarily, aerobically, and for long distances. That was particularly important to Pomp when he contacted Garland and envisioned a population of mice he could use to discover genes underlying the predisposition to exercise.
Selective breeding over many generations tends to fix genes responsible for the chosen trait, minimizing the phenotypic differences between individuals. If a researcher keeps selecting and breeding only the mice that run the most, the population ends up dominated by exercise lovers that vary little in the amount that they choose to exercise or in the genes that control that choice.
This is great if you’re studying exercise physiology, but for mapping genes responsible for that behavior, it won’t do. At its most basic, genetic mapping is matching variation in regions of DNA with variation in a particular trait. The absence of variation in either equals a blank map. The genes that were potentially fixed in the high-runners as a product of many generations of selection must be recombined with those of a strain of average runners to produce the variation needed for mapping.
In Pomp’s lab, we were ready to see to what extent the new mice differed in the amount they ran and whether we could find regions of DNA associated with the variation. We’d completed the breeding. In order to understand the effects of exercise on weight control, we’d given each mouse an MRI before and after exercise to measure fat and lean mass.
It took the team over a year to arrive at this point, but the result was a powerful experimental tool for dissecting and understanding the genetic architecture controlling voluntary exercise. In our lab mice, voluntary exercise levels vary widely — some run as little as 1.5 miles a night, and others as much as 17.
The next step: identify in each mouse regions of DNA associated with particular traits of interest — running distance, running speed, amount of time spent running, change in body mass resulting from running. Within these regions of DNA, is there one gene with a very large effect, or many genes with small effects? Are these genes similar in humans? What does this mean for weight maintenance, weight loss, obesity?
My wife the busy bee, Scott the sloth… soon we may know why.
I turn off my computer, push my chair under my desk, take one look at the elevator — and promptly head for the stairs.
Scott Kelly was a student who formerly contributed to Endeavors.
Kelly’s work in the Department of Genetics is supported through an Interdisciplinary Obesity Training program funded by the National Institutes of Mental Health. Daniel Pomp is a professor of genetics in the School of Medicine. The National Institutes of Health is funding Pomp’s work. Theodore Garland Jr. is a biology professor at the University of California, Riverside. The National Science Foundation funds Garland’s work.