Read our COVID-19 research and news.

Today’s ultramarathoners may go the distance thanks to a gene that broke millions of years ago.

This broken gene may have turned our ancestors into marathoners—and helped humans conquer the world

Despite our couch potato lifestyles, long-distance running is in our genes. A new study in mice pinpoints how a stretch of DNA likely turned our ancestors into marathoners, giving us the endurance to conquer territory, evade predators, and eventually dominate the planet.

“This is very convincing evidence,” says Daniel Lieberman, a human evolutionary biologist at Harvard University who was not involved with the work. “It’s a nice piece of the puzzle about how humans came to be so successful.”

Human ancestors first distinguished themselves from other primates by their unusual way of hunting prey. Instead of depending on a quick spurt of energy—like a cheetah—they simply outlasted antelopes and other escaping animals, chasing them until they were too exhausted to keep running. This ability would have become especially useful as the climate changed 3 million years ago, and forested areas of Africa dried up and became savannas. Lieberman and others have identified skeletal changes that helped make such long-distance running possible, like longer legs. Others have also proposed that our ancestors’ loss of fur and expansion of sweat glands helped keep these runners cool.

Still, scientists don’t know much about the cellular changes that gave us better endurance, says Herman Pontzer, an evolutionary anthropologist at Duke University in Durham, North Carolina, who was not involved with the work.

Some clues came 20 years ago, when Ajit Varki, a physician-scientist at the University of California, San Diego (UCSD), and colleagues unearthed one of the first genetic differences between humans and chimps: a gene called CMP-Neu5Ac Hydroxylase (CMAH). Other primates have this gene, which helps build a sugar molecule called sialic acid that sits on cell surfaces. But humans have a broken version of CMAH, so they don’t make this sugar, the team reported. Since then, Varki has implicated sialic acid in inflammation and resistance to malaria.

In the new study, Varki’s team explored whether CMAH has any impact on muscles and running ability, in part because mice bred with a muscular dystrophy–like syndrome get worse when they don’t have this gene. UCSD graduate student Jonathan Okerblom put mice with a normal and broken version of CMAH (akin to the human version) on small treadmills. UCSD physiologist Ellen Breen closely examined their leg muscles before and after running different distances, some after 2 weeks and some after 1 month.

After training, the mice with the human version of the CMAH gene ran 12% faster and 20% longer than the other mice, the team reports today in the Proceedings of the Royal Society B. “Nike would pay a lot of money” for that kind of increase in performance in their sponsored athletes, Lieberman says.

The team discovered that the “humanized” mice had more tiny blood vessels branching into their leg muscles, and—even when isolated in a dish—the muscles kept contracting much longer than those from the other mice. The humanlike mouse muscles used oxygen more efficiently as well. But the researchers still have no idea how the sugar molecule affects endurance, as it serves many functions in a cell.

Similar improvements probably benefitted our human ancestors, says Andrew Best, a biological anthropology graduate student at the University of Massachusetts (UMass) in Amherst, who was not involved with the work. Varki’s team calculated that this genetic change happened 2 million to 3 million years ago, based on the genetic differences among primates and other animals.

That’s “slightly earlier than I’d have expected for such a large shift in [endurance],” says Best, as it predates some of the skeletal modifications, which don’t show up in the fossil record until much later. But to Pontzer, the date makes sense, as these ancestors needed endurance for walking and for digging up food. “Maybe it’s more than about running,” he notes.

However, “Mice are not humans or primates,” says Best’s adviser at UMass, Jason Kamilar, a biological anthropologist also not involved with the new work. “The genetic mechanisms in mice may not necessarily translate to humans or other primates.”

Either way, says Pontzer, the study is exciting because it gets researchers looking beyond fossils and into what might actually have gone on in the bodies of ancient animals. “This is really energizing work; it tells us how much is out there to do.”