women running
Ohio State University

We, humans, are the products of evolution. Around two to three million years ago, after the functional loss of a single gene, a number of major changes occurred in the humans, which eventually helped us become modern human species that we are today. It changed everything.

Recently a group of researchers from the University of California San Diego School of Medicine published a new paper, which says that it might have been the loss of that gene, which caused the humans to become one of the best long-distance runners in the animal kingdom. The paper was published in the Proceedings of the Royal Society B's September 12 issue. As per the paper, the researchers conducted experiments on some mice that were engineered to not have that same gene, named CMAH.

At around the same time when the predecessors of humans were losing the CMAH gene, they were also starting to shift from the forests to the dry African savannahs. Major skeletal biomechanics and physiological changes were taking place in their bodies. It also led to the long, bouncy legs, big feet and strong gluteal muscles. Another thing appeared in the bodies of these human ancestors that made them different from all the other larger mammals - an expansive system of sweat glands, which were capable of driving the heat away more effectively. These kinds of changes allowed the human ancestors to run long distances less tirelessly compared to other mammals. So, they could hunt even during the daytime, when the temperature was higher, while other carnivores rested.

"We discovered this first clear genetic difference between humans and our closest living evolutionary relatives, the chimpanzees, more than 20 years ago," stated the senior author of the new paper, Ajit Varki, MD, Distinguished Professor of Medicine and Cellular and Molecular Medicine at UC San Diego School of Medicine. He is also the co-director of the UC San Diego/Salk Center for Academic Research and Training in Anthropogeny.

Varki started the investigation along with a professor of anthropology and pathology, Pascal Gagneux, PhD. They were trying to find out how the genetic difference might have added to the origin of Homo, the genus, which includes modern Homo sapiens as well as the extinct species, such as the Homo habilis and Homo erectus.

"Since the mice were also more prone to muscle dystrophy, I had a hunch that there was a connection to the increased long-distance running and endurance of Homo but I had no expertise on the issue and could not convince anyone in my lab to organize this long-shot experiment," Varki said.

Finally, Jon Okerblom, a graduate student built running wheels for mice and borrowed a mouse treadmill. "We evaluated the exercise capacity (of mice lacking the CMAH gene), and noted an increased performance during treadmill testing and after 15 days of voluntary wheel running," the first author of the study, said Okerblom said.

The team then discussed the matter with Ellen Breen, Ph.D., who is a research scientist in the division of physiology, a part of the UC San Diego School of Medicine's Department of Medicine. He observed that the mice were more resistant to fatigue. They also had increased mitochondrial respiration and hind-limb muscle, with more capillaries, which increased the supply of blood and oxygen in their bodies.

So, the data hinted towards the fact that loss of CMAH helped the mice to have a better and improved skeletal muscle capacity for oxygen use. "And if the findings translate to humans, they may have provided early hominids with a selective advantage in their move from trees to becoming permanent hunter-gatherers on the open range," he added.

During the CMAH gene mutation in the bodies of the humans' predecessors around two to three million years ago, it actually changed they used sialic acids, which is a family of sugar molecules that cover all the animals' cells' walls. At that place, they become as vital contact points for interaction between the cells and with the surrounding environment. The loss of that gene caused the hominids and modern humans to lose a sialic acid, N-glycolylneuraminic acid (Neu5Gc). Instead, it built up its precursor, called N-acetylneuraminic acid or Neu5Ac. The only difference between these two is one single oxygen atom.

Although the difference appears to be minor, it actually affects almost all the cells types in the human body. This change has been a blessing as well as a curse for the modern humans.

The researchers believe that CMAH gene mutation and loss of sialic acids are not only linked to humans' improved ability to run long-distance, but it also increased inborn immunity in the early hominids. They also concluded that Sialic acids might be a biomarker for cancer risk.

On the other hand, the paper stated that some sialic acids are linked with the elevated risk of type 2 diabetes and can trigger inflammation. They may also contribute to the increased cancer risk that is connected with eating red meat consumption.

"They are a double-edged sword. The consequence of a single lost gene and a small molecular change that appears to have profoundly altered human biology and abilities going back to our origins," said Varki.