How lost gene helped humans run the distance

Loss of the CMAH gene improved long-distance running ability and enhanced innate immunity

Two to three million years ago, the functional loss of a single gene triggered a series of significant changes in what would eventually become the modern human species, altering everything from fertility rates to increasing cancer risk from eating red meat.

The lost gene, CMAH, may also have contributed to humanity’s claim to be among the best long-distance runners in the animal kingdom.

At roughly the same time as the CMAH mutation took hold, human ancestors were transitioning from forest dwellers to life in the arid savannahs of Africa.

While they were already walking upright, the bodies and abilities of these early hominids were evolving dramatically, in particular major changes in skeletal biomechanics and physiology that resulted in long, springy legs, big feet, powerful gluteal muscles and an expansive system of sweat glands able to dissipate heat much more effectively than other larger mammals.

Such changes, say scientists, helped fuel the emergence of the human ability to run long distances relatively tirelessly, allowing ancestors to hunt in the heat of the day when other carnivores were resting, and to pursue prey to their point of exhaustion, a technique called persistence hunting.

“We discovered this first clear genetic difference between humans and our closest living evolutionary relatives, the chimpanzees, more than 20 years ago,” said senior author Ajit Varki.

Given the approximate timing of the mutation and its documented impact on fertility in a mouse model with the same mutation, researchers began investigating how the genetic difference might have contributed to the origin of Homo, the genus that includes modern Homo sapiens and extinct species like 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,” said Varki.

INCREASED PERFORMANCE

The researchers evaluated the exercise capacity of mice without the CMAH gene and noted an increased performance during treadmill testing and after 15 days of voluntary wheel running.

Ellen Breen, another researcher, added observations that the mice displayed greater resistance to fatigue, increased mitochondrial respiration and hind-limb muscle with more capillaries to increase blood and oxygen supply.

CMAH loss contributed to improved skeletal muscle capacity for oxygen utilisation.

“This may have provided early hominids with a selective advantage in their move from trees to becoming permanent hunter-gatherers on the open range.”

When the CMAH gene mutated, it altered how modern humans used sialic acids, sugar molecules that coat the surfaces of animal cells, serving as vital contact points for interaction with other cells and the environment.

Researchers have linked the loss of the CMAH gene and sialic acids to not just improved long-distance running ability, but also enhanced innate immunity in early hominids. Sialic acids may also be a biomarker for cancer risk.

Conversely, researchers have also reported that certain sialic acids are associated with increased risk of type 2 diabetes; may contribute to elevated cancer risk associated with red meat consumption; and trigger inflammation.

“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 in a paper published in the Proceedings of the Royal Society B.

 - Science Daily

FREEZE OR FLIGHT?

Like other animals, humans react to threats with one of three options: flee, fight or freeze in place. How does the brain decide which strategy to implement?

Researchers turned to fruit flies for answers. When exposed to a threat, many froze, but others ran away. If the fly was moving slowly, it would freeze, but if it was walking quickly, it would run away from the threat.

Freezing was controlled by two identical neurons, one on each side of the brain. When these neurons were turned off, the flies didn’t freeze, they escaped from the threat. When they were turned on even without a threat, flies would freeze in a manner that depended on their walking speed.

When the fly was walking slowly, it would freeze, but not if it was walking quickly.

The neurons were at the gateway of the circuit of choice, sending motor commands from the brain to the ‘spinal cord’ of the fly.