A genetic fluke two to three million years ago turned humans into the best endurance runners around.

Running man.

Image via Pixabay.

A new paper published by researchers from the University of California San Diego School of Medicine reports that our ancestors’ functional loss of one gene called CMAH dramatically shifted our species’ evolutionary path. The loss altered significant metabolic processes, with impacts on fertility rates and risk of developing cancer.

The same change may have also made humans one of the best long-distance runners on Earth, the team adds.

These genes were made for runnin’

Our ancestors were presumably quite busy two to three million years ago transitioning from living in trees to live on the savannah. They were able to walk upright by this time, but they weren’t particularly good at it.

However, soon after this, some of our ancestors’ physiology starts undergoing some striking changes. Most relevant are shifts we see in their skeletons, resulting in long legs, big feet, and large gluteal muscles (butts) — all very good for walking around. These shifts were also accompanied by the evolution of sweat glands with much the same layout and capacity as ours which, according to the team, is quite expansive and much better at dissipating heat than that of other large mammals.

In other words, humanity received powerful legs and one of the most solid cooling systems in one fell swoop.

Our ancestors proceeded to use their new toys to hunt and eat anything they could bring down. They did so by adopting a hunting pattern unique among primates (and very rare among animals in general) known as persistence hunting: they would go out in the heat of the day, when other carnivores were resting, relying on their legs and sweat glands to chase prey until — exhausted and overheated — it couldn’t physically run away anymore.

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We didn’t know much about the biological changes that underpinned this radical change, however. The first clues were uncovered around 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 species of primates also have this gene.

We, however, have a broken version of CMAH. 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.

More recent research has shown that mice models with a muscular dystrophy-like syndrome exhibit more acute symptoms when this gene is inactivated. This hinted to Varki that the faulty gene might be what led to the changes our ancestors experienced in the savannahs.

“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.

UCSD graduate student Jonathan Okerblom, the study’s first author, put the theory to the test. He built mouse running wheels, borrowed a mouse treadmill, and pitted mice with a normal and broken version of CMAH to the task.

“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,” Okerblom explained.

The two then consulted Ellen Breen, Ph.D., a research scientist in the division of physiology, part of the Department of Medicine in the UC San Diego School of Medicine. She examined the mice’s leg muscles before and after running different distances, some after 2 weeks and some after 1 month.

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After training, mice with the human-like version of CMAH ran 12% faster and 20% longer than the other mice, the team reports. Breen adds that the mice displayed greater resistance to fatigue, increased mitochondrial respiration and hind-limb muscle, with more capillaries to increase blood and oxygen supply. Taken together, Varki says the data suggest CMAH loss contributed to improved skeletal muscle capacity for oxygen utilization.

“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.”

The most likely cause of this change was evolutionary pressures associated with an ancient pathogen, the team explains.

The version of the gene we carry determines the loss of a sialic acid called N-glycolylneuraminic acid (Neu5Gc), and accumulation of its precursor, called N-acetylneuraminic acid or Neu5Ac, which differs by only a single oxygen atom. Sialic acids serve as vital contact points for cell-to-cell interaction and cellular interactions with the surrounding environment. This change likely led to enhanced innate immunity in early hominids, according to past research.

Sialic acids may also be a biomarker for cancer risk, and the team has 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,” said Varki. “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.”

The paper “Human-like Cmah inactivation in mice increases running endurance and decreases muscle fatigability: implications for human evolution” has been published in the journal Proceedings of the Royal Society B.

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