A single gene mutation may have helped humans become optimal long-distance runners

September 11, 2018, University of California - San Diego
Credit: CC0 Public Domain

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.

In a new paper, published in the September 12 issue of the Proceedings of the Royal Society B, researchers at University of California San Diego School of Medicine report on studies of mice engineered to lack the same gene, called CMAH, and resulting data that suggest the lost gene may also have contributed to humanity's well-documented 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 primarily upon 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 between humans and our closest living evolutionary relatives, the chimpanzees, more than 20 years ago," said senior author Ajit Varki, MD, Distinguished Professor of Medicine and Cellular and Molecular Medicine at UC San Diego School of Medicine and co-director of the UC San Diego/Salk Center for Academic Research and Training in Anthropogeny.

Given the approximate timing of the mutation and its documented impact on fertility in a mouse model with the same mutation, Varki and Pascal Gagneux, Ph.D., professor of anthropology and pathology, 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, "but I had no expertise on the issue and could not convince anyone in my lab to organize this long-shot experiment."

Ultimately, a graduate student named Jon Okerblom took up the task, building mouse running wheels and borrowing 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," said Okerblom, the study's first author. The researchers 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, who 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.

Taken together, Varki said 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."

When the CMAH gene mutated in the genus Homo two to three million years ago, perhaps in response to evolutionary pressures caused by an ancient pathogen, it altered how subsequent hominids and modern humans used sialic acids—a family of sugar molecules that coat the surfaces of all animal cells, where they serve as vital contact points for interaction with other cells and with the surrounding environment.

The human mutation causes 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.

This seemingly minor difference affects almost every cell type in the human body—and has proved to be a mixed blessing. Varki and others 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 . Sialic acids may also be a biomarker for .

Conversely, they 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," 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."

Explore further: Missing molecule raises diabetes risk in humans

More information: Human-like Cmah Inactivation in Mice Increases Running Endurance and Decreases Muscle Fatigability: Implications for Human Evolution, Proceedings of the Royal Society B, rspb.royalsocietypublishing.or … .1098/rspb.2018.1656

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4 / 5 (2) Sep 11, 2018
Am interesting conjecture. Which gave upright apes an advantage to discover new uses for their hands.

Encouraging an upright stance with advantage of being able to see over tall grasses and brush.

As bipedalism proved versatile for for using tools and weapons and collecting items. The ability to stride a long distance, strengthened low body structure.

Which eventually allowed wider pelvis that newborn's heads could be larger.

Eventually producing the hominid line. A pivoting mating dance where form followed function. Making further functions possible.
3 / 5 (1) Sep 12, 2018
Did the paper mention anything about testing the mice for enhanced swimming endurance?
1 / 5 (6) Sep 12, 2018
Humans are very slow runners. Dogs, cats, almost all other mammals run faster than us. Humans swim faster than all of those mammals. This mutation is obviously for swimming.

We are nocturnal. The sun burns our skin. We lost the primate brow that protects their eyes from the sun, to help us swim faster with less resistance. Primate feet look like hands. Our feet turned into flippers. Try outrunning an angry chimp.

We are the aquatic ape. The beach party ape. Buried ourselves in the sand during the day and woke up before sunset to spend the night at the ocean shore. Our instinct call this paradise. Predators don't roam the ocean shores because of the salt water. One group of apes, long ago, figured out they can transport fresh river water in coconuts and store it, allowing them to live and hunt in the ocean.

4.8 / 5 (5) Sep 12, 2018
Humans are very slow runners. Dogs, cats, almost all other mammals run faster than us. Humans swim faster than all of those mammals. This mutation is obviously for swimming.

There is no evidence I am aware of that the first humans likely did much swimming thus that isn't obvious at all.
More likely I think the mutation mainly helped us with slow long-distance running and for when speed isn't of critical importance such as to cover large amounts of ground in one day to search for food etc. Much more difficult to imagine how being a faster swimmer would give a big enough survival advantage to early humans for the mutation to be selected for because probably most of them didn't go swimming much and how would it help with survival much? We cannot out-swim the average fish.
3 / 5 (1) Sep 12, 2018
Assuming the mouse model actually maps to humans, does it much matter if this mutation first occurred near the beach or inland? Greater endurance (as described) might allow an early human to more fully exploit either (or both) habitats.
5 / 5 (1) Sep 12, 2018
This is possible, but they do not understand the mechanism and mouse model testing is not enough since many changes will differ in result. Also, famously the hominin lineage, as normal, show mosaic evolution. The increased sweat gland/decreased fur transition is narrowly dated to 1.2 million years ago, both from dating the key change in a known participating allele (in follicle development, making humans loose fetal hairs and not grow back) and from dating the acquisition of head and pubic lice.

@Gerrob: "Aquatic ape" is nonviable, "more popular with the lay public than with scientists" [ https://en.wikipe...pothesis ].
5 / 5 (1) Sep 12, 2018
Geerob. I've sen the videos of Orca packs flinging themselves into beach colonies of pinnipeds. Did you know that similar to cats, the Orca like to play with their food? Helps you visualize why they were called the "Sea Wolves" and "Killer Whales"!

Ny the way. Hominid hunting was compelled as much by the craving for blood-salt as for meaty fat. If our ancestrals were as "ocean bred" as you assumed? There would have been no lack of sodium in the ancestral diet.

Instead, they were usually land animals that from time to time gathered/scavenged along the beach. That is why we piss potassium salt but retain sodium salt.

You may need to be discussing your poor dietary choices with your doctor?
5 / 5 (1) Sep 14, 2018
@Gerrobb: then why do we sweat all over the body? That would be of no use in water.

Btw, you are missing the point. Humans are good as endurance runners not fast runners.
1 / 5 (1) Sep 14, 2018
Two to three million years ago, the functional loss of a single gene triggered

As if that is a verifiable FACT.... right?
So where is the science in that?
5 / 5 (1) Sep 14, 2018
Oh Freddie, the "Science" is no where accessible to your limited stuporstitious intellect.
not rated yet Sep 15, 2018
Two to three million years ago, the functional loss of a single gene triggered

As if that is a verifiable FACT.... right?
So where is the science in that?

Could be.

In my opinion, the main problem with creationists (not Creation) is the fact they assume God necessarily works inside time. That may not be the case. Maybe He creates outside of time. Maybe from a temporal point of view creation even looks like evolution - but this is a second-degree point in terms of importance.

I have no problem with God effectively creating humans, even with no evolution implied. This may have happened way outside time. It may be that the whole creation was determined at the beginning (or rather at some beginnings, 'days' of creation) starting from a purpose for creation, which effectively determined it. What we see as evolution in time may be the result of a more profound cause, which is not temporally determined.

But this is hard to discern clearly for us.
marc verhaegen
not rated yet Sep 16, 2018
This is a very interesting paper, but the anthropocentric interpretation is unscientific in my opinion. The paper states that "CMAH loss could have provided a selective advantage for ancestral Homo during the transition from forest dwelling to increased resource exploration and hunter/gatherer behaviour in the open savannah." But as far as is known, there was no transition from forest to savannah. In fact, 2.1 million years ago, Homo already had reached Nihewan in China (Z. Zhu et al. 2018 Nature doi 1038/s41586-018-0299-4), which could not have happened by running over open savannah, but most likely happened by following African and Eurasian coasts and rivers (google e.g. "Ape and Human Evolution 2018 biology vs anthropocentrism"), where they did not hunt in the first place, but simply collected waterside and shallow-aquatic foods, which are richest in brain-specific foods such as DHA, iodine, taurine and oligo-elements, explaining Homo's drastic brain enlargement since the early-Ple
marc verhaegen
not rated yet Sep 16, 2018
Interesting paper, but the anthropocentric interpretation is unscientific. The abstract says "CMAH loss could have provided a selective advantage for ancestral Homo during the transition from forest dwelling to increased resource exploration & hunter/gatherer behaviour in the open savanna." But there was no transition from forest to savanna. Homo already had reached NW.China 2.1 Ma (Zhu cs 2018 Nature doi 1038/s41586-018-0299-4), not running over savanna, but following African & Eurasian coasts & rivers (google: Ape & Human Evolution 2018 biology vs anthropocentrism), not hunting, but collecting waterside & shallow-aquatic foods: DHA, iodine, taurine etc best explain our Pleistocene brain enlargement (Cunnane 2005 Survival of the Fattest, World Scient.). Endurance running is only seen in a few human populations today, it is recent; there are indications of occasional scavenging of waterside carcasses >2 Ma, but not of hunting then (Verhaegen 2012 Hum.Evol.28:237-266).

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