Neanderthal life was not easy. Ice age hunter-gatherers barely survived throughout western Eurasia, hunting mammoths, bison, and other dangerous animals.

Now, a pioneering study of its genome, published in Current Biology, reveals that, despite their harsh existence, Neanderthals had a biological predisposition to perceive pain more intensely. Evolutionary geneticists discovered that these ancient human relatives carried three mutations in a gene that codes for the NaV1.7 protein, which transmits painful sensations to the spinal cord and brain. They also showed that, in a sample of British citizens, those who had inherited the Neanderthal version of NaV1.7 often feel more pain than others.

For me, it is a first example of how we started to get a possible idea about Neanderthal physiology taking current people as transgenic models as a reference, says Svante Pbo, from the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, who led the study. with Hugo Zeber of the Karolinska Institute in Stockholm.

A protein related to pain perception

The researchers have had access to only a few Neanderthal genomes, and most of them have been sequenced at low resolution. This has made it difficult to identify mutations that occurred after their lineage separated from that of todays humans, between 500,000 and 700,000 years ago. But in recent years, Pbo and his team have obtained three high-quality Neanderthal genomes from DNA found in caves in Croatia and Russia. This has allowed them to identify mutations that were surely very common in Neanderthals, but are very rare in humans today.

Mutations in a gene called SCN9A which codes for the NaV1.7 protein persisted because all Neanderthals had three mutations that altered the shape of the protein. The finding of the mutated form of the gene in both sets of chromosomes in the three Neanderthals indicates that it was common in all their populations.

NaV1.7 acts on the nerves in the body, controlling the extent to which pain signals are transmitted along the spinal cord to the brain. They have described it as a kind of volume control, which determines the amount of pain transmitted by nerve fibers, says Zeberg. Some people who have extremely unusual gene mutations that turn off the protein do not feel pain, while other changes may predispose people in question to suffer from chronic pain.

To investigate how mutations may have altered Neanderthal nerves, Zeberg introduced his version of NaV1.7 in frog eggs and human kidney cells useful model systems for characterizing the proteins that control nerve impulses. The protein was more active in cells that had all three mutations than in cells that had not undergone those changes. In nerve fibers, this could lower the threshold from which a painful signal would be transmitted, says Zeberg.

He and Pbo then searched for humans with the Neanderthal version of NaV1.7. About 0.4 percent of participants in the Britains biobank, a database of the genomes of half a million Britons, who claimed to have painful symptoms, had a copy of the mutated gene. No one had two, as was the case with Neanderthals. Participants with the mutated version of the gene were 7 percent more likely to experience pain in their daily lives than people without it.

Sensitive Neanderthals

It is a beautiful job, because it shows how some aspects of Neanderthal physiology can be reconstructed by studying modern humans, says Cedric Boeckx, a neuroscientist who works at the Catalan Institution for Research and Advanced Studies in Barcelona, Spain. In a 2019 study, Boeckx noted three other proteins involved in pain perception that are different in modern humans and Neanderthals. Those changes may be evidence of differences in resilience between the two species, Boeckx says.

Pbo and Zeberg caution that their findings do not necessarily mean that Neanderthals would have felt more pain than modern humans. The sensations transmitted by NaV1.7 are processed and modified in the spinal cord and in the brain, which also contributes to the subjective experience of pain.

Gary Lewin, a neuroscientist at the Max Delbrck Center for Molecular Medicine in Berlin, points out that Neanderthal variants have little influence on the function of NaV1.7 let alone other mutations that are associated with chronic pain. It is hard to imagine why a Neanderthal would want to be more sensitive to pain, he adds.

It is not clear if the mutations evolved because they were beneficial. Neanderthal populations were made up of few individuals and their genetic diversity was low conditions that can help harmful mutations persist. But Pbo believes that change smells like a product of natural selection. So he plans to sequence the genomes of about a hundred Neanderthals, which could help provide some answers.

In any case, pain is adaptive, says Zeberg. It is not particularly bad to feel pain.

Ewen Callaway

Reference: A neanderthal sodium channel increases pain sensitivity in present-day humans, by H. Zeberg et al., In Current Biology, published on July 23, 2020.

Article translated and adapted by Research and Science with permission from Nature Research Group.

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Neanderthal Gene Linked to Increased Pain Perception | Present - Explica