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Neanderthal gene linked to increased pain sensitivity

People who have inherited nerve-altering mutations from the ancient hominins tend to experience more pain.

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A model of the face of a man with a prominent nose and eyebrows, a beard and moustache, long hair and brown eyes.

Reconstruction of a Neanderthal.Credit: S. Entressangle/E. Daynes/SPL

Neanderthals lived hard lives. The ice-age hunter-gatherers eked out a living across western Eurasia, hunting mammoths, bison and other dangerous animals.

Despite their rough and tumble existence, Neanderthals had a biological predisposition to a heightened sense of pain, finds a first-of-its kind genome study published in Current Biology on 23 July1. Evolutionary geneticists found that the ancient human relatives carried three mutations in a gene encoding the protein NaV1.7, which conveys painful sensations to the spinal cord and brain. They also showed that in a sample of British people, those who had inherited the Neanderthal version of NaV1.7 tend to experience more pain than others.

“It’s a first example, to me, about how we begin to perhaps get an idea about Neanderthal physiology by using present-day people as transgenic models,” says Svante Pääbo at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, who led the work with Hugo Zeberg at the Karolinska Institute in Stockholm.

Pain-sensing protein

Researchers have access to only a few Neanderthal genomes, and most of those have been sequenced at a low resolution. This has made it hard to identify mutations that evolved after their lineage split from that of humans some 500,000–750,000 years ago. But in the past few years, Pääbo and his team have generated three high-quality Neanderthal genomes from DNA found in caves in Croatia and Russia. This allows them to confidently identify mutations that were probably common in Neanderthals, yet very rare in humans.

Mutations in a gene called SCN9A — which encodes the NaV1.7 protein — stood out because all of the Neanderthals had three mutations that alter the shape of the protein. The mutated version of the gene was found on both sets of chromosomes in all three Neanderthals, hinting that it was common across their populations.

NaV1.7 acts in the body’s nerves, where it is involved in controlling whether and to what extent painful signals are transmitted to the spinal cord and brain. “People have described it as a volume knob, setting the gain of the pain in nerve fibres,” says Zeberg. Some people with extremely rare genetic mutations that disable the protein do not feel pain2, whereas other changes can predispose people to chronic pain3.

To investigate how mutations might have altered Neanderthals’ nerves, Zeberg expressed their version of NaV1.7 in frog eggs and human kidney cells — model systems useful for characterizing proteins that control neural impulses. The protein was more active in cells with all three mutations than in cells without the changes. In nerve fibres, this would lower the threshold for conveying a painful signal, says Zeberg.

He and Pääbo then looked for humans with the Neanderthal version of NaV1.7. About 0.4% of participants in the UK Biobank, a genome database of half a million British people, who reported on their pain symptoms had one copy of the mutated gene. No one had two, like Neanderthals. Participants with the mutated version of the gene were about 7% more likely to report pain in their lives than were people without it.

Sensitive Neanderthals

“This is beautiful work”, because it shows how aspects of Neanderthal physiology can be reconstructed by studying modern humans, says Cedric Boeckx, a neuroscientist at the Catalan Institute for Research and Advanced Studies in Barcelona, Spain. In a 2019 study, Boeckx flagged three other proteins involved in pain perception that differ between modern humans and Neanderthals4. It’s possible that such changes indicate differences in resilience between the two species, he says.

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

Gary Lewin, a neuroscientist at the Max Delbrück Center for Molecular Medicine in Berlin, notes that the Neanderthal variants impart only a small effect on the function of NaV1.7 — and much less than other mutations that are associated with chronic pain. “It’s hard to imagine why a Neanderthal would want to be more sensitive to pain,” he adds.

It is unclear whether the mutations evolved because they were beneficial. Neanderthal populations were small and had low genetic diversity — conditions that can help harmful mutations linger. But Pääbo says the change “smells” like a product of natural selection. He plans to sequence the genomes of around 100 Neanderthals, which could help provide answers.

In any case, “pain is something adaptive”, points out Zeberg. “It’s not specifically bad to feel pain.”

References

  1. 1.

    Zeberg, H. et al. Curr. Biol. https://doi.org/10.1016/j.cub.2020.06.045 (2020)

  2. 2.

    Cox, J. J. et al. Nature 444, 894–898 (2006).

  3. 3.

    Dib-Hajj, S. D., Yang, Y., Black, J. A. & Waxman, S. G. Nature Rev. Neurosci. 14, 49–62 (2013).

  4. 4.

    Kuhlwilm, M. & Boeckx, C. Sci. Rep. 9, 8463 (2019).

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