The genetic legacy of Neanderthals: revealing its influence on pain perception today

Scientific analyzes of fossils have allowed specialists to trace the origins and mutations of the various conditions that reached from ancestors to today’s humans. Thanks to fossil and DNA evidence, for example, it is now known that Neanderthals lived alongside early humans for at least part of their existence. In fact, they may have done so very soon.

“Some of us carry, in our DNA, sequences that are genetically closer to Neanderthals than to Homo sapiens.. These sequences are usually very short, and when an individual’s complete genome is collected, they represent only a small percentage of that individual’s DNA. Pierre Vauxprincipal researcher at French National Institute of Agriculture, Food and Environmentand the leader of a new investigation in which more than 50 specialists from different study centers around the world participated.

This research shows that people carrying three genetic variants inherited from Neanderthals are more sensitive to some types of pain. This is what the results published in indicate Communication biology. These are the latest developments that show how interbreeding with Neanderthals in the past affected the genetics of modern humans.

The Neanderthal advance hypothesis suggests that these sequences are found in humans today As a result of the crossing of Homo sapiens with Neanderthals about 50 thousand years ago. “Recent scientific progress, particularly thanks to the high-resolution sequencing of Neanderthal genomes, has made this hypothesis a possible explanation for the convergence of these sequences,” Fu says.

Greater access to high-quality Neanderthal genomes helps scientists understand the lifestyles and biology of ancient ancestors. Although it has been 50,000 years since Neanderthals last shared the planet, comparing their genomes with those of today can help shed light on shared experiences, such as pain.

The voltage-gated sodium channel Nav1.7 plays a key role in nociception: The processing of noxious stimuli such as injury or temperature by the central and peripheral nervous systems. Pain is the unique subjective experience that arises as a result of this processing.. Mutations in the gene encoding Nav1.7, called SCN9A, are of clinical interest due to their association with human pain disorders, which often manifest as pain insensitivity or intense pain experience.

For several years, led by scientists Hugo ZebergThe assistant professor at Karolinska Institutet, discovered three SCN9A variants in sequenced Neanderthal genomes and in some modern humans. These variants – M932L, V991L and D1908G – were associated with increased pain sensitivity in UK Biobank (UKBB) participants.

All three variants are very rare in the European population. In this new study, Fu and his colleagues sought to replicate and extend Zeberg’s work by analyzing pain thresholds in populations where these mutations are more common and understanding which sensory responses are affected by them.

In recent years, the research team has performed genetic analyzes on volunteers from Brazil, Colombia, Chile, Peru and Mexico, known collectively as the Candela group. They also studied experimental pain specifically in Colombian participants, using a technique known as quantitative sensory testing, or QST. This protocol involves testing different pain thresholds at baseline and then retesting them after mustard oil application.

The researchers characterized the Neanderthal introgression in SCN9A in both groups, and found that all three variants were common in all groups, but were more common in populations with a higher proportion of Native American ancestry, such as Peruvians. Applying the QST protocol, they found that all three SCN9A variants were associated with a lower pain threshold in response to skin scratching after mustard oil application. This response was not observed in response to the application of heat or pressure, which helped scientists decipher how these variables affect sensory responses.

“By objectively measuring sensitivity and working with a population where these mutations occur frequently, we confirmed the Neanderthal origin of the mutations and their association with greater sensitivity,” he describes. Kaustubh Adhikari, professor of statistics at the Open University and co-author of the study. “Furthermore, we identified that mechanical allodynia after skin sensitization is the type of pain affected by these mutations.”

Opening sodium channels in the nerve membrane allows it to travel toward the nerve cell, generating A electric current. This is the driving force behind action potentials which, simply put, allows neurons to communicate with each other.

“In the case of sensory nerves, their terminals are located in the skin and convert signals from the environment that can cause injury, such as acute mechanical stimuli, high temperatures, or chemicals, into action potentials.” Dr. David Bennettprofessor of neuroscience and neurobiology at Nuffield Department of Clinical Neurosciences at the University of Oxford, senior clinical scientist at Wellcome and honorary consultant neurologist. We propose that genetic changes alter the structure and eventual function of these sodium channels, such that they become more likely to open, meaning neurons generate action potentials in response to stimulation, such as force. . “People will experience this as a lower pain threshold, that is, a lower force elicits pain perception.”

Pain is often an unpleasant experience, but it is important. The body’s response to painful stimuli helps it defend itself or move away from potentially harmful stimuli. Specialists still do not know whether mutations confer an evolutionary advantage.

“We still don’t have a clear idea of ​​how it works. For example, the same mutations may also have affected a completely different trait. In this case, it’s possible that selection has affected that non-specific trait, and indirectly affected pain sensitivity.” Only, says Fu. “It is currently a challenge to further investigate these evolutionary aspects.”

instead of, Researchers are focusing on understanding how other genes influence pain perceptionwhich would be an important step towards developing better tools to treat it.