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Pain sensitivity in modern humans linked to Neanderthal traits

Using CRISPR to investigate Neanderthal DNA and brains
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Step on a tack, get pinched on the playground, or stub your toe on the bathroom threshold—did that really hurt? If so, you might have Neanderthals to blame.

Well, more specifically, you have to blame pain sensitivity on three mutations in a gene encoding the protein Nav1.7, which sends pain sensations to the brain, and the Neanderthals, who—tough though they may seem—apparently had their own version of that protein and experience more pain than others. The notion of Neanderthal traits in modern humans is not new, but the Neanderthal predisposition to pain and that carryover to today’s humans is; the findings were recently described in Current Biology.

Is pain sensitivity genetic?

In that study, researchers synthesized two Neanderthal genes, including one which is the most abundant splice isoform in the dorsal root ganglia and is found in most modern humans and all three high-coverage Neanderthal genomes. Researchers historically have only had access to a few Neanderthal genomes, and most of them have been sequenced at low resolution, notes Nature, which makes it hard to identify some mutations. But more recently, three high-quality Neanderthal genomes were generated from caves in Croatia and Russia; this allowed them to say that the mutations were probably common in Neanderthals but rare in humans.

Is pain good for you?

So far, researchers don’t understand why Neanderthals had this relationship with pain—was it somehow beneficial? It is thought that Neanderthals populations were small and had low genetic diversity, which could mean that harmful mutations stick around, noted study co-author Svante Pääbo, from the Max Planck Institute for Evolutionary Anthropology. Pääbo told Nature he plans to sequence the genomes of around 100 Neanderthals, which could help provide answers.

The pain study comes as researchers discover more clues about the Neanderthal brain courtesy of having actually grown something that approximates one.

The multi-year process used ancient DNA extracted from fossils and CRISPR genome editing to insert Neanderthal DNA into stem cells, which then grew into a little brain in a petri dish, Discover explained.

The team in that project used the Homo sapiens’ master regulator gene NOVA1; when researchers inserted the Neanderthal NOVA1 equivalent, the mini-brain structure began to develop in unusual ways, mirroring developmental differences more usually seen in people with autism—although that does not indicate Neanderthals were autistic-like, since the CRISPR experiment looked at just one mutation at a time and not how multiple mutations would interact.

A follow-up study in Stem Cell Research, by researchers including Pääbo, demonstrated that a large induced pluripotent stem cell repository was home to extensive Neanderthal DNA, “including alleles that contribute to human phenotypes and diseases, encode hundreds of amino acid changes, and alter gene expression in specific tissues.” They also produced a database of inferred introgressed Neanderthal alleles and predicted functional variants.

One intriguing finding from the study? Researchers noted expressed cortical genes, which could be “exciting candidates to use CRISPR-Cas gene editing to study the effect of the ancestral or Neanderthal-specific alleles on cortex development.”

Researchers added that future lab-grown organoids, involving body-part tissues, hair and skin, and intestines, could help us learn more about Neanderthals by revealing how they processed food, what their hair and skin color was, and more. Further, the techniques could be extended to investigate Neanderthals’ cousins, the Denisovans.

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