What happens when you swap a human gene for a Neanderthal gene?

What are the main differences between modern humans and our closest relatives, Neanderthals and Denisovans? For Neanderthals, there doesn’t seem to be any obvious difference. They used sophisticated tools, made art, and established themselves in very harsh environments. But, as far as we can tell, their overall population has never been particularly high. When modern humans first arrived on the scene in Eurasia our numbers increased, we spread even further, and Neanderthals and Denisovans ended up being displaced and ultimately extinct.

Thanks to our ability to obtain ancient DNA, we now have insight into the genomes of Neanderthals and Denisovans, which allows us to ask a more specific question: Could some of our differences be due to genetics?

All three species are close relatives, so the number of differences in our proteins is relatively small. But a large international research team has identified one and reinvented it in stem cells obtained from modern humans. And the researchers found that the neural tissue made up of these cells had notable differences from the same tissue grown with the modern human version of this gene.

As the first step in their work, the researchers had to decide on a gene to target. As we mentioned above, the genomes of the three species are extremely similar. And the similarity only rises when you look at the parts of the genome that code for proteins. An additional complication is that some of the gene versions found in Neanderthals are still found in a fraction of the modern human population. What the researchers wanted to do was find a gene in which Neanderthals and Denisovans had one version and almost all modern humans had another.

Out of tens of thousands of genes, they found only 61 that passed this test. The one they chose to focus on was called NOVA1. Despite the explosive sounding name, NOVA1 was simply named after it was originally found associated with cancer: ventral neuro-oncologic antigen 1. Examination of the vertebrate family tree shows that Neanderthals and Denisovans share NOVA1 along with everything from other primates to chickens, which means it was present in the ancestor that mammals shared with dinosaurs.

Yet almost all humans have a different version of the gene (in a search of a quarter of a million genomes in a database, researchers were only able to identify three instances of the Neanderthal version). The difference is subtle – the exchange of a closely related amino acid at one place in the gene – but it is a difference. (For those who care, it’s isoleucine to valine.)

But NOVA1 is the kind of gene where small changes can potentially have a big impact. The RNAs that are used to make proteins are initially made up of a mixture of useful parts separated by unnecessary spacers that must be spliced. For some genes, the different parts can be spliced ‚Äč‚Äčtogether in more than one way, allowing distinct forms of a protein to be made from the same starting RNA. NOVA1 regulates the splicing process and can determine which form of several genes is produced in cells where it is active. For NOVA1, the cells in which it is active include many parts of the nervous system.

If that last paragraph was a little confusing, the short version is: NOVA1 can change the types of proteins made in nerve cells. And, since behavior is an area where modern humans may have been different from Neanderthals, it is an intriguing target of this type of study.

Obviously, there are ethical issues in trying to see what the Neanderthals version would do in actual humans. But certain technologies developed over the past ten years now allow us to approach the question in a very different way. First, the researchers were able to take cells from two different people and convert them into stem cells, capable of developing into any cell in the body. Then they used Crispr gene editing technology to convert the human version of the gene to a Neanderthal version. (Or, if you’re less charitable, you can call it the chicken version.)

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