Written by Lauren Robertson, Science Writer
It’s common knowledge that the (comparably) high intelligence of humans is down to the size of our brains. But fossil records show that Neanderthals shared a similar size brain to that of modern humans – so why are there marked differences in cognition?
In a recent paper, published in Science, a team of researchers suggest that this difference is the result of a single amino acid change in the transketolase-like (TKTL1) protein involved in neuron production.
The basis of the brain
Although fossil records show that Neanderthals had similarly sized brains to those of modern humans, they cannot provide any concrete information about the function and organization of brain layers such as the neocortex (the outer region of the cerebral cortex). It is thought that the advanced cognitive ability of humans is thanks to the expansion and subsequent folding of this region. Therefore, it is possible that despite their similarly sized brains, Neanderthals may not have had similar neo-cortical neuron production to that of modern humans.
To test this hypothesis further, the researchers looked more closely at the TKTL1 gene that is expressed in neuroprogenitors (drivers of neuron production) known as basal radial glia (bRG). Why did they choose this gene specifically? Because the resulting TKTL1 protein it is one of only a few proteins containing a single amino acid substitution that is present in modern humans, but not found in Neanderthals.
An amino acid makes all the difference
In modern humans, the TKTL1 protein exhibits an arginine in place of the lysine seen in archaic humans. To analyse the effect of this single amino acid change, the team expressed the modern human version of TKTL1 (hTKTL1) in mouse embryo cortex and found it increased bRG production. The archaic form (aTKTL1) was unable to increase bRG abundance. Over time, this led to an increase in cortical neuron production.
To further validate their findings, the researchers then created CRISPR/Cas9 knockouts of hTKTL1 in fetal human cortical tissues, finding that these knockouts reduced the number of bRGs present in the neocortex. hTKTL1 was then converted to the archaic form in embryonic stem cells and the team generated mini-brain structures (cerebral organoids). They were then able to confirm that these brain models contained fewer bRG and neurons than seen in the controls.
Finding the mechanism of action
The final step was to discern the mechanism of action – how exactly does hTKTL1 increase bRG production? The team discovered (through inhibition of the relevant pathways) that the metabolic action of hTKTL1 resulted in an increase in the concentration of acetyl-coenzyme A, the critical metabolite for fatty acid synthesis. Therefore, this protein variant is able to increase bRG abundance by promoting the synthesis of certain membrane lipids required in this synthesis pathway.
When asked whether people could be made more intelligent by tweaking the same genes, lead author Anneline Pinson was hesitant: “I don’t know if we could, having more neurons isn’t always a good thing.”
