Primates are our closest relatives with chimpanzees sharing almost 99% of our DNA genomes. Neanderthals are even closer to modern humans with genomes 99.7% identical to ours and with brains nearly the same size as modern humans. Neanderthals (Homo neanderthalensis) and humans (Homo sapiens) were so genetically similar that successful interbreeding occurred, resulting in a small amount (about 2%) of Neanderthal DNA in our genomes. Yet Neanderthals, along with other near-human species such as the Denisovans, went extinct and were supplanted by Homo sapiens, so what evolutionary advantage did we have? One suspicion is that Homo sapiens developed increased cognitive powers that allowed them to out-compete all the other near-human species, generating great interest in the scientific community to identify genetic differences that could account for our superior intellects. A report published last month in the journal Science explores how the difference in a single gene may have contributed to the enhanced cognitive abilities of modern humans compared to Neanderthals and primates.
The gene in question is known as TKTL1 and expresses an enzyme involved in cellular metabolism. TKTL1 is highly expressed in the human fetal neocortex, a brain region responsible for sensory perception (visual and auditory), emotions, and cognitive functions. In particular, high levels of TKTL1 are seen in cells called basal radial glia (bRG), a cell type that develops into cortical neurons. Interestingly, the TKTL1 protein in humans differs from the one in Neanderthals and primates by only a single amino acid at position 317. In humans, this amino acid is an arginine but in Neanderthals and primates it is a lysine. To investigate the functional significance of this single amino acid change, researchers performed a series of tests in mice, ferrets, and human tissues comparing the human form of TKTL1 (hTKTL1) with the archaic form (aTKTL1). When put into embryonic mouse brains, hTKTL1 caused an increase in both bRG cells and cortical neurons while the aTKTL1 had no effect. However, mouse brains have a low number of bRG cells to begin with and lack the folds seen in human brains. The deep folds in human brains allow us to pack more neurons into our skulls, so the researchers turned to ferrets which do have some folding in their brain structure. As in the mice, hTKTL1 increased both bRG cells and neurons in the ferrets and also produced larger brain folds. None of these effects in ferrets were seen with aTKTL1. Turning to human fetal tissue, they next showed that knocking out the endogenous hTKTL1 reduced the number of bRG cells, consistent with hTKTL1 being an important promoter of bRG cell production. Finally, they created human mini-brain organoids from embryonic stem cells expressing either hTKTL1 or aTKTL1. As with the other experiments, hTKTL1 expression in the organoids yielded more bRG cells and neurons than seen with aTKTL1. Collectively, the animal and tissue experiments demonstrate that TKTL1 is an important regulator of neuron development and that the human version of this gene is superior to the Neanderthal/primate version in stimulating neuron abundance. In related experiments, the investigators implicate a role for TKTL1 in the synthesis of cell membrane lipids. From this result, they suggest that the hTKTL1 may cause enhanced production of the fetal bRG cell membranes which allows these cells to grow and reproduce more and thus generate more neurons. The implication of this study is that one small mutation converting a single amino acid in aTKTL1 from lysine to an arginine significantly enhanced neuron production in individuals carrying the mutation. Presumably, this gave the hTKTL1 recipients a cognitive advantage that led to the persistence of this gene and eventually to its permanent establishment in Homo sapiens. It is unlikely that this one gene is the sole distinguisher between us and the extinct human species, but it seems to be a fascinating example of how random mutation can affect a single gene with powerful evolutionary effects on a species.