Did Mutation Shape the Homo Sapien Brain?

Neanderthals are cousins to modern humans and both are grouped in the genus Homo. While designated as different species (Homo neanderthalensis versusHomo sapiens), Neanderthals and humans are genetically close and likely co-existed for thousands of years, primarily in Eurasia. Once considered a more primitive species, evolving science indicates that Neanderthals had brains similar in size to modern humans and shared many of the same abilities as their Homo sapien contemporaries. Neanderthals used tools, created simple clothing, cooked and heated with fire, and even had rudimentary knowledge about treating injuries and using medicinal plants, all indications of high intelligence. Importantly, neanderthalensis and sapiens were so closely related that interbreeding was possible. Modern humans of Eurasian descent retain about 1-4% Neanderthal DNA in their genomes, a clear indication that our direct ancestors successfully reproduced with Neanderthals. Interbreeding is further supported by studies of the origin of human papillomaviruses which indicate that these sexually transmitted viruses were first introduced into Homo sapiens by Neanderthals. Thus, the historical evidence indicates that neanderthalensis and early sapiens shared common intellectual abilities, occupied similar regions in Eurasia, and at least occasionally interbred.

Given that these two species were initially so similar, why did Homo sapiens become the dominant species throughout the planet while Homo neanderthalensis (and other now-extinct Homo species) disappeared? Many theories have been proposed, and there is no definitive answer, but a new study in the journal Science looking at the neocortex offers another tantalizing clue as to why Homo sapiens might have outcompeted their neanderthalensis relatives. The neocortex is the portion of the cerebral cortex where thought, perception, reasoning, and memory functions are located. Human brains have a large neocortex with a high density of neurons, the individual cells that transmit information within the brain. While Neanderthal brains were similar in overall size to Homo sapien brains, nothing is known about how their neocortex compared to modern humans. To explore how human and Neanderthal brains might differ, the researchers looked for genes expressed in the brain that had sequence differences between humans and Neanderthals. One such gene they identified is called TKTL1. This gene is expressed in the fetal neocortex where it produces a protein called transketolase-like 1 (TKTL1 protein). Modern humans have a mutation in their TKTL1 gene that changes a single amino acid in the TKTL1 protein at position 317. Neanderthals and apes have a lysine amino acid at position 317 while humans have an arginine.

 Possible functional differences between human TKTL1 (hTKTL1) and ancestral TKTL1 (aTKTL1) were investigated in animal and cell culture models of brain development. When hTKTL1 was introduced into embryonic mice or ferrets, there was enhanced production of neuron progenitor cells and a subsequent expansion of neuron cells. No such effect was seen with aTKTL1 expression in either animal. Moving to human cells, the investigators showed that preventing endogenous hTKTK1 expression in human fetal neocortical tissue reduced neural progenitor cells, indicating an important role for this protein in neocortical development. Lastly, the researchers used human embryonic stem cells to create mini-brain structures called cerebral organoids that expressed either hTKTL1 or aTKTL1. As in the animal models, brain organoids with hTKLT1 produced a greater number of precursor cells and neurons than organoids expressing aTKTL1. The conclusion from these studies is that TKTL1 is important in the development of neurons in the human neocortex and that hTKTL1 is superior to the ancestral aTKTL1 in its ability to promote neuron formation. The implication is that this mutation resulted in greater neuron production during fetal development which led to a larger neocortex in individuals who possessed the mutation.

While TKTL1 may be only part of the story, it is intriguing to speculate that a single mutation resulting in 1 amino acid change in a human protein may have contributed to superior brain development and neocortical expansion in Homo sapiens. Was this neural advantage the evolutionary spark that slowly lead to increased intellectual capacity in sapiens compared to all the other Homo species? Did this small mutation drive our greater cognitive ability and allow us to adapt and thrive in different environments while our less fit ancestral cousins slowly declined and became extinct? We may never know the exact answer, but every year neuroscience brings us a greater understanding of the brain and the genetic underpinnings of human intelligence.

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