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Boost to Modern Human Brain Linked to Single Amino Acid Substitution

NEW YORK – A team from the Max Planck Institute of Molecular Cell Biology and Genetics and other centers in Germany has linked a modern human-specific amino acid substitution to development of the brain's frontal neocortex, leading to higher levels of a specific neural progenitor cell population and enhanced cortical neuron production.

"This study implies that the production of neurons in the neocortex during fetal development is greater in modern humans than it was in Neanderthals, in particular in the frontal lobe," Max Planck's Wieland Huttner, senior and corresponding author on a paper published in Science on Thursday, said in a statement, adding that it is "tempting to speculate that this promoted modern human cognitive abilities associated with the frontal lobe."

Although past studies have indicated that the overall size of the Neanderthal brain was comparable to that of modern humans, the human brain is marked by more pronounced neuron production.

Following from a comparative genomic analysis that highlighted differences between Neanderthals and modern humans, the researchers set out to investigate potential neocortex impacts of a human-specific lysine-to-arginine substitution transketolase-like 1, a protein encoded by a gene called TKTL1 that is expressed in the developing human neocortex, particularly in neuron production-boosting neuroprogenitor cells and in another neural progenitor cell type.

Perhaps most promisingly, the authors of the new study explained, TKTL1 "is one of the few proteins with a single amino acid substitution found in essentially all present-day humans but absent from extinct archaic humans, the Neanderthals and Denisovans, and other primates."

With a series of gene overexpression, gene knockout, and genome editing experiments, the researchers investigated the consequences of the human-specific amino acid substitution, comparing it to effects of human and archaic hominin forms of TKTL1.

When they expressed or overexpressed the modern human version of TKTL1 in mouse or ferret embryos, for example, the researchers saw an uptick in a group of basal radial glia neuroprogenitor cells implicated in cortical neuron production — an effect not found when they used the Neanderthal version of the gene. On the other hand, levels of other neuroprogenitors such as basal intermediate progenitors or apical progenitors appeared to hold steady in the presence of the substitution-coding human gene.

The team noted that results from its CRISPR-Cas9-based gene editing experiments suggested that human cerebral neocortex organoid models missing human TKTL1 contained fewer basal radial glia neuroprogenitors, while the Neanderthal version of the gene was linked to lower basal radial glia neuroprogenitor cell levels and reduced neuron representation.

"We found that with the Neanderthal-type of amino acid in TKTL1, fewer basal radial glial cells were produced than with the modern human-type and, as a consequence, also fewer neurons," first author Anneline Pinson, a researcher with the Max Planck Institute of Molecular Cell Biology and Genetics, said in a statement.

Based on these genetic findings, she added that "even though we do not know how many neurons the Neanderthal brain had, we can assume that modern humans have more neurons in the frontal lobe of the brain, where TKTL1 activity is highest, than Neanderthals."

In a related perspectives article in Science, University of Liege researchers Laurent Nguyen and Brigitte Malgrange who were not involved in the study, commended the team for its findings and for the combined model organism and human cerebral organoid culture approaches used in the analyses.

"Together, [the study's observations] open the path to discovering more specific evolutionary changes that shaped the modern human brain and may also help us predict the next steps of its evolution," Nguyen and Malgrange wrote.