The Evolution of the Human Brain: Genomic and Molecular Mechanisms

 

Ikuo K. Suzuki

 

Department of Biological Sciences, Graduate School of Science, The University of Tokyo

 

Human cognitive abilities are primarily attributed to the significant increase in neurons in the cerebral cortex. Recent research is uncovering the molecular mechanisms responsible for the unique architecture of the human cortex, including the identification of human-specific genes that promote neurogenesis and contribute to cortical expansion. Many human-specific genes arose through the duplication of existing genes, and variations in the number of copies of these gene families are frequently linked to congenital neurodevelopmental disorders. However, the functional significance of individual paralogs within these expanded gene families remains an open question. Traditional short-read sequencing has posed challenges for genotyping closely related paralogs. Our study identified a novel allele of a NOTCH2NL paralog exhibiting evidence of a selective sweep in modern humans. By comprehensively analyzing NOTCH2NL paralogs and alleles using human pangenome references, population genomics simulations revealed that this novel allele underwent evolutionary adaptation and rapid spread within human populations. Molecular experiments demonstrated that this specific mutation enhances the neurogenic activity of cortical progenitor cells in a cell-autonomous manner. This enhancement is achieved by subtly altering the folding of the Notch ligand protein within the endoplasmic reticulum. In conclusion, our findings illuminate a novel evolutionary mechanism driving human brain enlargement. Specifically, a single nucleotide mutation in a particular allele of a NOTCH2NL paralog, which increases the production of cortical neurons, underwent rapid adaptation in the human population shortly before the migration out of Africa. This research highlights the potential for single nucleotide mutations within complexly duplicated genes to play a crucial role in human evolutionary adaptation.