Summary: Researchers have identified a genetic element called HAR123 that may help explain features that make the human brain distinct. Functioning as a transcriptional enhancer, HAR123 influences the formation and behavior of neural progenitor cells—the precursors that produce neurons and glial cells—and affects the balance between these two cell types.
This regulatory effect appears to support cognitive flexibility, a hallmark human ability to revise thinking and replace outdated knowledge with new strategies. The finding advances our understanding of brain evolution and offers a molecular lead for studying neurodevelopmental disorders, including autism.
Key Facts
- Genetic Switch: HAR123 acts as a transcriptional enhancer that modulates gene activity in the developing brain.
- Cognitive Impact: The enhancer is linked to traits associated with advanced human cognition, especially cognitive flexibility.
- Evolutionary Difference: The human HAR123 sequence produces different molecular and cellular effects than the chimpanzee ortholog, suggesting evolutionary modification.
Source: UCSD
Researchers at the University of California San Diego School of Medicine have identified a specific human-accelerated region—HAR123—that plays a role in shaping human neural development.
Human-accelerated regions (HARs) are stretches of DNA that have accumulated rapid change during the course of human evolution. Scientists have long been interested in HARs because they are candidates for DNA elements that contributed to the traits that distinguish humans from other primates. HARs have also been associated with neurodevelopmental disorders, making them a focus for both evolutionary biology and medical genetics.
The UC San Diego team focused on HAR123, a 442-nucleotide sequence located in a chromosomal region known to be linked with neurological defects (17p13.3). While HAR123 is conserved across mammals, it has undergone rapid sequence evolution in the human lineage since our divergence from chimpanzees. Rather than encoding a protein, HAR123 functions as a noncoding regulatory element—specifically, a transcriptional enhancer—that controls when and how strongly nearby genes are expressed during neural development.
Key experimental observations reported by the researchers include:
- HAR123 enhances the formation of neural progenitor cells (NPCs), which give rise to both neurons and glial cells during brain development.
- HAR123 affects the ratio of neurons to glial cells produced from NPCs, shifting cellular outcomes in a manner that could influence circuitry and brain function.
- The human HAR123 sequence and the chimpanzee ortholog produce subtly different effects on neural development in stem cell and precursor cell models, indicating that evolutionary changes to HAR123 altered its regulatory impact.
The authors link these cellular effects to cognitive flexibility—the ability to modify behavior and update knowledge when circumstances change—suggesting that regulatory changes in HAR123 may have contributed to advanced aspects of human cognition. In animal models, removing HAR123 led to measurable changes in behavior and hippocampal cell composition that are consistent with altered cognitive flexibility and a shifted neural-to-glia ratio in specific regions.
Beyond evolutionary insight, the discovery provides a framework for exploring how changes in regulatory DNA contribute to neurodevelopmental conditions. Many such disorders are characterized by altered proportions of neurons and glia, and HARs have been implicated in neurodevelopmental risk. Identifying direct target genes downstream of HAR123 helps clarify which molecular pathways are involved; the study highlights HIC1 as one downstream factor that promotes NPC formation in the HAR123 regulatory network.
The research integrates cell-based experiments with genetic and behavioral analyses in model systems to connect sequence evolution, gene regulation, cellular outcomes, and behavioral consequences. While these findings are compelling, the authors note that additional work is necessary to fully map HAR123’s molecular mechanisms and to determine the extent to which the human-specific sequence produces uniquely human neural traits.
The study was published online in Science Advances and was led by Miles Wilkinson, Ph.D., and Kun Tan, Ph.D., in the Department of Obstetrics, Gynecology, & Reproductive Sciences at UC San Diego School of Medicine. Funding included grants from the National Institutes of Health and support from 10x Genomics. The authors declare no competing interests.
About this genetics and neuroscience research news
Author: Miles Martin
Source: UCSD
Contact: Miles Martin – UCSD
Image: The image is credited to Neuroscience News
Original Research: Open access.
Title: “An ancient enhancer rapidly evolving in the human lineage promotes neural development and cognitive flexibility” by Miles Wilkinson et al., Science Advances
Abstract
An ancient enhancer rapidly evolving in the human lineage promotes neural development and cognitive flexibility
Genetic changes that shaped the evolution of human cognition after the split from chimpanzees have been difficult to pinpoint. This study identifies a promising candidate within the 17p13.3 chromosomal region associated with neurological abnormalities. The 442-nucleotide element HAR123 is a conserved neural enhancer that promotes neural progenitor cell formation. Although present across mammals, HAR123 has evolved rapidly in the human lineage. Human and chimpanzee HAR123 orthologs show subtle differences in neural developmental effects, and the human version uniquely regulates numerous genes involved in neural differentiation. The authors identify direct targets of the HAR123 enhancer and demonstrate that HIC1 acts downstream to promote human NPC formation. HAR123-knockout mice display deficits in cognitive flexibility and shifts in the neural–glia ratio in particular hippocampal regions. These findings have implications for understanding neurodevelopmental disorders, which often involve altered neural–glia balance and have been linked to human-accelerated regions.