How specific changes in DNA shape human brain structure
Why do human brains vary in size and shape, and how did our brains expand over evolutionary time to give us our enhanced cognitive abilities? Researchers at the UNC Department of Genetics and the UNC Neuroscience Center have mapped functional "switches" in our DNA that address these fundamental questions.
Scientists at the University of North Carolina have uncovered how tiny changes in DNA influence the structure of the human brain. Led by researchers Nana Matoba and Jesicca McAfee, the study reveals that the cerebral cortex, responsible for complex thinking and language, exhibits shape variations due to regulatory changes in noncoding DNA.
Utilizing a technique called massively parallel reporter assay (MPRA), the team tested over 9,000 DNA variants associated with brain structure in human neural progenitor cells. This allowed them to observe the impact of thousands of DNA changes simultaneously on gene activity. Remarkably, more than three-quarters of the examined DNA regions contained at least one variant that affected gene regulation.
A significant driver of this regulatory activity was found to be Alu elements, a type of "jumping gene" that can insert itself into new positions in the genome. These elements have proliferated rapidly over evolutionary time, coinciding with the enlargement of human brains. Younger Alu elements showed a higher regulatory activity compared to older ones, suggesting that they played a crucial role in the development of the complex gene networks underlying human brain expansion.
The research also provided insights into why certain genetic variants affect specific regions of the brain rather than the entire organ. Associate Professor Jason Stein explained that the regions impacted by a genetic variant correspond to areas with higher expression levels of specific transcription factors—proteins that bind to DNA. When a variant disrupts a transcription factor's binding site, its effect is most pronounced in the brain regions where that transcription factor is most active during development.
This comprehensive study establishes a genome-scale roadmap for understanding how noncoding genetic variations shape human brain development, shedding light on the intricate relationship between our DNA and the remarkable complexity of our brains.
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