UNC Scientists Reveal How Specific Changes in DNA Shape Human Brain Structure

The study offers new insight into how genetic changes affect the structure of the human cortex, a brain region important for thinking and memory.

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 the functional "switches" in our DNA that address these fundamental questions.

Led by research associate Nana Matoba, PhD, and graduate student Jesicca McAfee, PhD, in the labs of geneticists Jason L. Stein, PhD, and Hyejung Won, PhD, the study provides a functional framework for how tiny variations in non-coding DNA shape the cerebral cortex, the brain's outer layer responsible for complex thinking, memory, and language. Their results were published in Nature Neuroscience.

Large-scale genetic studies have identified hundreds of genetic variants associated with brain surface area and thickness, but almost all of these variants lie in the regions of our DNA that do not code for proteins.

"The fact that brain structure associated genetic variants lie in non-coding regions of DNA has made it difficult for us to determine which specific genetic variants have regulatory function and how they influence cortical surface area and thickness," said Won, who is an associate professor of genetics and expert on functional genomics.

To solve this puzzle, the research team used a technique called a Massively Parallel Reporter Assay (MPRA). The method allowed them to test 9,092 brain-structure-associated variants simultaneously in human neural progenitor cells-the foundational cells that generate the neurons of the cortex.

The researchers tested thousands of DNA changes at the same time to identify which ones affect how genes turn on or off. They found that more than 75% of the DNA regions they studied included at least one change that influenced gene activity.

One of the study's most striking discoveries is that a significant portion of this brain-shaping regulatory activity is driven by Alu elements. Alu elements are a type of "jumping gene" that can copy and paste themselves into new positions across the genome.

These elements have multiplied rapidly over evolutionary time, parallel to the expansion of brain size in primates. The researchers found that younger Alu elements (those that inserted themselves more recently in our evolutionary history) show much higher regulatory activity in developing brain cells than older ones. These findings suggest that our evolutionary ancestors used these jumping genes to build the complex gene networks that drive human brain expansion.

Their research also addressed a long-standing puzzle in brain genetics. Stein says that their findings were crucial for understanding why certain inherited variants affect specific regions of the brain rather than the entire brain.

"We found that the regions most affected by a genetic variant are those that naturally express higher levels of specific transcription factors-proteins that bind to DNA," said Stein, who is an associate professor genetics and expert on the genetics of brain structure and development. "When a genetic variant disrupts a transcription factor's binding site, its impact is observed most strongly in the brain regions where that transcription factor is most active during development."

This work establishes a genome-scale roadmap for understanding how non-coding genetic variation shapes human brain development.

The study was supported by the PsychENCODE Consortium (R01MH122509) and the Impact of Genomic Variation on Function (IGVF) Consortium (UM1HG012003).

Media contact: Kendall Rovinsky, Communications Specialist, UNC Health | UNC School of Medicine