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E. Shyam P. Reddy: How Four Small DNA Changes Helped Shape the Human Brain

E. Shyam P. Reddy/LinkedIn

May 19, 2025, 13:27

E. Shyam P. Reddy: How Four Small DNA Changes Helped Shape the Human Brain

E. Shyam P. Reddy, Professor and Director of the Cancer Biology Program at Morehouse School of Medicine, shared a post on LinkedIn:

“How Four Small DNA Changes Helped Shape the Human Brain.

A tiny sliver of our genome may hold the key to what makes us human. Duke scientists have zeroed in on ‘Human Accelerated Regions,’ mysterious stretches of DNA that don’t code for proteins but play a crucial role in brain development.

Unlocking the Genetic Secrets That Set Humans Apart

While humans share 98.8% of their DNA with chimpanzees, it’s the tiny remaining difference that holds the key to what sets us apart. Now, scientists at Duke University are uncovering how small genetic changes help shape the human brain in powerful ways. Their findings were recently published in Nature.

Led by Dr. Debby Silver, a professor of molecular genetics and microbiology, and senior research associate Dr. Jing Liu, the team zeroed in on mysterious stretches of DNA known as Human Accelerated Regions, or HARs. These parts of our genome don’t code for proteins, but they’re located near genes that play crucial roles in brain development.

Small Genetic Tweaks, Big Brain Effects

There are about 3,000 HARs scattered throughout the human genome. The researchers focused on just one of them and discovered that it plays a surprising role in how brain cells are formed. Specifically, they found that this tiny DNA region can influence how neural progenitor cells – early-stage cells that later become neurons – multiply and develop.

This is important because the human cerebral cortex, the outer layer of the brain responsible for higher thinking, is both larger and more intricately folded than in other primates. That extra space allows for more neurons, which support complex brain functions like abstract thinking, emotional control, language, and creativity.

Embryonic Mouse Brain Cross Section

Cross section of an embryonic mouse brain. Progenitors are green, mitotic cells are red, and neurons are purple. Credit: Duke University

E. Shyam P. Reddy: How Four Small DNA Changes Helped Shape the Human Brain

Mouse Models Reveal the Power of HARs

Using a genetically engineered mouse model with this human HAR, they observed that these mice had slightly larger cerebral cortexes and more neurons than the control mice. These changes trace back to activity in the Wnt signaling pathway – a key regulator of progenitor cell proliferation and neuronal differentiation.

They also edited human stem cells to include the chimpanzee version of the HAR, which differs by just four nucleotides, and saw less neural progenitor proliferation. But if they put the human nucleotide sequence into chimpanzee stem cells, neural progenitor proliferation increased.

The Price of Cognitive Evolution

‘We’re exposing one of the mysteries of how these small differences in our DNA can contribute to known anatomical differences.’ Silver said.

There is a downside, though, to having bigger brains.

‘Over the course of evolution, we’ve acquired changes that have helped to collectively contribute to making us human, but with those changes, there also becomes an increased propensity for disease.’ Silver said.”

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