Rapidly Evolving DNA May Explain Human Brain Complexity – Neuroscience News

Summary: A new study reveals that human accelerated regions (HARs)—segments of DNA that evolved much faster than expected—may be key to the brain’s advanced cognitive abilities. Researchers compared human and chimpanzee neurons and found that HARs drive the growth of multiple neural projections, which enhance communication between brain cells.

When human HARs were introduced into chimp neurons, they also grew more projections, suggesting a direct link between HARs and neural complexity. However, these same genetic changes may also contribute to neurodevelopmental disorders like autism, highlighting the delicate balance of human brain evolution.

Key Facts

• Fast-Evolving DNA: Human accelerated regions (HARs) evolved 10 times faster than expected, shaping neural development.
• Enhanced Brain Connectivity: HARs drive the growth of multiple neurites in human neurons, improving communication between brain cells.
• Risk for Brain Disorders: While HARs support cognitive complexity, their disruption may contribute to conditions like autism.

Source: UCSF

How did humans evolve brains capable of complex language, civilization, and more?   

The answer could lie in exceptional DNA. Scientists at UC San Francisco found that parts of our chromosomes have evolved at breakneck speeds to give us an edge in brain development compared to apes. But it might also put us at risk for uniquely human brain disorders.  

The study, which was supported by grants from the National Institutes of Health, appears in Nature on Feb. 26. 

The research focused on parts of chromosomes known as human accelerated regions (HARs), which have evolved most rapidly since humans split from chimpanzees on the evolutionary tree – changing 10 times faster than the expected rate of evolution in mammals.  

The scientists, led by Yin Shen, PhD, professor in the UCSF Weill Institute for Neurosciences and the UCSF Institute for Human Genetics, studied the effects of HARs in artificial neurons derived from human and chimpanzee cell lines.   

The human and chimpanzee genomes are 99% similar. HARs make up a big portion of the 1% difference, which can lead to dramatically different outcomes in human and chimp neurons in petri dishes.

The human neurons grew multiple neurites, or wiry projections that help the nerve cells send and receive signals. But the chimp neurons only grew single neurites.  When human HARs were engineered into artificial chimp neurons, the chimp neurons grew many more of these wires.   

“More neurites during development could mean more complexity in our neural networks,” Shen said.

“These networks facilitate the transmission of signals in the nervous system and support our higher cognitive functions. But disruptions in their development may contribute to neurodevelopmental disorders like autism.”  

Authors: Other UCSF authors are Xiekui Cui, PhD, Han Yang, PhD, Charles Cai, Cooper Beaman, Xiaoyu Yang, PhD, Hongjiang Liu, Xingjie Ren, PhD, Zachary Amador, Ian R. Jones, Kathleen C. Keough, PhD, Meng Zhang, PhD, MS, Tyler Fair, PhD, Zhen Ye, Alex A. Pollen, PhD, and Katherine S. Pollard, PhD. For all authors see the paper. 

Funding: This work was supported by the US National Institutes of Health (NIH) grants U01DA052713, UM1HG009402, R21DA056293, R21HG010065, R01MH109907, U01MH116438, DP2MH122400-01, P30DK063720, and S101S10OD021822-01; the Schmidt Futures Foundation; the Chan Zuckerberg Biohub; and the Gladstone Institutes. For all funding see the paper.   

About this genetics and cognition research news

Author: Levi Gadye
Source: UCSF
Contact: Levi Gadye – UCSF
Image: The image is credited to Neuroscience News

Original Research: Closed access.
“Comparative characterization of human accelerated regions in neurons” by Yin Shen et al. Nature

Abstract

Comparative characterization of human accelerated regions in neurons

Human accelerated regions (HARs) are conserved genomic loci that have experienced rapid nucleotide substitutions following the divergence from chimpanzees.

HARs are enriched in candidate regulatory regions near neurodevelopmental genes, suggesting their roles in gene regulation. However, their target genes and functional contributions to human brain development remain largely uncharacterized.

Here we elucidate the cis-regulatory functions of HARs in human and chimpanzee induced pluripotent stem (iPS) cell-induced excitatory neurons. Using genomic and chromatin looping information, we prioritized 20 HARs and their chimpanzee orthologues for functional characterization via single-cell CRISPR interference, and demonstrated their species-specific gene regulatory functions.

Our findings reveal diverse functional outcomes of HAR-mediated cis-regulation in human neurons, including attenuated NPAS3 expression by altering the binding affinities of multiple transcription factors in HAR202 and maintaining iPS cell pluripotency and neuronal differentiation capacities through the upregulation of PUM2 by 2xHAR.319.

Finally, we used prime editing to demonstrate differential enhancer activity caused by several HAR26;2xHAR.178 variants. In particular, we link one variant in HAR26;2xHAR.178 to elevated SOCS2 expression and increased neurite outgrowth in human neurons.

Thus, our study sheds new light on the endogenous gene regulatory functions of HARs and their potential contribution to human brain evolution.