Abstract: A new study reveals that the human accelerated region (HAR) (removal of DNA that evolved much faster than expected) is key to the brain’s advanced cognitive abilities. Researchers compared human and chimpanzee neurons and found that HAR promotes the growth of multiple neurites and promotes communication between brain cells.
When human HAR was introduced into chimpanzee neurons, they grew more projections, suggesting a direct link between HAR and neural complexity. However, these same genetic changes can also contribute to neurodevelopmental disorders such as autism, highlighting the delicate balance of human brain evolution.
Important facts
The rapidly evolving DNA: Human Acceleration Region (HAR) evolved 10 times faster than expected, forming neurodevelopment. It strengthens brain connection. HARS promotes the growth of multiple neurites in human neurons and improves the risk of brain damage.
Source: UCSF
How did humans evolve their brains that can create complex languages and civilizations?
The answer could be in exceptional DNA. Scientists in San Francisco, California have discovered that some of the chromosomes are evolving at a ferocious rate to give them a brain development advantage compared to apes. But it may also put us at risk of human brain damage.
Supported by a grant from the National Institutes of Health, the study will appear in nature on February 26th.
This study focused on a portion of a chromosome known as the human accelerated region (HAR). This is the fastest evolution since humans split from the chimpanzees in evolutionary trees, changing 10 times faster than the expected rate of evolution for mammals.
Scientists led by Dr. Yin Shen of the UCSF Weill Neurosciences Institute and UCSF Institute for Human Genetics Research have studied the effects of HAR on artificial neurons derived from human and chimpanzee cell lines.
Human and chimpanzee genomes are 99% similar. HAR accounts for the majority of the 1% difference, which can lead to dramatically different outcomes in human and chimpanzee neurons in Petri dishes.
Human neurons have grown multiple neurites, or intense projections, that help neurons transmit and receive signals. However, chimpanzee neurons only grew a single neurite. When human HAR was designed for artificial chimpanzee neurons, chimpanzee neurons increased many of these wires.
“As more neurites are developed, the complexity of neural networks can become more complicated,” Shen said.
“These networks promote the transmission of signals in the nervous system and support our higher cognitive functions. However, disruptions in their development may contribute to neurodevelopmental disorders, such as autism.”
Author: Other UCSF authors include 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, Mengzhang, Phd, Phd, Phd, Phd, Phd, Phd, Alex A. Penn, PhD, Katherine S. Pollard, All authors, see the paper.
This work was supported by the National Institutes of Health (NIH). S101S10OD021822-01;Schmidt Futures Foundation. Chan Zuckerberg Biohub. And then the Gladstone Institute. See the paper for all funding.
About this genetics and cognitive research news
Author: Levi Gadye
Source: UCSF
Contact: Levi Gadye – UCSF
Image: Image credited to Neuroscience News
Original Research: Closed Access.
“Comparative properties of human accelerated regions of neurons” by Yin Shen et al. Nature
Abstract
Comparative properties of human accelerated regions of neurons.
Human accelerated regions (HARs) are conserved genomic loci that have undergone rapid nucleotide substitutions following divergence from chimpanzees.
HARs are enriched in candidate regulatory regions near neurodevelopmental genes, suggesting their role in gene regulation. However, their target genes and functional contributions to human brain development have been largely uncharacterized.
Here we elucidate the cis-regulatory function of HAR in human and chimpanzee-induced pluripotent stem (IP) cell-induced excitatory neurons. Using genomic and chromatin loop information, we preferred 20 HARs and their chimpanzee orthologs for functional characterization via single-cell CRISPR interference, demonstrating species-specific gene regulatory functions.
Our findings reveal a variety of functional consequences of HAR-mediated CIS regulation in human neurons, including altering the binding affinity of multiple transcription factors in HAR202 and attenuating NPAS3 expression by maintaining the pluripotency and neuronal differentiation capacity of IPS cells through upregulation of Pum2 by 2xHAR.319.
Finally, we demonstrated differential enhancer activity caused by several har26;2xhar.178 variants using Prime Editing. In particular, one variant of HAR26;2xhar.178 links to elevated SOCS2 expression and increases neurite outgrowth in human neurons.
Therefore, our research sheds new light on the endogenous gene regulatory functions of HAR and its potential contribution to human brain evolution.
