Many of the fastest-evolving human genes linked to evolutionary changes
in brain development

Date:
September 2, 2021
Source:
Cell Press
Summary:
More than 3,000 regions in the human genome are very different in
people from in any other mammals, including our closest primate
relatives. Now, a study has evidence to confirm that nearly
half of these so-called human accelerated regions (HARs) have
played an important role in rewriting the course of human brain
development, offering important insight into the genetic basis of
human evolution.



FULL STORY ==========================================================================
More than 3,000 regions in the human genome are very different in people
from in any other mammals, including our closest primate relatives. Now,
a study reported in the journal Neuron on September 2 has evidence to
confirm that nearly half of these so-called human accelerated regions
(HARs) have played an important role in rewriting the course of human
brain development, offering important insight into the genetic basis of
human evolution.


========================================================================== "Probably one of the most interesting questions in neuroscience is,
'What makes us human?'" says Christopher Walsh (@chrisawalsh1) of
Harvard University and the Allen Discovery Center for Human Brain
Evolution. "Specifically, what is it about the human brain that
differentiates it from those of other closely related species? Looking
at human accelerated regions provided us with a very targeted way to investigate that question from a genetic perspective." To systematically identify which of the 3,171 previously identified HARs are most likely
to be contributing to recent evolution of the human cerebral cortex,
the researchers examined the role of these regions in regulating genes
in studies of multiple human and mouse cell types and tissues.

"We knew going into this study that many HARs were likely to function
as regulators of gene expression in the brain, but we knew very little
about which cell types in the brain they worked in, where, or at what
time in the human lifespan," explains Ellen DeGennaro (@ViolinPlots),
one of the study's first authors in the Walsh lab. "Our goal was to fill
in these gaps of knowledge about which HARs had important roles in the
brain, and how, so that we and other researchers could take the most
important 'brain HARs' and perform deeper tests of their evolutionary function." To overcome the limitations of earlier methods, Walsh and
his colleagues developed an applied approach called CaptureMPRA. The new
method leverages barcoded molecular inversion probes to capture target sequences that capture entire HAR elements and their surrounding DNA, overcoming some limitations of prior techniques. Using this approach,
they looked for important differences in HAR enhancer function between
humans and chimpanzees.

They also integrated this data with epigenetic data at HARs in human fetal neural cells to identify HARs that looked likely to have an important
role in guiding human-specific brain development. Some of the activity
they uncovered was specific to the brain, as compared to other organs
in the body. They also found activity that was even more specific to
certain cell types in the fetal brain, as opposed to brains of adults.

Overall, the new findings show that many HARs do indeed appear to act
as neurodevelopmental enhancers, the researchers report. The new data
suggests that, as those human sequences diverged from other mammals,
they have largely increased their role as neuronal enhancers.

The researchers also show that one HAR-regulated gene in particular,
called PPP1R17, has undergone rapid change in both cell-type and
developmental expression patterns between non-primates and primates
and between non-human primates and humans. They went on to show that
PPP1R17 slows the progression of neural progenitor cells through the
cell cycle. This is notable given that lengthening of the cell cycle in non-human primates and humans is known to force a slowing of neurological development, an important feature of the human brain.

The new findings define many HARs that play key roles in neuronal
gene regulatory programs; nearly half of all HARs show reproducible
chromatin accessibility and enhancer activity in neural cells and tissue, according to the researchers. They've also developed an easily searchable online resource (the HARHub) consisting of the new data and previously published datasets of common and rare human HAR sequence variation. This databank now serves as a resource for scientists to make even more
discoveries. Already, it has offered intriguing insights.

"Our work provides an important advance in studying many genomic regions
at once to help us piece together the very complicated but compelling
picture of human brain evolution," Walsh says. "Our data suggest that
evolution of the human brain involved changes in dozens or perhaps even hundreds of sites in the genome, rather than just a single key gene." ========================================================================== Story Source: Materials provided by Cell_Press. Note: Content may be
edited for style and length.


========================================================================== Journal Reference:
1. Kelly M. Girskis, Andrew B. Stergachis, Ellen M. DeGennaro, Ryan
N. Doan,
Xuyu Qian, Matthew B. Johnson, Peter P. Wang, Gabrielle M. Sejourne,
M.

Aurel Nagy, Elizabeth A. Pollina, Andre' M.M. Sousa, Taehwan Shin,
Connor J. Kenny, Julia L. Scotellaro, Brian M. Debo, Dilenny
M. Gonzalez, Lariza M. Rento, Rebecca C. Yeh, Janet H.T. Song,
Marc Beaudin, Jean Fan, Peter V. Kharchenko, Nenad Sestan, Michael
E. Greenberg, Christopher A. Walsh.

Rewiring of human neurodevelopmental gene regulatory
programs by human accelerated regions. Neuron, 2021; DOI:
10.1016/j.neuron.2021.08.005 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/09/210902124922.htm

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