Human evolution; ncRNA drove brain evolution (Introduction)

by David Turell , Tuesday, September 13, 2022, 17:01 (800 days ago) @ David Turell

Research still in its infancy:

https://www.the-scientist.com/features/the-noncoding-regulators-of-the-brain-70457?utm_...

"When the Human Genome Project published the first draft of the human genome sequence in 2001, "many researchers expected to be able to pinpoint protein alterations that would explain the distinctive features of human brains compared to those of other animals—larger size relative to the body, increased neuronal connectivity, and other contributors to our superior cognitive complexity. Instead, “it was frustrating to see how few protein-coding genes exist,” says Geraldine Zimmer-Bensch, a neuroepigeneticist at Rheinisch-Westfälische Technische Hochschule Aachen in Germany, “and even more frustrating, how little difference there is between the mouse and the human protein-coding genome.” Yes, there are proteins and variants of proteins that are unique to our species, she says, but there simply aren’t enough of them to explain humans’ singular cognitive prowess.

"This was particularly surprising because at least a tenth of the human proteome consists of proteins whose main function is in the brain—some estimates say it’s more like a third.

"According to Zimmer-Bensch and an increasing number of neuroscientists, the missing piece of the puzzle is RNA—specifically, the myriad RNAs that don’t code for proteins, such as long noncoding RNAs (lncRNAs) and microRNAs (miRNAs). Noncoding RNAs are likely protagonists in our brain’s evolutionary story because they are pivotal regulators of gene expression, especially during development, experts say. Changes in traits such as tissue size and shape are easily made by tweaking when and in what cells different proteins are made—precise alterations that generally occur as the result of changes in noncoding regions of the genome, researchers are finding.

"And RNAs aren’t just stars of the evolutionary and developmental past; they are essential for brain functioning now, and evidence is mounting that regulating gene expression is just one of noncoding RNAs’ many neurological tasks. For instance, some noncoding RNAs are actively transported to the ends of axons to play roles completely divorced from gene expression. Plus, notes Zimmer-Bensch, noncoding RNAs can be passed from cell to cell via vesicles and junctions. “The functional diversity [of noncoding RNAs] is tremendous and impressive.”

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"But now, cutting-edge sequencing technologies are giving researchers unprecedented insights into cells, allowing RNA studies to be conducted on the spatial and temporal scales needed for the discipline to begin to catch up to protein biology. And findings from this work are pointing to an inevitable conclusion: RNAs rule the brain.

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"This research has led to a shift in understanding of how the brain evolved, Silver says. “In the last 10 years, the idea that RNAs can have an impact, and that layers of regulation between a DNA and a protein are meaningful, has gotten a lot more attention.”

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"A common hypothesis for how these RNAs function is in the control of gene expression, especially during brain development. Individual noncoding RNAs can alter the expression of multiple genes, meaning that small changes in the RNAs can have cascading effects. For example, miRNAs, short (20–26 base pairs) molecules whose most well-studied function is to bind to messenger RNAs (mRNAs) and interfere with their translation into proteins, may each have hundreds of targets—which means even single base changes could impact the expression levels of as many genes.

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"Kosik’s work on miRNAs has found that miRNAs may sculpt brain size and shape—and therefore, cognitive complexity—via alterations to the cell cycle. “If you’re controlling the cell cycle, then in some ways you also are controlling cell divisions, and the number of neurons that are being made,” he explains. “And we know that in primates, the number of neurons increased a lot. Same is true in cephalopods.” In addition to cell number, humans are unique in the number of different neuronal cell types and other important cells in the brain, Kosik adds, and different cell types tend to have distinct miRNA profiles. “MicroRNAs are important in development and taking precursor cells along the path to various terminal differentiated outcomes . . . so they do have some correlation with cell specialization in the brain.”

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"And specific RNAs have been proven to play pivotal roles in activities like memory formation, and especially, in creating the high degree of neuronal plasticity that is a hallmark of human brains. “The brain is rewiring itself on the fly in response to experience,” Mattick explains,"

Comment: A highly technical review article, which begins to show how our brain developed.