Rome wasn’t built in a day. Neither was the human brain. The intricate organ was crafted over millions of years before it developed into the functionally sophisticated masterpiece it is today. Just like the numerous workers who toiled in the hot Mediterranean sun to construct the roads, buildings and aqueducts of Rome, countless different biological components labored for years to construct the neurons, lobes and synapses of the human brain. One class of these biological laborers is microRNAs.
A team of researchers from the University of California, Santa Barbara’s Neuroscience Research Institute has elucidated the role of microRNAs in a section of the brain called the outer sub-ventricular zone (OSVZ). Belonging to a special category of non-coding genes, these microRNAs inhibit the formation of proteins.
At only 22 nucleotides in length, microRNAs are tiny, though they play a significant role in the evolution of organisms.
“A set of genes called microRNAs that do not code for any protein, but just a tiny RNA molecule, are critically important for evolutionary change,” Kenneth Kosik, study leader and co-director of the Neuroscience Research Institute, wrote in an email to The News-Letter. “MicroRNAs can rewire the basic set of protein coding genes, which have not changed very much over enormous time periods, and by re-wiring the existing gene set, evolution can make new things.” Even though microRNAs do not encode proteins, they are able to regulate which proteins are manufactured. If gene expression in a cell operated like a factory, the microRNAs would be the factory supervisors.
“It’s the microRNAs that provide the wiring diagram, dictating which genes are turned on, when they’re turned on and where they’re turned on,” Kosik said in a press release from the University of California Santa Barbara. “There’s a core set with which all kinds of really complex things can be built, and these non-coding genes know how to put it together.”
This core set of basic building blocks can be used to assemble many different gene products. “It’s like making new things with Legos — one simply uses more or less of certain pieces and assembles them in different ways, and in that way the same basic Legos blocks can transform a Legos teeter-totter into a helicopter,” Kosik wrote. “By regulating genes in the same way — how much of each gene product to make and where to locate it — an organism can make new things.”
The researchers at the University of California, Santa Barbara were looking for non-coding genes because, unlike coding genes, they have greatly increased in number as organisms have become more complex. “The coding genes — the ones that make proteins — have really not changed very much,” Kosik said in a press release from the University of California Santa Barbara. “The action has been in this non-coding area and what that part of the genome is doing is controlling the genes.”
Additionally, Kosik and his colleagues were interested in studying microRNAs because of their versatile and adaptable sequences. “Because [microRNAs] are so small and simple, they are easy for nature to invent from some stretch of DNA,” Kosik wrote. “We had been interested in this facet of microRNA biology for some time and ... we sought to see if innovations in the primate brain are associated with the invention of novel microRNAs.”
Using brain tissue from developing macaque monkeys, Kosik and his research team found and sequenced an assortment of microRNAs. “In a part of the developing monkey brain called the outer sub-ventricular zone, which is present in primates but not rodents, many newly invented microRNAs are present,” Kosik wrote.
In addition to elucidating new microRNAs, the results of the study indicate that the appearance of the OSVZ is closely associated with the invention of novel microRNAs. “There might be some relationship – although we can’t prove it – between the invention of some of these new non-coding genes, microRNAs, and the appearance of a new structure, the OSVZ,” Kosik said in a press release from the University of California Santa Barbara. “Trying to connect an anatomical, morphological invention with genes is very difficult, but our work shows a possible molecular basis for the tools that were needed to build this novel structure.”
Through analysis of the data from their study, Kosik and his team found that the novel microRNAs play a role in regulating the cell cycle, which controls cell division. “Among the genes [microRNAs] regulate are very ancient genes involved in the cell cycle,” Kosik wrote in an email to the News-Letter. “In other words, new microRNAs appear in primates in a part of the brain, which is critical for the growth in brain size, and these new microRNAs rewire genes related to one of the oldest functions in biology, the cell cycle.”
The importance of this finding derives from the critical role of the cell cycle in the processes driving evolution. “Nearly all cells throughout evolution have a cell cycle,” Kosik said in a press release from the University of California Santa Barbara. “We can watch the evolutionary process at a very molecular level, see what is novel and how molecular innovation affects what already exists, like the cell cycle. When new things are invented in evolution, they have to be integrated with what already exists.”
Kosik’s team hopes that their findings will serve as a springboard for conducting new clinical research and developing new medical treatments. “Some of the genes we found that are the targets of these new microRNAs are also involved in certain human developmental disorders that are genetic,” Kosik said in a press release from the University of California Santa Barbara. “One place we would like to go with this information is to explore pathways that may be manipulated to help patients in some way. We know people with developmental disorders may be missing a critical gene involved in brain formation and wiring, so maybe if we understood the control of those genes – as these new data are pointing to – we might be able to do something that could be applied to a human condition.”
The application of microRNAs to find solutions for scientific problems does not stop there. These short nucleotide sequences will continue to evolve new functions as their environments change. Thanks to the process of evolution, these environments are virtually guaranteed to continue changing. For example, even though the cell cycle is an ancient process, its continued evolution indicates that it is never a finished product. “Hundreds of millions years after the cell cycle appeared in organisms, nature continues to find ways to tinker with this basic biologic function to develop a primate brain organization that led to the remarkable abilities of the human brain,” Kosik wrote in an email to the News-Letter.
The continued development of microRNAs and cell processes indicates that as far as evolution is concerned, there’s always room for improvement in organisms. “What I find fascinating is that the whole ancient cellular mechanism of cell division still has enough evolutionary space left to make something new and to make something new that’s really complex,” Kosik said in a press release from the University of California Santa Barbara. “The OSVZ gave rise to primates’ expanded brains and to the cells that ultimately brought us Shakespeare.”
Thanks to Kosik’s team, we now know that microRNAs have been invaluable to this process. Over the course of evolution, minuscule RNA sequences, each one with a nucleotide count fewer than the number of letters in the English alphabet, were able to shape the brains of Shakespeare, Aristotle, Newton, and Einstein. Imagine that.
