Revolutionary Genetics Research Shows RNA May Rule Our Genome

Philip Ball reports via Scientific American: Thomas Gingeras did not intend to upend basic ideas about how the human body works. In 2012 the geneticist, now at Cold Spring Harbor Laboratory in New York State, was one of a few hundred colleagues who were simply trying to put together a compendium of human DNA functions. Their Aproject was called ENCODE, for the Encyclopedia of DNA Elements. About a decade earlier almost all of the three billion DNA building blocks that make up the human genome had been identified. Gingeras and the other ENCODE scientists were trying to figure out what all that DNA did. The assumption made by most biologists at that time was that most of it didn't do much. The early genome mappers estimated that perhaps 1 to 2 percent of our DNA consisted of genes as classically defined: stretches of the genome that coded for proteins, the workhorses of the human body that carry oxygen to different organs, build heart muscles and brain cells, and do just about everything else people need to stay alive. Making proteins was thought to be the genome's primary job. Genes do this by putting manufacturing instructions into messenger molecules called mRNAs, which in turn travel to a cell's protein-making machinery. As for the rest of the genome's DNA? The "protein-coding regions," Gingeras says, were supposedly "surrounded by oceans of biologically functionless sequences." In other words, it was mostly junk DNA. So it came as rather a shock when, in several 2012 papers in Nature, he and the rest of the ENCODE team reported that at one time or another, at least 75 percent of the genome gets transcribed into RNAs. The ENCODE work, using techniques that could map RNA activity happening along genome sections, had begun in 2003 and came up with preliminary results in 2007. But not until five years later did the extent of all this transcription become clear. If only 1 to 2 percent of this RNA was encoding proteins, what was the rest for? Some of it, scientists knew, carried out crucial tasks such as turning genes on or off; a lot of the other functions had yet to be pinned down. Still, no one had imagined that three quarters of our DNA turns into RNA, let alone that so much of it could do anything useful. Some biologists greeted this announcement with skepticism bordering on outrage. The ENCODE team was accused of hyping its findings; some critics argued that most of this RNA was made accidentally because the RNA-making enzyme that travels along the genome is rather indiscriminate about which bits of DNA it reads. Now it looks like ENCODE was basically right. Dozens of other research groups, scoping out activity along the human genome, also have found that much of our DNA is churning out "noncoding" RNA. It doesn't encode proteins, as mRNA does, but engages with other molecules to conduct some biochemical task. By 2020 the ENCODE project said it had identified around 37,600 noncoding genes -- that is, DNA stretches with instructions for RNA molecules that do not code for proteins. That is almost twice as many as there are protein-coding genes. Other tallies vary widely, from around 18,000 to close to 96,000. There are still doubters, but there are also enthusiastic biologists such as Jeanne Lawrence and Lisa Hall of the University of Massachusetts Chan Medical School. In a 2024 commentary for the journal Science, the duo described these findings as part of an "RNA revolution." What makes these discoveries revolutionary is what all this noncoding RNA -- abbreviated as ncRNA -- does. Much of it indeed seems involved in gene regulation: not simply turning them off or on but also fine-tuning their activity. So although some genes hold the blueprint for proteins, ncRNA can control the activity of those genes and thus ultimately determine whether their proteins are made. This is a far cry from the basic narrative of biology that has held sway since the discovery of the DNA double helix some 70 years ago, which was all about DNA leading to proteins. "It appears that we may have fundamentally misunderstood the nature of genetic programming," wrote molecular biologists Kevin Morris of Queensland University of Technology and John Mattick of the University of New South Wales in Australia in a 2014 article. Another important discovery is that some ncRNAs appear to play a role in disease, for example, by regulating the cell processes involved in some forms of cancer. So researchers are investigating whether it is possible to develop drugs that target such ncRNAs or, conversely, to use ncRNAs themselves as drugs. If a gene codes for a protein that helps a cancer cell grow, for example, an ncRNA that shuts down the gene might help treat the cancer.

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