Let’s put this one in the category of “more things that we didn’t know about human biology”. We’ve known for some time now about ribozymes – catalytic enzyme-like structures made out of RNA instead of proteins. But they’ve been studied more in lower organisms overall. We know that the hammerhead ribozymes are widely distributed (and were found in human cells in 2010), and RNase P is an RNA that cuts other RNAs. And if you take the broad view (which you should, I think) then the ribosomes themselves have to be included, since the ribosomal RNA parts are crucial to their catalytic function. But overall, it’s true that catalytic RNAs have been more studied in viruses and bacteria than in higher organisms. There are two varieties of hammerhead ribozyme known in human cells, for example, which is nothing compared to the situation down in the prokaryotes.
But this new paper describes one, from a previously unknown class, that seems to be specific to primates (and of course, us). The evolutionary history of its sequence points to the acquisition of its self-cleaving activity about 10 to 13 million years ago, which would put it back around the time of the common ancestor of humans, gorillas, and chimpanzees – it’s not present at all in marsupials and monotremes. A later mutation in the gorilla lineage abolished the self-cleaving, though, so now it’s specific to hominims. It’s also quite interesting that this thing is found in a stretch of long noncoding RNA. These lnc species have been the subject of a lot of research, because they’re so ubiquitous. They obviously have functions outside the “normal” roles that we assign to RNA in our mental models (as intermediates to making proteins), and dealing with this has been a big part in the shift in biological thinking over the last decades. The classic picture has protein function as where so much of the action is – catalysis, scaffolding, localization, signaling and so on. But the profile of the various RNA species (and an appreciation for their variety) has been rising steadily for a long time now, and that shows no signs of stopping.
This new one, named “hovlinc”, appears to be the prototype of a whole new class of ribozymes in general – it doesn’t fit into any of the existing ones. It’s 168 base pairs long and has pH-dependent behavior similar to the hammerhead ribozymes, but has a metal ion dependence all its own. It has a complex structure that is also unique, with helical regions, two large loops, and “pseudoknots” near what seems to be the catalytic site. RNA structures in general seem a bit alien if you’re used to protein structural motifs, but this is more alien than most.
The discovery raises several questions. One feature of the ribozyme field is a general view that such things are a look back in time to the “RNA world” that may have existed before proteins became such a part of the biomolecular suite. And while that’s still a reasonable hypothesis, there’s also no reason why catalytic RNAs couldn’t still be evolving (even under “modern” protein-dominated conditions), and hovlinc seems to be just such an example and an evolutionary recent one, too. Finding this inside a long noncoding RNA also makes you immediately start to wonder if there are other catalytic activities hiding in those things, and hovlinc’s unique mechanism argues that we might be missing some of these by not assaying broadly enough when we look for them. And finally, of course, there’s the question of what hovlinc is actually doing in human biology. It’s down to us, the chimpanzees, and bonobos – as mentioned, gorillas now get along without it. The authors searched genomic databases for human mutants, and estimate that over 99% of the human population carries a functional version of it – but why? Its expression seems to be specific to certain cell types, but its overall function remains (for now) a mystery.