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Mysteries in Human RNA

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.

22 comments on “Mysteries in Human RNA”

  1. Lappan says:

    Douglas Adams’ best joke about the universe surely applies to RNA:

    “There is a theory which states that if ever anyone discovers exactly what the Universe is for and why it is here, it will instantly disappear and be replaced by something even more bizarre and inexplicable. There is another theory which states that this has already happened.”

    1. anon the II says:

      Those two theories aren’t mutually exclusive.

    2. Tony says:

      I have a theory that this has happened more than once.

  2. Heisenberg says:

    I’m uncertain about that theory

    1. Schroedinger says:

      Should we try and measure it?

      1. sgcox says:

        You already do it routinely on the macroscopic level.
        Take a pair of identical socks. They are superposition of “left” spin and “right” spin states.
        But once you assign one by putting on your feet, the second immediately collapsed to opposite state.
        It does not matter how large is the separation in space, be in the same pack or one left in some flat across the town.

        1. Wallace Grommet says:

          Ah, but I wear two socks on one foot, and none on the other

          1. sgcox says:

            You are probably slightly boson after yesterday…

        2. ScientistSailor says:

          The black hole that is my dryer consumes half of the socks resulting in a new signature called Socking Radiation…

          1. Qbit says:

            …you mean random appearance of one sock outside the horizon (drier door) ?

        3. Another Idiot says:

          With socks I don’t go by color. I go by thickness.

  3. Barry says:

    Do the 1% if humans who lack a funding copy of hovlinc display any phenotype?

    1. Fei Qi says:

      Hi Barry,

      We didn’t say that there are 1% of human lacking an active copy of hovlinc.

      Our statement is:
      (1) most people have the “wild type” of hovlinc which is active;
      (2) we only find one SNP with MAF >1% in the region of hovlinc (rs72720496), and it’s also active;
      (3) and thus we can conclude that even if some rare (MAF 99% of human have an active copy of hovlinc (either the “wild type” or the rs72720496).

  4. Its discoveries like this that fire my imagination. What can we uncover next? What else is hiding in our cells? I particularly enjoy your post today Derek, not because this is a big news breaking story, but that it is the result of basic science. This discovery may not be impactful now, but it gets us one step further. Sometimes the biggest things aren’t discovered with a “Eureka!” but with a “That’s weird.” I am excited to see what we can learn next about this new class of ribozymes.

  5. Blaine White, M.D. says:

    Anti-sense knockdown in cultured cells? What does this thing do?

  6. 이웅견 says:

    Now that’s a funny coincidence. “bŏsŏn” (버선) happens to be traditional Korean socks.

    1. 이웅견 says:

      meh, that was @sgcox above.

  7. Save my rat ass says:

    This begs the question: how far can we go seeking to understand human physiology using non human species?
    Can you imagine how many more human-specific secrets cells are waiting to share with us… if we only stopped seeking answers in rodents…

    1. Iggy says:

      Perhaps we should use our elected politicians to fill in the breach until a better rat model is discerned

    2. AVS-600 says:

      Unfortunately, even though we know there are flaws in this system, rodents are still our best bet for discovery work in most cases. Ethics review boards will probably view any proposal to sacrifice a human volunteer and slice them up for histology plates with extreme skepticism.

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