A difficult landscape for the RNA world?

I’m back, and right now I can’t really decide if I should be squeeful or sad about Jiménez et al. (2013).

On the side of squeeing, I have some pretty compelling arguments.

  1. It’s an RNA world paper. I’m an unabashedly biased fan of the RNA world. (Not that my opinion matters, seeing as that’s the only origin-of-life hypothesis I actually know anything about. It’s like voting for the only party whose campaign ads you’ve seen.)
  2. I find the actual experiment ridiculously cool. It’s a bit like that mutation study about heat shock protein 90 that I wrote about aaaaages ago, except these guys evaluated the relative fitness of pretty much every single possible RNA molecule of 24 nucleotides. Yes, that is 4^24 different RNA molecules, each in many copies. And they did it twice, just to make sure they weren’t mistaking statistical flukes for results [1].
  3. It explores the landscape of evolution and digs into Big Questions like, how inevitable/reproducible is evolution? Or, as Stephen Jay Gould would put it, what would happen if we replayed the tape of life?

On the other hand, the findings are a bit… bleak. So the experimental setup was to select from this huge pool of RNA sequences for ones that could bind GTP, which is basically a building block of RNA with an energy package attached. In each round of selection, RNAs that could attach the most strongly to GTP did best. (The relative abundances of different sequences were measured with next-generation sequencing.) The main question was the shape of the fitness landscape of these RNAs: how common are functional GTP-binding sequences, how similar do they have to be to perform this function, how easily one functional sequence might mutate into another, that sort of thing.

And, well.

  1. There were only 15 fitness peaks that consistently showed up in both experiments. (A fitness peak consists of a group of similar sequences that are better at the selected function than the “masses”.) That sounds like GTP-binding RNAs of this size are pretty rare.
  2. The peaks were generally isolated by deep valleys – that is, if you were an RNA molecule sitting on one peak and you wanted to cross to another, you’d have to endure lots of deleterious mutations to get there. In practical terms, that means you might never get there, since evolution can’t plan ahead [2].

On the other other hand…

  1. This study considered only one function and only one environment. We have no idea how the look of the landscape would change if an experiment took into account that a primordial RNA molecule might have to do many jobs to “survive”, and it might “live” in an environment full of other molecules, ions, changing temperatures, whatever. (That would be a hell of an experiment. I think I might spontaneously explode into fireworks if someone did it.)
  2. It’s not like this is really a problem from a plausibility perspective. The early earth did have a fair amount of time and potentially, quite a lot of RNA on its hands. I don’t think it originally would have had much longer RNA molecules than the ones in this experiment, not until RNA figured out how to make more of itself, but I’m pretty sure it had more than enough to explore sequence space.

4^24 molecules is about 2.8 x 10^14, or about half a nanomole (one mole is 6 x 10^23 molecules). One mole of 24-nt single-stranded RNA is roughly 8.5 kilos – I’d think you can fit quite a bit more than a billionth of that onto an entire planet with lots of places conducive to RNA synthesis. So I see no need to panic about the plausibility of random prebiotic RNA molecules performing useful (in origin-of-life terms) functions. (My first thought when I read this paper was “oh my god, creationism fodder,” but on closer inspection, you’d have to be pretty mathematically challenged to see it as such.)

So, in the end… I think I’ll settle for *SQUEEE!* After all, this is a truly fascinating experiment that doesn’t end up killing my beloved RNA world. On the question of replaying the tape, I’m not committed either way, but I am intrigued by anything that offers an insight. And this paper does – within its limited scope, it comes down on the side of evolution being very dependent on accidents of history.

Yeah. What’s not to like?

***

Notes:

[1] I’ve worked a bit with RNA, and I have nothing but admiration for folks who do it all the time. The damned molecule is a total, fickle, unstable pain in the arse. And literally everything is full of almost unkillable enzymes that eat it just to mock your efforts. Or maybe I just really suck at molecular biology.

[2] I must point out that deleterious mutations aren’t always obstacles for evolution. They can contribute quite significantly to adaptation or even brand new functions. I’m racking my brain for studies of real living things related to this issue, but all I can find at the moment is the amazing Richard Lenski and co’s experiments with digital organisms, so Lenski et al. (2003)  and Covert et al. (2013) will have to do for citations.

***

References:

Covert AW et al. (2013) Experiments on the role of deleterious mutations as stepping stones in adaptive evolution. PNAS 110:E3171-3178

Jiménez JI et al. (2013) Comprehensive experimental fitness landscape and evolutionary network for small RNA. PNAS advance online publication, 26/08/2013, doi: 10.1073/pnas.1307604110

Lenski RE et al. (2003) The evolutionary origin of complex features. Nature 423:139-144

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