Central Dogma of Genetics May Not Be So Central

Amorymeltzer writes "RNA molecules aren't always faithful reproductions of the genetic instructions contained within DNA, a new study shows (abstract). The finding seems to violate a tenet of genetics so fundamental that scientists call it the central dogma: DNA letters encode information, and RNA is made in DNA's likeness. The RNA then serves as a template to build proteins. But a study of RNA in white blood cells from 27 different people shows that, on average, each person has nearly 4,000 genes in which the RNA copies contain misspellings not found in DNA."

Comments

Why is this news?

[jd]

We have known for many years that the same DNA codes to different proteins, with the adjustments given the information in the non-coding regions AND the information in the epigenome. That people have discovered that the intermediate step is also adjusted can hardly be called a shock. The proteins have to get built differently somehow, so some alteration in the intermediate coding was inevitable. Honestly! If geneticists aren't even reading their own bloody papers, maybe the government grants should be issued to those Slashdot readers who do.

Re:Why is this news?

[Fluffeh]

Honestly! If geneticists aren't even reading their own bloody papers, maybe the government grants should be issued to those Slashdot readers who do.

Tell us how you feel. Don't hold anything back. You are in a SAFE environment here... Now, show me on the dolly where the geneticist touched you...

Side note: Totally agree with the comment :)

Re:Why is this news?

[RobinEggs]

That people have discovered that the intermediate step is also adjusted can hardly be called a shock.

Yes, it is a shock. The prevailing thought was that the RNA was transcribed faithfully and then that perfect transcript of the DNA was sliced up in strange ways. These people have discovered that the transcript may never have been perfect at all.

Imagine cutting up a loaf of bread: The geneticists were quibbling about how thick the slices were and how to arrange it on the plate, all without paying attention to what kind of bread they used. Now suddenly they've noticed that the recipe for french bread gave them a sourdough loaf while they aren't looking, and it may not be about the slicing as much as about how the right recipe is giving them the wrong thing to cut up.

Re:Why is this news?

[jd]

Well, no. The transcription cannot be faithful because there are more letters in RNA than in DNA. Even if you ignore that aspect, geneticists knew that there was a data-driven transform somewhere. Assuming that it is in point A rather than looking is not the hallmark of a scientist. That is the hallmark of the incompetent. Never, ever extrapolate further than the data will permit on the assumption that the extrapolation is valid. Extrapolation should only ever be done for the purpose of creating a hypothesis. Leave articles of faith to religion. On second thoughts, the religious tend to extrapolate beyond limits too, so that might not help.

Anyways, the fact is that there are only two possible places in which a transform could happen (and it could happen in both). This gives you a total of three possibilities. Now, only the DNA-to-RNA step could include information from the non-coding regions. It's possible that either stage could be effected by the epigenome. From this, it follows that two of the three cases involve the DNA-to-RNA step and two of the three methods involve the DNA-to-RNA step. It may be unexpected, in that they may not have considered that possibility sufficiently, but to call it a shock implies that they ignored the mechanisms entirely -- mechanisms the genetic scientists have been studying in depth for a very long time.

Re:Why is this news?

[Artifakt]

I don't see why you claim there isn't a spell checker. Using DNA for the long term storage itself increases fidelity over RNA. Putting the DNA in a nucleus to protect it from some chemical processes that can cause data malformation also means an increase in fidelity. Multicellularity means (admittedly among other things), moving the reproductive cells deep in the organism so they are again protected from some more sources of copying errors. Simultaniously, it allows apoptosis (as there's no advantage for cell death in a single celled organism), and that's a second spell checker of sorts for multicelled organisms only. A lot of the more complex organism's defenses against diseases such as cancer could all be described as spell checkers (for example, P53 tumor suppressor). The form of DNA polymerase used in the complex organisms itself improves copying accuracy by about 100fold over what's possible for the non-eukarotes and even some of the fairly complex bacteria, and it's been described in operation as 'wiggling the part it has just put together to make sure it hasn't allowed the wrong base to pair before it moves on to the next bit, and having a digestive capability to strip out such mistakes when it finds them'. (See "Our Molecular Nature", by David Goodsell for more on this). Then there's snRNPs (Small Nuclear Ribonucleoproteins, which are formed to snip out introns from RNA copies for those RNA strands that aren't self splicing ribozymes (and of course rybozymes themselves even in organisms too simple to have snRNPs). It looks to me like most of the major changes in organic complexity are also spell checkers of one sort or another. I don't really like to anthropomorphise evolution as having long term goals, but it's probably at least as fair to say evolution is trying to produce totally accurate transcription, as it is to say it is trying to make organisms more ideally suited to their environments.

It's called an "error rate"

[sam_handelman]

This is not nearly as earth-shattering as the journo makes out.

  When DNA is copied to make new DNA, you get a certain number of copying errors, called mutations - most of them harmless. I assume everyone knows about those.

  When DNA is copied to make a temporary-working-copy RNA, you get a larger number of these copying errors because, in general, they are one-shot non-critical deals. The need for stringency is much lower, the selective advantage for stringency is not so great, so it comes as no surprise that the level of proof-reading is also reduced.

  Now, it's also possible that there are mechanisms by which these RNA molecules can be purposefully edited. As mentioned in the article, significant post-transcriptional editing (including in eukaryotes the readaction of big chunks, which are called "Introns".) But this finding doesn't speak much to that, although the rate is a *sconch* higher than I might expect for random errors. Even so, this doesn't shake the central dogma of molecular biology in any meaningful way, as for example Reverse Transcriptases did.

Slashdot

[BitHive]

News for nerds who never took a biology course and are deeply suspicious of the so-called "sciences"

Conservative subs or not?

[RobinEggs]

The summary and the abstract really say almost nothing other than to confirm that the misspellings aren't random and don't seem like lab artifacts.

I'd be interested to know how conservative these mistakes tend to be. If the mistakes generally replace amino acids with very similar ones it might be a programmed method of prodding just how much variation a structure can take while remaining functional. Weird and random events, which can be only so weird and so frequent before everything breaks entirely, are necessary for evolutionary adaptation, and these weird protein errors might be a previously unknown mechanism of exploring slightly different structures for proteins and seeing how far an organism can push the envelope.

Re:NEWS FLASH

[canajin56]

Yes, just random mistakes is why 10,000 "accidents" happen to the same exact gene exactly the same way in exactly the same spot every time, 100% of the time, in every cell their bodies, for multiple individuals. Random transcription error. Yes, you sure thought that one through. How embarrassing. No, but seriously, too bad you weren't on the peer review for the paper. You could have saved them from publishing such garbage!

Re:Central Dogma?

[mauthbaux]

Actually, as I was taught it (which, I will readily admit, could be wrong), Central Dogma is in fact the proper term, though the definition has been tweaked over time.
Originally it stated something along the lines of, One DNA gene is transcribed into one RNA transcript, which is then translated into one protein.
The discovery of antibodies threw that concept out the window. Variability in intron splicing and recombination means that a small handful of genes can yield a huge variety of protein products (See VDJ recombination).
Yet another twist was added with the discovery of retroviruses which reverse the direction of transcription, turning RNA into DNA. Previously we had thought the central dogma to be unidirectional.
The more we learn about life's mechanisms, the less surprised we are when exceptions to the rules are discovered. Evolution really is the ultimate hacker; constantly expanding the usefulness of very simple resources.

Also, kudos on the evangelion reference.

Re:RTFA, the errors weren't random.

[SETIGuy]

Even that's not amazing. It would be amazing if it made a different mistake every time.

The simple model of transcription had always been that single nucleotides in DNA are matched to the complementary nucleotide on the RNA strand. But, of course, nobody thought the simple model was always correct. You've got the interaction of a DNA strand trying to fold back on itself and an RNA strand trying to fold back on itself, and a big honking RNA polymerase molecule with an extremely complicated electric field. It's to complicated for the simple model to work. Maybe on occasion the order of the codons a few hundred bases from the transcription site will interact with the RNA polymerase to insert a different base than expected. (Just throwing that out as a possibility. It could be any of a million things, like an induced change in the structure of RNA polymerase.) That's fine, as long as it happens the same way every time. In that case it's not an error in the DNA or the RNA. It's an error in our oversimplified model of how RNA transcription works. So now we need a better model that can predict how a DNA sequence will be transcrived. Don't look now, science is working the way it should!

I hate that they are even using the word dogma. Because actually dogma is never based on or swayed by evidence. And in this case the dogma was "it's simpler than any realistic biochemical system." I'd like to see a poll of how many biochemist, molecular geneticists, virologists and microbiologists actually believed this dogma.

Not so Surprising...

[Genda]

The fact that the "errors" are consistent, suggest this is not an error at all. There was a famous experiment utilizing genetic algorithms to build an optimal circuit with the least possible number of components. It was a simple circuit, and the optimal circuit was well understood. It was an attempt to prove that the genetic methodology would quickly yield this optimal circuit. To everyone's surprise, the process yielded a circuit with fewer parts than the theoretically optimal circuit. What the designers of the experiment hadn't taken into consideration was that the genetic algorithm didn't care about theory, only outcome. It had discovered a heretofore unknown capacitive reactance on the closely spaces lines of the experimental circuit board, and found a way to use that capacitance to reduce the number of parts in it's design. Given the nature of the system, evolution found a clever way to engineer around the believed limitations of the experiment, and utilize any and all real world resources to create a solution transcending of the point of view of the experimenters.

Likewise, there's something interesting going on here with the RNA, well outside of the obvious perspective of the researchers. Bring in biochemists, theoretical physicists, and maybe a couple applied organic chemical engineers. Let them figure out what's happening at the quantum and molecular level to have this outcome be the result. Start doing simulations. Look at topologies and protein folding.

Look at CJD (Creutzfeldt-Jakob Disease) or BSE (Bovine Spongiform Encephalopathy) the causative agent is a prion. A vital protein that in its normal state is essential to neurological function, which can fold in more that one way, and folded the wrong way destroys brain tissue and ultimately causes dementia and death. I'll bet dollars to donuts, that there is some funny quantum state, or a protein folding problem, or some simple nonbiological chemical process whose probable result is a code misspelling in protein formation. Its an interesting problem, but not at all surprising. We are complex systems, and trying to force the world processes that make us possible into a box is at once myopic and foolish.