Comments on: The error-prone ways of RNA synthesis

By: Daniel Condurachi

Daniel Condurachi — Mon, 31 Jan 2011 20:54:00 +0000

where do you get all those diagrams from? Do they exist in vectorial format as well?

By: Scott

Scott — Mon, 13 Sep 2010 08:33:54 +0000

great! very useful information.

By: Dan

Dan — Mon, 07 Jun 2010 16:55:39 +0000

I'm studying medicine and your diagrams were very helpful.

By: BacterialiyspeakingQS

BacterialiyspeakingQS — Sun, 23 May 2010 02:16:30 +0000

Wow…this was a very nice thing to my article discussion on CTV (Citrus tristeza virus)…thanks a lot

By: This Week In Virology – Esta Semana en Virología « Gripe por A (H1N1) Blog

Mon, 05 Oct 2009 17:06:51 +0000

[...] The error-prone ways of RNA synthesis [...]

By: Pandemic H1N1 influenza virus outcompetes seasonal strains in ferrets

Pandemic H1N1 influenza virus outcompetes seasonal strains in ferrets — Thu, 10 Sep 2009 17:53:35 +0000

[...] and reassortment to be two distinct phenomena. The mutation rate of the virus is determined by error-prone RNA synthesis. The host applies the selection pressure that enriches for a particular phenotype. The [...]

By: profvrr

profvrr — Thu, 21 May 2009 09:10:08 +0000

An interesting question. According to wikipedia: The fossil record
indicates that single celled life began to proliferate on the planet
at some point during the Precambrian period, although exactly when
recognizably modern life first emerged is unclear. Nucleic acids
became the sole and universal means of encoding genetic information,
requiring DNA repair mechanisms that in their basic form have been
inherited by all extant life forms from their common ancestor. The
emergence of Earth's oxygen-rich atmosphere (known as the "oxygen
catastrophe") due to photosynthetic organisms, as well as the presence
of potentially damaging free radicals in the cell due to oxidative
phosphorylation, necessitated the evolution of DNA repair mechanisms
that act specifically to counter the types of damage induced by
oxidative stress.

In general we believe that RNA viruses lack error correction
mechanisms, but there may be some exceptions. For example, there is
some evidence that a coronavirus might have error correction
machinery.

By: profvrr

profvrr — Thu, 21 May 2009 02:10:08 +0000

By: Matt Dubuque

Matt Dubuque — Mon, 18 May 2009 23:40:07 +0000

Here is a link to that 1948 paper which led to the birth of information theory and electrical engineering.

http://cm.bell-labs.com/cm/ms/what/shannonday/s...

Notice on page 6 how similar their coding schema is to CG AT CG GC AT, etc!

By: Matt Dubuque

Matt Dubuque — Mon, 18 May 2009 23:35:13 +0000

I don't want to go to far afield here, but when did error repair first begin? Are there more primitive forms of error repair to be contrasted with extremely sophisticated ones? Is that a distinguishing difference between RNA and DNA viruses, i.e. the former always lacks error repair mechanisms but the latter generally contains them?

Interesting stuff. Shannon and Weaver's Mathematical Theory of Communication 1948, which is the seminal work that founded electrical engineering (and indeed made the modem possible) is all about efficiently reducing error rates in a noisy channel (stop bits and parity bits).

By: profvrr

profvrr — Mon, 18 May 2009 21:16:36 +0000

This is a fabulous question. I'll speculate because there is no known
answer, as far as I know. The known RNA viral genomes are no longer
than 27-31 kb, probably because they would sustain too many lethal
mutations if they were longer. DNA viral genomes can be up to 1.2
million bases in length - probably because they have error correction
mechanisms. So I would speculate that DNA viruses have evolved to keep
error repair pathways so that the genomes can be longer. Smaller DNA
viruses don't have their own DNA polymerases, but use those of the
host. Host DNA systems need to have error repair, otherwise they will
sustain mutations that lead to diseases such as cancer. Both forms of
reproduction are evolutionarily sustainable: shorter RNAs with lots of
errors; longer DNAs with fewer errors.

By: Massey

Massey — Sat, 16 May 2009 15:47:01 +0000

thanks Vincent for the blog – I've enjoyed following the discussions

Here's a tough question. In the follow up blog to this, you say that the high mutation rates of RNA viruses is beneficial to survival in a complex environment. If this is true, why don't DNA viruses evolve high mutation rates also? It would be simple for them to delete their proofreading domain

By: Carlos Villarreal

Carlos Villarreal — Wed, 13 May 2009 22:47:12 +0000

Apparently, RNA viruses form quasi-species because they have a mutation rate similar to the 1/(number of bases)
in their genome. In the case of DNA organisms, the DNA polymerase reduces this mutation rate to 1/10^7 – 1/10^9.
This is also the order of magnitude of their genome. This would mean that many DNA organisms (including humans) would form quasi-species if all its genome were codifying. As a consequence, a possible role for
introns would be to allow for unharmful mutations in order to stabilize the species. Is this argument right?

By: phogdog

phogdog — Mon, 11 May 2009 22:48:14 +0000

Good article, great illustrations, once again.

By: profvrr

profvrr — Mon, 11 May 2009 16:38:10 +0000

You are not at all full of crap; in fact those are excellent ideas.
Often amateurs (or should we say, those not in the field) have
excellent ideas because they are not saddled with the baggage of
familiarity.

As you'll see in coming posts, in fact the 'errors' do help the virus
to survive, by allowing it to adapt to new hosts, to evade antivirals,
immunue responses, etc. But only to a certain extent - if there are
too many errors they will interfere with viral replication.

As for your idea of lowering the error rate as an antiviral approach -
you'll see in the coming posts that this can be done experimentally,
and it has dramatic consequences on viral fitness. On the other hand,
what about pushing the error rate the other way, so that you
mutagenize the virus out of existence? This is in fact the mode of
action of at least one antiviral drug, ribavirin, which we'll discuss
here in a few days.

By: thor183

thor183 — Mon, 11 May 2009 16:29:20 +0000

This isn't my field (I'm a software guy), but I have a certain fascination with your field. I say this, because I have a speculation I'd like to throw out there, but it's likely kinda ill informed. Nevertheless, I'm curious as to what you might think.

You refer to this viral RNA synthesis as error-prone, which I understand what you mean when you say this. But the word "error" carries with it a certain deviation from "correctness", at least in common parlance. In the viral RNA synthesis case, might this "error rate" actually be a primary survival mechanism for the virus in the sense that it helps its genome evade immune system defenses and anti-viral molecules.

If so, might there be a drug strategy which instead of targeting the replication cycle of the virus, instead attacks its error rate. The idea being that by lowering the error rate of the viral RNA synthesis one reduces the rate at which the virus produces immune-evading, or anti-viral drug evading mutations. Supposing one found this "exonuclease as a drug" molecule, you could administer it seasonally to make this year's vaccine more likely to be effective on successive years, or something like that.

But I am an amateur, so I'm probably full of crap.

By: Ascription is an Anathema to any Enthusiasm › Searching the Alternate Routes

Mon, 11 May 2009 13:17:14 +0000

[...] the copy step is notable. In quantity and quality. a typical RNA viral genome of 10,000 bases, a mutation frequency of 1 in [...]

By: Mauricio Carrillo-Tripp

Mauricio Carrillo-Tripp — Mon, 11 May 2009 13:02:25 +0000

Mind blowing. Again, excellent reading!