Why don’t DNA based organisms discard error repair?

20 May 2009

quasispecies1The recent series of posts on polymerase error rates and viral evolution has elicited many excellent and thought provoking comments from readers of virology blog. Here is one that I had not thought of before, and which I’ll use on an exam in my virology course:

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.

There is no answer to this question, so I’ll speculate. I believe that DNA viruses have error correction mechanisms so that they can have very long genomes. RNA viral genomes are no longer than 27-31 kb. This limit is probably imposed by their high error rate: if RNA genomes were longer, they would likely sustain too many lethal mutations to survive. Error correction mechanisms allow for DNA viral genomes up to 1.2 million bases in length. Smaller DNA viruses don’t have their own DNA polymerases – they use those of the cell. Cellular DNA polymerases have error repair to avoid 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.

The reader who posed the original question then came back with this retort:

If reduced fidelity is beneficial to RNA viruses, because of the complex environment they are in, why don’t DNA viruses do the same thing?

I think the same endpoint, in terms of surviving in complex environments, is achieved by both strategies. RNA viruses have high diversity; DNA genomes have many more gene products which allow them to survive in diverse situations. Both strategies appear to be evolutionarily sustainable.

It’s important to keep in mind that the goal of viral evolution is survival. Evolution does not move a viral genome from “simple” to “complex”, or along a trajectory aimed at “perfection”. Change is effected by elimination of the ill adapted of the moment, not on the prospect of building something better for the future.

While researching this subject I came across a series of papers on DNA synthesis by African swine fever virus, a virus with a DNA genome of 168-189 kb. The viral genome encodes a complete DNA replication apparatus, including DNA polymerase and DNA repair enzymes. Incredibly, the DNA repair pathway itself is error-prone, which is believed to contribute to the genetic variability of the virus. There is some controversy concerning the error rate for this virus, so we don’t know the consequence of this observation for fidelity of DNA replication. Nevertheless, these observations suggest that evolution has seen fit to tinker with, and perhaps increase, the error rates of certain DNA based organisms.

Lamarche, B., Kumar, S., & Tsai, M. (2006). ASFV DNA Polymerase X Is Extremely Error-Prone under Diverse Assay Conditions and within Multiple DNA Sequence Contexts. Biochemistry, 45 (49), 14826-14833 DOI: 10.1021/bi0613325

  • mauricio carrillo-tripp

    “It’s important to keep in mind that the goal of viral evolution is survival.” So I'm curious, why do (all, most, some?) viruses make the host ill, or worst, kill it? If the virus needs the host replicating mechanisms, killing it is not a very good survival strategy, is it. why isn't it more like a symbiosis, if at all possible?

  • http://www.facebook.com/people/Corey-Philipp/799897312 Corey Philipp

    To add further to your speculation about the advantages DNA may confer upon a virus, I would submit the following. The may be selection pressures that would drive a DNA virus to adapt to a host well and then maintain this state with high fidelity. One example of this might be the Herpesviridae which is well adapted to a number of mammals as hosts. Its integration into the host’s genome not only highlights this selection pressure but it is a direct consequence of become latent. The virus can continue to replicate down the germ line of all of the cells it infects and jump to new hosts when environmental factors are preferable. My assertion is that DNA viruses continue to survive because it has high fidelity. If Herpesviridae were RNA viruses they might integrate but never come out of their latent state because of the high mutation rate would select against this integration or may mutate to a point where latency is permanent. I hope my ideas were clear and I tried not to over anthropomorphize the virus to much :)

  • Frank

    What you say here is very important point. It seems strange that viruses, which would like to replicate within a host and spread to other host kill their host instead. I would like to point out one possible explanations for this :

    Sometimes a virus infects a host which is not its natural host. That means, the virus is not well adapted to this new host. Therefore the fine “equilibrium” between viral replication (most often going hand in hand with killing host cells) and the survival of the host has not yet been established. A “sucessfull” virus is well adapted to its host, that means it can replicate without killing its host.

    One example for this is the Lassa virus. Its natural host are rodents, in which the virus replicates, but doesn`t kill the host. It kind of “stays” within the rodents and infected animals shed the virus through their whole life. This is a very sucessfull strategy for Lassa virus to survive and spread. But rather often also humans are infected with this virus. In man, Lassa virus causes a severe illness, most often ending in death of the infected individual. In this case, the virus is not adapted to humans, it wildly replicates, spreads within the host and eventually kills it, which is -in the long run- not benificial for the virus.

    But there are also examples for viruses which infect humans, but are very well adapted to them. To me, Herpesviridae are among the most striking examples for this. Herpes simplex type I is able to infect humans. But it doesn`t cause severe illness. Instead it replicates slowly and furthermore, it even integrates into the host cell genome, going “dormant”. With this strategy, a host is infected a whole lifetime, but it doesn`t die from it (in most cases). Instead, the virus goes through several phases of replication, depending on the status of the host. When the infected human gets ill or is stressed, the virus goes out of its dormancy and replicates, with the “goal” to infect new host. Nevertheless, it still remains within the human and can be shed by it at other times. With this strategy, the virus is able to spread very efficiently within a population (as is shown by the high numbers of infected people worldwide).

    To summerize : the most “successful” viruses (in terms of long-run survival) are those, who indeed parasitize their host without killing it. Most often they are well adapted to their hosts. But as for viruses it is -also because of high mutation rates- quite easy to cross species barriers, they also infect new host, but are not well adapted to them (yet) and as a consequence kill those hosts or at least cause severe illness.

    If i haven`t bored you to tears by now, let my point out a third example, although i want you to now that all i write form here on is just SPECULATION. One example of a virus killing its host is HIV. But compared to influenza for example it doesn`t kill its host very fast. Instead, most often it takes some time until the host dies, so the virus can spread within a population before that. Now one can ask, if the virus has such a succesfull strategy of letting the host survive long enough to spread the virus, why does it kill it`s host after all?
    One explanation i could think of is this : HIV is currently in the state of adapting to humans. This virus is quite new to man as a host, as its worldwide distribution is known since the 1960s. As the virus originates from simian monkey, it maybe allready adapted to humans a little bit, as the phyiology of monkey and humans are quite similiar to some point. But there are also important differences, which the virus has to adapt to, in order to become what -for example- herpes viruses allready are : latent viruses, that means viruses that stay within their host for its lifetime, but without killing it. The estabslishment of this state could be what we currently observe for HIV.
    Again, let me point ot that this was just speculation. But i hope, i could make my thoughts clear to you with this. Of course, there are other possible explanations why some viruses kill their host and i really look forward to hear them.

    Frank

  • Lee

    I'm not entirely certain that there is a broad difference between fidelity in DNA and RNA viruses.

    Before you shriek at what seems like my ignorance, let me explain. What I mean to say is that RNA viruses–let's use Influenza as an example–have copying mechanisms that produce a certain number of errors per genome copied. It's possible that it is this number, not the number of errors per base pair, that is important for proper evasion of host defenses without compromising genomic integrity. While a virus could probably sustain a few mutations per genome per copy cycle, more than that are probably bad…

    Therefore, by virtue of their larger genomes, DNA viruses should have a lower error rate to avoid increasing the number of errors per genome.

    Another thing that no one really seems to think about is that these mutations are not really “random” per se; they are based on thermodynamics, and that science teaches us that when God plays dice, they are loaded.

  • Kagy

    Great discussion on essentially acute vs. pesistent viruses. Are persistent viruses the ultimate achievement of a virus, such as polyomavirus or herpesviruses? Are the acute viruses simply a snapshot of a virus trying to infect a new host? There are dozens of examples…influenza viruses happily in the guts of geese and ducks (without causing illness) or hantavirus in deer mice…all happily persistent in their 'natural' host, but acute in humans and other perhaps 'new' hosts.

    In a question upon poliovirus, essentially a virus that is persistent in the human population (without an animal reservoir), but generally causes what would be considered an accute disease (unless post-polio syndrome has anything to do with persistent poliovirus)…why has poliovirus not adapted in the face of the vaccine and mutated (or selected a species among the quasispecies) to a version that can grow in a vaccinated person (such as the way influenza does this regularly)? This could be true of measles virus as well, which certainly would seem to have the ability to mutate and survive even in vaccinated individuals, but doesn't.

  • mauricio carrillo-tripp

    Not boring at all. it makes sense, even as an speculation. I haven't seen it like that before. I'll be thinking about your thoughts for a while…
    thanks for the answer

  • http://www.facebook.com/people/Corey-Philipp/799897312 Corey Philipp

    It’s interesting that you bring up Retroviridae and they have reverse transcriptase. Moloney murine leukemia virus is thought to make errors every 1 in 30000 which is a little better that Influenza's RNA dependent RNA polymerase. Could this be a kind of middle ground between the RNA error rate and the DNA error rate? Since Retroviridae store their genome as RNA but translate new viron particles using DNA so they have error rates from both camps including the error rates from reverse transcriptase. This may give HIV some advantages that may not be realized by RNA or DNA only viruses.

  • Matt Dubuque

    Having lower error rates in transcription also enables more consistent assembly of very large genomes.

    Lynn Margulis provides some fascinating insight into this.

    Many years ago this biologist, influenced by the perspectives of Gregory Bateson, was the first to postulate that mitochondrial DNA had a distinct evolutionary history than the rest of cellular DNA. This view was met with widespread snickering and derision at the time.

    Now it is not only mainstream thinking, but most geneticists believe that all sorts of other intracellular organelles also evolved with distinct and separate evolutionary trajectories.

    In her latest book “Acquiring Genomes: A Theory of the Origins of Species”, Ms. Margulis revolutionizes evolutionary theory in a way that will likely reverberate down future generations of evolutionary biologists for hundreds of years.

    What Ms. Margulis meticulously describes in this book are evolutionary genomic acquisition strategies extant throughout the natural world, whereby organisms incorporate the entire genome of other organisms into new forms.

    Discussing examples from diverse species such as wood-digesting bacteria incorporated into termites to the symbiotic coevolution of bacteria inside certain species of blue-green algae, to nitrogen fixing bacterial colonies in legumes, her pioneering work is a compelling read.

    Controversial? Yes. But she is a microbiologist basically with very few peers and her pioneering work in mitochondrial DNA makes her views non-trivial.

    Why this is relevant to the discussion at hand is as genomes become exponentially more complex through genomic acquisition, reduced transcription error rates of sigma 9 (i.e. an error is 9 standard deviations from the norm) become necessary.

  • Matt Dubuque

    Here is a link to Lynn's book:

    http://tinyurl.com/qopp7d

  • Anthony

    So we find DNA viruses that exploit both error-prone and high-fidelity lifestyle niches.

    Doesn't the real question the become why haven't we found a high-fidelity viral RNA polymerase? Perhaps it just comes down to nucleic acid chemistry? Or maybe the truth is still out there…

  • bhyde

    Does the ecologist's concept of r/K selection bring something to this discussion?

    I.e. the high fidelity reproductive strategy is K selected and the high diversity reproductive strategy is r selected. The ecologist model suggests that these strategies tell us something about the nature of the niche. The r strategies fit a situation where things are unstable; in that case lots of resources are expended on searching for an available niche. The maple tree drops millions and millions of seeds in the hope one will find a suitable bit of real estate for the next generation tree. Similar the virus is looking for a bit of real estate on a landscape with a very aggressive owner.

    Ah, it's too much fun playing with ideas outside one's area of expertise :).

  • http://masseybioinformatics.hpcf.upr.edu/ Massey

    The r/K idea seems like a good hypothesis. If RNA viruses are known to have high 'fecundity' compared to DNA viruses then this could be an answer…….can any of the virologists answer this one???

    Anthony's comment about nucleic acid chemistry also seems like a valid hypothesis. The question would be in this case whether the presence of a 2'OH in RNA prevents proofreading by RNA polymerase or reverse transcriptase…..I think I need to do some reading!

  • http://masseybioinformatics.hpcf.upr.edu/ Massey

    The r/K idea seems like a good hypothesis. If RNA viruses are known to have high 'fecundity' compared to DNA viruses then this could be an answer…….can any of the virologists answer this one???

    Anthony's comment about nucleic acid chemistry also seems like a valid hypothesis. The question would be in this case whether the presence of a 2'OH in RNA prevents proofreading by RNA polymerase or reverse transcriptase…..I think I need to do some reading!