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RNA pol, replication fidelity

brett brett at BORCIM.WUSTL.EDU
Fri Dec 1 11:31:08 EST 1995

>Question for anyone.   
>Recently, I've attended a few seminars on viral pathogenesis.  An 
>interesting topic that seemed to crop up from time to time was that a few 
>RNA viruses (most notably Ebola and Dengue) show a high replication 
>fidelity.  This is interesting since to my understanding RNA viruses tend 
>toward high rates of mutation, the idea is that the replicative machinery 
>is inefficient.  The question of course is why?  Why, should one virus 
>show high rates of mutation and others not.  Is there any evidence that 
>the replicative machinery (RNA pol, etc.)  of some viruses are more 
>efficient.  Is there something inherent in the secondary structure of 
>some viruses that may lead to lowered mutation rates.  To what degree 
>does natural selection play a role?  I could envision a situtation in 
>which a number of progeny are made (the replicative machinery is just as 
>inefficient as other viruses) but the conditions are so stringent for 
>survival that only those sequences that show a few base pair changes can 
>still be viable.  This however begs certain other questions.  For 
>example, as I understand it, Dengue reaches high virus titers.  As it 
>turns out, each virus is as viable as the next, and for good reason:  The 
>mosquito vector requires high virus titers to become infected.  No 
>vector infection - no transmission.  It seems counterintuitive that 
>selective pressures play a huge role, if they did then one would expect 
>lower virus titers (unless of course, that virus replication continues 
>at very high speeds).  Well, I feel as if I'm beginning to babble. So 
>I'll leave the question open.   Does anyone have any ideas, thoughts or
> information?  Do I even have all the facts straight?    Thanks.
>Scott Hoffman
>Graduate Student
>schoffma at badlands.nodak.edu

I know of no work that directly examines the fidelity of flavivirus
polymerase, mainly beacuse it is rather difficult to purify. I don't know
the situation for
ebola, but I bet even less is known. What you are probably referring to is
the difficulty in obtaining mutants, and in particular, defective
interferring RNAs of dengue. However, by growing the virus, you are
imposing selection for the virus which grows best. Since we don't know all
the interactions these viruses have with their host, its hard to speculate
how well adapted a "wild type" strain is. However, bear in mind that the
viruses you mention have compact
genomes, and mutations are often likely to be deleterious, (although they
are much larger than picornas, for example which can bear a large mutation
load). A better way to measure mutation for these viruses would be
reversion frequency of an engineered mutation, but no-one has done this
yet, to my knowledge.

Brett Lindenbach
Program in Immunology                              
Washington University - St Louis                  
brett at borcim.wustl.edu                             

"I own my own pet virus. I get to pet and name her." - Cobain

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