Fast RNA evolution – a recipe for disaster

RNA evolution is a fascinating topic. Molecular evolutionists have used RNA virus examples for many years because RNA evolves fast and displays many of the principles we are trying to get across to our students. Take for example the concept of ‘error catastrophe’. Error catastrophe is a wonderful phrase to pop into any science conversation. Basically it means that when the mutation rate is high, just a little more can push an RNA organism over the edge into extinction. 

Alright, this sounds very Frankenstein mutant monster-ish but put in context, RNA viruses are organisms that use RNA as their genome and include HIV, Hepatitis, SARS, Rubella, Poliovirus and Measles. To succeed in replicating in their host (us) they need to overcome the host defences (like all that RNAi) so they mutate so the virus particles that have the best fitness will pass onto the next host. So within an infected host you do not have clonal (identical) copies of a virus but instead you have a population with minor differences between them.  However, the down side to having high error rates that can permit high mutation is that if you go over the limit you produce too many errors and your genes fail. Mutation is good, so long as you still function.

Going over this limit (or error threshold) was investigated by Manfried Eigen in 1971 and there are some beautiful mathematical scratchings involved in calculating this limit based on mutation rate and genome size. Breathe a sigh of relief because I am not going to go into them. In short, unless you control your errors you can only sustain a genome size of about 200 nucleotides. To go beyond that genome size you need error checking enzymes and sacrifice the ability to mutate super-fast. Humans have 2.9 billion base pairs in their DNA and a lot of checking.

This brings up the idea of ‘if I mutate the hell out a virus, will it die’. The answer is...yes...for some.

A famous experiment by Crotty et al. used Ribavirin (an mutagen) on the Hepatitis C virus and showed that the action of this drug was to increase error and it did kill the virus (see the graph below). There is a lot of research around that looks at mutagens and viruses but you do have to watch out for what is happening to the host. If you take movies as your source of science you could say it was no good killing the virus if your host becomes something from ‘Splice’.  RNA viruses really do live life on the edge, and despite all other life being against them, they persist.   Not a happy thought as the northern hemisphere moves into cold and flu season. Sorry but as you sniffle you can always check up on Error Catastrophe and imagine mutating your invaders to extinction.

 

Crotty et al. 2001 PNAS 107:6895-6900

The graph shows that poliovirus populations exist near the edge of error catastrophe, as there is a rapid decline in RNA genome infectivity at levels of mutagenesis only slightly higher than normal. The LI50 (50% loss of specific infectivity) is the mutation frequency at which 50% of the viral genomes are lethally mutated, indicated by the dashed line. Wild-type poliovirus genomes contain an average 1.5 mutations/genome. 100mM ribavirin treatment caused about 1.9 mutations/genome, 400mM ribavirin caused about 6.9 mutations/genome, and 1,000mM ribavirin caused about mutations/genome.