The Concept of Quasispecies

RNA Polymerase
RNA Polymerase (Photo credit: ynse)

Today’s topic is directly related to my own research with RNA viruses and is what I consider a very interesting topic: quasispecies.

Many of us are familiar with the concept of a species at the macro (visible) scale. Dogs are dogs; pigs are pigs, and so on. Each is a distinct species based on the fact that they can only reproduce and generate fertile offspring with other members of the same species. Over the course of many generations mutations may arise in these populations which lead to different genotypes in the species. Left long enough, these two subpopulations may keep mutating to the point where they can no longer interbreed and become their own genetically distinct species. However, when you get down to the viral scale species becomes a much more difficult concept. Viruses don’t have sex in the traditional sense, so how can they be a species?

Modern virology deals with this by categorizing viruses based primarily on genetic sequencing. In the past this was once an extremely labor and resource intensive process, but as science has progressed the level of sophistication has allowed us to making sequencing a routine task with a wide variety of applications. Now that many viruses have been sequenced, scientists have been able to categorize viral species based on their genetic sequence (this is much more accurate than methods used in the past as well). For example, if two viruses differ enough genetically they would be considered different species. This is where things begin to get more complicated though, because some viruses mutate at such a high rate that during an infection a whole population of closely related but genetically different viruses arise. These are termed a quasispecies due to the fact that they are all from the same species, but some of the mutants may have slightly different behavior/function from the parental virus leading them to be almost (quasi) that species.

The founder virus with no mutations is on the left. After being copied though, mutations (shown as different colored spots on the genome) are introduced randomly across the genome.
The founder virus genomewith no mutations is on the left as a black line. After being copied, mutations (shown as different colored spots on the genome) are introduced randomly across the genome to make an expanded viral quasispecies.

This concept is the most important in relation to RNA viruses. These viruses, by the very nature of their genetic structure, have to make for what is known as a viral RNA-dependent RNA polymerase (RdRp) in order to replicate their RNA-based genetic code. This protein is capable of reading the viral genetic message and making a duplicate copy out of the 4 RNA bases: uracil, guanine, cytosine, and adenine. While this is a limited alphabet from which to spell, the viral RdRp has spell-check issues and (depending on the virus) make a spelling error once out of every 10,000 or so base pairs of RNA. While this doesn’t sound like that many spelling errors for an essay, in the context of an RNA virus this can be a significant number of mutations.

For example, let’s imagine an RNA virus with a genome of 10,000 bases. This means that every single copy that is made will have, on average, one random mutation. If this mutation doesn’t change the viral proteins it is considered a “silent” mutation and has no direct effect on viral proteins or on viral fitness. However, when a mutation occurs in where it changes the amino acid code in a protein it can create mutants with different levels of fitness in the host environment. What results is a “cloud” of very closely related but genetically distinct progeny virus.  Multiple different mutants then make up this quasispecies population in a single host.

At this point you’re probably wondering why this is important. This breadth of different sequences can be advantageous for a viral species infecting a host. With so many mutations taking place there is always the risk of a mutation resulting in a fatal error that makes the virus incapable of replicating. However, part of the sequence may still be good and there is the chance that it could recombine with another strand of viral RNA to generate a new sequence that can produce infectious copies. This can keep the viral population from accumulating so many mutations that they suffer what is known as error catastrophe, or the moment where there are so many mutations that the virus is no longer infectious or functional.

Aside from allowing for the avoidance of error catastrophe, the quasispecies cloud can actually be advantageous for some viruses because the different mutants may work together in ways that a genetically identical population cannot. Essentially, these minor differences may work together in favor of the virus.

This is a young area of research, but one study using polio virus found that a mutant that made less spelling errors couldn’t cause disease in the brain. The researchers proposed that this is because a virus with less spelling errors will make fewer mutants in the quasispecies and that some of these mutants have to be present for the virus to make it into the brain. However, if this virus was treated with UV light to introduce random mutations (which would make the quasispecies bigger and more varied) virus was able to make it into the brain, indicating that some of these mutants do facilitate entry into the nervous system.

Much research needs to be done in order for researchers to really understand the implications of viral quasispecies in human infection. However, these initial results suggest that it is a phenomenon worth further investigation.

I know this is a rather brief overview of the topic, so feel free to ask any and all questions in the comments section. I am more than happy to spend more time talking about such an interesting topic!

Look for some applied quasispecies research in next week’s article where I will go into a paper about the transmissibility of the hepatitis C virus.

 

[Featured image credit to Flickr user AJ Chan, used under creative commons license.]

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