Until the late 1970s the diversity of viral populations was not widely appreciated. The first study to quantitatively describe viral diversity employed the RNA bacteriophage Q-beta. The authors made a startling conclusion based on their analysis of variation within stocks of the virus:
A Q-beta phage population is in a dynamic equilibrium with viral mutants arising at a high rate on the one hand, and being strongly selected against on the other. The genome of Q-beta cannot be described as a defined unique structure, but rather as a weighted average of a large number of different individual sequences.
This variation, which is a consequence of the error prone nature of viral replication, has since been confirmed using other viral systems. Virologists now understand that virus populations are not made of a single member with a defined nucleic acid sequence. Rather, they are dynamic distributions of nonidentical but related members called a quasispecies. It was given this name because the classical definition of species – an interbreeding population of individuals – has little meaning for viruses.
The consequence of a quasispecies is that most viral infections are initiated not by a single virion, but a population of particles. The progeny produced after this infection results from selective forces that operate inside the infected host. The virions that go on to infect a new host have passed through another set of external selective forces. A steady-state population of a viral quasispecies consists of a vast number of particles.
The diagram above shows a small subset of the viral genomes that are present in a virus stock. Genomes are indicated by lines, and mutations are shown by different symbols. The consensus sequence for this population is shown as a line at the bottom. There are no mutations in the consensus sequence, even though every viral genome contains mutations. This is because no mutation is present at sufficiently high levels to achieve a consensus at any position.
Although this concept may seem abstract, as we consider more aspects of viral biology it will become obvious. A key point is that the genome sequences of viruses cluster around an average sequence, but every genome is probably different from that consensus. This means that sequences of the new influenza H1N1 viruses on NCBI or GISAID sequences represent a consensus, and do not represent the population that infected any of the thousands of individuals in Mexico during the past month. Luis Villareal, a prominent evolutionary virologist, had the following thoughts about quasispecies and the current influenza epidemic:
Flu researchers believe in the master template as being the fittest type. I think this has been to their detriment and is currently confusing the field as we witness the evolution of emergence. I would be willing to bet money, that if the quasispecies composition were measured, we would see clear differences between those patients that died in Mexico compared to the much less virulent outcome in the USA.
Until recently it was not possible to know the sequences of all the viral genomes present in a population such as that illustrated in the figure. The development of deep sequencing methods such as 454 pyrosequencing has now made it possible to study the quasispecies. This method can detect the individual variants within a viral population.
Tomorrow we’ll consider how selection pressures within a host can change the quasispecies.
Domingo, E. (1978). Nucleotide sequence heterogeneity of an RNA phage population Cell, 13 (4), 735-744 DOI: 10.1016/0092-8674(78)90223-4