Figure 1.

Failure to establish population bottlenecks leads to rapid accumulation of deleterious mutations as viral infection progresses in consecutive cells. Meanings of the symbols used are given on the very top. Abbreviations: RdRp, RNA-dependent RNA polymerase; ORF, open reading frame. The three gray rectangular boxes immediately underneath the symbols depict three cells consecutively infected by a virus population, unconstrained by population bottlenecks. Absence of bottlenecks allows all internalized genomes, including the one with a deleterious mutation in RdRp (red star), to replicate, leading to the retention of existing mutation, as well as emergence of new mutations. As a result, the viral population entering the second round cells contains higher proportion of mutant genomes encoding defective RdRp than does the initial population. The correspondingly lower proportion of genomes encoding functional RdRp is predicted to lead to less robust replication. This trend continues in subsequent cells, eventually causing the viral population to collapse. By contrast, the three green rectangles at the bottom depict different primary cells invaded by viral populations with essentially the same composition, but this time the populations are bottlenecked. As a result, only one of the internalized genomes stochastically escapes the bottleneck to replicate. In both the left and right cells, the genomes succeeding in replication encode functional RdRp, producing progeny genomes that are mostly capable of launching renewed replication in the next set of cells. In the middle cell, the stochastically escaping genome encodes a defective RdRp but can nevertheless replicate using RdRps encoded by other genome copies. However, the defective progenies are unable to replicate in the next set of cells they invade. For simplicity, only five founding genomes were drawn to represent the dozens, if not hundreds, of viral genomes received by most of the susceptible cells in a typical host individual. Furthermore, our discussions also omitted detrimental, yet non-lethal mutations.