A Linear Relationship between Fitness and the Logarithm of the Critical Bottleneck Size in Vesicular Stomatitis Virus Populations

Abstract

We explored the relationship between fitness change and population size during transmission in vesicular stomatitis populations of very high fitness. The results show a linear correlation between the logarithm of the critical bottleneck size (population size at which there are no significant fitness changes after 20 passages) and the initial fitness of the population. In addition, limits to fitness increases during large-population passages of very-high-fitness strains were abolished by increasing the population size during transmission, indicating that beneficial variation is still available in these populations. Viral evolution is the result of selection and random drift operating on the genetic variation that arises during replication. Random drift dominates during bottleneck transmissions because sampling effects lead to the loss of beneficial mutations or the fixation of deleterious mutations. Bottlenecks are common during natural infections, particularly among respiratory viruses. In an earlier report, we found a correlation between the fitness of vesicular stomatitis virus (VSV) strains and the critical bottleneck size (CBS) in low-fitness populations subjected to repeated severe bottlenecks (transmission sizes of 2 to 30 PFU) (8). We defined the CBS as the number of virus particles used for transmission that resulted in no net fitness changes at the end of 20 passages. Later, we and others reported that limits to fitness gains (and fitness losses) during large-population passages were consistent with a linear relationship between initial fitness and the logarithm of the CBS (9, 10). Miralles et al. (6) argued against this relationship and proposed that limits to further fitness gains reflected the exhaustion of beneficial variation. Their main criticism was that a linear relationship observed at small bottleneck sizes could not be extrapolated to bottleneck sizes that were several orders of magnitude larger. To resolve this question, we tested whether the relationship between the logarithm of the CBS and fitness was still linear for strains with high fitness.We generated several VSV populations with fitness levels between 5.5 and 15 in BHK-21 cells (Table 1) through 35 to 50 large-population passages (2 ϫ 10 5 PFU/passage unless otherwise indicated) of monoclonal antibody-resistant mutant (MARM) U, a strain that has neutral fitness compared to the wild type (wt) and differs from the wt only in a genetic marker that provides resistance to monoclonal antibody I1 (5). Each strain was obtained from an independent replica of MARM U passages except strain Marilyn, which is the progeny of Bonnie after 20 additional passages at 2 ϫ 10 4 PFU/passage, and Victoria, which is the progeny of Marilyn after 20 additional passages at 4 ϫ 10 6 PFU/passage. All passages were done at a constant multiplicity of infection of 0.1 PFU/cell by using flasks of the appropriate size for each population size; for all passages, the number of cells infected equals the number of PFU used for infection. For each population, we carried ...

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