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the magnitude of the mean fitness across subpopulations and, with less support, a decrease in the fitness difference among subpopulations with the magnitude of the migration. The results, in full agreement with population genetics theory, can be explained by the spread of beneficial mutations, originated in single isolated populations, through the entire population.

CLONAL INTERFERENCE IMPOSES A LIMIT ON THE RATE OF VIRUS ADAPTATION

Viral populations adapt through the appearance and fixation of beneficial mutations. In large asexual populations such as of VSV, where mutation rate and population size are the key state variables, beneficial mutations may arise frequently enough that two or more are coexisting. When this happens, among other properties of the clonal interference model (Guerrish and Lenski, 1992), we expect, for increasing population sizes, that (i) the fitness effect associated with a fixed beneficial mutation will be larger, and (ii) the rate of adaptation will tend toward a limit. These two predictions were demonstrated to hold in experimental populations of VSV (Miralles et al., 1999). As already described, we carried out experiments with two competing populations of initially similar fitness (i.e., MARM C and wild type). Experiments were done at seven (five times replicated) different effective population sizes ranging from 100 to 108 viral particles. Once one of two variants became fixed, we measured its fitness relative to its nonevolved counterpart. The major results are summarized in Fig. 3. The larger the population size, the bigger the effect associated with a beneficial mutation that becomes fixed in the population ( Fig. 3A). In addition (Fig. 3B), the rate of adaptation slows down with increasing effective population size as a consequence of longer times required for fixation of beneficial mutations: in other words, the winning clone must outblock more alternative less-beneficial genotypes.

From data shown in Fig. 3 it is possible to estimate the rate at which beneficial mutations are generated, as well as its average effect on fitness (Guerrish and Lenski, 1992). The estimated value for the beneficial mutation rate (Miralles et al., 1999) was 6.4 × 10-8 beneficial mutations per genome and generation. The effective population sizes studied, all higher than 109, warranted the possibility of appearance of a beneficial mutation, giving support to the assumption that a single beneficial mutation in each lineage is responsible for the fitness increase (Fig. 3). Comparing our estimate with that of the total mutation rate in VSV (2-3.5 substitutions per genome and generation), we can infer that one of 2 × 108 mutations produced in VSV can be considered as beneficial. On the other hand, the maximum-likelihood estimate of the mean selective advantage of all ben-



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