Résumé
Fisher's geometrical model (FGM) has been widely used to depict the
fitness effects of mutations. It is a general model with few underlying
assumptions that gives a large and comprehensive view of adaptive
processes. It is thus attractive in several situations, e.g. adaptation to
antibiotics, but comes with limitations, so that more mechanistic
approaches are often preferred to interpret experimental data. It might be
possible however to extend FGM assumptions to better account for
mutational data. This is theoretically challenging in the context of
antibiotic resistance because resistance mutations are assumed to be rare.
In this paper, we show with Escherichia coli how the fitness effects of
resistance mutations screened at different doses of nalidixic acid vary
across a dose-gradient. We found experimental patterns qualitatively
consistent with the basic FGM (rate of resistance across doses, gamma
distributed costs) but also unexpected patterns such as a decreasing mean
cost of resistance with increasing screen-dose. We show how different
extensions involving mutational modules and variations in trait covariance
across environments, can be discriminated based on these data. Overall,
simple extensions of the FGM accounted well for complex mutational effects
of resistance mutation across antibiotic doses.