Figure 1.

Pleiotropy and epistasis are key factors in the evolution of antibiotic resistance. (a) Definition of pleiotropy and epistasis. Phenotypes P1 and P2 affect fitness (or antibiotic resistance) and are determined by genes a and b. Plus/minus signs indicate positive/negative effects. Gene a has antagonistic pleiotropic effects on both phenotypes, while gene b is not pleiotropic. Epistasis is the dependence of the phenotypic or fitness effect of a gene on the effect of another gene; epistasis at the level of fitness may thus arise from gene interactions determining underlying phenotypes or from interactions among phenotypes in their effect on fitness, or both (opportunity for epistasis indicated by double-headed red arrows). (b) Knowledge of pleiotropy and epistasis allows evolutionary predictions. Shown are fitness effects of alleles A and B in a red and in a blue environment. In both environments, AB is the fittest (or most resistant) combination. In the red environment, A and B are not epistatic and both pathways from ab to AB (shown by red arrows) are equally likely. However, in the blue environment, alleles A and B show sign epistasis, leading to the low-fitness combination Ab. As a result, one pathway (ab > aB > AB, shown by blue arrows) is much more likely under the influence of natural selection than the other (ab > Ab > AB), making evolution relatively predictable.