Hidden randomness between fitness landscapes limits reverse evolution.

In biological evolution, adaptations to one environment can in some cases reverse adaptations to another environment. To study this "reverse evolution" on a genotypic level, we measured the fitness of E. coli strains with each possible combination of five mutations in an antibiotic-resistance gene in two distinct antibiotic environments. While adaptations to one environment generally lower fitness in the other, we find that reverse evolution is rarely possible and falls as the complexity of adaptations increases, suggesting a probabilistic, molecular form of Dollo's law.