Rank orders and signed interactions in evolutionary biology.

Rank orders have been studied in evolutionary biology for almost a hundred years. Constraints on the order in which mutations accumulate are known from cancer drug treatment, and order constraints for species invasions are important in ecology. However, current theory on rank orders in biology is somewhat fragmented. Here, we show how our previous work on inferring genetic interactions from comparative fitness data (Crona et al., 2017) is related to an influential approach to rank orders based on sign epistasis. Our approach depends on order perturbations that indicate interactions. We apply our results to malaria parasites and find that order perturbations beyond sign epistasis are prevalent in the antimalarial drug-resistance landscape. This finding agrees with the observation that reversed evolution back to the ancestral type is difficult. Another application concerns the adaptation of bacteria to a methanol environment.