Illustrations of compensatory substitution pathways. The frequency of the two high fitness (blues) and low fitness (reds) haplotypes in a population are shown over time. (a) Type 1. Under weak selection the deleterious intermediate can readily fix in the population. (b) Type 2. Under strong selection the deleterious intermediates cannot rise above low frequency, and compensatory substitution must await the second mutation arising while the first is still polymorphic. (c) Under intermediate selection both Type 1 and Type 2 events are possible. Shown is a Type 2 event. Although the deleterious intermediate aB does become fixed, the eventual path to fixation of the double mutant ab begins with AB once again fixed and does not have the deleterious intermediate being fixed.