Furthermore, the four most deleterious steps across all lines accounted for 42.3% of the total fitness decrease throughout the entire experiment.
However, these large deleterious steps showed a significantly higher frequency of mutations in highly conserved core genes than other steps (χ goodness-of-fit test: P = 0.049, χ1 = 3.882; Table S2).
While there are many degrees of freedom that evolution can potentially access in altering cellular networks, only those mutational pathways that do not include deleterious intermediate steps are likely to be realized in most populations (Bridgham et al., 2006, 2009; Weinreich et al., 2006).
Genetic interaction (epistasis) between mutations is thus emphasized here, as often the adaptive phenotypes are more than a single mutation away, and if the intermediate step is deleterious, transversing to the potentially advantageous genotype can be impossible with single-step mutations.
Although the average fitness effect of a step was deleterious, there were numerous steps in which fitness increased.
Here, we report a novel, minimally invasive, localized drug delivery system for delivering MP to the contused adult rat spinal cord that potentially side-steps the deleterious consequences of systemic cortico-steroid therapy.
Despite these increases, no deleterious tests or treatment steps were added by subjects to their plans following DDSS consultation.
By contrast, 32 of these 46 mutational steps were deleterious when assayed in the +EQU environment, a further nine were neutral, and only five were beneficial.
This conclusion is consistent with our experiment based on mutants acting downstream to the ER translocation; the toxicity in some of these mutants was clearly lower, indicating that crucial steps for deleterious effects are required in addition to the translocation event.
The final individually deleterious mutation, V280A, fixed in Step 35.
