Epistasis as a Determinant of the HIV-1 Protease’s Robustness to Mutation


Capel E, Parera M, Martinez MA (2014) Epistasis as a Determinant of the HIV-1 Protease’s Robustness to Mutation. PLoS ONE 9(12): e116301. doi:10.1371/journal.pone.0116301


The robustness of phenotypes to mutation is critical to protein evolution; robustness may be an adaptive trait if it promotes evolution. We hypothesised that native proteins subjected to natural selection in vivo should be more robust than proteins generated in vitro in the absence of natural selection. We compared the mutational robustness of two human immunodeficiency virus type 1 (HIV-1) proteases with comparable catalytic efficiencies, one isolated from an infected individual and the second generated in vitro via random mutagenesis. Single mutations in the protease (82 and 60 in the wild-type and mutant backgrounds, respectively) were randomly generated in vitro and the catalytic efficiency of each mutant was determined. No differences were observed between these two protease variants when lethal, neutral, and deleterious mutations were compared (P50.8025, chisquared test). Similarly, average catalytic efficiency (272.6% and 264.5%, respectively) did not significantly differ between protease mutant libraries (P50.3414, Mann Whitney test). Overall, the two parental proteins displayed similar mutational robustness. Importantly, strong and widespread epistatic interactions were observed when the effect of the same mutation was compared in both proteases, suggesting that epistasis can be a key determinant of the robustness displayed by the in vitro generated protease.


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Elena Capel, Mariona Parera, Miguel Angel Martinez


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