Abstract
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 (P = 0.8025, chi-squared test). Similarly, average catalytic efficiency (−72.6% and −64.5%, respectively) did not significantly differ between protease mutant libraries (P = 0.3414, 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.
Highlights
Genetic robustness is defined as the invariance of phenotypes in the presence of mutations [1, 2]
Protease 17a was derived from HXB2, has four mutations (I15V, I62V, H69R, and I85V), and was selected from a mutant HXB2 protease library generated via random mutagenesis [15]
When the infrequently occurring H69R and I85V substitutions were individually incorporated into the HXB2 background, H69R was moderately deleterious (65% of wild-type catalytic efficiency) and I85V was highly deleterious (8% of wild-type catalytic efficiency; Fig. 2)
Summary
Genetic robustness is defined as the invariance of phenotypes in the presence of mutations [1, 2]. Robustness may increase the amount of neutral genetic variation in a population; if these neutral mutations have epistatic interactions with subsequent mutations (their combined effect on fitness differs from that expected from their effects in isolation), the number of available phenotypes may be increased in a particular sequence space. In infected individuals, HIV-1 circulates as a quasispecies, that is, as genetically related viruses that are closely distributed around a consensus sequence [10]. This strong mutational pressure suggests that robustness may be an adaptive trait for HIV-1. It is still unclear whether RNA viruses have evolved to become robust to mutation
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