Abstract
Viruses are highly evolvable, but what traits endow this property? The high mutation rates of viruses certainly play a role, but factors that act above the genetic code, like protein thermostability, are also expected to contribute. We studied how the thermostability of a model virus, bacteriophage λ, affects its ability to evolve to use a new receptor, a key evolutionary transition that can cause host-range evolution. Using directed evolution and synthetic biology techniques we generated a library of host-recognition protein variants with altered stabilities and then tested their capacity to evolve to use a new receptor. Variants fell within three stability classes: stable, unstable, and catastrophically unstable. The most evolvable were the two unstable variants, whereas seven of eight stable variants were significantly less evolvable, and the two catastrophically unstable variants could not grow. The slowly evolving stable variants were delayed because they required an additional destabilizing mutation. These results are particularly noteworthy because they contradict a widely supported contention that thermostabilizing mutations enhance evolvability of proteins by increasing mutational robustness. Our work suggests that the relationship between thermostability and evolvability is more complex than previously thought, provides evidence for a new molecular model of host-range expansion evolution, and identifies instability as a potential predictor of viral host-range evolution.
Highlights
IntroductionThe evolvability of life is evident in its remarkable diversity of forms and persistence through time
For this study we examined the evolutionary potential of different strains of a model virus, bacteriophage λ, to gain the ability to use a new receptor, a key step in host shifts
We discovered that λ variants with destabilized host-recognition proteins were more likely to evolve the necessary mutations to use the new receptor than stabilized variants
Summary
The evolvability of life is evident in its remarkable diversity of forms and persistence through time. The most straightforward is evolving a higher mutation rate which allows populations to explore phenotypic variation that results from genetic changes [3]. This mechanism is constrained by concomitant increases in mutation load that can slow adaptation [4]. There are other qualities of biological systems that can facilitate phenotypic novelty, these too can have conflicting effects This manuscript focuses on one such trait, protein thermostability, which is the propensity to resist misfolding when heated. The conformational flexibility of unstable proteins can be essential for evolvability by allowing non-native conformers, protein molecules that fold into conformations other than the ground-state conformation, to explore promiscuous functions [18,19]. While the most widely accepted view is that thermostability promotes faster protein evolution, most scholars recognize that the relationship between thermostability and evolvability is more complex and that certain types of proteins may be more or less sensitive to either mechanism
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