UC San Diego

For decades, scientists have been fascinated by the ease with which viruses, seemingly simple life forms, evolve new feats of innovation. One viral innovation relevant to humans is gaining infectivity on a new host type. Although numerous instances of viral host-range expansion have been documented, we still lack the ability to predict them reliably. In part, this is because many factors affect whether a host shift will occur, ranging from molecular interactions to host behavior. To increase the tractability of this problem, scientists are beginning to ask whether viruses might vary in their innate evolvability, or capacity for adaptive evolution. I focused on the role of stability, here defined as thermodynamic stability, an intrinsic trait of viral proteins thought to enhance evolvability. Using the well-studied host-range expansion of bacteriophage λ, I first showed how mutations that confer expanded host range destabilize the receptor binding protein and allow it to assume alternative conformations with new binding activity. Then, I showed that among λ genotypes varying in stability, the most evolvable tended to be the most unstable, and the stable genotypes that did evolve gained destabilizing mutations. Instability promoted the evolution of new host range, in contrast to the widely cited consensus that stability enhances evolvability. I discovered one λ genotype that exhibited high stability and evolvability, but it grew poorly, suggesting a three-way tradeoff between stability, evolvability, and reproduction. This result led to another question: if traits that affect current fitness, like stability and reproductive rate, trade off with future evolutionary capacity, then which traits most influence the outcome of coevolutionary arms races between viruses and their hosts? I examined which traits influence λ’s ability to overcome host resistance and maintain infectivity on its coevolving host bacteria. The fast-reproducing, evolvable, but unstable genotype emerged most successful, suggesting that lineages that initially appear poorly adapted may give rise to progeny that persist due to their capacity to evolve. This work suggests that a positive, linear relationship between stability and evolvability does not hold in all scenarios, with important implications for predicting viral emergence and selecting genotypes for phage therapy.