Biology subjects

Wylie, C. S.

Publications and source records attributed to Wylie, C. S..

3 recordsLinked to original sources

bioRxiv2020

Predicting the Viability of Beta-Lactamase: How Folding and Binding Free Energies Correlate with Beta-Lactamase Fitness

One of the long-standing holy grails of molecular evolution has been the ability to predict an organisms fitness directly from its genotype. With such predictive abilities in hand, researchers would be able to more accurately forecast how organisms will evolve and how proteins with novel functions could be engineered, leading to revolutionary advances in medicine and biotechnology. In this work, we assemble the largest reported set of experimental TEM-1 {beta}-lactamase folding free energies and use this data in conjunction with previously acquired fitness data and computational free energy predictions to determine how much of the fitness of {beta}-lactamase can be directly predicted by thermodynamic folding and binding free energies. We focus upon {beta}-lactamase because of its long history as a model enzyme and its central role in antibiotic resistance. Based upon a set of 21 {beta}-lactamase single and double mutants expressly designed to influence protein folding, we first demonstrate that modeling software such as FoldX and PyRosetta designed to compute folding free energies can meaningfully, although not perfectly, predict the experimental folding free energies of single mutants. Interestingly, while these techniques also yield sensible double mutant free energies, we show that they do so for the wrong physical reasons. We then go on to assess how well both experimental and computational folding free energies explain single mutant fitness. We find that folding free energies account for, at most, 24% of the variance in {beta}-lactamase fitness values according to linear models and, somewhat surprisingly, complementing folding free energies with computationally-predicted binding free energies of residues near the active site only increases the folding-only figure by a few percent. This strongly suggests that the majority of {beta}-lactamases fitness is controlled by factors other than free energies. Overall, our results shed a bright light on to what extent the community is justified in using thermodynamic measures to infer protein fitness as well as how applicable modern computational techniques for predicting free energies will be to the large data sets of multiply-mutated proteins forthcoming.

biophysics↗

bioRxiv2017

Sign of selection on mutation rate modifiers depends on population size

The influence of population size (N) on natural selection acting on alleles that affect fitness has been understood for over half a century1. As N declines, genetic drift overwhelms selection and alleles with direct fitness effects are rendered neutral. Often, though, alleles experience so called indirect selection, meaning they affect not the fitness of an individual but the fitness distribution of its offspring. Some of the best studied examples of indirect selection include alleles that modify aspects of the genetic system such as recombination2 and mutation3 rates. Here we use analytics, simulations and experimental populations of S. cerevisiae to show that modifiers that increase the genomic mutation rate (mutators) are favored by indirect selection in large populations but become disfavored as N declines. This surprising phenomenon of sign inversion in selective effect demonstrates that indirect selection on a mutator exhibits a qualitatively novel dependence on N. Sign inversion may help understand the relatively sporadic distribution of mutators in nature despite their frequent emergence in laboratory populations. More generally, sign inversion may be broadly applicable to other instances of indirect selection, suggesting a previously unappreciated but critical role of population size in evolution.

evolutionary biology↗

bioRxiv2017

Natural selection can favor the evolution of ratchet robustness over evolution of mutational robustness

The vast majority of fitness-affecting mutations are deleterious. How natural populations evolve to cope is a question of fundamental interest. Previous studies have reported the evolution of mutational robustness, that is, natural selection favoring populations with less deleterious mutations. By definition, mutational robustness provides a short-term fitness advantage. However, this overlooks the fact that mutational robustness decreases finite asexual populations ability to purge recurrent deleterious mutations. Thus, mutational robustness also results in higher risk of long-term extinction by Mullers ratchet. Here, we explore the tension between short- and long- term response to deleterious mutations. We first show that populations can resist the ratchet if either the selection coefficient or the ratio of beneficial to deleterious mutations increases as fitness declines. We designate these properties as ratchet robustness, which fundamentally reflects a negative feedback between mutation rate and the tendency to accumulate more mutations. We also find in simulations that populations can evolve ratchet robustness when challenged by deleterious mutations. We conclude that mutational robustness cannot be selected for in the long term, but it can be favored in the short-term, purely because of temporary fitness advantage. We also discuss other potential causes of mutational robustness in nature.

evolutionary biology↗