skip to main content


Title: Epistasis and evolution: recent advances and an outlook for prediction
Abstract

As organisms evolve, the effects of mutations change as a result of epistatic interactions with other mutations accumulated along the line of descent. This can lead to shifts in adaptability or robustness that ultimately shape subsequent evolution. Here, we review recent advances in measuring, modeling, and predicting epistasis along evolutionary trajectories, both in microbial cells and single proteins. We focus on simple patterns of global epistasis that emerge in this data, in which the effects of mutations can be predicted by a small number of variables. The emergence of these patterns offers promise for efforts to model epistasis and predict evolution.

 
more » « less
Award ID(s):
1914916
NSF-PAR ID:
10415620
Author(s) / Creator(s):
; ;
Publisher / Repository:
Springer Science + Business Media
Date Published:
Journal Name:
BMC Biology
Volume:
21
Issue:
1
ISSN:
1741-7007
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
More Like this
  1. null (Ed.)
    Epistasis between mutations can make adaptation contingent on evolutionary history. Yet despite widespread ‘microscopic’ epistasis between the mutations involved, microbial evolution experiments show consistent patterns of fitness increase between replicate lines. Recent work shows that this consistency is driven in part by global patterns of diminishing-returns and increasing-costs epistasis, which make mutations systematically less beneficial (or more deleterious) on fitter genetic backgrounds. However, the origin of this ‘global’ epistasis remains unknown. Here, we show that diminishing-returns and increasing-costs epistasis emerge generically as a consequence of pervasive microscopic epistasis. Our model predicts a specific quantitative relationship between the magnitude of global epistasis and the stochastic effects of microscopic epistasis, which we confirm by reanalyzing existing data. We further show that the distribution of fitness effects takes on a universal form when epistasis is widespread and introduce a novel fitness landscape model to show how phenotypic evolution can be repeatable despite sequence-level stochasticity. 
    more » « less
  2. Abstract

    The structure, function, and evolution of proteins depend on physical and genetic interactions among amino acids. Recent studies have used new strategies to explore the prevalence, biochemical mechanisms, and evolutionary implications of these interactions—called epistasis—within proteins. Here we describe an emerging picture of pervasive epistasis in which the physical and biological effects of mutations change over the course of evolution in a lineage‐specific fashion. Epistasis can restrict the trajectories available to an evolving protein or open new paths to sequences and functions that would otherwise have been inaccessible. We describe two broad classes of epistatic interactions, which arise from different physical mechanisms and have different effects on evolutionary processes. Specific epistasis—in which one mutation influences the phenotypic effect of few other mutations—is caused by direct and indirect physical interactions between mutations, which nonadditively change the protein's physical properties, such as conformation, stability, or affinity for ligands. In contrast, nonspecific epistasis describes mutations that modify the effect of many others; these typically behave additively with respect to the physical properties of a protein but exhibit epistasis because of a nonlinear relationship between the physical properties and their biological effects, such as function or fitness. Both types of interaction are rampant, but specific epistasis has stronger effects on the rate and outcomes of evolution, because it imposes stricter constraints and modulates evolutionary potential more dramatically; it therefore makes evolution more contingent on low‐probability historical events and leaves stronger marks on the sequences, structures, and functions of protein families.

     
    more » « less
  3. Abstract

    Interactions between mutations (epistasis) can add substantial complexity to genotype-phenotype maps, hampering our ability to predict evolution. Yet, recent studies have shown that the fitness effect of a mutation can often be predicted from the fitness of its genetic background using simple, linear relationships. This phenomenon, termedglobal epistasis, has been leveraged to reconstruct fitness landscapes and infer adaptive trajectories in a wide variety of contexts. However, little attention has been paid to how patterns of global epistasis may be affected by environmental variation, despite this variation frequently being a major driver of evolution. This is particularly relevant for the evolution of drug resistance, where antimicrobial drugs may change the environment faced by pathogens and shape their adaptive trajectories in ways that can be difficult to predict. By analyzing a fitness landscape of four mutations in a gene encoding an essential enzyme ofP. falciparum(a parasite cause of malaria), here we show that patterns of global epistasis can be strongly modulated by the concentration of a drug in the environment. Expanding on previous theoretical results, we demonstrate that this modulation can be quantitatively explained by how specific gene-by-gene interactions are modified by drug dose. Importantly, our results highlight the need to incorporate potential environmental variation into the global epistasis framework in order to predict adaptation in dynamic environments.

     
    more » « less
  4. As an adapting population traverses the fitness landscape, its local neighborhood (i.e., the collection of fitness effects of single-step mutations) can change shape because of interactions with mutations acquired during evolution. These changes to the distribution of fitness effects can affect both the rate of adaptation and the accumulation of deleterious mutations. However, while numerous models of fitness landscapes have been proposed in the literature, empirical data on how this distribution changes during evolution remains limited. In this study, we directly measure how the fitness landscape neighborhood changes during laboratory adaptation. Using a barcode-based mutagenesis system, we measure the fitness effects of 91 specific gene disruption mutations in genetic backgrounds spanning 8000–10,000 generations of evolution in two constant environments. We find that the mean of the distribution of fitness effects decreases in one environment, indicating a reduction in mutational robustness, but does not change in the other. We show that these distribution-level patterns result from differences in the relative frequency of certain patterns of epistasis at the level of individual mutations, including fitness-correlated and idiosyncratic epistasis. 
    more » « less
  5. Natural selection drives populations toward higher fitness, but second-order selection for adaptability and mutational robustness can also influence evolution. In many microbial systems, diminishing-returns epistasis contributes to a tendency for more-fit genotypes to be less adaptable, but no analogous patterns for robustness are known. To understand how robustness varies across genotypes, we measure the fitness effects of hundreds of individual insertion mutations in a panel of yeast strains. We find that more-fit strains are less robust: They have distributions of fitness effects with lower mean and higher variance. These differences arise because many mutations have more strongly deleterious effects in faster-growing strains. This negative correlation between fitness and robustness implies that second-order selection for robustness will tend to conflict with first-order selection for fitness.

     
    more » « less