Perspective: Sign epistasis and genetic constraint on evolutionary trajectories.

Department of Organismic and Evolutionary Biology, Harvard University, 16 Divinity Avenue, Cambridge, Massachusetts 02138, USA.
Evolution (Impact Factor: 4.66). 07/2005; 59(6):1165-74. DOI: 10.1554/04-272
Source: PubMed

ABSTRACT Epistasis for fitness means that the selective effect of a mutation is conditional on the genetic background in which it appears. Although epistasis is widely observed in nature, our understanding of its consequences for evolution by natural selection remains incomplete. In particular, much attention focuses only on its influence on the instantaneous rate of changes in frequency of selected alleles via epistatic contribution to the additive genetic variance for fitness. Thus, in this framework epistasis only has evolutionary importance if the interacting loci are simultaneously segregating in the population. However, the selective accessibility of mutational trajectories to high fitness genotypes may depend on the genetic background in which novel mutations appear, and this effect is independent of population polymorphism at other loci. Here we explore this second influence of epistasis on evolution by natural selection. We show that it is the consequence of a particular form of epistasis, which we designate sign epistasis. Sign epistasis means that the sign of the fitness effect of a mutation is under epistatic control; thus, such a mutation is beneficial on some genetic backgrounds and deleterious on others. Recent experimental innovations in microbial systems now permit assessment of the fitness effects of individual mutations on multiple genetic backgrounds. We review this literature and identify many examples of sign epistasis, and we suggest that the implications of these results may generalize to other organisms. These theoretical and empirical considerations imply that strong genetic constraint on the selective accessibility of trajectories to high fitness genotypes may exist and suggest specific areas of investigation for future research.

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    ABSTRACT: The importance of historical contingency in evolution has been extensively debated over the last few decades, but direct empirical tests have been rare. Twelve initially identical populations of E. coli were founded in 1988 to investigate this issue. They have since evolved for more than 50,000 generations in a glucose-limited medium that also contains a citrate. However, the inability to use citrate as a carbon source under oxic conditions is a species-defining trait of E. coli. A weakly Cit+ variant capable of aerobic citrate utilization finally evolved in one population just prior to 31,500 generations. Shortly after 33,000 generations, the population experienced a several-fold expansion as strongly Cit+ variants rose to numerical dominance (but not fixation). The Cit+ trait was therefore a key innovation that increased both population size and diversity by opening a previously unexploited ecological opportunity. The long-delayed and unique evolution of the Cit+ innovation might be explained by two possible hypotheses. First, evolution of the Cit+ function may have required an extremely rare mutation. Alternately, the evolution of Cit+ may have been contingent upon one or more earlier mutations that had accrued over the population’s history. I tested these hypotheses in a series of experiments in which I “replayed” evolution from different points in the population’s history. I observed no Cit+ mutants among 8.4 x 1012 ancestral cells, nor among 9 x 1012 cells from 60 clones sampled in the first 15,000 generations. However, I observed a significantly greater tendency to evolve Cit+ among later clones. These results indicate that one or more earlier mutations potentiated the evolution of Cit+ by increasing the rate of mutation to Cit+ to an accessible, though still very low, level. The evolution of the Cit+ function was therefore contingent on the particular history of the population in which it occurred. I investigated the Cit+ innovation’s history and genetic basis by sequencing the genomes of 29 clones isolated from the population at various time points. Analysis of these genomes revealed that at least 3 distinct clades coexisted for more than 10,000 generations prior to the innovation’s evolution. The Cit+ trait originated in one clade by a tandem duplication that produced a new regulatory module in which a silent citrate transporter was placed under the control of an aerobically-expressed promoter. Subsequent increases in the copy number of this new regulatory module refined the initially weak Cit+ phenotype, leading to the population expansion. The 3 clades varied in their propensity to evolve the novel Cit+ function, though genotypes able to do so existed in all 3, implying that potentiation involved multiple mutations. My findings demonstrate that historical contingency can significantly impact evolution, even under the strictest of conditions. Moreover, they suggest that contingency plays an especially important role in the evolution of novel innovations that, like Cit+, require prior construction of a potentiating genetic background, and are thus not easily evolved by gradual, cumulative selection. Contingency may therefore have profoundly shaped life’s evolution given the importance of evolutionary novelties in the history of life. Finally, the genetic basis of the Cit+ function illustrates the importance of promoter capture and altered gene regulation in mediation the exaptation events that often underlie evolutionary innovations.
    03/2011, Degree: PhD, Supervisor: Richard E. Lenski
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    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 (P50.8025, chi-squared test). Similarly, average catalytic efficiency (272.6% and 264.5%, respectively) did not significantly differ between protease mutant libraries (P50.3414, 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.
    PLoS ONE 12/2014; 9(12). · 3.53 Impact Factor
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    ABSTRACT: Defining the extent and significance of epistasis - the non-independence of the effects of mutations - is critical for understanding the relationship of genotype, phenotype, and ultimately fitness in biological systems. Distinct theoretical approaches have been introduced to analyze epistatic interactions to arbitrary order (pairwise, 3-way, 4-way, etc.), and currently there is no formal exposition of the relationship of these approaches. First, in biochemistry, the formalism of thermodynamic mutant-cycles is used to measure the energetic non-additivity of mutations in equilibrium measurements. Second, in evolutionary genetics, a formalism originating from the field of telecommunication called the Walsh-Hadamard transform has been introduced, which captures the non-independence of mutational effects across different genetic backgrounds. Third, with the emergence of high-throughput mutational data, linear regression has been applied to estimate the relative importance of higher-order epistasis. Here, we demonstrate that simple mathematical relationships link these different formalisms, a finding that brings together definitions from otherwise distinct scientific fields into a single framework. We show that both thermodynamic mutant cycles and regression-based methods represent special cases of the more general definition of epistasis in evolutionary genetics. We discuss approaches to handle the common situation in which the combinatorial complexity of possible epistatic terms exceeds the actual number of data points and examine the applicability of these approaches depending on the specific reasons underlying the interest in epistasis.

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May 20, 2014