Global epistasis makes adaptation predictable despite sequence-level stochasticity

Kryazhimskiy, Sergey; Rice, Daniel P.; Jerison, Elizabeth R.; Desai, Michael M.

doi:10.1126/science.1250939

Cited by 443 publications

(542 citation statements)

References 27 publications

(37 reference statements)

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“…Similarly, in selection experiments with the methylotrophic alphaproteobacterium Methylobacterium extorquens AM1, growing on a single-carbon substrate, mean fitness increased at a rate of 0.054% per generation over the initial 300 generations of growth and decreased to 0.009% per generation between generations 900 and 1,500 (37). In five hundred generations of evolution on nutrient-rich medium, 640 separate lines of the model eukaryotic microbe Saccharomyces cerevisiae exhibited a mean fitness that increased at a rate of 0.013% per generation (38). With a wide range of microorganisms and in a variety of selective environments, it seems that experimental evolutionary adaptation produces a common pattern of generally decreasing rates of fitness increase, often with strikingly similar magnitudes in the deceleration of the actual rates.…”

Section: Resultsmentioning

confidence: 99%

“…Both of these processes may play a role in setting the powerlaw trajectory of fitness, as adapting microbial populations sample a larger and larger number of mutations (51). However, both apparently are underlain by an inherent unpredictability regarding which groups of beneficial mutations actually become fixed (38,52). Detailed examinations of whole genomes are required to determine whether the parallel fitness trajectories of the evolved DVH-wt lineages reflect these more stochastic events or the deterministic fixation of shared beneficial mutations.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Sulfur Isotope Fractionation during the Evolutionary Adaptation of a Sulfate-Reducing Bacterium

Pellerin

Anderson-Trocmé

Whyte

et al. 2015

Appl Environ Microbiol

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c Dissimilatory sulfate reduction is a microbial catabolic pathway that preferentially processes less massive sulfur isotopes relative to their heavier counterparts. This sulfur isotope fractionation is recorded in ancient sedimentary rocks and generally is considered to reflect a phenotypic response to environmental variations rather than to evolutionary adaptation. Modern sulfate-reducing microorganisms isolated from similar environments can exhibit a wide range of sulfur isotope fractionations, suggesting that adaptive processes influence the sulfur isotope phenotype. To date, the relationship between evolutionary adaptation and isotopic phenotypes has not been explored. We addressed this by studying the covariation of fitness, sulfur isotope fractionation, and growth characteristics in Desulfovibrio vulgaris Hildenborough in a microbial evolution experiment. After 560 generations, the mean fitness of the evolved lineages relative to the starting isogenic population had increased by ϳ17%. After 927 generations, the mean fitness relative to the initial ancestral population had increased by ϳ20%. Growth rate in exponential phase increased during the course of the experiment, suggesting that this was a primary influence behind the fitness increases. Consistent changes were observed within different selection intervals between fractionation and fitness. Fitness changes were associated with changes in exponential growth rate but changes in fractionation were not. Instead, they appeared to be a response to changes in the parameters that govern growth rate: yield and cell-specific sulfate respiration rate. We hypothesize that cell-specific sulfate respiration rate, in particular, provides a bridge that allows physiological controls on fractionation to cross over to the adaptive realm. Dissimilatory sulfate reduction (DSR) is a microbial metabolism that consumes sulfate and utilizes this sulfur as a terminal electron acceptor, excreting sulfide. This process creates characteristic enrichments and depletions in the stable isotopes of sulfur that are preserved in sediments and sedimentary rocks as a legacy of the metabolic processing (1). In this way, sulfur isotope fractionation can be thought of as a phenotypic trait of the specific microbes that perform DSR. When the rock record is examined like this, the S isotope phenotype has been interpreted to be continually present in ancient sediments back to at least Ϸ3.5 billion years ago (2). However, the interpretation of S isotope fractionation as a phenotypic trait that can be preserved in ancient rocks opens up a basic question: does evolutionary adaptation influence the S isotope phenotype?Evolution-driven modifications to lineages of sulfate reducers (3, 4) may be capable of influencing the isotope phenotype by modifying the relative processing rates within the DSR pathway. If growth and, in turn, the energy supplied by sulfate respiration influence survival, then the controls on sulfate uptake, the internal regulation of concentrations of metabolites, and the struct...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Sulfur Isotope Fractionation during the Evolutionary Adaptation of a Sulfate-Reducing Bacterium

Pellerin

Anderson-Trocmé

Whyte

et al. 2015

Appl Environ Microbiol

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“…In this case, the assayed population may be far from its optimum in the new environment, increasing the likelihood a mutation will be beneficial, as has been observed with experimental studies of microorganisms (Burch & Chao, 1999; Khan, Dinh, Schneider, Lenski, & Cooper, 2011; Kryazhimskiy, Rice, Jerison, & Desai, 2014; MacLean, Perron, & Gardner, 2010; Perfeito, Sousa, Bataillon, & Gordo, 2014) and in one field study with A. thaliana (Stearns & Fenster, 2016). It is also possible that there was within‐plant selection during the propagation of the mutation accumulation lines (Otto & Orive, 1995).…”

Section: Discussionmentioning

confidence: 97%

Quantifying natural seasonal variation in mutation parameters with mutation accumulation lines

Rutter

Roles

Fenster

2018

Ecology and Evolution

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Mutations create novel genetic variants, but their contribution to variation in fitness and other phenotypes may depend on environmental conditions. Furthermore, natural environments may be highly heterogeneous. We assessed phenotypes associated with survival and reproductive success in over 30,000 plants representing 100 mutation accumulation lines of Arabidopsis thaliana across four temporal environments at a single field site. In each of the four assays, environmental variance was substantially larger than mutational variance. For some traits, whether mutational variance was significantly varied between seasons. The founder genotype had mean trait values near the mean of the distribution of the mutation accumulation lines in all field experiments. New mutations also contributed more phenotypic variation than would be predicted, given phenotypic and sequence‐level divergence among natural populations of A. thaliana. The combination of large environmental variance with a mean effect of mutation near zero suggests that mutations could contribute substantially to standing genetic variation.

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“…To improve the accuracy of molecular diagnostics, detailed analyses assessing differential effects of the gyr mutations on resistance to early-versus late-generation fluoroquinolones is important, as resistance to the latter more active agents is the increasingly clinically relevant readout. In addition, the identification of more than one mutation in the gyr genes in a given isolate is not uncommon, and although there is compelling evidence that these can affect the MIC in laboratory strains (15) and in other bacterial systems (16), the role of mutation additive effects and mutation-mutation interactions (17,18) in clinical isolates has been rarely reported on. Because the incorporation of any additive and interaction effects can improve the prediction of fluoroquinolone resistance from the gyr genotype, we sought to systematically examine these associations in 240 MDR and XDR clinical M. tuberculosis isolates.…”

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confidence: 99%

Gyrase Mutations Are Associated with Variable Levels of Fluoroquinolone Resistance in Mycobacterium tuberculosis

et al. 2016

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g Molecular diagnostics that rapidly and accurately predict resistance to fluoroquinolone drugs and especially later-generation agents promise to improve treatment outcomes for patients with multidrug-resistant tuberculosis and prevent the spread of disease. Mutations in the gyr genes are known to confer most fluoroquinolone resistance, but knowledge about the effects of gyr mutations on susceptibility to early-versus later-generation fluoroquinolones and about the role of mutation-mutation interactions is limited. Here, we sequenced the full gyrA and gyrB open reading frames in 240 multidrug-resistant and extensively drugresistant tuberculosis strains and quantified their ofloxacin and moxifloxacin MIC by testing growth at six concentrations for each drug. We constructed a multivariate regression model to assess both the individual mutation effects and interactions on the drug MICs. We found that gyrB mutations contribute to fluoroquinolone resistance both individually and through interactions with gyrA mutations. These effects were statistically significant. In these clinical isolates, several gyrA and gyrB mutations conferred different levels of resistance to ofloxacin and moxifloxacin. Consideration of gyr mutation combinations during the interpretation of molecular test results may improve the accuracy of predicting the fluoroquinolone resistance phenotype. Further, the differential effects of gyr mutations on the activity of early-and later-generation fluoroquinolones requires further investigation and could inform the selection of a fluoroquinolone for treatment. Global surveillance for drug-resistant tuberculosis (TB) suggests that at least 3.5% of the 9 million incident TB cases are multidrug resistant (MDR), i.e., resistant to isoniazid and rifampin. Fluoroquinolones are among the most effective drugs available for the treatment of MDR TB (1, 2). The importance of the fluoroquinolone drug class is implied in how extensively drugresistant (XDR) TB is defined, i.e., as MDR TB with additional in vitro resistance to second-line injectables and any member of the fluoroquinolone drug class. The different fluoroquinolone agents vary in their potency against Mycobacterium tuberculosis, with third-and fourth-generation agents (e.g., levofloxacin, gatifloxacin, and moxifloxacin) having higher activity than second-generation agents (e.g., ciprofloxacin or ofloxacin) (3, 4). These differences have led the World Health Organization (WHO) to recommend against extrapolating in vitro culture-based resistance results from second-to later-generation fluoroquinolones and to revise the in vitro testing drug concentration upward to 2 mg/liter for moxifloxacin (4, 5). Revisions of drug testing concentrations also highlight the need for quantitative resistance testing with MIC measurements when new diagnostic technologies are being compared to culture-based drug susceptibility tests.Fluoroquinolones exert their antibacterial activity by inhibiting DNA gyrase and topoisomerase IV, limiting the cell's capacity for DNA replicat...

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Global epistasis makes adaptation predictable despite sequence-level stochasticity

Cited by 443 publications

References 27 publications

Sulfur Isotope Fractionation during the Evolutionary Adaptation of a Sulfate-Reducing Bacterium

Sulfur Isotope Fractionation during the Evolutionary Adaptation of a Sulfate-Reducing Bacterium

Quantifying natural seasonal variation in mutation parameters with mutation accumulation lines

Gyrase Mutations Are Associated with Variable Levels of Fluoroquinolone Resistance in Mycobacterium tuberculosis

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