Biology subjects

Couce, A.

Publications and source records attributed to Couce, A..

8 recordsLinked to original sources

bioRxiv2025

Mutation-biased adaptation is consequential even in large bacterial populations

Adaptive variation is typically presented to selection in a biased manner, owing to vast differences in effective mutation rates across genomes, organisms and environments. Yet, how strongly and how generally such bias shapes adaptation remains poorly understood. Here we used a well-known experimental system in which two Escherichia coli mutator variants evolve antibiotic resistance via two mutationally favored, but genetically distinct routes. Through simulations and experiments, we show that the scaling of mutation-biased adaptation with population size is complex, highly dependent on biological details, and--most critically--on how closely mutation bias aligns with selection. Contrary to the common view, we find that mutation-biased adaptation may not wane in large populations but instead intensify depending on the nature of the bias. Crucially, we demonstrate that distinct mutation biases can produce markedly different collateral sensitivity profiles to multiple antibiotics, even at large population sizes. These findings suggest that mutation-biased adaptation may not only be widespread but also have far-reaching and unpredictable consequences both within and beyond the original selective context.

evolutionary biology↗

bioRxiv2025

Idiosyncratic evolvability among single-point ribosomal mutants towards multi-aminoglycoside resistance

Newly-arising mutations can impact not only fitness but also an organisms capacity for further adaptation (i.e., its evolvability). Understanding what determines evolvability differences is of great interest from both fundamental and applied perspectives. A general pattern observed across multiple microbes is that evolvability tends to decline with genotype fitness (i.e., the "rule of declining adaptability"), typically attributed to epistatic rather than mutational differences among genotypes. Here, we investigate whether common rpsL point mutations in Escherichia coli, conferring streptomycin resistance, may potentiate or hinder adaptation towards secondary aminoglycosides. We find a version of the rule of declining adaptability in which initially more-fit genotypes experience higher effective beneficial mutation rates but smaller effect sizes than their less-fit counterparts. Genome sequencing reveals the ribosome and electron transport chain as primary targets for adaptation. Second-step mutations typically confer cross-resistance across aminoglycosides, and some even restore fitness costs in the absence of drugs. However, some genotypes deviate markedly from the overall pattern, being completely unable to develop resistance to the secondary aminoglycosides. Such idiosyncratic dead-ends, if common among other systems involving single-point mutants, would expand the pool of potential targets for strategies to promote evolutionary robustness in biotechnology and combat multidrug resistance in clinical microbiology. Author SummaryIdentifying features that predict an organisms ability to evolve (evolvability) is highly desirable in fundamental and applied microbial genetics. Here we show that outstanding disparities in evolvability can arise from single-point variants within a single gene. Specifically, we investigated whether common streptomycin-resistance mutations can facilitate or hinder adaptation against other aminoglycosides. Most mutations facilitated resistance evolution, prompting further resistance gains in proportion to initial resistance levels. However, a few cases totally diverged from this trend, acting as evolutionary dead-ends. These findings suggest a scenario in which strong, unpredictable genetic interactions stand out against a backdrop of predictable trends, bearing implications for ongoing debates on which model best captures global fitness patterns in microbes. From an applied standpoint, since streptomycin is commonly used in mycobacterial infections and agriculture, our results suggest that some circulating pathogenic strains may already be predisposed to developing multi-aminoglycoside resistance, potentially informing surveillance and intervention strategies.

evolutionary biology↗

bioRxiv2025

The evolution of robustness and fragility during long-term bacterial adaptation

Most mutations affecting fitness are harmful, and their inevitable occurrence reduces mean population fitness. Theory predicts that well-adapted populations may evolve mechanisms to minimize this deleterious load. Direct selection to increase mutational robustness can be achieved in the laboratory. However, its spontaneous evolution during general adaptation remains uncertain, with mixed evidence across model systems. Here, we studied the effects of highly pleiotropic point mutations in Escherichia coli over a 15,000-generation adaptive trajectory. The fitness effects of both beneficial and deleterious mutations were attenuated with increased adaptation over time. In contrast, pleiotropic effects in new environments became more severe and widespread with greater adaptation. These results show that trade-offs between robustness and fragility can rapidly evolve in regulatory networks, regardless of whether driven by adaptive or non-adaptive processes. More broadly, these results show that adaptation can generate a hidden potential for phenotypic diversity, unpredictably shaping evolutionary prospects in new environments.

evolutionary biology↗

bioRxiv2024

Epistasis drives rapid divergence across multiple traits during the adaptive evolution of a carbapenemase

Interactions among beneficial mutations (i.e., epistasis) are often strong enough as to direct adaptation through alternative mutational paths. While alternative solutions should display similar fitness under the primary selective conditions, their properties across secondary environments may differ widely. The extent to which these cryptic differences are to be expected is largely unknown, despite their fundamental and practical importance, such as in the search for exploitable collateral sensitivities among antibiotic resistance mutations. Here we use directed evolution to characterize the diversity of mutational paths through which the prevalent carbapenemase KPC-2 can evolve high activity against the clinically-relevant antibiotic ceftazidime, an initially poor substrate. We identified 40 different substitutions, including many common clinical settings, spread along 18 different mutational trajectories. Initial mutations determined four major groups into which the trajectories can be classified, a signature of strong epistasis. Of note, despite minor variation in final ceftazidime resistance, groups diverged markedly across multiple phenotypic dimensions, from molecular traits such as stability and hydrolitic efficiency to macroscopic traits such as growth rate and activity against other {beta}-lactam antibiotics. Our results indicate that cryptic yet consequential phenotypic differences can readily accumulate under strong selective pressures, bearing implications for efforts to prevent unwanted evolution in microbes.

evolutionary biology↗

bioRxiv2024

Reversion to metabolic autonomy underpins evolutionary rescue of a bacterial obligate mutualism

Populations facing lethal environmental change can avoid extinction by undergoing rapid genetic adaptation, a phenomenon termed evolutionary rescue. While this phenomenon has been the focus of much theoretical and empirical research, our understanding of evolutionary rescue in communities consisting of interacting species is still limited, especially in mutualistic communities, where evolutionary rescue is expected to be constrained by the less adaptable partner. Here, we explored empirically the likelihood, population dynamics, and genetic mechanisms underpinning evolutionary rescue in an obligate mutualism in which auxotrophic Escherichia coli strains exchanged essential amino acids reciprocally. We observed that >80% of the communities avoided extinction when exposed to two different types of lethal and abrupt stresses. Of note, only one of the strains survived in all cases. Genetic and phenotypic analyses show that this strain reverted to autonomy by metabolically bypassing the auxotrophy, but we found little evidence of specific adaptation to the stressors. Crucially, we found that the mutualistic partners were substantially more sensitive to both stresses than prototrophs, so that reversion to autonomy was sufficient to alleviate stress below lethal levels. We observed that increased sensitivity was common across several other stresses, suggesting that this may be a general property of obligate mutualisms mediated by amino acid exchange. Our results reveal that evolutionary rescue may depend critically on the specific genetic and physiological details of the interacting partners, adding rich layers of complexity to the endeavor of predicting the fate of microbial communities facing intense environmental deterioration.

evolutionary biology↗

bioRxiv2022

The evolution of fitness effects during long-term adaptation in bacteria

The distribution of fitness effects of new mutations is central to predicting adaptive evolution, but observing how it changes as organisms adapt is challenging. Here we use saturated, genome-wide insertion libraries to quantify how the fitness effects of new mutations changed in two E. coli populations that adapted to a constant environment for 15,000 generations. The proportions of neutral and deleterious mutations remained constant, despite large fitness gains. In contrast, the beneficial fraction declined rapidly, approximating an exponential distribution, with strong epistasis profoundly changing the genetic identity of adaptive mutations. Despite this volatility, many important targets of selection were predictable from the ancestral distribution. This predictability occurs because genetic target size contributed to the fixation of beneficial mutations as much as or more than their effect sizes. Overall, our results demonstrate that short-term adaptation can be idiosyncratic but empirically predictable, and that long-term dynamics can be described by simple statistical principles. One-Sentence SummaryCouce et al. demonstrate that short-term bacterial adaptation is predictable at the scale of individual genes, while long-term adaptation is predictable at a global scale.

evolutionary biology↗

bioRxiv2019

The role of mutational spectrum in the selection against mutator alleles

Rapidly adapting microbe and cancer cell populations often evolve high mutation rates. Yet, once adaptive opportunity declines, antimutator alleles are expected to take over as a result of indirect selection against deleterious mutations. Theory indicates that the most important determinant of antimutator invasions is the extent of mutation rate reduction. However, inconsistent results from evolution experiments suggest that additional factors may also play a major role in antimutator dynamics. Here we show that the idiosyncratic mutation bias exhibited by different mutators - a previously unrecognized factor - can greatly alter mutator susceptibility to antimutator invasions. Using a simulation model calibrated to mimic a well-known long-term evolution experiment with bacteria, we show that differences in average deleterious load can account for order-of-magnitude changes in antimutator fitness for a realistic range of parameters. Since these parameters are known to vary with the environment, our results reveal an unanticipated source of variability in antimutator dynamics. Finally, we estimated the genome-wide average disruptive effect on proteins of mutations caused by different mutators, and found marked and systematic differences emerging across mutators and species with different genomic GC compositions. Taken together, our results suggest that antimutator dynamics may be highly dependent on the specific genetic, ecological and evolutionary history of a given population. Such dependence reveals a more complex picture than anticipated, being relevant for understanding mutators in clinical settings, as well as how hypermutability shapes the evolution of bacterial genome size and composition.

evolutionary biology↗

bioRxiv2018

The molecular basis of genetic interaction diversity in a metabolic pathway

Our ability to predict the impact of mutations on traits relevant for disease and evolution remains severely limited by the dependence of their effects on the genetic background and environment. Even when molecular interactions between genes are known, it is unclear how these translate to organism-level interactions between alleles. We therefore characterized the interplay of genetic and environmental dependencies in determining fitness by quantifying ~4,000 fitness interactions between expression variants of two metabolic genes, in different environments. We detect a remarkable variety of environment-dependent interactions, and demonstrate they can be quantitatively explained by a mechanistic model accounting for catabolic flux, metabolite toxicity and expression costs. Complex fitness interactions between mutations can therefore be predicted simply from their simultaneous impact on a few connected molecular phenotypes.

genetics↗