Biology subjects

Kassen, R.

Publications and source records attributed to Kassen, R..

9 recordsLinked to original sources

bioRxiv2024

Rapid adaptation and increased genetic parallelism in experimental metapopulations of Pseudomonas aeruginosa

Natural populations are often spatially structured, meaning they are best described as metapopulations composed of subpopulations connected by migration. We know little about how the topology of connections in metapopulations impacts adaptive evolution. Topologies that concentrate dispersing individuals through a central hub can accelerate adaptation above that of a well-mixed system in some models, however empirical support is lacking. We provide evidence to support this claim and show acceleration is accompanied by high rates of parallel evolution resulting from a reduced probability that rare beneficial mutations are stochastically lost. Our results suggest metapopulation topology can be a potent force driving evolutionary dynamics and patterns of genomic repeatability in structured landscapes such as those involving the spread of pathogens or invasive species.

evolutionary biology↗

bioRxiv2023

Unpredictability of the fitness effects of antimicrobial resistance mutations across environments in Escherichia coli

The evolution of antimicrobial resistance (AMR) in bacteria is a major public health concern. When resistant bacteria are highly prevalent in microbial populations, antibiotic restriction protocols are often implemented to reduce their spread. These measures rely on the existence of deleterious fitness effects (i.e., costs) imposed by AMR mutations during growth in the absence of antibiotics. According to this assumption, resistant strains will be outcompeted by susceptible strains that do not pay the cost during the period of restriction. Hence, the success of a given intervention depends on the magnitude and direction of fitness effects of mutations, which can vary depending on the genetic and environmental context. However, the fitness effects of AMR mutations are generally studied in laboratory reference strains and estimated in a limited number of environments, usually a standard laboratory growth medium. In this study, we systematically measure how three sources of variation impact the fitness effects of AMR mutations: the type of resistance mutation, the genetic background of the host, and the growth environment. We demonstrate that while AMR mutations are generally costly in antibiotic-free environments, their fitness effects vary widely and depend on complex interactions between the AMR mutation, genetic background, and environment. We test the ability of the Rough Mount Fuji genotype-fitness model to reproduce the empirical data in simulation. We identify model parameters that reasonably capture the variation in fitness effects due to genetic variation. However, the model fails to accommodate variation when considering multiple growth environments. Overall, this study reveals a wealth of variation in the fitness effects of resistance mutations owing to genetic background and environmental conditions, that will ultimately impact their persistence in natural populations. Authors AbstractThe emergence and spread of antimicrobial resistance in bacterial populations poses a continuing threat to our ability to successfully treat bacterial infections. During exposure to antibiotics, resistant microbes outcompete susceptible ones, leading to increases in prevalence. This competitive advantage, however, can be reversed in antibiotic-free environments, due to deleterious fitness effects imposed by resistance determinants, a concept referred to as the cost of resistance. The extent of these fitness effects is an important factor governing the prevalence of resistance in natural populations. However, predicting the fitness effects of resistance mutations is challenging, since their magnitude can change depending on the genetic background in which the mutation arose and the environmental context. Comprehensive data on these sources of variation is lacking, and we address this gap by determining the fitness effects of resistance mutations introduced in a range of Escherichia coli clinical isolates, measured in different antibiotic-free environments. Our results reveal wide variation in the fitness effects, driven by irreducible interactions between resistance mutations, genetic backgrounds, and growth environments. We evaluate the performance of a fitness landscape model to reproduce the data in simulation, highlight its strengths and weaknesses, and call for improvements to accommodate these important sources of variation.

evolutionary biology↗

bioRxiv2021

Experimental evidence that metapopulation structure can accelerate adaptive evolution

Whether the spatial arrangement of a population influences adaptive evolution has puzzled evolutionary biologists. Theoretical models make contrasting predictions about the probability a beneficial mutation will become fixed in a population for certain topologies like stars, where leaf populations are connected through a hub. To date, these predictions have not been evaluated under realistic conditions. Here, we test the prediction that topology can change the fixation probability both in vitro and in silico by tracking the dynamics of a beneficial mutant under positive selection as it spreads through networks of different topologies. Our results provide empirical support that metapopulation topology can increase the likelihood that a beneficial mutation spreads, broadens the conditions under which this phenomenon is thought to occur, and points the way towards using network topology to amplify the effects of weakly favored mutations under directed evolution in industrial applications.

evolutionary biology↗

bioRxiv2020

The Evolution and Fate of Diversity Under Hard and Soft Selection

How genetic variation arises and persists over evolutionary time despite the depleting effects of natural selection remains a long-standing question. Here, we investigate the impacts of two extreme forms of population regulation - at the level of the total, mixed population (hard selection) and at the level of local, spatially distinct patches (soft selection) - on the emergence and fate of diversity under strong divergent selection. We find that while the form of population regulation has little effect on rates of diversification it can modulate the long-term fate of genetic variation, diversity being more readily maintained under soft selection compared to hard selection. The mechanism responsible for coexistence is negative frequency dependent selection which, while present initially under both forms of population regulation, persists over the long-term only under soft selection. Importantly, coexistence is robust to continued evolution of niche specialist types under soft selection but not hard selection. These results suggest that soft selection could be a general mechanism for the maintenance of ecological diversity over evolutionary time scales.

evolutionary biology↗

bioRxiv2020

Genomics of experimental diversification of Pseudomonas aeruginosa in cystic fibrosis lung-like conditions

Pseudomonas aeruginosa is among the most problematic opportunistic pathogens for adults with cystic fibrosis (CF), causing repeated and resilient infections in the lung and surrounding airways. Evidence suggests that long-term infections are associated with diversification into specialized types but the underlying cause of that diversification and the effect it has on the persistence of infections remains poorly understood. Here, we use evolve and resequence experiments to investigate the genetic changes accompanying rapid, de novo phenotypic diversification in lab environments designed to mimic two aspects of human lung ecology: spatial structure and complex nutritional content. After [~]220 generations of evolution, we find extensive genetic variation present in all environments, including those that most closely resemble the CF lung, attributable to a combination of high mutation supply rates resulting from large population sizes and the complex ecological conditions imposed by resource complexity and spatial structure. We use the abundance and frequency of nonsynonymous and synonymous mutations to estimate the ratio of mutations that are selectively neutral (hitchhikers) to those that are under selection (drivers). A significantly lower proportion of driver mutations in spatially structured populations suggests that reduced dispersal generates subpopulations with reduced effective population size, decreasing the supply of beneficial mutations and causing more divergent evolutionary trajectories. The genes most commonly mutated tend to impact regulatory functions linked to a range of CF-associated phenotypes, including one gene that confers antibiotic resistance despite the absence of antibiotic selection in our experiment, but do not appear to be specific to CF-like conditions arising from antimicrobial treatment, immune system suppression, or competition from other microbial species. Our results are consistent with models of adaptation that see the first mutations fixed during adaptation to a stressful environment being those that are broadly beneficial across a range of environments.

evolutionary biology↗

bioRxiv2019

The distribution of fitness effects among synonymous mutations in a gene under selection

The fitness effects of synonymous mutations, nucleotide changes that do not alter the encoded amino acid, have often been assumed to be neutral, but a growing body of evidence suggests otherwise. We used site-directed mutagenesis coupled with direct measures of competitive fitness to estimate the distribution of fitness effects among synonymous mutations for a gene under selection. Synonymous mutations had highly variable fitness effects, both deleterious and beneficial, resembling those of nonsynonymous mutations in the same gene. This variation in fitness was underlain by changes in transcription linked to the creation of internal promoter sites. A positive correlation between fitness and the presence of synonymous substitutions across a phylogeny of related Pseudomonads suggests these mutations may be common in nature. Taken together, our results provide the most compelling evidence to date that synonymous mutations with non-neutral fitness effects may in fact be commonplace.

evolutionary biology↗

bioRxiv2018

The idiosyncratic drivers of correlated evolution

The ultimate causes of correlated evolution among sites in a genome remain difficult to tease apart. To address this problem directly, we performed a high-throughput search for correlated evolution among sites associated with resistance to a fluoroquinolone antibiotic using whole genome data from clinical strains of Pseudomonas aeruginosa, before validating our computational predictions experimentally. We show that for at least two sites, this correlation is underlain by epistasis. Our analysis also revealed eight additional pairs of synonymous substitutions displaying correlated evolution underlain by physical linkage, rather than selection associated with antibiotic resistance. Our results provide direct evidence that both epistasis and physical linkage among sites can drive the correlated evolution identified by high throughput computational tools. In other words, the observation of correlated evolution is not by itself sufficient evidence to guarantee that the sites in question are epistatic; such a claim requires additional evidence, ideally coming from direct estimates of epistasis, based on experimental evidence.

bioinformatics↗

bioRxiv2017

Rapid diversification of Pseudomonas aeruginosa in cystic fibrosis lung-like conditions

Chronic infection of the cystic fibrosis (CF) airway by the opportunistic pathogen Pseudomonas aeruginosa is the leading cause of morbidity and mortality for adult CF patients. Prolonged infections are accompanied by adaptation of P. aeruginosa to the unique conditions of the CF lung environment as well as marked diversification of the pathogen into phenotypically and genetically distinct strains that can coexist for years within a patient. Little is known, however, about the causes of this diversification and its impact on patient health. Here, we show experimentally that, consistent with ecological theory of diversification, the nutritional conditions of the CF airway can cause rapid and extensive diversification of P. aeruginosa. The increased viscosity associated with the thick mucous layer in the CF airway had little impact on within-population diversification but did promote divergence among populations. Notably, in vitro evolution recapitulated patho-adaptive traits thought to be hallmarks of chronic infection, including reduced motility and increased biofilm formation, and the range of phenotypes observed in a collection of clinical isolates. Our results suggest that nutritional complexity and reduced dispersal can drive evolutionary diversification of P. aeruginosa independent of other features of the CF lung such as an active immune system or the presence of competing microbial species. They also underscore the need to obtain diverse samples of P. aeruginosa when developing treatment plans. We suggest that diversification, by generating extensive phenotypic and genetic variation on which selection can act, may be a key first step in the transition from transient to chronic infection.\n\nSignificance StatementChronic infection with the opportunistic pathogen Pseudomonas aeruginosa is the leading cause of lung transplant or death in cystic fibrosis patients. P. aeruginosa diversifies in the CF lung, although why this happens remains a mystery. We allowed P. aeruginosa to evolve in the laboratory under a range of conditions approximating the CF lung. The diversity of evolved populations was highest, and most closely resembled the range of phenotypes among clinical isolates, in environments resembling the spectrum of nutritional resources available in the CF lung. Our results point to the nutritional complexity of the CF lung as a major driver of diversification and they suggest that diversity could be important in the development of chronic infections.

evolutionary biology↗

bioRxiv2017

The emergence, maintenance and demise of diversity in a spatially variable antibiotic regime

Antimicrobial resistance (AMR) is a growing global threat that, in the absence of new antibiotics, requires effective management of existing drugs. Here, we explore how changing patterns of drug delivery modulates the spread of resistance in a population. Resistance evolves readily under both temporal and spatial variation in drug delivery and fixes rapidly under temporal, but not spatial, variation. Resistant and sensitive genotypes coexist in spatially varying conditions due to a resistance-growth rate trade-off which, when coupled to dispersal, generates negative frequency-dependent selection and a quasi-protected polymorphism. Coexistence is ultimately lost, however, because resistant types with improved growth rates in the absence of drug spread through the population. These results suggest that spatially variable drug prescriptions can delay but not prevent the spread of resistance and provide a striking example of how the emergence and eventual demise of biodiversity is underpinned by evolving fitness trade-offs.

evolutionary biology↗