scholarly journals Cost of resistance: an unreasonably expensive concept

2018 ◽  
Author(s):  
Thomas Lenormand ◽  
Noémie Harmand ◽  
Romain Gallet
Keyword(s):  
Evolutionary Biology ◽  
Resistance Mutation ◽  
Evolutionary Genetics ◽  
Resistance Mutations ◽  
Fitness Effects ◽  
Current Usage ◽  
Important Addition ◽  
Cost Of Resistance ◽  
Peer Community ◽  
The Cost

AbstractThis preprint has been reviewed and recommended by Peer Community In Evolutionary Biology (https://doi.org/10.24072/pci.evolbiol.100052). The cost of resistance, or the fitness effect of resistance mutation in absence of the drug, is a very widepsread concept in evolutionary genetics and beyond. It has represented an important addition to the simplistic view that resistance mutations should solely be considered as beneficial mutations. Yet, this concept also entails a series of serious difficulties in its definition, interpretation and current usage. In many cases, it may be simpler, clearer, and more insightful to study, measure and analyze the fitness effects of mutations across environments and to better distinguish those effects from ‘pleiotropic effects’ of those mutations.

scholarly journals Epistasis between antibiotic resistance mutations and genetic background shape the fitness effect of resistance across species of Pseudomonas

2016 ◽  
Vol 283 (1830) ◽  
pp. 20160151 ◽  
Author(s):  
T. Vogwill ◽  
M. Kojadinovic ◽  
R. C. MacLean
Keyword(s):  
Antibiotic Resistance ◽  
Resistance Mutations ◽  
Bacterial Strains ◽  
Fitness Effect ◽  
Epistatic Interactions ◽  
Fitness Effects ◽  
Cost Of Resistance ◽  
Pathogen Populations ◽  
The Cost ◽  
Antibiotic Resistance Mutations

Antibiotic resistance often evolves by mutations at conserved sites in essential genes, resulting in parallel molecular evolution between divergent bacterial strains and species. Whether these resistance mutations are having parallel effects on fitness across bacterial taxa, however, is unclear. This is an important point to address, because the fitness effects of resistance mutations play a key role in the spread and maintenance of resistance in pathogen populations. We address this idea by measuring the fitness effect of a collection of rifampicin resistance mutations in the β subunit of RNA polymerase ( rpoB ) across eight strains that span the diversity of the genus Pseudomonas . We find that almost 50% of rpoB mutations have background-dependent fitness costs, demonstrating that epistatic interactions between rpoB and the rest of the genome are common. Moreover, epistasis is typically strong, and it is the dominant genetic determinant of the cost of resistance mutations. To investigate the functional basis of epistasis, and because rpoB plays a central role in transcription, we measured the effects of common rpoB mutations on transcriptional efficiency across three strains of Pseudomonas . Transcriptional efficiency correlates strongly to fitness across strains, and epistasis arises because individual rpoB mutations have differential effects on transcriptional efficiency in different genetic backgrounds.

scholarly journals Increased Survival of Antibiotic-Resistant Escherichia coli inside Macrophages

2012 ◽  
Vol 57 (1) ◽  
pp. 189-195 ◽  
Author(s):  
Migla Miskinyte ◽  
Isabel Gordo
Keyword(s):  
Escherichia Coli ◽  
Antibiotic Resistance ◽  
Bacterial Infections ◽  
Resistance Mutation ◽  
Fitness Cost ◽  
Resistance Mutations ◽  
Content Type ◽  
E Coli ◽  
Fitness Effects ◽  
K 12

ABSTRACTMutations causing antibiotic resistance usually incur a fitness cost in the absence of antibiotics. The magnitude of such costs is known to vary with the environment. Little is known about the fitness effects of antibiotic resistance mutations when bacteria confront the host's immune system. Here, we study the fitness effects of mutations in therpoB,rpsL, andgyrAgenes, which confer resistance to rifampin, streptomycin, and nalidixic acid, respectively. These antibiotics are frequently used in the treatment of bacterial infections. We measured two important fitness traits—growth rate and survival ability—of 12Escherichia coliK-12 strains, each carrying a single resistance mutation, in the presence of macrophages. Strikingly, we found that 67% of the mutants survived better than the susceptible bacteria in the intracellular niche of the phagocytic cells. In particular, allE. colistreptomycin-resistant mutants exhibited an intracellular advantage. On the other hand, 42% of the mutants incurred a high fitness cost when the bacteria were allowed to divide outside of macrophages. This study shows that single nonsynonymous changes affecting fundamental processes in the cell can contribute to prolonged survival ofE. coliin the context of an infection.

scholarly journals The genomic basis of adaptation to the fitness cost of rifampicin resistance in Pseudomonas aeruginosa

2016 ◽  
Vol 283 (1822) ◽  
pp. 20152452 ◽  
Author(s):  
Qin Qi ◽  
Macarena Toll-Riera ◽  
Karl Heilbron ◽  
Gail M. Preston ◽  
R. Craig MacLean
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antibiotic Resistance ◽  
Low Cost ◽  
Fitness Cost ◽  
Clinical Settings ◽  
Resistance Mutations ◽  
Beneficial Mutations ◽  
Cost Of Resistance ◽  
Compensatory Mutations ◽  
The Cost

Antibiotic resistance carries a fitness cost that must be overcome in order for resistance to persist over the long term. Compensatory mutations that recover the functional defects associated with resistance mutations have been argued to play a key role in overcoming the cost of resistance, but compensatory mutations are expected to be rare relative to generally beneficial mutations that increase fitness, irrespective of antibiotic resistance. Given this asymmetry, population genetics theory predicts that populations should adapt by compensatory mutations when the cost of resistance is large, whereas generally beneficial mutations should drive adaptation when the cost of resistance is small. We tested this prediction by determining the genomic mechanisms underpinning adaptation to antibiotic-free conditions in populations of the pathogenic bacterium Pseudomonas aeruginosa that carry costly antibiotic resistance mutations. Whole-genome sequencing revealed that populations founded by high-cost rifampicin-resistant mutants adapted via compensatory mutations in three genes of the RNA polymerase core enzyme, whereas populations founded by low-cost mutants adapted by generally beneficial mutations, predominantly in the quorum-sensing transcriptional regulator gene lasR . Even though the importance of compensatory evolution in maintaining resistance has been widely recognized, our study shows that the roles of general adaptation in maintaining resistance should not be underestimated and highlights the need to understand how selection at other sites in the genome influences the dynamics of resistance alleles in clinical settings.

scholarly journals Is the cost of herbicide resistance expressed in the breakdown of the relationships between characters? A case study using synthetic-auxin-resistant Arabidopsis thaliana mutants

2005 ◽  
Vol 85 (2) ◽  
pp. 101-110 ◽  
Author(s):  
FABRICE ROUX ◽  
XAVIER REBOUD
Keyword(s):  
Resource Allocation ◽  
Arabidopsis Thaliana ◽  
Herbicide Resistance ◽  
Resource Acquisition ◽  
Resistance Mutations ◽  
Herbicide Resistant ◽  
Dominance Level ◽  
Cost Of Resistance ◽  
The Cost

A mutation endowing herbicide resistance is often found to induce a parallel morphological or fitness penalty. To test whether such ‘cost’ of resistance to herbicides is expressed through lower resource acquisition, changes in resource allocation, or both, is of ecological significance. Here, we analysed 12 morphological traits in 900 plants covering three herbicide resistance mutations at genes AUX1, AXR1 and AXR2 in the model species Arabidopsis thaliana. Comparing these 2,4-D herbicide-resistant homozygous (RR) and heterozygous (RS) plants to homozygous susceptible (SS) plants, this analysis estimates the dominance level of the resistance allele on morphology. We also demonstrated that the herbicide resistance cost was primarily expressed as a change in resource acquisition (62·1–94% of the analysed traits). Although AUX1, AXR1 and AXR2 genes act in the same metabolic pathway of auxin response, each resistance factor was found to have its own unique signature in the way the cost was expressed. Furthermore, no link was observed between the absolute fitness penalty and the respective modifications of resource acquisition and/or resource allocation in the resistant plants. These results and their implications for herbicide resistance spread and establishment are discussed.

scholarly journals Coevolution of virulence and immunosuppression in multiple infections

2017 ◽  
Author(s):  
Tsukushi Kamiya ◽  
Nicole Mideo ◽  
Samuel Alizon
Keyword(s):  
Evolutionary Biology ◽  
Adaptive Dynamics ◽  
Multiple Infections ◽  
Research Attention ◽  
Background Mortality ◽  
Evolution Of Virulence ◽  
Duration Of Infection ◽  
Peer Community ◽  
The Cost ◽  
Host Parasite

AbstractThis preprint has been reviewed and recommended by Peer Community In Evolutionary Biology (http://dx.doi.org/10.24072/pci.evolbiol.100043). Many components of host-parasite interactions have been shown to affect the way virulence (i.e., parasite-induced harm to the host) evolves. However, coevolution of multiple parasite traits is often neglected. We explore how an immunosuppressive mechanism of parasites affects and coevolves with virulence through multiple infections. Applying the adaptive dynamics framework to epidemiological models with coinfection, we show that immunosuppression is a double-edged-sword for the evolution of virulence. On one hand, it amplifies the adaptive benefit of virulence by increasing the abundance of coinfections through epidemiological feedbacks. On the other hand, immunosuppression hinders host recovery, prolonging the duration of infection and elevating the cost of killing the host. The balance between the cost and benefit of immunosuppression varies across different background mortality rates of hosts. In addition, we find that immunosuppression evolution is influenced considerably by the precise trade-off shape determining the effect of immunosuppression on host recovery and susceptibility to further infection. These results demonstrate that the evolution of virulence is shaped by immunosuppression while highlighting that the evolution of immune evasion mechanisms deserves further research attention.

scholarly journals The Fitness Cost of Mutations Associated with Human Immunodeficiency Virus Type 1 Drug Resistance Is Modulated by Mutational Interactions

2006 ◽  
Vol 81 (6) ◽  
pp. 3037-3041 ◽  
Author(s):  
Mian-er Cong ◽  
Walid Heneine ◽  
J. Gerardo García-Lerma
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Fitness Cost ◽  
Resistance Mutations ◽  
Drug Pressure ◽  
Critical Determinant ◽  
Immunodeficiency Virus ◽  
Cost Of Resistance

ABSTRACT It is generally accepted that the fitness cost of resistance mutations plays a role in the persistence of transmitted drug-resistant human immunodeficiency virus type 1 and that mutations that confer a high fitness cost are less able to persist in the absence of drug pressure. Here, we show that the fitness cost of reverse transcriptase (RT) mutations can vary within a 72-fold range. We also demonstrate that the fitness cost of M184V and K70R can be decreased or enhanced by other resistance mutations such as D67N and K219Q. We conclude that the persistence of transmitted RT mutants might range widely on the basis of fitness and that the modulation of fitness cost by mutational interactions will be a critical determinant of persistence.

scholarly journals Inference of distribution of fitness effects and proportion of adaptive substitutions from polymorphism data

2016 ◽  
Author(s):  
Paula Tataru ◽  
Maéva Mollion ◽  
Sylvain Glemin ◽  
Thomas Bataillon
Keyword(s):  
Molecular Evolution ◽  
Evolutionary Genetics ◽  
Deleterious Mutations ◽  
Probabilistic Framework ◽  
Evolutionary Trajectory ◽  
Beneficial Mutations ◽  
Fitness Effects ◽  
Polymorphism Data ◽  
Inference Methods ◽  
Biased Estimates

ABSTRACTThe distribution of fitness effects (DFE) encompasses deleterious, neutral and beneficial mutations. It conditions the evolutionary trajectory of populations, as well as the rate of adaptive molecular evolution (α). Inference of DFE and α from patterns of polymorphism (SFS) and divergence data has been a longstanding goal of evolutionary genetics. A widespread assumption shared by numerous methods developed so far to infer DFE and α from such data is that beneficial mutations contribute only negligibly to the polymorphism data. Hence, a DFE comprising only deleterious mutations tends to be estimated from SFS data, and α is only predicted by contrasting the SFS with divergence data from an outgroup. Here, we develop a hierarchical probabilistic framework that extends on previous methods and also can infer DFE and α from polymorphism data alone. We use extensive simulations to examine the performance of our method. We show that both a full DFE, comprising both deleterious and beneficial mutations, and α can be inferred without resorting to divergence data. We demonstrate that inference of DFE from polymorphism data alone can in fact provide more reliable estimates, as it does not rely on strong assumptions about a shared DFE between the outgroup and ingroup species used to obtain the SFS and divergence data. We also show that not accounting for the contribution of beneficial mutations to polymorphism data leads to substantially biased estimates of the DFE and α. We illustrate these points using our newly developed framework, while also comparing to one of the most widely used inference methods available.

scholarly journals Larotrectinib (Vitrakvi)

2021 ◽  
Vol 1 (9) ◽  
Author(s):  
Reimbursement Team
Keyword(s):  
Gene Fusion ◽  
Treatment Options ◽  
Single Agent ◽  
Locally Advanced ◽  
Acquired Resistance ◽  
Resistance Mutation ◽  
Solid Tumours ◽  
The Cost ◽  
Tyrosine Receptor Kinase ◽  
Public Drug

CADTH recommends that Vitrakvi be reimbursed by public drug plans for treating adult and pediatric patients with locally advanced or metastatic solid tumours who have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion without a known acquired resistance mutation, or where surgical resection is likely to result in severe morbidity and have no satisfactory treatment options, but only if certain conditions are met. Vitrakvi should only be covered to treat patients with advanced solid tumours who have an NTRK gene fusion, who have previously failed on all standard treatments for their current tumour site, and who will be able to tolerate the treatment. Vitrakvi should only be reimbursed as single-agent therapy if it is prescribed by a clinician with expertise in the use of antineoplastic drugs and if the cost of Vitrakvi is reduced.

Evolution: Medicine’s most basic science

2020 ◽  
pp. 39-42
Author(s):  
Randolph M. Nesse ◽  
Richard Dawkins
Keyword(s):  
Population Genetics ◽  
Natural Selection ◽  
Basic Science ◽  
Evolutionary Biology ◽  
Phylogenetic Trees ◽  
The Body ◽  
Clinical Implications ◽  
Trade Offs ◽  
The Cost

The role of evolutionary biology as a basic science for medicine is expanding rapidly. Some evolutionary methods are already widely applied in medicine, such as population genetics and methods for analysing phylogenetic trees. Newer applications come from seeking evolutionary as well as proximate explanations for disease. Traditional medical research is restricted to proximate studies of the body’s mechanism, but separate evolutionary explanations are needed for why natural selection has left many aspects of the body vulnerable to disease. There are six main possibilities: mismatch, infection, constraints, trade-offs, reproduction at the cost of health, and adaptive defences. Like other basic sciences, evolutionary biology has limited direct clinical implications, but it provides essential research methods, encourages asking new questions that foster a deeper understanding of disease, and provides a framework that organizes the facts of medicine.

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