scholarly journals Population persistence under high mutation rate: from evolutionary rescue to lethal mutagenesis

2019 ◽  
Author(s):  
Yoann Anciaux ◽  
Amaury Lambert ◽  
Ophelie Ronce ◽  
Lionel Roques ◽  
Guillaume Martin
Keyword(s):  
Mutation Rate ◽  
Geometric Model ◽  
Resistance Mutation ◽  
Theoretical Work ◽  
Mutation Rates ◽  
Moderate Increase ◽  
Asexual Population ◽  
Lethal Mutagenesis ◽  
Recent Theoretical Work ◽  
Evolutionary Rescue

AbstractPopulations may genetically adapt to severe stress that would otherwise cause their extirpation. Recent theoretical work, combining stochastic demography with Fisher’s geometric model of adaptation, has shown how evolutionary rescue becomes unlikely beyond some critical intensity of stress. Increasing mutation rates may however allow adaptation to more intense stress, raising concerns about the effectiveness of treatments against pathogens. This previous work assumes that populations are rescued by the rise of a single resistance mutation. However, even in asexual organisms, rescue can also stem from the accumulation of multiple mutations in a single genome. Here, we extend previous work to study the rescue process in an asexual population where the mutation rate is sufficiently high so that such events may be common. We predict both the ultimate extinction probability of the population and the distribution of extinction times. We compare the accuracy of different approximations covering a large range of mutation rates. Moderate increase in mutation rates favors evolutionary rescue. However, larger increase leads to extinction by the accumulation of a large mutation load, a process called lethal mutagenesis. We discuss how these results could help design “evolution-proof” anti-pathogen treatments that even highly mutable strains could not overcome.

Seventy Years on from the Luria and Delbrûck Fluctuation Analysis: A Comparison of three Methods for Estimating Mutation Rate

2015 ◽  
Vol 6 ◽  
pp. 50-58
Author(s):  
I W Nyinoh
Keyword(s):  
Mutation Rate ◽  
Resistance Mutation ◽  
Model Organism ◽  
Relative Fitness ◽  
Mutation Rates ◽  
Fluctuation Analysis ◽  
Cellular Processes ◽  
Scientific Disciplines ◽  
Rate Fluctuation ◽  
Contemporary Interpretation

Seventy years ago, Luria and Delbrûck discovered fluctuation assay for estimating mutation rates. While this method is slightly dated, it is one of the few methods for estimating mutation rates in batch culture. Mutation rates when determined expose information on cellular processes and fundamental mutagenic mechanisms. Formerly, inferences drawn from fluctuation assay were sufficient to answer a specific question inbacterial genetics. However, contemporary interpretation of results goes far beyond the motive originally intended. As the fluctuation assay has gained popularity in various scientific disciplines, analyses of results obtained are not same. This study aims to compare the estimation of mutation rates using the Poison distribution (Po) method with, the Ma-Sarka Sandri maximum likelihood estimator and the Lea-Coulson median estimator. Mycobacterium smegmatismc 2 155was used as a model organism for Mycobacterium tuberculosis, and spontaneous mutations that arose in stationary phase cells exposed to antibiotic stress were investigated. Ten to twenty-four parallel cultures were tested with various anti-tuberculosis drugs; isoniazid, kanamycin, rifampicin and streptomycin. Minimum Inhibitory Concentration (MIC) of the drugs were also determinedto be; 8 ìg/mL, 0.24 ìg/mL, 16 ìg/mL and 0.5 ìg/mL for isoniazid, kanamycin, rifampicin and streptomycin respectively. The mutation rates obtained with the methods were very similar. To improve the power of deductions drawn from fluctuation assay, efforts should be made to experimentally determine the relative fitness of wild-type to mutant bacteria.This comparison is only a guide providing evidence regarding the authenticity of some of the methods currently available to researchers interested in estimating bacterial mutation rates.Keywords: antibiotic resistance, mutation rate, fluctuation assay, fluctuation analysis calculator.

scholarly journals Epistatic interactions within the influenza virus polymerase complex mediate mutagen resistance and replication fidelity

2017 ◽  
Author(s):  
Matthew D. Pauly ◽  
Daniel M. Lyons ◽  
Adam S. Lauring
Keyword(s):  
Genetic Diversity ◽  
Drug Resistance ◽  
Influenza Virus ◽  
Mutation Rate ◽  
Rna Viruses ◽  
Nucleoside Analogs ◽  
Mutation Rates ◽  
Epistatic Interactions ◽  
Polymerase Complex ◽  
Lethal Mutagenesis

AbstractLethal mutagenesis is a broad-spectrum antiviral strategy that employs mutagenic nucleoside analogs to exploit the high mutation rate and low mutational tolerance of many RNA viruses. Studies of mutagen-resistant viruses have identified determinants of replicative fidelity and the importance of mutation rate to viral population dynamics. We have previously demonstrated the effective lethal mutagenesis of influenza virus using three nucleoside analogs as well as the virus’s high genetic barrier to mutagen resistance. Here, we investigate the mutagen-resistant phenotypes of mutations that were enriched in drug-treated populations. We find that PB1 T123A has higher replicative fitness than the wild type, PR8, and maintains its level of genome production during 5-fluorouracil treatment. Surprisingly, this mutagen-resistant variant also has an increased baseline rate of C to U and G to A mutations. A second drug-selected mutation, PA T97I, interacts epistatically with PB T123A to mediate high-level mutagen resistance, predominantly by limiting the inhibitory effect of nucleosides on polymerase activity. Consistent with the importance of epistatic interactions in the influenza polymerase, we find that nucleoside analog resistance and replication fidelity are strain dependent. Two previously identified ribavirin-resistance mutations, PB1 V43I and PB1 D27N, do not confer drug resistance in the PR8 background, and the PR8-PB1 V43I polymerase exhibits a normal baseline mutation rate. Our results highlight the genetic complexity of the influenza virus polymerase and demonstrate that increased replicative capacity is a mechanism by which an RNA virus can counter the negative effects of elevated mutation rates.ImportanceRNA viruses exist as genetically diverse populations. This standing genetic diversity gives them the potential to adapt rapidly, evolve resistance to antiviral therapeutics, and evade immune responses. Viral mutants with altered mutation rates or mutational tolerance have provided insights into how genetic diversity arises and how it affects the behavior of RNA viruses. To this end, we identified variants within the polymerase complex of influenza virus that are able tolerate drug-mediated increases in viral mutation rates. We find that drug resistance is highly dependent on interactions among mutations in the polymerase complex. In contrast to other viruses, influenza virus counters the effect of higher mutation rates primarily by maintaining high levels of genome replication. These findings suggest the importance of maintaining large population sizes for viruses with high mutation rates and show that multiple proteins can affect both mutation rate and genome synthesis.

scholarly journals Epigenetically Inherited Mutation Rates Predicted to Maximize Adaptation Rates

2021 ◽  
Author(s):  
Yoav Ram ◽  
Yitzhak Tzachi Pilpel ◽  
Gabriela Aleksandra Lobinska
Keyword(s):  
Mutation Rate ◽  
Adaptive Evolution ◽  
Evolutionary Dynamics ◽  
Epigenetic Inheritance ◽  
Fitness Landscapes ◽  
Mutation Rates ◽  
Switching Rate ◽  
Asexual Population ◽  
Parental Phenotype ◽  
Rugged Fitness Landscapes

The mutation rate is an important determinant of evolutionary dynamics. Because the mutation rate determines the rate of appearance of beneficial and deleterious mutations, it is subject to second-order selection. The mutation rate varies between and within species and populations, increases under stress, and is genetically controlled by mutator alleles. The mutation rate may also vary among genetically identical individuals: empirical evidence from bacteria suggests that the mutation rate may be affected by translation errors and expression noise in various proteins (1). Importantly, this non-genetic variation may be heritable via transgenerational epigenetic inheritance. Here we investigate how the inheritance mode of the mutation rate affects the rate of adaptive evolution on rugged fitness landscapes. We model an asexual population with two mutation rate phenotypes, non-mutator and mutator. An offspring may switch from its parental phenotype to the other phenotype. The rate of switching between the mutation rate phenotypes is allowed to span a range of values. Thus, the mutation rate can be interpreted as a genetically inherited trait when the switching rate is low, as an epigenetically inherited trait when the switching rate is intermediate, or as a randomly determined trait when the switching rate is high. We find that epigenetically inherited mutation rates result in the highest rates of adaptation on rugged fitness landscapes for most realistic parameter sets. This is because an intermediate switching rate can maintain the association between a mutator phenotype and pre-existing mutations, which facilitates the crossing of fitness valleys. Our results provide a rationale for the evolution of epigenetic inheritance of the mutation rate, suggesting that it could have been selected because it facilitates adaptive evolution.

scholarly journals Localized hypermutation drives the evolution of unstable colistin resistance in small populations of Pseudomonas aeruginosa

2021 ◽  
Author(s):  
Natalia Kapel ◽  
Julio Felix Diaz Caballero ◽  
Craig MacLean
Keyword(s):  
Antimicrobial Peptides ◽  
Mutation Rate ◽  
Resistance Mutation ◽  
Host Immunity ◽  
Mutation Rates ◽  
High Dose ◽  
Small Populations ◽  
Colistin Resistance ◽  
Two Component System ◽  
Antibiotic Resistant

Colistin has emerged as an important last line of defence for the treatment of infections caused by antibiotic resistant Gram-negative pathogens. Here we investigate the responses of ≈1,000 small populations (≈104 CFU) of an MDR strain of P. aeruginosa to a high dose of colistin (2 mg/L). Colistin exposure resulted in rapid cell death, but a sub-set of populations eventually recovered due to the outgrowth of heteroresistant cells. Genome sequencing revealed that heteroresistance was primarily driven by mutations in the PmrAB two-component system that occurred at a rate (≈2x10-5 per cell division) that was 103-104 fold higher than typical resistance mutation rates. Crucially, this elevated mutation rate was only found in pmrB, demonstrating that hypermutability is localized to this gene. PmrAB provides resistance to antimicrobial peptides that are involved in host immunity, suggesting that this pathogen may have evolved a high mutation rate as an adaption to generate mutants that are resistant to host antimicrobial peptides that are secreted during infection. Interestingly, we found no mutations in some heteroresister populations, suggesting that a small sub-set of P. aeruginosa cells are intrinsically resistant to colistin as a result of phenotypic plasticity.

scholarly journals Beneficial Mutations, Hitchhiking and the Evolution of Mutation Rates in Sexual Populations

Genetics ◽  
1999 ◽  
Vol 151 (4) ◽  
pp. 1621-1631 ◽  
Author(s):  
Toby Johnson
Keyword(s):  
Mutation Rate ◽  
Indirect Selection ◽  
Mutation Rates ◽  
Deleterious Mutations ◽  
Heritable Variation ◽  
Asexual Population ◽  
Beneficial Mutations ◽  
Long Term Effect ◽  
The Cost ◽  
Substantial Change

Abstract Natural selection acts in three ways on heritable variation for mutation rates. A modifier allele that increases the mutation rate is (i) disfavored due to association with deleterious mutations, but is also favored due to (ii) association with beneficial mutations and (iii) the reduced costs of lower fidelity replication. When a unique beneficial mutation arises and sweeps to fixation, genetic hitchhiking may cause a substantial change in the frequency of a modifier of mutation rate. In previous studies of the evolution of mutation rates in sexual populations, this effect has been underestimated. This article models the long-term effect of a series of such hitchhiking events and determines the resulting strength of indirect selection on the modifier. This is compared to the indirect selection due to deleterious mutations, when both types of mutations are randomly scattered over a given genetic map. Relative to an asexual population, increased levels of recombination reduce the effects of beneficial mutations more rapidly than those of deleterious mutations. However, the role of beneficial mutations in determining the evolutionarily stable mutation rate may still be significant if the function describing the cost of high-fidelity replication has a shallow gradient.

scholarly journals Population persistence under high mutation rate: From evolutionary rescue to lethal mutagenesis

Evolution ◽  
2019 ◽  
Vol 73 (8) ◽  
pp. 1517-1532 ◽  
Author(s):  
Yoann Anciaux ◽  
Amaury Lambert ◽  
Ophélie Ronce ◽  
Lionel Roques ◽  
Guillaume Martin
Keyword(s):  
Mutation Rate ◽  
Population Persistence ◽  
High Mutation Rate ◽  
Lethal Mutagenesis ◽  
Evolutionary Rescue

scholarly journals Replication Mode and Landscape Topology Differentially Affect RNA Virus Mutational Load and Robustness

2009 ◽  
Vol 83 (23) ◽  
pp. 12579-12589 ◽  
Author(s):  
Josep Sardanyés ◽  
Ricard V. Solé ◽  
Santiago F. Elena
Keyword(s):  
Mutation Rate ◽  
Fitness Landscape ◽  
Rna Virus ◽  
Geometric Model ◽  
Mutation Rates ◽  
Machine Model ◽  
Wide Range ◽  
String Models ◽  
Complementary Sense ◽  
Geometric Growth

ABSTRACT Regardless of genome polarity, intermediaries of complementary sense must be synthesized and used as templates for the production of new genomic strands. Depending on whether these new genomic strands become themselves templates for producing extra antigenomic ones, thus giving rise to geometric growth, or only the firstly synthesized antigenomic strands can be used to this end, thus following Luria's stamping machine model, the abundances and distributions of mutant genomes will be different. Here we propose mathematical and bit string models that allow distinguishing between stamping machine and geometric replication. We have observed that, regardless the topology of the fitness landscape, the critical mutation rate at which the master sequence disappears increases as the mechanism of replication switches from purely geometric to stamping machine. We also found that, for a wide range of mutation rates, large-effect mutations do not accumulate regardless the scheme of replication. However, mild mutations accumulate more in the geometric model. Furthermore, at high mutation rates, geometric growth leads to a population collapse for intermediate values of mutational effects at which the stamping machine still produces master genomes. We observed that the critical mutation rate was weakly dependent on the strength of antagonistic epistasis but strongly dependent on synergistic epistasis. In conclusion, we have shown that RNA viruses may increase their robustness against the accumulation of deleterious mutations by replicating as stamping machines and that the magnitude of this benefit depends on the topology of the fitness landscape assumed.

scholarly journals Evolution of mutation rates in rapidly adapting asexual populations

2016 ◽  
Author(s):  
Benjamin H. Good ◽  
Michael M. Desai
Keyword(s):  
Mutation Rate ◽  
Evolutionary Dynamics ◽  
Empirical Work ◽  
Indirect Selection ◽  
Microbial Evolution ◽  
Mutation Rates ◽  
Fixation Probability ◽  
Deleterious Mutations ◽  
Clonal Interference ◽  
Asexual Population

Mutator and antimutator alleles often arise and spread in both natural microbial populations and laboratory evolution experiments. The evolutionary dynamics of these mutation rate modifiers are determined by indirect selection on linked beneficial and deleterious mutations. These indirect selection pressures have been the focus of much earlier theoretical and empirical work, but we still have a limited analytical understanding of how the interplay between hitchhiking and deleterious load influences the fates of modifier alleles. Our understanding is particularly limited when clonal interference is common, which is the regime of primary interest in laboratory microbial evolution experiments. Here, we calculate the fixation probability of a mutator or antimutator allele in a rapidly adapting asexual population, and we show how this quantity depends on the population size, the beneficial and deleterious mutation rates, and the strength of a typical driver mutation. In the absence of deleterious mutations, we find that clonal interference enhances the fixation probability of mutators, even as they provide a diminishing benefit to the overall rate of adaptation. When deleterious mutations are included, natural selection pushes the population towards a stable mutation rate that can be suboptimal for the adaptation of the population as a whole. The approach to this stable mutation rate is not necessarily monotonic, and selection can favor mutator and antimutator alleles that overshoot the stable mutation rate by substantial amounts.

The light-scattering Mueller matrices for Rayleigh and Rayleigh-Gans-Debye approximation

1990 ◽  
Vol 55 (12) ◽  
pp. 2889-2897
Author(s):  
Jaroslav Holoubek
Keyword(s):  
Light Scattering ◽  
Theoretical Work ◽  
Matrix Elements ◽  
Elastic Light Scattering ◽  
Yield Information ◽  
Recent Theoretical Work ◽  
Particle Parameters ◽  
Complete Set ◽  
Single Matrix ◽  
Scattering Matrix Elements

Recent theoretical work has shown that the complete set of polarized elastic light-scattering studies should yield information about scatterer structure that has so far hardly been utilized. We present here calculations of angular dependences of light-scattering matrix elements for spheres near the Rayleigh and Rayleigh-Gans-Debye limits. The significance of single matrix elements is documented on examples that show how different matrix elements respond to changes in particle parameters. It appears that in the small-particle limit (Rg/λ < 0.1) we do not loose much information by ignoring "large particle" observables.

scholarly journals Magnetospheric Structure of Rotation-Powered Neutron Stars

1992 ◽  
Vol 128 ◽  
pp. 56-77 ◽  
Author(s):  
Jonathan Arons
Keyword(s):  
Radio Emission ◽  
Gamma Radiation ◽  
Heavy Ions ◽  
Theoretical Work ◽  
Future Research ◽  
Observational Constraints ◽  
Polar Caps ◽  
Recent Theoretical Work ◽  
Density Flow ◽  
Promising Avenue

AbstractI survey recent theoretical work on the structure of the magnetospheres of rotation-powered pulsars, within the observational constraints set by their observed spindown, their ability to power synchrotron nebulae and their ability to produce beamed collective radio emission, while putting only a small fraction of their energy into incoherent X- and gamma radiation. I find no single theory has yet given a consistent description of the magnetosphere, but I conclude that models based on a dense outflow of pairs from the polar caps, permeated by a lower density flow of heavy ions, are the most promising avenue for future research.

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