scholarly journals Death and population dynamics affect mutation rate estimates and evolvability under stress in bacteria

2017 ◽  
Author(s):  
Antoine Frénoy ◽  
Sebastian Bonhoeffer
Keyword(s):  
Population Dynamics ◽  
Mutation Rate ◽  
Death Rate ◽  
Mutation Rates ◽  
Resistance Mutations ◽  
Bacterial Populations ◽  
Plasmid Segregation ◽  
Genome Wide ◽  
Response To Stress ◽  
Induced Mutagenesis

AbstractThe stress-induced mutagenesis paradigm postulates that in response to stress, bacteria increase their genome-wide mutation rate, in turn increasing the chances that a descendant is able to withstand the stress. This has implications for antibiotic treatment: exposure to sub-inhibitory doses of antibiotics has been reported to increase bacterial mutation rates, and thus probably the rate at which resistance mutations appear and lead to treatment failure.Measuring mutation rates under stress, however, is problematic, because existing methods assume there is no death. Yet sub-inhibitory stress levels may induce a substantial death rate. Death events need to be compensated by extra replication to reach a given population size, thus giving more opportunities to acquire mutations. We show that ignoring death leads to a systematic overestimation of mutation rates under stress.We developed a system using plasmid segregation to measure death and growth rates simultaneously in bacterial populations. We use it to replicate classical experiments reporting antibiotic-induced mutagenesis. We found that a substantial death rate occurs at the tested sub-inhibitory concentrations, and taking this death into account lowers and sometimes removes the signal for stress-induced mutagenesis. Moreover even when antibiotics increase mutation rate, sub-inhibitory treatments do not increase genetic diversity and evolvability, again because of effects of the antibiotics on population dynamics.Beside showing that population dynamic is a crucial but neglected parameter affecting evolvability, we provide better experimental and computational tools to study evolvability under stress, leading to a re-assessment of the magnitude and significance of the stress-induced mutagenesis paradigm.

scholarly journals Molecular mechanisms involved in the regulation of mutation rates in bacteria

2017 ◽  
Vol 118 (4) ◽  
Author(s):  
Ivan Matic
Keyword(s):  
Mutation Rate ◽  
Molecular Mechanisms ◽  
Point Of View ◽  
Mutation Rates ◽  
Beneficial Mutations ◽  
Bacterial Populations ◽  
Multiple Strategies ◽  
Induced Mutagenesis ◽  
The Cost ◽  
Evolutionary Point

Organisms live in constantly changing environments in which, the nature, severity and frequency of the environmental stresses are very variable. Organisms possess multiple strategies for coping with the environmental fluctuations. One such strategy is modulation of mutation rates as a function of the degree of adaptation to the environment. When adaptation is limited by the available genetic variability, natural selection favors cells having high mutation rates in bacterial populations. High mutation rates can be advantageous because they increase the probability of generation of beneficial mutations. Constitutive mutator alleles are carried to high frequency through hitchhiking with beneficial mutations they generate. However, once the adaptation is achieved, the cost of deleterious mutations generated by constitutive mutator alleles reduces cellular fitness. For this reason, the possibility of adapting the mutation rate to environmental conditions is interesting from an evolutionary point of view. Stress-induced mutagenesis allows rapid adaptation to complex environmental challenges without compromising the population fitness because it reduces the overall cost of a high mutation rate. Here we review the molecular mechanisms involved in the control of modulation of mutation rates in bacteria.

scholarly journals The evolution of bacterial mutation rates under simultaneous selection by interspecific and social parasitism

2013 ◽  
Vol 280 (1773) ◽  
pp. 20131913 ◽  
Author(s):  
Siobhán O'Brien ◽  
Antonio M. M. Rodrigues ◽  
Angus Buckling
Keyword(s):  
Mutation Rate ◽  
Social Parasitism ◽  
Mutation Rates ◽  
Bacterial Populations ◽  
Simultaneous Selection ◽  
Bacterial Mutation ◽  
Selection For ◽  
Intraspecific Parasitism ◽  
Theory And Experiments ◽  
Mutation Rate Evolution

Many bacterial populations harbour substantial numbers of hypermutable bacteria, in spite of hypermutation being associated with deleterious mutations. One reason for the persistence of hypermutators is the provision of novel mutations, enabling rapid adaptation to continually changing environments, for example coevolving virulent parasites. However, hypermutation also increases the rate at which intraspecific parasites (social cheats) are generated. Interspecific and intraspecific parasitism are therefore likely to impose conflicting selection pressure on mutation rate. Here, we combine theory and experiments to investigate how simultaneous selection from inter- and intraspecific parasitism affects the evolution of bacterial mutation rates in the plant-colonizing bacterium Pseudomonas fluorescens. Both our theoretical and experimental results suggest that phage presence increases and selection for public goods cooperation (the production of iron-scavenging siderophores) decreases selection for mutator bacteria. Moreover, phages imposed a much greater growth cost than social cheating, and when both selection pressures were imposed simultaneously, selection for cooperation did not affect mutation rate evolution. Given the ubiquity of infectious phages in the natural environment and clinical infections, our results suggest that phages are likely to be more important than social interactions in determining mutation rate evolution.

scholarly journals Errors in mutagenesis and the benefit of cell-to-cell signalling in the evolution of stress-induced mutagenesis

2017 ◽  
Vol 4 (11) ◽  
pp. 170529 ◽  
Author(s):  
Eynat Dellus-Gur ◽  
Yoav Ram ◽  
Lilach Hadany
Keyword(s):  
Natural Selection ◽  
Mutation Rate ◽  
Cell Signalling ◽  
Theoretical Models ◽  
Error Rates ◽  
Order Selection ◽  
Beneficial Mutations ◽  
Response To Stress ◽  
Induced Mutagenesis

Stress-induced mutagenesis is a widely observed phenomenon. Theoretical models have shown that stress-induced mutagenesis can be favoured by natural selection due to the beneficial mutations it generates. These models, however, assumed an error-free regulation of mutation rate in response to stress. Here, we explore the effects of errors in the regulation of mutagenesis on the evolution of stress-induced mutagenesis, and consider the role of cell-to-cell signalling. Using theoretical models, we show (i) that stress-induced mutagenesis can be disadvantageous if errors are common; and (ii) that cell-to-cell signalling can allow stress-induced mutagenesis to be favoured by selection even when error rates are high. We conclude that cell-to-cell signalling can facilitate the evolution of stress-induced mutagenesis in microbes through second-order selection.

scholarly journals Epigenetic modifications affect the rate of spontaneous mutations in a pathogenic fungus

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Michael Habig ◽  
Cecile Lorrain ◽  
Alice Feurtey ◽  
Jovan Komluski ◽  
Eva H. Stukenbrock
Keyword(s):  
Temperature Stress ◽  
Mutation Rate ◽  
Cytosine Methylation ◽  
Pathogenic Fungus ◽  
Epigenetic Modifications ◽  
Mutation Rates ◽  
Adaptive Mutation ◽  
Spontaneous Mutations ◽  
Evolutionary Trajectory ◽  
Genome Wide

AbstractMutations are the source of genetic variation and the substrate for evolution. Genome-wide mutation rates appear to be affected by selection and are probably adaptive. Mutation rates are also known to vary along genomes, possibly in response to epigenetic modifications, but causality is only assumed. In this study we determine the direct impact of epigenetic modifications and temperature stress on mitotic mutation rates in a fungal pathogen using a mutation accumulation approach. Deletion mutants lacking epigenetic modifications confirm that histone mark H3K27me3 increases whereas H3K9me3 decreases the mutation rate. Furthermore, cytosine methylation in transposable elements (TE) increases the mutation rate 15-fold resulting in significantly less TE mobilization. Also accessory chromosomes have significantly higher mutation rates. Finally, we find that temperature stress substantially elevates the mutation rate. Taken together, we find that epigenetic modifications and environmental conditions modify the rate and the location of spontaneous mutations in the genome and alter its evolutionary trajectory.

scholarly journals De novo mutations across 1,465 diverse genomes reveal novel mutational insights and reductions in the Amish founder population

2019 ◽  
Author(s):  
Michael D. Kessler ◽  
Douglas P. Loesch ◽  
James A. Perry ◽  
Nancy L. Heard-Costa ◽  
Brian E. Cade ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Mutation Rate ◽  
De Novo ◽  
Population Level ◽  
Mutation Rates ◽  
Founder Population ◽  
Single Nucleotide ◽  
Genome Wide ◽  
Nucleotide Mutation ◽  
Rare Genetic Variation

Abstractde novo Mutations (DNMs), or mutations that appear in an individual despite not being seen in their parents, are an important source of genetic variation whose impact is relevant to studies of human evolution, genetics, and disease. Utilizing high-coverage whole genome sequencing data as part of the Trans-Omics for Precision Medicine (TOPMed) program, we directly estimate and analyze DNM counts, rates, and spectra from 1,465 trios across an array of diverse human populations. Using the resulting call set of 86,865 single nucleotide DNMs, we find a significant positive correlation between local recombination rate and local DNM rate, which together can explain up to 35.5% of the genome-wide variation in population level rare genetic variation from 41K unrelated TOPMed samples. While genome-wide heterozygosity does correlate weakly with DNM count, we do not find significant differences in DNM rate between individuals of European, African, and Latino ancestry, nor across ancestrally distinct segments within admixed individuals. However, interestingly, we do find significantly fewer DNMs in Amish individuals compared with other Europeans, even after accounting for parental age and sequencing center. Specifically, we find significant reductions in the number of T→C mutations in the Amish, which seems to underpin their overall reduction in DNMs. Finally, we calculate near-zero estimates of narrow sense heritability (h2), which suggest that variation in DNM rate is significantly shaped by non-additive genetic effects and/or the environment, and that a less mutagenic environment may be responsible for the reduced DNM rate in the Amish.SignificanceHere we provide one of the largest and most diverse human de novo mutation (DNM) call sets to date, and use it to quantify the genome-wide relationship between local mutation rate and population-level rare genetic variation. While we demonstrate that the human single nucleotide mutation rate is similar across numerous human ancestries and populations, we also discover a reduced mutation rate in the Amish founder population, which shows that mutation rates can shift rapidly. Finally, we find that variation in mutation rates is not heritable, which suggests that the environment may influence mutation rates more significantly than previously realized.

scholarly journals Statistical concepts in the theory of bacterial mutation

1953 ◽  
Vol 51 (2) ◽  
pp. 162-184 ◽  
Author(s):  
P. Armitage
Keyword(s):  
Mutation Rate ◽  
Phenotypic Expression ◽  
Theoretical Distribution ◽  
Mutation Rates ◽  
Safe Procedure ◽  
Short Term ◽  
Mutant Type ◽  
Bacterial Populations ◽  
Long Term Experiment

This paper is a short exposition of the mathematical and statistical theory of the growth of bacterial populations subject to mutation.A mathematical model for the long-term development of a mixed population with two types of organism is proposed. The proportion of organisms which are of the mutant type eventually approaches an asymptotic value, which is independent of the initial composition of the population. A procedure is outlined for estimating the forward and backward mutation rates from a long-term experiment.The exact interpretation of the constants representing mutation rates requires some assumption about the point of time, during an individual life cycle, at which mutations occur. The usual assumption is that mutations can occur with equal frequency at all instants during the cycle.In short-term experiments, in which the proportion of mutants is at all times negligible, it is important to consider the variation between the numbers of mutants developing in replicate cultures. The theoretical distribution of Lea & Coulson may be disturbed by the failure of any one of a number of assumptions; the effects of such disturbances are considered in some detail.Various methods of estimating the mutation rate from an observed series of replicate cultures are examined. Two of the main sources of disturbance of the theoretical distribution may be delay of phenotypic expression, and the existence of multinucleate cells with dominant mutation. These factors affect particularly the lower tail of the distribution, and it is suggested that a fairly safe procedure may be to estimate the mutation rate from the upper quartile of the observed distribution. Tables 3 and 4 enable the estimate of the mutation rate, together with 95% confidence limits, to be readily calculated.

scholarly journals A deep learning-based framework for estimating fine-scale germline mutation rates

2021 ◽  
Author(s):  
Yiyuan Fang ◽  
Shuyi Deng ◽  
Cai Li
Keyword(s):  
Deep Learning ◽  
Mutation Rate ◽  
Germline Mutation ◽  
Homo Sapiens ◽  
Predictive Performance ◽  
Training Data ◽  
Mutation Rates ◽  
Fine Scale ◽  
Current State ◽  
Genome Wide

Germline mutation rates are essential for genetic and evolutionary analyses. Yet, estimating accurate fine-scale mutation rates across the genome is a great challenge, due to relatively few observed mutations and intricate relationships between predictors and mutation rates. Here we present MuRaL (Mutation Rate Learner), a deep learning-based framework to predict fine-scale mutation rates using only genomic sequences as input. Harnessing human germline variants for comprehensive assessment, we show that MuRaL achieves better predictive performance than current state-of-the-art methods. Moreover, MuRaL can build models with relatively few training mutations and a moderate number of sequenced individuals. It can leverage transfer learning to build models with further less training data and time. We apply MuRaL to produce genome-wide mutation rate profiles for four species - Homo sapiens, Macaca mulatta, Arabidopsis thaliana and Drosophila melanogaster, demonstrating its high applicability. The generated mutation rate profiles and open source software can greatly facilitate related research.

scholarly journals Stress-induced mutagenesis and complex adaptation

2014 ◽  
Vol 281 (1792) ◽  
pp. 20141025 ◽  
Author(s):  
Yoav Ram ◽  
Lilach Hadany
Keyword(s):  
Natural Selection ◽  
Deleterious Mutation ◽  
Raw Material ◽  
Mutation Rates ◽  
Asexual Population ◽  
Trade Off ◽  
Response To Stress ◽  
Mean Fitness ◽  
Induced Mutagenesis ◽  
Theoretical Results

Because mutations are mostly deleterious, mutation rates should be reduced by natural selection. However, mutations also provide the raw material for adaptation. Therefore, evolutionary theory suggests that the mutation rate must balance between adaptability —the ability to adapt—and adaptedness —the ability to remain adapted. We model an asexual population crossing a fitness valley and analyse the rate of complex adaptation with and without stress-induced mutagenesis (SIM)—the increase of mutation rates in response to stress or maladaptation. We show that SIM increases the rate of complex adaptation without reducing the population mean fitness, thus breaking the evolutionary trade-off between adaptability and adaptedness . Our theoretical results support the hypothesis that SIM promotes adaptation and provide quantitative predictions of the rate of complex adaptation with different mutational strategies.

scholarly journals Cross-sectional genomic perspective of epidemic waves of SARS-CoV-2: a pan India study

2021 ◽  
Author(s):  
Sanjeet Kumar ◽  
Kanika Bansal
Keyword(s):  
Mutation Rate ◽  
Large Scale ◽  
Mutational Analysis ◽  
Silent Mutation ◽  
Mutation Rates ◽  
Rna Dependent Rna Polymerase ◽  
Cross Sectional ◽  
Genome Wide ◽  
Sectional Analysis ◽  
Second Wave

COVID-19 has posed unforeseen circumstances and throttled major economies worldwide. India has witnessed two waves affecting around 31 million people representing 16% of the cases globally. To date, the epidemic waves have not been comprehensively investigated to understand pandemic progress in India. In the present study, we aim for a cross-sectional analysis since its first incidence up to 26th July 2021. We have performed the pan Indian evolutionary study using 20,086 high-quality complete genomes of SARS-CoV-2. Based on the number of cases reported and mutation rates, we could divide the Indian epidemic into seven different phases. First, three phases constituting the pre-first wave had a very less average mutation rate (<11), which increased in the first wave to 17 and then doubled in the second wave (~34). In accordance with the mutation rate, variants of concern (alpha, beta, gamma and delta) and interest (eta and kappa) also started appearing in the first wave (1.5% of the genomes), which dominated the second (~96% of genomes) and post-second wave (100% of genomes) phases. Whole genome-based phylogeny could demarcate the post-first wave isolates from previous ones by the point of diversification leading to incidences of VOCs and VOIs in India. Nation-wide mutational analysis depicted more than 0.5 million events with four major mutations in ~97% of the total 20,086 genomes in the study. These included two mutations in coding (spike (D614G) and NSP 12b (P314L) of RNA dependent RNA polymerase), one silent mutation (NSP3 F106F) and one extragenic mutation (5 UTR 241). Large scale genome-wide mutational analysis is crucial in expanding knowledge on evolution of deadly variants of SARS-CoV-2 and timely management of the pandemic.

scholarly journals De novo mutation rates at the single-mutation resolution in a human HBB gene-region associated with adaptation and genetic disease

2022 ◽  
pp. gr.276103.121
Author(s):  
Daniel Melamed ◽  
Yuval Nov ◽  
Assaf Malik ◽  
Michael B Yakass ◽  
Evgeni Bolotin ◽  
...  
Keyword(s):  
Mutation Rate ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Region Of Interest ◽  
De Novo Mutation ◽  
Mutation Rates ◽  
Single Mutation ◽  
Random Mutation ◽  
Genome Wide ◽  
Specific Manner

While it is known that the mutation rate varies across the genome, previous estimates were based on averaging across various numbers of positions. Here we describe a method to measure the origination rates of target mutations at target base positions and apply it to a 6-bp region in the human hemoglobin subunit beta (HBB) gene and to the identical, paralogous hemoglobin subunit delta (HBD) region in sperm cells from both African and European donors. The HBB region of interest (ROI) includes the site of the hemoglobin S (HbS) mutation, which protects against malaria, is common in Africa and has served as a classic example of adaptation by random mutation and natural selection. We found a significant correspondence between de novo mutation rates and past observations of alleles in carriers, showing that mutation rates vary substantially in a mutation-specific manner that contributes to the site frequency spectrum. We also found that the overall point mutation rate is significantly higher in Africans than in Europeans in the HBB region studied. Finally, the rate of the 20A→T mutation, called the 'HbS mutation' when it appears in HBB, is significantly higher than expected from the genome-wide average for this mutation type. Nine instances were observed in the African HBB ROI, where it is of adaptive significance, representing at least three independent originations; no instances were observed elsewhere. Further studies will be needed to examine mutation rates at the single-mutation resolution across these and other loci and organisms and to uncover the molecular mechanisms responsible.

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