scholarly journals Modifiers of mutation-selection balance: general approach and the evolution of mutation rates

1995 ◽  
Vol 66 (1) ◽  
pp. 53-69 ◽  
Author(s):  
Alexey S. Kondrashov
Keyword(s):  
Mutation Rate ◽  
Mutant Allele ◽  
Deleterious Mutation ◽  
Mutation Rates ◽  
Quasi Equilibrium ◽  
Selection Differential ◽  
Selection Coefficient ◽  
Modifier Locus ◽  
Ratio Of Variances ◽  
The Cost

SummaryA general approach is developed to estimate secondary selection at a modifier locus that influences some feature of a population under mutation-selection balance. The approach is based on the assumption that the properties of all available genotypes at this locus are similar. Then mutation-selection balance and weak associations between genotype distributions at selectable loci and the modifier locus are established rapidly. In contrast, changes of frequencies of the modifier genotypes are slow, and lead to only slow and small changes of the other features of the population. Thus, while these changes occur, the population remains in a state of quasi-equilibrium, where the mutation-selection balance and the associations between the selectable loci and the modifier locus are almost invariant. Selection at the modifier locus can be estimated by calculating quasiequilibrium values of these associations. This approach is developed for the situation where distributions of the number of mutations per genome within the individuals with a given modifier genotype are close to Gaussian. The results are used to study the evolution of the mutation rate. Because beneficial mutations are ignored, secondary selection at the modifier locus always diminishes the mutation rate. The coefficient of selection against an allele which increases the mutation rate by υ is approximately υδ2/[U(2−ρ)] = υŝ, where υ is the genomic deleterious mutation rate, δ is the selection differential of the number of mutations per individual in units of the standard deviation of the distribution of this number in the population, ρ is the ratio of variances of the number of mutations after and before selection, and ŝ is the selection coefficient against a mutant allele in the quasiequilibrium population. However, the decline of the mutation rate can be counterbalanced by the cost of fidelity, which can lead to an evolutionary equilibrium mutation rate.

scholarly journals Sign of selection on mutation rate modifiers depends on population size

2018 ◽  
Vol 115 (13) ◽  
pp. 3422-3427 ◽  
Author(s):  
Yevgeniy Raynes ◽  
C. Scott Wylie ◽  
Paul D. Sniegowski ◽  
Daniel M. Weinreich
Keyword(s):  
Population Size ◽  
Mutation Rate ◽  
Genetic System ◽  
Indirect Selection ◽  
Mutation Rates ◽  
Deleterious Mutations ◽  
Fitness Effects ◽  
Sign Inversion ◽  
Large Populations ◽  
The Cost

The influence of population size (N) on natural selection acting on alleles that affect fitness has been understood for almost a century. AsNdeclines, genetic drift overwhelms selection and alleles with direct fitness effects are rendered neutral. Often, however, alleles experience so-called indirect selection, meaning they affect not the fitness of an individual but the fitness distribution of its offspring. Some of the best-studied examples of indirect selection include alleles that modify aspects of the genetic system such as recombination and mutation rates. Here, we use analytics, simulations, and experimental populations ofSaccharomyces cerevisiaeto examine the influence ofNon indirect selection acting on alleles that increase the genomic mutation rate (mutators). Mutators experience indirect selection via genomic associations with beneficial and deleterious mutations they generate. We show that, asNdeclines, indirect selection driven by linked beneficial mutations is overpowered by drift before drift can neutralize the cost of the deleterious load. As a result, mutators transition from being favored by indirect selection in large populations to being disfavored asNdeclines. This surprising phenomenon of sign inversion in selective effect demonstrates that indirect selection on mutators exhibits a profound and qualitatively distinct dependence onN.

scholarly journals The Effect of Overdominance on Characterizing Deleterious Mutations in Large Natural Populations

Genetics ◽  
1999 ◽  
Vol 151 (2) ◽  
pp. 895-913 ◽  
Author(s):  
Jin-Long Li ◽  
Jian Li ◽  
Hong-Wen Deng
Keyword(s):  
Genetic Variation ◽  
Mutation Rate ◽  
Deleterious Mutation ◽  
Natural Populations ◽  
Mutation Accumulation ◽  
Statistical Properties ◽  
Alternative Methods ◽  
Deleterious Mutations ◽  
Selection Coefficient ◽  
New Approaches

Abstract Alternatives to the mutation-accumulation approach have been developed to characterize deleterious genomic mutations. However, they all depend on the assumption that the standing genetic variation in natural populations is solely due to mutation-selection (M-S) balance and therefore that overdominance does not contribute to heterosis. Despite tremendous efforts, the extent to which this assumption is valid is unknown. With different degrees of violation of the M-S balance assumption in large equilibrium populations, we investigated the statistical properties and the robustness of these alternative methods in the presence of overdominance. We found that for dominant mutations, estimates for U (genomic mutation rate) will be biased upward and those for h̄ (mean dominance coefficient) and s̄ (mean selection coefficient), biased downward when additional overdominant mutations are present. However, the degree of bias is generally moderate and depends largely on the magnitude of the contribution of overdominant mutations to heterosis or genetic variation. This renders the estimates of U and s̄ not always biased under variable mutation effects that, when working alone, cause U and s̄ to be underestimated. The contributions to heterosis and genetic variation from overdominant mutations are monotonic but not linearly proportional to each other. Our results not only provide a basis for the correct inference of deleterious mutation parameters from natural populations, but also alleviate the biggest concern in applying the new approaches, thus paving the way for reliably estimating properties of deleterious mutations.

scholarly journals Effects of mutation on selection limits in finite populations with multiple alleles.

Genetics ◽  
1989 ◽  
Vol 122 (4) ◽  
pp. 977-984
Author(s):  
Z B Zeng ◽  
H Tachida ◽  
C C Cockerham
Keyword(s):  
Mutation Rate ◽  
Present Model ◽  
Substantial Effect ◽  
Mutation Rates ◽  
Additive Effects ◽  
Selection Coefficient ◽  
Effective Population ◽  
Weak Selection ◽  
Multiple Alleles ◽  
Selection Limit

Abstract The ultimate response to directional selection (i.e., the selection limit) under recurrent mutation is analyzed by a diffusion approximation for a population in which there are k possible alleles at a locus. The limit mainly depends on two scaled parameters S (= 4Ns sigma a) and theta (= 4Nu) and k, the number of alleles, where N is the effective population size, u is the mutation rate, s is the selection coefficient, and sigma 2a is the variance of allelic effects. When the selection pressure is weak (S less than or equal to 0.5), the limit is given approximately by 2S sigma a[1 - (1 + c2)/k]/(theta + 1) for additive effects of alleles, where c is the coefficient of variation of the mutation rates among alleles. For strong selection, other approximations are devised to analyze the limit in different parameter regions. The effect of mutation on selection limits largely relies on the potential of mutation to introduce new and better alleles into the population. This effect is, however, bounded under the present model. Unequal mutation rates among alleles tend to reduce the selection limit, and can have a substantial effect only for small numbers of alleles and weak selection. The selection limit decreases as the mutation rate increases.

scholarly journals Pedigree Derived Mutation Rate Across the Entire Mitochondrial Genome of the Norfolk Island Population

2021 ◽  
Author(s):  
Jasmine Connell ◽  
Miles Benton ◽  
Rodney Lea ◽  
Heidi Sutherland ◽  
Janet Chaseling ◽  
...  
Keyword(s):  
Phylogenetic Analysis ◽  
Mitochondrial Genome ◽  
Mutation Rate ◽  
Mutation Rates ◽  
Island Population ◽  
Coding Region ◽  
Research Fields ◽  
Norfolk Island ◽  
The Cost ◽  
Entire Mitochondrial Genome

Abstract Estimates of mutation rates for various regions of the mitochondrial genome (mtGenome) vary widely, depending on whether they are inferred using a phylogenetic approach or obtained directly from pedigrees. Traditionally, only the control region, or small portions of the coding region have been targeted for analysis due to the cost and effort required to produce whole mtGenome Sanger profiles. Here, we report one of the first pedigree derived mutation rates for the entire human mtGenome. The entire mtGenome from 225 individuals originating from Norfolk Island was analysed to estimate the population mutation rate and compared against published mutation rates. These individuals were from 45 maternal lineages spanning 345 generational events. Mutation rates for various portions of the mtGenome were calculated. Nine mutations (including two transitions and seven cases of heteroplasmy) were observed, resulting in a rate of 0.063 mutations/site/million years (95% confidence interval: 0.033 – 0.118). These mutation rates are approximately 17 times higher than estimates derived from phylogenetic analysis with heteroplasmy detected in 13 samples (n=225, 5.8% individuals). Providing one of the first pedigree derived estimates for the entire mtGenome, this study provides a better understanding of mtGenome evolution and has relevance to many research fields, including medicine, anthropology and forensics.

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 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 SELECTION DIFFERENTIALS AND SELECTION COEFFICIENTS

Genetics ◽  
1978 ◽  
Vol 88 (2) ◽  
pp. 391-403
Author(s):  
Roger Milkman
Keyword(s):  
Cost Efficiency ◽  
Differential Effect ◽  
Nondecreasing Function ◽  
Heterogeneous Environment ◽  
Selection Differential ◽  
Selection Coefficient ◽  
Truncation Selection ◽  
The Cost ◽  
Selection Differentials ◽  
Normally Distributed

ABSTRACT Proof is offered that s ≃ ig for all forms of selection where fitness is a nondecreasing function of a normally distributed phenotype (called fitness potential); s is selection coefficient, i is standard selection differential, and g is standard differential effect of a locus genotype. Evidence is presented that the cost of selection does not limit genic polymorphism; that truncation selection is not necessary for high cost-efficiency; and that opposing directions of selection in a heterogeneous environment do not reduce cost-efficiency critically.

scholarly journals Mutation-Selection Balance at a Modifier-of-Imprinting Locus

Genetics ◽  
1996 ◽  
Vol 144 (1) ◽  
pp. 361-367
Author(s):  
Hamish G Spencer ◽  
Janine A Barnett
Keyword(s):  
Mutation Rate ◽  
Population Genetic ◽  
Stable Equilibrium ◽  
Large Population ◽  
Genetic Models ◽  
Selection Coefficient ◽  
Modifier Locus ◽  
Target Locus ◽  
Mutant Phenotypes

Abstract We propose a pair of population genetic models for a modifier-of-imprinting locus for which different genotypes imprint different proportions of an imprintable target locus in their gametes. The two models examine the situations in which imprinting is advantageous or disadvantageous, and we discuss three cases for which the modifier is respectively partially dominant, dominant, or recessive. The models predict the stable equilibrium frequencies of the mutant modifier and functionally diploid individuals in a large population in terms of up to four parameters: the mutation rate at the modifier locus, v; the selection coefficient against the disadvantageous phenotype, s; the proportion of unimprinted eggs produced by homozygotes for the mutant modifier, 8, and, in the partially dominant models, the dominance parameter, k. The equilibrium frequency of the mutant phenotypes is shown to be approximately twice that of standard Mendelian models: 2v/s or 4v/s when the modifier is recessive or dominant, respectively. Mathematical equivalences between these and nonimprinting models are noted.

scholarly journals Likelihoods and Simulation Methods for a Class of Nonneutral Population Genetics Models

Genetics ◽  
2001 ◽  
Vol 159 (2) ◽  
pp. 853-867 ◽  
Author(s):  
Peter Donnelly ◽  
Magnus Nordborg ◽  
Paul Joyce
Keyword(s):  
Population Genetics ◽  
Population Size ◽  
Mutant Allele ◽  
Mutation Rates ◽  
Simulation Methods ◽  
Large Populations ◽  
Selection Intensities ◽  
Infinite Alleles Model

Abstract Methods for simulating samples and sample statistics, under mutation-selection-drift equilibrium for a class of nonneutral population genetics models, and for evaluating the likelihood surface, in selection and mutation parameters, are developed and applied for observed data. The methods apply to large populations in settings in which selection is weak, in the sense that selection intensities, like mutation rates, are of the order of the inverse of the population size. General diploid selection is allowed, but the approach is currently restricted to models, such as the infinite alleles model and certain K-models, in which the type of a mutant allele does not depend on the type of its progenitor allele. The simulation methods have considerable advantages over available alternatives. No other methods currently seem practicable for approximating likelihood surfaces.

scholarly journals Nature of Deleterious Mutation Load in Drosophila

Genetics ◽  
1996 ◽  
Vol 144 (4) ◽  
pp. 1993-1999 ◽  
Author(s):  
Peter D Keightley
Keyword(s):  
Deleterious Mutation ◽  
Spontaneous Mutation ◽  
Mutation Accumulation ◽  
Mutation Rates ◽  
Mutation Load ◽  
Spontaneous Mutation Rate ◽  
A Minor ◽  
Chromosome I ◽  
Balancer Chromosomes ◽  
Balancer Chromosome

Much population genetics and evolution theory depends on knowledge of genomic mutation rates and distributions of mutation effects for fitness, but most information comes from a few mutation accumulation experiments in Drosophila in which replicated chromosomes are sheltered from natural selection by a balancer chromosome. I show here that data from these experiments imply the existence of a large class of minor viability mutations with approximately equivalent effects. However, analysis of the distribution of viabilities of chromosomes exposed to EMS mutagenesis reveals a qualitatively different distribution of effects lacking such a minor effects class. A possible explanation for this difference is that transposable element insertions, a common class of spontaneous mutation event in Drosophila, frequently generate minor viability effects. This explanation would imply that current estimates of deleterious mutation rates are not generally applicable in evolutionary models, as transposition rates vary widely. Alternatively, much of the apparent decline in viability under spontaneous mutation accumulation could have been nonmutational, perhaps due to selective improvement of balancer chromosomes. This explanation accords well with the data and implies a spontaneous mutation rate for viability two orders of magnitude lower than previously assumed, with most mutation load attributable to major effects.

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