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 On the Rate and Linearity of Viability Declines in Drosophila Mutation-Accumulation Experiments: Genomic Mutation Rates and Synergistic Epistasis Revisited

Genetics ◽  
2004 ◽  
Vol 166 (2) ◽  
pp. 797-806 ◽  
Author(s):  
James D Fry
Keyword(s):  
Mutation Rate ◽  
Average Rate ◽  
Natural Populations ◽  
Mutation Accumulation ◽  
High Rate ◽  
Deleterious Mutations ◽  
Order Of Magnitude ◽  
Contamination Event ◽  
Genomic Mutation ◽  
The 1960S

Abstract High rates of deleterious mutations could severely reduce the fitness of populations, even endangering their persistence; these effects would be mitigated if mutations synergize each others’ effects. An experiment by Mukai in the 1960s gave evidence that in Drosophila melanogaster, viability-depressing mutations occur at the surprisingly high rate of around one per zygote and that the mutations interact synergistically. A later experiment by Ohnishi seemed to support the high mutation rate, but gave no evidence for synergistic epistasis. Both of these studies, however, were flawed by the lack of suitable controls for assessing viability declines of the mutation-accumulation (MA) lines. By comparing homozygous viability of the MA lines to simultaneously estimated heterozygous viability and using estimates of the dominance of mutations in the experiments, I estimate the viability declines relative to an appropriate control. This approach yields two unexpected conclusions. First, in Ohnishi’s experiment as well as in Mukai’s, MA lines showed faster-than-linear declines in viability, indicative of synergistic epistasis. Second, while Mukai’s estimate of the genomic mutation rate is supported, that from Ohnishi’s experiment is an order of magnitude lower. The different results of the experiments most likely resulted from differences in the starting genotypes; even within Mukai’s experiment, a subset of MA lines, which I argue probably resulted from a contamination event, showed much slower viability declines than did the majority of lines. Because different genotypes may show very different mutational behavior, only studies using many founding genotypes can determine the average rate and distribution of effects of mutations relevant to natural populations.

scholarly journals Rate and effects of spontaneous mutations that affect fitness in mutator Escherichia coli

2010 ◽  
Vol 365 (1544) ◽  
pp. 1177-1186 ◽  
Author(s):  
Sandra Trindade ◽  
Lilia Perfeito ◽  
Isabel Gordo
Keyword(s):  
Escherichia Coli ◽  
Mutation Rate ◽  
Deleterious Mutation ◽  
Natural Populations ◽  
Estimation Methods ◽  
Single Individual ◽  
Deleterious Mutations ◽  
Spontaneous Mutations ◽  
Mutator Strain ◽  
Mean Fitness

Knowledge of the mutational parameters that affect the evolution of organisms is of key importance in understanding the evolution of several characteristics of many natural populations, including recombination and mutation rates. In this study, we estimated the rate and mean effect of spontaneous mutations that affect fitness in a mutator strain of Escherichia coli and review some of the estimation methods associated with mutation accumulation (MA) experiments. We performed an MA experiment where we followed the evolution of 50 independent mutator lines that were subjected to repeated bottlenecks of a single individual for approximately 1150 generations. From the decline in mean fitness and the increase in variance between lines, we estimated a minimum mutation rate to deleterious mutations of 0.005 (±0.001 with 95% confidence) and a maximum mean fitness effect per deleterious mutation of 0.03 (±0.01 with 95% confidence). We also show that any beneficial mutations that occur during the MA experiment have a small effect on the estimate of the rate and effect of deleterious mutations, unless their rate is extremely large. Extrapolating our results to the wild-type mutation rate, we find that our estimate of the mutational effects is slightly larger and the inferred deleterious mutation rate slightly lower than previous estimates obtained for non-mutator E. coli .

scholarly journals Mutation accumulation and the effect of copia insertions in Drosophila melanogaster

2004 ◽  
Vol 83 (1) ◽  
pp. 7-18 ◽  
Author(s):  
DAVID HOULE ◽  
SERGEY V. NUZHDIN
Keyword(s):  
Drosophila Melanogaster ◽  
Mutation Rate ◽  
Deleterious Mutation ◽  
Mutation Accumulation ◽  
Inbred Lines ◽  
High Rate ◽  
Confidence Limits ◽  
Laboratory Environment ◽  
Element Number ◽  
Mutational Variance

Repeated efforts to estimate the genomic deleterious mutation rate per generation (U) in Drosophila melanogaster have yielded inconsistent estimates ranging from 0·01 to nearly 1. We carried out a mutation-accumulation experiment with a cryopreserved control population in hopes of resolving some of the uncertainties raised by these estimates. Mutation accumulation (MA) was carried out by brother–sister mating of 150 sublines derived from two inbred lines. Fitness was measured under conditions chosen to mimic the ancestral laboratory environment of these genotypes. We monitored the insertions of a transposable element, copia, that proved to accumulate at the unusually high rate of 0·24 per genome per generation in one of our MA lines. Mutational variance in fitness increased at a rate consistent with previous studies, yielding a mutational coefficient of variation greater than 3%. The performance of the cryopreserved control relative to the MA lines was inconsistent, so estimates of mutation rate by the Bateman–Mukai method are suspect. Taken at face value, these data suggest a modest decline in fitness of about 0·3% per generation. The element number of copia was a significant predictor of fitness within generations; on average, insertions caused a 0·76% loss in fitness, although the confidence limits on this estimate are wide.

scholarly journals Comparing Analysis Methods for Mutation-Accumulation Data: A Simulation Study

Genetics ◽  
2003 ◽  
Vol 164 (2) ◽  
pp. 807-819 ◽  
Author(s):  
Aurora García-Dorado ◽  
Araceli Gallego
Keyword(s):  
Mutation Rate ◽  
Gamma Distribution ◽  
Deleterious Mutation ◽  
Empirical Distribution ◽  
Mutation Accumulation ◽  
High Rate ◽  
Good Precision ◽  
Appreciable Increase ◽  
Fitness Trait ◽  
The Mean

Abstract We simulated single-generation data for a fitness trait in mutation-accumulation (MA) experiments, and we compared three methods of analysis. Bateman-Mukai (BM) and maximum likelihood (ML) need information on both the MA lines and control lines, while minimum distance (MD) can be applied with or without the control. Both MD and ML assume gamma-distributed mutational effects. ML estimates of the rate of deleterious mutation had larger mean square error (MSE) than MD or BM had due to large outliers. MD estimates obtained by ignoring the mean decline observed from comparison to a control are often better than those obtained using that information. When effects are simulated using the gamma distribution, reducing the precision with which the trait is assayed increases the probability of obtaining no ML or MD estimates but causes no appreciable increase of the MSE. When the residual errors for the means of the simulated lines are sampled from the empirical distribution in a MA experiment, instead of from a normal one, the MSEs of BM, ML, and MD are practically unaffected. When the simulated gamma distribution accounts for a high rate of mild deleterious mutation, BM detects only ∼30% of the true deleterious mutation rate, while MD or ML detects substantially larger fractions. To test the robustness of the methods, we also added a high rate of common contaminant mutations with constant mild deleterious effect to a low rate of mutations with gamma-distributed deleterious effects and moderate average. In that case, BM detects roughly the same fraction as before, regardless of the precision of the assay, while ML fails to provide estimates. However, MD estimates are obtained by ignoring the control information, detecting ∼70% of the total mutation rate when the mean of the lines is assayed with good precision, but only 15% for low-precision assays. Contaminant mutations with only tiny deleterious effects could not be detected with acceptable accuracy by any of the above methods.

scholarly journals Estimation of Deleterious-Mutation Parameters in Natural Populations

Genetics ◽  
1996 ◽  
Vol 144 (1) ◽  
pp. 349-360 ◽  
Author(s):  
Hong-Wen Deng ◽  
Michael Lynch
Keyword(s):  
Genetic Variance ◽  
Deleterious Mutation ◽  
Natural Populations ◽  
Breeding Systems ◽  
Deleterious Mutations ◽  
Empirical Estimates ◽  
Mean Fitness ◽  
The Mean ◽  
New Mutations

Abstract The rate and average effects of spontaneous deleterious mutations are important determinants of the evolution of breeding systems and of the vulnerability of small populations to extinction. Nevertheless, few attempts have been made to estimate the properties of such mutations, and those studies that have been performed have been extremely labor intensive, relying on long-term, laboratory mutation-accumulation experiments. We present an alternative to the latter approach. For populations in which the genetic variance for fitness is a consequence of selection-mutation balance, the mean fitness and genetic variance of fitness in outbred and inbred generations can be expressed as simple functions of the genomic mutation rate, average homozygous effect and average dominance coefficient of new mutations. Using empirical estimates for the mean and genetic variance of fitness, these expressions can then be solved to obtain joint estimates of the deleterious-mutation parameters. We employ computer simulations to evaluate the degree of bias of the estimators and present some general recommendations on the application of the technique. Our procedures provide some hope for obtaining estimates of the properties of deleterious mutations from a wide phylogenetic range of species as well as a mechanism for testing the validity of alternative models for the maintenance of genetic variance for fitness.

scholarly journals Evolution of mutation rates in hypermutable populations of Escherichia coli propagated at very small effective population size

2017 ◽  
Vol 13 (3) ◽  
pp. 20160849 ◽  
Author(s):  
Tanya Singh ◽  
Meredith Hyun ◽  
Paul Sniegowski
Keyword(s):  
Escherichia Coli ◽  
Genetic Variation ◽  
Mutation Rate ◽  
Mutation Rates ◽  
Deleterious Mutations ◽  
Effective Population ◽  
Ultimate Source ◽  
Systematic Evolution ◽  
Small Effective Size ◽  
Small Effective Population Size

Mutation is the ultimate source of the genetic variation—including variation for mutation rate itself—that fuels evolution. Natural selection can raise or lower the genomic mutation rate of a population by changing the frequencies of mutation rate modifier alleles associated with beneficial and deleterious mutations. Existing theory and observations suggest that where selection is minimized, rapid systematic evolution of mutation rate either up or down is unlikely. Here, we report systematic evolution of higher and lower mutation rates in replicate hypermutable Escherichia coli populations experimentally propagated at very small effective size—a circumstance under which selection is greatly reduced. Several populations went extinct during this experiment, and these populations tended to evolve elevated mutation rates. In contrast, populations that survived to the end of the experiment tended to evolve decreased mutation rates. We discuss the relevance of our results to current ideas about the evolution, maintenance and consequences of high mutation rates.

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 Dynamics and fate of beneficial mutations under lineage contamination by linked deleterious mutations

2016 ◽  
Author(s):  
Sophie Pénisson ◽  
Tanya Singh ◽  
Paul Sniegowski ◽  
Philip Gerrish
Keyword(s):  
Mutation Rate ◽  
Branching Process ◽  
Deleterious Mutation ◽  
Selective Advantage ◽  
Single Type ◽  
Deleterious Mutations ◽  
Beneficial Mutations ◽  
Multitype Branching Process ◽  
Fitness Effects ◽  
Adaptive Substitution

ABSTRACTBeneficial mutations drive adaptive evolution, yet their selective advantage does not ensure their fixation. Haldane’s application of single-type branching process theory showed that genetic drift alone could cause the extinction of newly-arising beneficial mutations with high probability. With linkage, deleterious mutations will affect the dynamics of beneficial mutations and might further increase their extinction probability. Here, we model the lineage dynamics of a newly-arising beneficial mutation as a multitype branching process; this approach allows us to account for the combined effects of drift and the stochastic accumulation of linked deleterious mutations, which we call lineage contamination. We first study the lineage contamination phenomenon in isolation, deriving extinction times and probabilities of beneficial lineages. We then put the lineage contamination phenomenon into the context of an evolving population by incorporating the effects of background selection. We find that the survival probability of beneficial mutations is simply Haldane’s classical formula multiplied by the correction factor , where U is deleterious mutation rate, is mean selective advantage of beneficial mutations, κ ∈ (1, ε], and ε = 2 – e−1. We also find there exists a genomic deleterious mutation rate, , that maximizes the rate of production of surviving beneficial mutations, and that . Both of these results, and others, are curiously independent of the fitness effects of deleterious mutations. We derive critical mutation rates above which: 1) lineage contamination alleviates competition among beneficial mutations, and 2) the adaptive substitution process all but shuts down.

scholarly journals Evolutionary consequences of mutation and selection within an individual.

Genetics ◽  
1995 ◽  
Vol 141 (3) ◽  
pp. 1173-1187 ◽  
Author(s):  
S P Otto ◽  
M E Orive
Keyword(s):  
Mutation Rate ◽  
Deleterious Mutation ◽  
Cell Lineage ◽  
Deleterious Mutations ◽  
Cell Replication ◽  
Mutation Load ◽  
Ploidy Levels ◽  
Cell Lineages ◽  
Evolutionary Consequences ◽  
Mutant Cells

Abstract Whether in sexual or asexual organisms, selection among cell lineages during development is an effective way of eliminating deleterious mutations. Using a mathematical analysis, we find that relatively small differences in cell replication rates during development can translate into large differences in the proportion of mutant cells within the adult, especially when development involves a large number of cell divisions. Consequently, intraorganismal selection can substantially reduce the deleterious mutation rate observed among offspring as well as the mutation load within a population, because cells rather than individuals provide the selective "deaths" necessary to stem the tide of deleterious mutations. The reduction in mutation rate among offspring is more pronounced in organisms with plastic development than in those with structured development. It is also more pronounced in asexual organisms that produce multicellular rather than unicellular offspring. By effecting the mutation rate, intraorganismal selection may have broad evolutionary implications; as an example, we consider its influence on the evolution of ploidy levels, finding that cell-lineage selection is more effective in haploids and tends to favor their evolution.

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