Estimation of Deleterious Genomic Mutation Parameters in Natural Populations by Accounting for Variable Mutation Effects Across Loci

Genetics ◽  
2002 ◽  
Vol 162 (3) ◽  
pp. 1487-1500 ◽  
Author(s):  
Hong-Wen Deng ◽  
Guimin Gao ◽  
Jin-Long Li
Keyword(s):  
Statistical Method ◽  
Mutation Rate ◽  
Genetic Variance ◽  
Natural Populations ◽  
Evolutionary Genetics ◽  
Simulation Studies ◽  
Fitness Effects ◽  
Mean Fitness ◽  
The Mean ◽  
Genomic Mutation

Abstract The genomes of all organisms are subject to continuous bombardment of deleterious genomic mutations (DGM). Our ability to accurately estimate various parameters of DGM has profound significance in population and evolutionary genetics. The Deng-Lynch method can estimate the parameters of DGM in natural selfing and outcrossing populations. This method assumes constant fitness effects of DGM and hence is biased under variable fitness effects of DGM. Here, we develop a statistical method to estimate DGM parameters by considering variable mutation effects across loci. Under variable mutation effects, the mean fitness and genetic variance for fitness of parental and progeny generations across selfing/outcrossing in outcrossing/selfing populations and the covariance between mean fitness of parents and that of their progeny are functions of DGM parameters: the genomic mutation rate U, average homozygous effect s, average dominance coefficient h, and covariance of selection and dominance coefficients cov(h, s). The DGM parameters can be estimated by the algorithms we developed herein, which may yield improved estimation of DGM parameters over the Deng-Lynch method as demonstrated by our simulation studies. Importantly, this method is the first one to characterize cov(h, s) for DGM.

scholarly journals Genotype-environment interactions and the maintenance of polygenic variation.

Genetics ◽  
1989 ◽  
Vol 121 (1) ◽  
pp. 129-138 ◽  
Author(s):  
J H Gillespie ◽  
M Turelli
Keyword(s):  
Genetic Variance ◽  
Balancing Selection ◽  
Additive Genetic Variance ◽  
Natural Populations ◽  
Extensive Literature ◽  
Multilocus Genotype ◽  
Polygenic Inheritance ◽  
Mean Fitness ◽  
The Mean ◽  
Polygenic Variation

Abstract Genotype-environment interactions may be a potent force maintaining genetic variation in quantitative traits in natural populations. This is shown by a simple model of additive polygenic inheritance in which the additive contributions of alleles vary with the environment. Under simplifying symmetry assumptions, the model implies that the variance of the phenotypes produced across environments by a multilocus genotype decreases as the number of heterozygous loci increases. In the region of an optimal phenotype, the mapping from the quantitative trait into fitness is concave, and the mean fitness of a genotype will increase with the number of heterozygous loci. This leads to balancing selection, polymorphism, and potentially high levels of additive genetic variance, even though all allelic effects remain additive within each specific environment. An important implication of the model is that the variation maintained by genotype-environment interactions is difficult to study with the restricted range of environments represented in typical experiments. In particular, if fluctuations in allelic effects are pervasive, as suggested by the extensive literature on genotype-environment interactions, efforts to estimate genetic parameters in a single environment may be of limited value.

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 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 GENETIC LOAD IN NATURAL POPULATIONS: IS IT COMPATIBLE WITH THE HYPOTHESIS THAT MANY POLYMORPHISMS ARE MAINTAINED BY NATURAL SELECTION?

Genetics ◽  
1974 ◽  
Vol 77 (3) ◽  
pp. 569-589
Author(s):  
Martin L Tracey ◽  
Francisco J Ayala
Keyword(s):  
Drosophila Melanogaster ◽  
Natural Selection ◽  
Natural Population ◽  
Natural Populations ◽  
Genetic Load ◽  
Structural Genes ◽  
Invertebrate Species ◽  
Average Proportion ◽  
Mean Fitness ◽  
The Mean

ABSTRACT Recent studies of genetically controlled enzyme variation lead to an estimation that at least 30 to 60% of the structural genes are polymorphic in natural populations of many vertebrate and invertebrate species. Some authors have argued that a substantial proportion of these polymorphisms cannot be maintained by natural selection because this would result in an unbearable genetic load. If many polymorphisms are maintained by heterotic natural selection, individuals with much greater than average proportion of homozygous loci should have very low fitness. We have measured in Drosophila melanogaster the fitness of flies homozygous for a complete chromosome relative to normal wild flies. A total of 37 chromosomes from a natural population have been tested using 92 experimental populations. The mean fitness of homozygous flies is 0.12 for second chromosomes, and 0.13 for third chromosomes. These estimates are compatible with the hypothesis that many (more than one thousand) loci are maintained by heterotic selection in natural populations of D. melanogaster.

scholarly journals Some sampling properties of selectively neutral alleles

1979 ◽  
Vol 34 (3) ◽  
pp. 253-267 ◽  
Author(s):  
Ranajit Chakraborty ◽  
Paul A. Fuerst
Keyword(s):  
Monte Carlo Simulation ◽  
Monte Carlo ◽  
Genetic Variability ◽  
Mutation Rate ◽  
Natural Populations ◽  
Single Locus ◽  
Population Parameter ◽  
Mean And Variance ◽  
The Mean

SUMMARYSome sampling properties related with the mean and variance of the number of alleles and single locus heterozygosity are derived to study the effect of variations in mutation rate of selectively neutral alleles. The correlation between single locus heterozygosity and the number of alleles is also derived. Monte Carlo simulation is conducted to examine the effect of stepwise mutations. The relevance of these results in estimating the population parameter, 4Neν, is discussed in connexion with neutralist-selectionist controversy over the maintenance of genetic variability in natural populations.

The action of evolutionary forces on metric traits

2011 ◽  
Vol 1 (3) ◽  
pp. 532-537
Author(s):  
C. López-Fanjul
Keyword(s):  
Genetic Variance ◽  
Natural Populations ◽  
Substantial Contribution ◽  
Additive Variance ◽  
Evolutionary Forces ◽  
Bristle Number ◽  
Laboratory Populations ◽  
Component Traits ◽  
Mean Fitness ◽  
Metric Traits

Fisher's theorem of natural selection implies that the population genetic variance of quasi-neutral traits should be mostly additive. In the case of fitness component traits, however, that variance would be characterised by a substantial contribution from non-additive loci. In parallel, Robertson's theorem states that selection will change the population mean of a trait proportionally to the magnitude of the genetic correlation between that trait and fitness, which should be weak for quasi-neutral traits or strong for the mean fitness components. Drosophila data from inbreeding and artificial selection experiments are discussed within that theoretical framework. In addition, the process of regeneration by mutation of the genetic variance of a quasi-neutral trait (abdominal bristle number) in a Drosophila population initially homozygous at all loci has been analysed. After 485 generations of mutation accumulation, the levels of additive variance found in this population closely approached those commonly observed in laboratory populations. Furthermore, these values, together with previously reported estimates for natural populations, could be jointly explained by a model assuming weak causal stabilising selection.

scholarly journals Genetic variance and fixation probabilities at quantitative trait loci in mutation-selection balance

1991 ◽  
Vol 58 (2) ◽  
pp. 139-144 ◽  
Author(s):  
Peter D. Keightley
Keyword(s):  
Quantitative Trait Loci ◽  
Mutation Rate ◽  
Quantitative Trait ◽  
Genetic Variance ◽  
Additive Genetic Variance ◽  
Natural Populations ◽  
Fixation Rate ◽  
Trait Loci ◽  
Fixation Probabilities

SummaryGenetic variance and fixation probabilities are evaluated for a model of a quantitative trait at a balance between mutation, selection and drift in which many alleles can segregate at each locus. If the distribution of effects of new mutant alleles is such that mutations are unconditionally deleterious, as might be the case in natural populations, genetic variance maintained is proportional to the number of mutations occurring in the genome per generation, but is independent of the number of loci at which they appear. If selectively advantageous alleles can occur these tend to interfere to a greater extent with each others' fixation and increasing mutation rate leads to a decrease in the genetic variance as a fraction of the variance maintained in the absence of selection. Fixation probabilities of new mutant alleles approach that for neutral alleles with increasing mutation rate at a locus irrespective of their effects on fitness. The additive genetic variance contributed by the locus may appear to be ‘decoupled’ from the fixation rate of mutant alleles.

scholarly journals Mutational fitness effects in RNA and single-stranded DNA viruses: common patterns revealed by site-directed mutagenesis studies

2010 ◽  
Vol 365 (1548) ◽  
pp. 1975-1982 ◽  
Author(s):  
Rafael Sanjuán
Keyword(s):  
Site Directed Mutagenesis ◽  
Directed Mutagenesis ◽  
Nucleotide Substitutions ◽  
Single Nucleotide ◽  
Single Stranded Dna ◽  
Dna Viruses ◽  
Fitness Effects ◽  
Lethal Mutations ◽  
Mean Fitness ◽  
The Mean

The fitness effects of mutations are central to evolution, yet have begun to be characterized in detail only recently. Site-directed mutagenesis is a powerful tool for achieving this goal, which is particularly suited for viruses because of their small genomes. Here, I discuss the evolutionary relevance of mutational fitness effects and critically review previous site-directed mutagenesis studies. The effects of single-nucleotide substitutions are standardized and compared for five RNA or single-stranded DNA viruses infecting bacteria, plants or animals. All viruses examined show very low tolerance to mutation when compared with cellular organisms. Moreover, for non-lethal mutations, the mean fitness reduction caused by single mutations is remarkably constant (0.10–0.13), whereas the fraction of lethals varies only modestly (0.20–0.41). Other summary statistics are provided. These generalizations about the distribution of mutational fitness effects can help us to better understand the evolution of RNA and single-stranded DNA viruses.

Inbreeding Depression and Inferred Deleterious-Mutation Parameters in Daphnia

Genetics ◽  
1997 ◽  
Vol 147 (1) ◽  
pp. 147-155 ◽  
Author(s):  
Hong-Wen Deng ◽  
Michael Lynch
Keyword(s):  
Inbreeding Depression ◽  
Genetic Variance ◽  
Deleterious Mutation ◽  
Fitness Traits ◽  
Selection Equilibrium ◽  
Cyclical Parthenogens ◽  
The Mean ◽  
Genomic Mutation ◽  
True Values ◽  
Mutational Variance

Abstract Deng and Lynch recently proposed a method for estimating deleterious genomic mutation parameters from changes in the mean and genetic variance of fitness traits upon inbreeding in outcrossing populations. Such observations are readily acquired in cyclical parthenogens. Selfing and life-table experiments were performed for two such Daphnia populations. We observed a significant inbreeding depression and an increase of genetic variance for all traits analyzed. Deng and Lynch's original procedures were extended to estimate genomic mutation rate (U), mean dominance coefficient (h‒), mean selection coefficient (s‒) and scaled genomic mutational variance (Vm/Ve). On average, U^, h‒̂, s‒̂ and V^m∕Vs (^ indicates an estimate) are 0.74, 0.30, 0.14 and 4.6E-4, respectively. For the true values, the U^ and h‒̂ are lower bounds, and s‒̂ and V^m∕Ve, upper bounds. The present U^, h‒̂ and V^m∕Ve are in general concordance with earlier results. The discrepancy between the present V^m∕Ve and that from mutation-accumulation experiments in Drosophila (~0.04) is discussed. It is shown that different reproductive modes do not affect gene frequency at mutation-selection equilibrium if mutational effects on fitness are multiplicative and not completely recessive.

scholarly journals Adapting the engine to the fuel: mutator populations can reduce the mutational load by reorganizing their genome structure

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Jacob Pieter Rutten ◽  
Paulien Hogeweg ◽  
Guillaume Beslon
Keyword(s):  
Mutation Rate ◽  
Genome Structure ◽  
Mutational Load ◽  
Bacterial Populations ◽  
Long Run ◽  
Stable Conditions ◽  
Long Time ◽  
Natural Isolates ◽  
Mean Fitness ◽  
The Mean

Abstract Background Mutators are common in bacterial populations, both in natural isolates and in the lab. The fate of these lineages, which mutation rate is increased up to 100 ×, has long been studied using population genetics models, showing that they can spread in a population following an environmental change. However in stable conditions, they suffer from the increased mutational load, hence being overcome by non-mutators. However, these results don’t take into account the fact that an elevated mutation rate can impact the genetic structure, hence changing the sensitivity of the population to mutations. Here we used Aevol, an in silico experimental evolution platform in which genomic structures are free to evolve, in order to study the fate of mutator populations evolving for a long time in constant conditions. Results Starting from wild-types that were pre-evolved for 300,000 generations, we let 100 mutator populations (point mutation rate ×100) evolve for 100,000 further generations in constant conditions. As expected all populations initially undergo a fitness loss. However, after that the mutator populations started to recover. Most populations ultimately recovered their ancestors fitness, and a significant fraction became even fitter than the non-mutator control clones that evolved in parallel. By analyzing the genomes of the mutators, we show that the fitness recovery is due to two mechanisms: i. an increase in robustness through compaction of the coding part of the mutator genomes, ii. an increase of the selection coefficient that decreases the mean-fitness of the population. Strikingly the latter is due to the accumulation of non-coding sequences in the mutators genomes. Conclusion Our results show that the mutational burden that is classically thought to be associated with mutator phenotype is escapable. On the long run mutators adapted their genomes and reshaped the distribution of mutation effects. Therewith the lineage is able to recover fitness even though the population still suffers the elevated mutation rate. Overall these results change our view of mutator dynamics: by being able to reduce the deleterious effect of the elevated mutation rate, mutator populations may be able to last for a very long time; A situation commonly observed in nature.

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