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 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 The causes of mutation accumulation in mitochondrial genomes

2009 ◽  
Vol 276 (1660) ◽  
pp. 1201-1209 ◽  
Author(s):  
Maurine Neiman ◽  
Douglas R Taylor
Keyword(s):  
Mutation Accumulation ◽  
High Rate ◽  
Mitochondrial Genomes ◽  
Sequence Evolution ◽  
Deleterious Mutations ◽  
Effective Population ◽  
Mitochondrial Mutation ◽  
Evolutionary Forces ◽  
Body Of Knowledge ◽  
Primary Determinant

A fundamental observation across eukaryotic taxa is that mitochondrial genomes have a higher load of deleterious mutations than nuclear genomes. Identifying the evolutionary forces that drive this difference is important to understanding the rates and patterns of sequence evolution, the efficacy of natural selection, the maintenance of sex and recombination and the mechanisms underlying human ageing and many diseases. Recent studies have implicated the presumed asexuality of mitochondrial genomes as responsible for their high mutational load. We review the current body of knowledge on mitochondrial mutation accumulation and recombination, and conclude that asexuality, per se , may not be the primary determinant of the high mutation load in mitochondrial DNA (mtDNA). Very little recombination is required to counter mutation accumulation, and recent evidence suggests that mitochondrial genomes do experience occasional recombination. Instead, a high rate of accumulation of mildly deleterious mutations in mtDNA may result from the small effective population size associated with effectively haploid inheritance. This type of transmission is nearly ubiquitous among mitochondrial genomes. We also describe an experimental framework using variation in mating system between closely related species to disentangle the root causes of mutation accumulation in mitochondrial genomes.

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 Deleterious genomic mutation rate for viability in Drosophila melanogaster using concomitant sibling controls

2005 ◽  
Vol 1 (4) ◽  
pp. 492-495 ◽  
Author(s):  
Yi Gong ◽  
R.C Woodruff ◽  
J.N Thompson
Keyword(s):  
Drosophila Melanogaster ◽  
Experimental Design ◽  
Mutation Rate ◽  
Biological Processes ◽  
Deleterious Mutations ◽  
Health And Fitness ◽  
Genomic Mutation

New deleterious mutations may reduce health and fitness and are involved in the evolution and maintenance of numerous biological processes. Hence, it is important to estimate the deleterious genomic mutation rate ( U ) in representative higher organisms. However, these estimated rates vary widely, mainly because of inadequate experimental controls. Here we describe an experimental design (the Binscy assay) with concomitant sibling controls and estimate U for viability in Drosophila melanogaster to be 0.31. This estimate, like most published studies, focuses on viability mutations and the overall deleterious genomic mutation rate would therefore be higher.

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 Estimate of the Mutation Rate per Nucleotide in Humans

Genetics ◽  
2000 ◽  
Vol 156 (1) ◽  
pp. 297-304 ◽  
Author(s):  
Michael W Nachman ◽  
Susan L Crowell
Keyword(s):  
Mutation Rate ◽  
X Chromosome ◽  
Deleterious Mutation ◽  
Purifying Selection ◽  
High Rate ◽  
Nucleotide Substitutions ◽  
Cpg Dinucleotides ◽  
Rates Of Evolution ◽  
Processed Pseudogenes ◽  
Order Of Magnitude

Abstract Many previous estimates of the mutation rate in humans have relied on screens of visible mutants. We investigated the rate and pattern of mutations at the nucleotide level by comparing pseudogenes in humans and chimpanzees to (i) provide an estimate of the average mutation rate per nucleotide, (ii) assess heterogeneity of mutation rate at different sites and for different types of mutations, (iii) test the hypothesis that the X chromosome has a lower mutation rate than autosomes, and (iv) estimate the deleterious mutation rate. Eighteen processed pseudogenes were sequenced, including 12 on autosomes and 6 on the X chromosome. The average mutation rate was estimated to be ~2.5 × 10−8 mutations per nucleotide site or 175 mutations per diploid genome per generation. Rates of mutation for both transitions and transversions at CpG dinucleotides are one order of magnitude higher than mutation rates at other sites. Single nucleotide substitutions are 10 times more frequent than length mutations. Comparison of rates of evolution for X-linked and autosomal pseudogenes suggests that the male mutation rate is 4 times the female mutation rate, but provides no evidence for a reduction in mutation rate that is specific to the X chromosome. Using conservative calculations of the proportion of the genome subject to purifying selection, we estimate that the genomic deleterious mutation rate (U) is at least 3. This high rate is difficult to reconcile with multiplicative fitness effects of individual mutations and suggests that synergistic epistasis among harmful mutations may be common.

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 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 .

Are Status of Women and Contraceptive Prevalence Correlated in Pakistan?

2000 ◽  
Vol 39 (4II) ◽  
pp. 1057-1073
Author(s):  
Abdul Hakem
Keyword(s):  
Economic Development ◽  
Annual Growth ◽  
High Rate ◽  
High Fertility ◽  
Historical Trends ◽  
Social And Economic Development ◽  
Contraceptive Prevalence ◽  
The 1960S ◽  
Populous Country ◽  
Status Of Women

Pakistan with an estimated population of around 142.5 million in mid 2001 is the seventh most populous country in the world and fourth in Asia and Pacific countries. The historical trends indicate a continuously increasing growth in population (Table 1). The population of the area now constituting Pakistan was 16.6 million in 1901. Since then the population has increased over eight-fold. Annual growth rates have risen from 1 percent in the first three decades of the century to around 2 percent in the next three decades and after peaking at little over 3 percent in the 1960s, has started showing a declining trend. Currently it is estimated that Pakistan’s population is growing at around 2.1 percent, still a very high rate of annual growth in population. Major contributing factor to the fast growth in population of Pakistan has been high fertility which has remained high for a very long period. It is evident that nearly 100 million population has been added to the population of Pakistan since 1961, that is, during the last four decades. Such rapid growth in population has several adverse implications for the socio-economic development of the country which has been offsetting the gains in social and economic development.

scholarly journals Estimation of Parameters of Deleterious Mutations in Partial Selfing or Partial Outcrossing Populations and in Nonequilibrium Populations

Genetics ◽  
2000 ◽  
Vol 154 (4) ◽  
pp. 1893-1906 ◽  
Author(s):  
Jian Li ◽  
Hong-Wen Deng
Keyword(s):  
Computer Simulations ◽  
Natural Populations ◽  
Deleterious Mutations ◽  
Selfing Rate ◽  
Estimation Of Parameters ◽  
Animal Populations ◽  
Rapid Pace ◽  
Dynamics Of Populations ◽  
Mutation And Selection

Abstract The Deng-Lynch method was developed to estimate the rate and effects of deleterious genomic mutations (DGM) in natural populations under the assumption that populations are either completely outcrossing or completely selfing and that populations are at mutation-selection (M-S) balance. However, in many plant and animal populations, selfing or outcrossing is often incomplete in that a proportion of populations undergo inbreeding while the rest are outcrossing. In addition, the degrees of deviation of populations from M-S balance are often not known. Through computer simulations, we investigated the robustness and the applicability of the Deng-Lynch method under different degrees of partial selfing or partial outcrossing and for nonequilibrium populations approaching M-S balance at different stages. The investigation was implemented under constant, variable, and epistatic mutation effects. We found that, generally, the estimation by the Deng-Lynch method is fairly robust if the selfing rate (S) is <0.10 in outcrossing populations and if S > 0.8 in selfing populations. The estimation may be unbiased under partial selfing with variable and epistatic mutation effects in predominantly outcrossing populations. The estimation is fairly robust in nonequilibrium populations at different stages approaching M-S balance. The dynamics of populations approaching M-S balance under various parameters are also studied. Under mutation and selection, populations approach balance at a rapid pace. Generally, it takes 400–2000 generations to reach M-S balance even when starting from homogeneous individuals free of DGM. Our investigation here provides a basis for characterizing DGM in partial selfing or outcrossing populations and for nonequilibrium populations.

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