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 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 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 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.

Scaphoid Nonunion Is a Disabling Problem in a Military Population

Hand ◽  
2021 ◽  
pp. 155894472110031
Author(s):  
Nicholas H. Lake ◽  
Rafae Khan ◽  
Kyle W. Mombell ◽  
Mary Fergus ◽  
Dominic Gomez-Leonardelli
Keyword(s):  
Functional Outcome ◽  
Military Service ◽  
Functional Outcomes ◽  
High Rate ◽  
Scaphoid Nonunion ◽  
Military Population ◽  
Outcome Scores ◽  
The Mean ◽  
Return To Duty

Background Scaphoid nonunion can occur in up to 55% of displaced scaphoid fractures. Long-term functional outcomes of this injury are lacking. In addition, no study has published rate of return to active military service after this injury. Our goal was to educate providers and patients on expected functional outcomes and return to duty after treatment of scaphoid nonunion. Methods We conducted a retrospective review of patients who underwent scaphoid nonunion repair at our institution from 2008 to 2017. The primary outcome measures were union rates, return to duty rates, and functional outcome scores obtained by telephone call. A total of 144 patients were included and 40 responded to our call for long-term follow-up. Results A total of 72% of patients achieved union after surgery, 18% required revision surgery, and 74% of patients were able to return to full duty after surgery. However, this number progressively decreased at 1, 2, and 5 years after surgery. At an average of 5.9 years after surgery, the mean Quick Disabilities of the Arm, Shoulder, and Hand (qDASH) score was 23.9. The mean qDASH for patients who achieved union (21.9) was significantly lower than those with persistent nonunion (29.2) ( P = .0115). Conclusion Scaphoid nonunion is a difficult problem in the military. We found a high rate of persistent nonunion often requiring revision to partial or full wrist arthrodesis. In addition, our long-term functional outcome scores demonstrate significant disability after this injury, even when union is achieved. This information can help us better counsel our patients and set expectations after treatment of this injury.

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.

scholarly journals The mutation load under tetrasomic inheritance and its consequences for the evolution of the selfing rate in autotetraploid species

1999 ◽  
Vol 74 (1) ◽  
pp. 31-42 ◽  
Author(s):  
J. RONFORT
Keyword(s):  
Inbreeding Depression ◽  
Deleterious Mutation ◽  
Stable State ◽  
Approximate Solutions ◽  
Balance Model ◽  
Deleterious Mutations ◽  
Selfing Rate ◽  
Mutation Load ◽  
Mean Fitness ◽  
The Mean

Single-locus equilibrium frequencies of a partially recessive deleterious mutation under the mutation–selection balance model are derived for partially selfing autotetraploid populations. Assuming multiplicative fitness interactions among loci, approximate solutions for the mean fitness and inbreeding depression values are also derived for the multiple locus case and compared with expectations for the diploid model. As in diploids, purging of deleterious mutations through consanguineous matings occurs in autotetraploid populations, i.e. the equilibrium mutation load is a decreasing function of the selfing rate. However, the variation of inbreeding depression with the selfing rate depends strongly on the dominance coefficients associated with the three heterozygous genotypes. Inbreeding depression can either increase or decrease with the selfing rate, and does not always vary monotonically. Expected issues for the evolution of the selfing rate consequently differ depending on the dominance coefficients. In some cases, expectations for the evolution of the selfing rate resemble expectations in diploids; but particular sets of dominance coefficients can be found that lead to either complete selfing or intermediate selfing rates as unique evolutionary stable state.

Scope of action of the immunoglobulin mutator system

Genome ◽  
1989 ◽  
Vol 31 (1) ◽  
pp. 118-121 ◽  
Author(s):  
Matthias R. Wabl ◽  
Hans-Martin Jäck ◽  
R. C. von Borstel ◽  
Charles M. Steinberg
Keyword(s):  
B Cell ◽  
Mutation Rate ◽  
Heavy Chain ◽  
B Lymphocyte ◽  
Somatic Hypermutation ◽  
Spontaneous Mutation ◽  
Cell Lineage ◽  
Variable Region ◽  
High Rate ◽  
Spontaneous Mutation Rate

The authors have developed a method to measure the rate of spontaneous mutations taking place in IgH, the gene encoding the immunoglobulin heavy chain. When an amber chain-termination codon mutates to a sense codon, translation of the polypeptide chain will be completed, and mutant cells producing the heavy chain can be detected with a fluorescent labelled antibody. The protocol used is the compartmentalization test which minimizes any effect of selection. In subclones of the pre-B lymphocyte line 18–81, the spontaneous mutation rate in the part of IgH encoding the variable region is somewhat greater than 10−5 mutations per base pair per generation. This supports the hypothesis that hypermutation is not dependent on cell stimulation by an antigen. In a hybrid between a cell of this line and a myeloma (which represents the terminal stage of the B-cell lineage), the mutation rate was too low to be determined by this test, less than 10−9. When the same loss to gain procedure system was used with an opal chain-terminating codon in the part of IgH encoding the constant region (Cμ), a high rate of reversion by deletion was found. Long (more than one exon) and short (less than one exon) deletions occurred at rates of 1.7 × 10−5 and 1.4 × 10−7 per generation, respectively. It is thought that the high rate of deletion is not related to somatic hypermutation but rather to DNA rearrangement during the heavy-chain class switch, which is occurring in these pre-B cell lines. The point mutation rate was too low to be detected above the background of deletion mutants, less than 5 × 10−8. The immunoglobulin mutator system works weakly, if at all, on two other, nonimmunoglobulin, genes tested: B2m (β2 microglobulin) and the gene for ouabain resistance.Key words: pre-B lymphocyte, B lymphocyte, spontaneous mutation rate, compartmentalization test, deletion mutation, hypermutation.

The density variation of the earth's central core*

1942 ◽  
Vol 32 (1) ◽  
pp. 19-29
Author(s):  
K. E. Bullen
Keyword(s):  
Pure Iron ◽  
Outer Boundary ◽  
Density Variation ◽  
Central Core ◽  
Good Precision ◽  
Wide Margin ◽  
The Core ◽  
The Earth ◽  
The Mean ◽  
Published Paper

ABSTRACT A detailed analysis of the problem of the earth's density variation has been extended to the earth's central core. It is shown that in the region between the outer boundary of the core and a distance of about 1400 km. from the earth's center the density ranges from 9.4 gm/cm.3 to 11.5 gm/cm.3 within an uncertainty which, if certain general assumptions are true, does not exceed 3 per cent. The density and pressure figures are, moreover, compatible with the existence of fairly pure iron in this part of the earth. The result for the earth's outer mantle as given in a previously published paper, together with those in the present paper, are found to give with good precision the density distribution in a region occupying 99 per cent of the earth's volume. Values of the density within 1400 km. of the earth's center are subject, however, to a wide margin of uncertainty, and there appears to be no means of resolving this uncertainty for the present. The most that can be said is that the mean density in the latter region is greater than 12.3 gm/cm.3 and may quite possibly be several gm/cm.3 in excess of this figure. In the present paper figures are also included for the variation of gravity and the distribution of pressure within the central core. The gravity results are shown to be subject to an appreciable uncertainty except within about 1000 km. of the outer boundary of the core, but the pressure results are expected to be closely accurate at all depths.

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