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PubMed2003

Effects of short-term spontaneous mutation accumulation for life history traits in grape phylloxera, Daktulosphaira vitifoliae.

Mutation is the source of all genetic variation, but rate of input and effects of new mutations for phenotypic traits related to fitness and the role they play in the maintenance of genetic variation are still subject to controversy. These parameters are important in models of the evolution of sex and recombination, the persistence of asexual populations, and the extinction of small populations. Most estimates have come from a few model organisms. Here, mutation accumulation experiments were conducted with three clones of grape phylloxera, Daktulosphaira vitifoliae Fitch, a gall forming herbivore and pest of grapes, to estimate the rate of input and effects of spontaneous mutation on life history traits. This is perhaps the first such experiment using a non-model organism of economic importance. Significant heritable genetic variation accrued in one of three sets of lines for one of four traits measured, and deleterious effects of mutation were found for two of four traits in two of the three sets of lines. Estimates of the parameters by the Bateman-Mukai (BM) method were within the range found in previous studies but at the lower end for genomic mutation rate, U approximately 0.023 and mutational variance, V(M) approximately 0.0003, the upper end for average heterozygous effect, alpha, of approximately -0.11, and on the order of previous estimates for mutational heritability, hM approximately 0.007. Under a model of equal effects of mutations, maximum likelihood (ML) estimates of U were slightly higher, and of alpha lower, than the BM estimates. Support limits were too large to provide much confidence in the ML estimates, however, and models of mutational effects assuming a gamma distribution of effects under different values of the shape parameter, beta, could not be distinguished though likelihoods tended to be lower at lower values of beta (more leptokurtic). Rapid accumulation of deleterious mutations suggest that for many pest species, adaptive response under agricultural conditions may depend more on the standing variation derived from introductions than new mutation.

Adaptation, Physiological↗
PubMed2001

Muscle-specific mutations accumulate with aging in critical human mtDNA control sites for replication.

The recently discovered aging-dependent large accumulation of point mutations in the human fibroblast mtDNA control region raised the question of their occurrence in postmitotic tissues. In the present work, analysis of biopsied or autopsied human skeletal muscle revealed the absence or only minimal presence of those mutations. By contrast, surprisingly, most of 26 individuals 53 to 92 years old, without a known history of neuromuscular disease, exhibited at mtDNA replication control sites in muscle an accumulation of two new point mutations, i.e., A189G and T408A, which were absent or marginally present in 19 individuals younger than 34 years. These two mutations were not found in fibroblasts from 22 subjects 64 to 101 years of age (T408A), or were present only in three subjects in very low amounts (A189G). Furthermore, in several older individuals exhibiting an accumulation in muscle of one or both of these mutations, they were nearly absent in other tissues, whereas the most frequent fibroblast-specific mutation (T414G) was present in skin, but not in muscle. Among eight additional individuals exhibiting partial denervation of their biopsied muscle, four subjects >80 years old had accumulated the two muscle-specific point mutations, which were, conversely, present at only very low levels in four subjects < or =40 years old. The striking tissue specificity of the muscle mtDNA mutations detected here and their mapping at critical sites for mtDNA replication strongly point to the involvement of a specific mutagenic machinery and to the functional relevance of these mutations.

Adult↗
PubMed1995

Modelling the effects of age-related mtDNA mutation accumulation; complex I deficiency, superoxide and cell death.

Deleterious mitochondrial mutations accumulate during normal human aging in postmitotic tissues. How these mutations affect aging cells is currently unknown. This issue has been addressed in two ways. The first is to determine the likeliest effect of random mutations in the mitochondrial genome, and of the 4977 bp deletion and MELAS point mutation that rise in frequency with age. The results indicate that Complex I is statistically much more likely to be affected than any other product of the mitochondrial genome. We have also attempted to model Complex I deficiency in animals with the drug MPTP, a specific inhibitor of Complex I. We find that MPTP causes massive damage in brains of mice with a genetic deficiency in the mitochondrial superoxide dismutase, MnSOD, but less in mice that overexpress the enzyme. We conclude from these data that MPTP-induced cell death must be mediated through an increase in the steady-state concentration of superoxide anion in mitochondria. Since the likeliest target of mitochondrial mutation is Complex I, deficiency of which causes MnSOD-inhibitable lethality, we propose that rising mtDNA mutations with age will cause an increase in superoxide-mediated cell death. Such a mechanism for age-related cell death has the potential to explain several age-related phenotypes.

Aging↗
PubMed2006

Mutation accumulation in space and the maintenance of sexual reproduction.

The maintenance of sexual reproduction remains one of the major puzzles of evolutionary biology, since, all else being equal, an asexual mutant should have a twofold fitness advantage over the sexual wildtype. Most theories suggest that sex helps either to purge deleterious mutations, or to adapt to changing environments. Both mechanisms have their limitations if they act in isolation because they require either high genomic mutation rates or very virulent pathogens, and it is therefore often thought that they must act together to maintain sex. Typically, however, these theories have in common that they are not based on spatial processes. Here, we show that local dispersal and local competition can explain the maintenance of sexual reproduction as a means of purging deleterious mutations. Using a spatially explicit individual-based model, we find that even with reasonably low genomic mutation rates and large total population sizes, asexual clones cannot invade a sexual population. Our results demonstrate how spatial processes affect mutation accumulation such that it can fully erode the twofold benefit of asexuality faster than an asexual clone can take over a sexual population. Thus, the cost of sex is generally overestimated in models that ignore the effects of space on mutation accumulation.

Adaptation, Physiological↗
PubMed1994

Molecular analysis of Gpdh null mutations that arose in mutation accumulation experiments in Drosophila melanogaster.

In order to clarify the cause of null mutations in enzyme loci, the molecular structure of six null mutations in the Gpdh locus (encoding alpha GPDH: alpha glycerol-3-phosphate dehydrogenase (NAD+), E.C. 1.1.1.8; map position at 2-17.8) that arose in mutation accumulation experiments was examined. A restriction map analysis showed that five of the mutations are insertional mutations whereas the sixth is a deletion. The Gpdh regions of these null mutations were then cloned and sequenced. The inserted DNA fragments are all internally deleted P elements measuring 1.1 kb in length. Two are a KP element and two others are a HP element. All the insertions occur in the region near the initiation signal of transcription. The deletion encompasses the seventh and eighth exons over a length of 1.1 kb. These results therefore indicate that the null mutation rate at the Gpdh locus is largely influenced by P elements.

Animals↗
PubMed2005

A mutation accumulation assay reveals a broad capacity for rapid evolution of gene expression.

Mutation is the ultimate source of biological diversity because it generates the variation that fuels evolution. Gene expression is the first step by which an organism translates genetic information into developmental change. Here we estimate the rate at which mutation produces new variation in gene expression by measuring transcript abundances across the genome during the onset of metamorphosis in 12 initially identical Drosophila melanogaster lines that independently accumulated mutations for 200 generations. We find statistically significant mutational variation for 39% of the genome and a wide range of variability across corresponding genes. As genes are upregulated in development their variability decreases, and as they are downregulated it increases, indicating that developmental context affects the evolution of gene expression. A strong correlation between mutational variance and environmental variance shows that there is the potential for widespread canalization. By comparing the evolutionary rates that we report here with differences between species, we conclude that gene expression does not evolve according to strictly neutral models. Although spontaneous mutations have the potential to generate abundant variation in gene expression, natural variation is relatively constrained.

Animals↗
PubMed1977

Mutation in continuous cultures of Schizosaccharomyces pombe. I. Dependence of the kinetics of mutation accumulation upon the growth-limiting nutrilite.

The rate of spontaneous mutation to resistance to the 12,13-epoxytrichothecene trichodermin has been determined under different growth limiting conditions in continuous cultures of the microbial eukaryote Schizosaccharomyces pombe. In agreement with data obtained in bacterial systems by previous workers the kinetics observed for the accumulation of mutations is found to be dependent upon the nutrient used to limit the growth of the population. Under conditions of glucose-limitation mutation accumulation is directly proportional to the rate of cell division, while under histidine-limitation it is proportional to chronological time. Various possible explanations for these observations are discussed.

Ascomycota↗
PubMed2000

Multigeneration maximum-likelihood analysis applied to mutation-accumulation experiments in Caenorhabditis elegans.

We develop a maximum-likelihood (ML) approach to estimate genomic mutation rates (U) and average homozygous mutation effects (s) from mutation-accumulation (MA) experiments in which phenotypic assays are carried out in several generations. We use simulations to compare the procedure's performance with the method of moments traditionally used to analyze MA data. Similar precision is obtained if mutation effects are small relative to the environmental standard deviation, but ML can give estimates of mutation parameters that have lower sampling variances than those obtained by the method of moments if mutations with large effects have accumulated. The inclusion of data from intermediate generations may improve the precision. We analyze life-history trait data from two Caenorhabditis elegans MA experiments. Under a model with equal mutation effects, the two experiments provide similar estimates for U of approximately 0.005 per haploid, averaged over traits. Estimates of s are more divergent and average at -0.51 and -0.13 in the two studies. Detailed analysis shows that changes of mean and variance of genetic values of MA lines in both C. elegans experiments are dominated by mutations with large effects, but the analysis does not rule out the presence of a large class of deleterious mutations with very small effects.

Animals↗
PubMed2002

Age-related mutation accumulation at a lacZ reporter locus in normal and tumor tissues of Trp53-deficient mice.

Increased genomic instability has been found associated with cancer and aging. The p53 tumor suppressor protein is a major determinant of genomic instability as a regulator of cell cycle control and apoptosis in response to DNA damage. To investigate the rate of age-related mutation accumulation in the absence of p53, we crossed Trp53 null mice with transgenic mice harboring a lacZ mutational target gene. In the hybrid animals, lacZ mutation frequencies at early age (i.e. at about 2 months) were found to be the same as in the control lacZ animals. However, up until about 6 months, when the Trp53-knockout mice usually die from cancer, mutations were found to accumulate with age in the spleen, and to a lesser extent in the liver, at a more rapid rate than in the control Trp53(+/+) or Trp53(+/-), lacZ hybrid mice. Treatment of 2-3-month-old Trp53(-/-), lacZ hybrid mice with the powerful mutagen ethyl nitrosourea (ENU) resulted in a higher number of mutations induced in the liver but not in the spleen, as compared to the Trp53(+/+), lacZ mice. These results suggest that p53 is not an important determinant of gene mutation induction, either spontaneously during development or after treatment with a mutagen. The accelerated age-related accumulation of mutations in normal spleen and liver could be explained by the defect in apoptosis, which would prevent severely damaged cells from being eliminated.

Aging↗
PubMed1996

Mutation accumulation in transfer RNAs: molecular evidence for Muller's ratchet in mitochondrial genomes.

The accumulation of deleterious mutations is thought to be a major factor preventing the long-term persistence of obligately asexual lineages relative to their sexual ancestors. This phenomenon is also of potential relevance to sexual species that harbor asexually propagating organelle genomes. A comparative study of the transfer RNA genes in animal mitochondrial and nuclear genomes demonstrates that the former accumulate nucleotide substitutions much more rapidly than do the latter, and several lines of evidence are consistent with the idea that the excess substitutions are mildly deleterious. First, the average binding stability between complementary strands in the stems of mitochondrial tRNAs is less than half that in nuclear tRNAs. Second, most loop sizes in the mitochondrial tRNAs have experienced a net reduction in size over evolutionary time, and they are nearly 50 times more variable in the mitochondrial than in the nuclear genome. Third, although nearly 20% of the nucleotides in nuclear tRNA genes (particularly those involved in tertiary interactions) are invariant across all animal taxa and all tRNA species, there are no invariant sites in the mitochondrial tRNAs. These observations, as well as results from recent laboratory experiments, are consistent with the hypothesis that nonrecombining organelle genomes are subject to gradual loss of fitness due to the cumulative chance fixation of mildly deleterious mutations.

Animals↗
PubMed2003

Comparing analysis methods for mutation-accumulation data: a simulation study.

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 approximately 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 approximately 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.

Computer Simulation↗
PubMed1995

A quantitative analysis of modifier mutations which occur in mutation accumulation lines in Drosophila melanogaster.

Seven enzyme activities were measured in Drosophila melanogaster lines in which spontaneous mutations had accumulated over about 300 generations under the minimum pressure of natural selection. These enzymes included alcohol dehydrogenase (ADH), alpha-glycerol-3-phosphate dehydrogenase (alpha GPDH), malate dehydrogenase (MDH), isocitrate dehydrogenase (IDH), glucose-6-phosphate dehydrogenase (G6PD), 6-phosphogluconate dehydrogenase (6PGD) and alpha-amylase (AMY). A significant genetic variance was observed for some enzyme activities. The mutations which alter the enzyme activities are called modifier mutations. The magnitudes of the genetic variance in modifier mutations differed greatly among enzymes but were often similar between two series of mutation accumulation lines (AW and JH). This may therefore indicate that the number of modifiers is specific for each enzyme system. The modifier mutation rate is suggested to be one of the clues for assessing the maintenance mechanism of protein polymorphism in natural populations.

Alcohol Dehydrogenase↗
PubMed2005

Inferences on the role of insertion in a mutation accumulation experiment with Drosophila melanogaster using RAPDs.

The genetic variability for RAPDs band pattern was studied in a set of 157 mutation accumulation (MA) lines of Drosophila melanogaster. These MA lines were derived from the same isogenic base population and subsequently maintained by full-sib mating during 132 generations. The ancestral pattern of the original isogenic base can be unambiguously established as the consensus pattern of the MA lines and, because these lines are expected to be homozygous, dominance for band pattern is not a concern. Only repeatable changes in band pattern were considered. The number of ancestral bands detected implies that nine-nucleotide targets are enough for repeatable PCR amplification. Compared with the ancestral pattern, one MA line lost one band and two MA lines gained a new one. These results can be accounted for by the insertion of transposable elements occurring at a rate 0.07 < i < 0.21 per whole haploid genome and generation. This range is typical for Drosophila and consistent with the previously observed mobility for the roo family, supporting the generality of previous estimates of spontaneous mutation rates for morphological and fitness traits based on these MA lines. The sequence of one of the new bands suggests that the Idefix family is also active in the lines.

Animals↗
PubMed2000

Effect of deleterious mutation-accumulation on the fitness of RNA bacteriophage MS2.

RNA viruses show the highest mutation rate in nature. It has been extensively demonstrated that, in the absence of purifying selection, RNA viruses accumulate deleterious mutations at a high rate. However, the parameters describing this accumulation are, in general, poorly understood. The present study reports evidences for fitness declines by the accumulation of deleterious mutations in the bacteriophage MS2. We estimated the rate of fitness decline to be as high as 16% per bottleneck transfer. In addition, our results agree with an additive model of fitness effects.

Base Sequence↗
PubMed2004

Mutation accumulation in populations of varying size: the distribution of mutational effects for fitness correlates in Caenorhabditis elegans.

The consequences of mutation for population-genetic and evolutionary processes depend on the rate and, especially, the frequency distribution of mutational effects on fitness. We sought to approximate the form of the distribution of mutational effects by conducting divergence experiments in which lines of a DNA repair-deficient strain of Caenorhabditis elegans, msh-2, were maintained at a range of population sizes. Assays of these lines conducted in parallel with the ancestral control suggest that the mutational variance is dominated by contributions from highly detrimental mutations. This was evidenced by the ability of all but the smallest population-size treatments to maintain relatively high levels of mean fitness even under the 100-fold increase in mutational pressure caused by knocking out the msh-2 gene. However, we show that the mean fitness decline experienced by larger populations is actually greater than expected on the basis of our estimates of mutational parameters, which could be consistent with the existence of a common class of mutations with small individual effects. Further, comparison of the total mutation rate estimated from direct sequencing of DNA to that detected from phenotypic analyses implies the existence of a large class of evolutionarily relevant mutations with no measurable effect on laboratory fitness.

Amino Acid Substitution↗
PubMed1993

Antagonistic pleiotropy, mutation accumulation, and human genetic disease.

The antagonistic pleiotropy theory of senescence is the most convincing theoretical explanation of the existence of aging. As yet, no locus or allele has been identified in a wild population with the features predicted by the pleiotropic theory. Human genetic diseases offer the opportunity to identify potentially pleiotropic alleles/loci. Four human genetic diseases--Huntington's disease, idiopathic hemochromatosis, myotonic dystrophy, and Alzheimer's disease--may exhibit pleiotropic effects and further study of these diseases might result in the identification of pleiotropic genes causing aging. Inability to find an early life selective benefit associated with these disease-causing alleles would favor the major alternative genetic explanation for aging, the mutation accumulation theory.

Aging↗
PubMed2005

Biased mutation-assembling: an efficient method for rapid directed evolution through simultaneous mutation accumulation.

We have developed an efficient optimization technique, 'biased mutation-assembling', for improving protein properties such as thermostability. In this strategy, a mutant library is constructed using the overlap extension polymerase chain reaction technique with DNA fragments from wild-type and phenotypically advantageous mutant genes, in which the number of mutations assembled in the wild-type gene is stochastically controlled by the mixing ratio of the mutant DNA fragments to wild-type fragments. A high mixing ratio results in a mutant composition biased to favor multiple-point mutants. We applied this strategy to improve the thermostability of prolyl endopeptidase from Flavobacterium meningosepticum as a case study and found that the proportion of thermostable mutants in a library increased as the mixing ratio was increased. If the proportion of thermostable mutants increases, the screening effort needed to find them should be reduced. Indeed, we isolated a mutant with a 1200-fold longer activity half-life at 60 degrees C than that of wild-type prolyl endopeptidase after screening only 2000 mutants from a library prepared with a high mixing ratio. Our results indicate that an aggressive accumulation of advantageous mutations leads to an increase in the quality of the mutant library and a reduction in the screening effort required to find superior mutants.

Chryseobacterium↗
PubMed2006

Mitochondrial DNA-deletion mutations accumulate intracellularly to detrimental levels in aged human skeletal muscle fibers.

Skeletal muscle-mass loss with age has severe health consequences, yet the molecular basis of the loss remains obscure. Although mitochondrial DNA (mtDNA)-deletion mutations have been shown to accumulate with age, for these aberrant genomes to be physiologically relevant, they must accumulate to high levels intracellularly and be present in a significant number of cells. We examined mtDNA-deletion mutations in vastus lateralis (VL) muscle of human subjects aged 49-93 years, using both histologic and polymerase-chain-reaction (PCR) analyses, to determine the physiological and genomic integrity of mitochondria in aging human muscle. The number of VL muscle fibers exhibiting mitochondrial electron-transport-system (ETS) abnormalities increased from an estimated 6% at age 49 years to 31% at age 92 years. We analyzed the mitochondrial genotype of 48 single ETS-abnormal, cytochrome c oxidase-negative/succinate dehydrogenase-hyperreactive (COX-/SDH++) fibers from normal aging human subjects and identified mtDNA-deletion mutations in all abnormal fibers. Deletion mutations were clonal within a fiber and concomitant to the COX-/SDH++ region. Quantitative PCR analysis of wild-type and deletion-containing mtDNA genomes within ETS-abnormal regions of single fibers demonstrated that these deletion mutations accumulate to detrimental levels (>90% of the total mtDNA).

Aged↗