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Results for “Mutation Rate”

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PubMed1992

Direct determination of the point mutation rate of a murine retrovirus.

The point mutation rate of a murine leukemia virus (MuLV) genome (AKV) was determined under conditions in which the number of replicative cycles was carefully controlled and the point mutation rate was determined by direct examination of the RNA genomes of progeny viruses. A clonal cell line infected at a low multiplicity of infection (2 x 10(-3)) was derived to provide a source of virus with high genetic homogeneity. Virus stocks from this cell line were used to infect cells at a low multiplicity of infection, and the cells were seeded soon after infection to obtain secondary clonal cell lines. RNase T1-oligonucleotide fingerprinting analyses of virion RNAs from 93 secondary lines revealed only 3 base changes in nearly 130,000 bases analyzed. To obtain an independent assessment of the mutation rate, we directly sequenced virion RNAs by using a series of DNA oligonucleotide primers distributed across the genome. RNA sequencing detected no mutations in over 21,000 bases analyzed. The combined fingerprinting and sequencing analyses yielded a mutation rate for infectious progeny viruses of one base change per 50,000 (2 x 10(-5)) bases per replication cycle. Our results suggest that over 80% of infectious progeny MuLVs may be replicated with complete fidelity and that only a low percentage undergo more than one point mutation during a replication cycle. Previous estimates of retroviral mutation rates suggest that the majority of infectious progeny viruses have undergone one or more point mutations. Recent studies of the mutation rates of marker genes in spleen necrosis virus-based vectors estimate a base substitution rate lower than estimates for infectious avian retroviruses and nearly identical to our determinations with AKV. The differences between mutation rates observed in studies of retroviruses may reflect the imposition of different selective conditions.

Animals↗

PubMed1973

Ligase-defective bacteriophage T4. I. Effects on mutation rates.

Temperature-sensitive mutations in bacteriophage T4 gene 30 (polynucleotide ligase) were examined for their effects on spontaneous and proflavine-induced frameshift mutagenesis in the rII and ac (acridine resistance) cistrons. Only small (fourfold or less) effects on mutation rates were observed, even when selection artifacts involving suppression of gene 30 mutations by rII mutations were taken into account. The deoxyribonucleic acid ligase gene of T4 therefore appears to be only a minor determinant of frameshift mutation rates. This result is consistent with the particular nature of frameshift mutagenesis in bacteriophage T4.

Acridines↗

PubMed2004

Effect of exogenous MSH6 and POLD1 expression on the mutation rate of the HPRT locus in a human colon cancer cell line with mutator phenotype, DLD-1.

The DLD-1 human colon cancer cell line displays an elevated spontaneous mutation rate. Since DLD-1 carries frameshift mutations in both alleles of the MSH6 gene and missense mutations in the POLD1 gene, either or both of these mutations were suggested to be involved in this mutator phenotype. Therefore, we examined the effect of exogenous wild-type MSH6 and POLD1 expression on the spontaneous mutation rate at the HPRT locus in DLD-1 cells. POLD1 genotypes were first determined, since four POLD1 missense mutations were previously reported in DLD-1 cells. Sequencing analyses on the genomic DNA and cDNA of the POLD1 gene revealed that DLD-1 cells are a mixture of two distinct sublines with regard to POLD1 genotypes. Moreover, the wild-type POLD1 allele was not present in either of the two DLD-1 sublines. We next established MSH6- and POLD1-transfected DLD-1 clones from both sublines, respectively. The two DLD-1 sublines exhibited HPRT mutation rates of 4.8 x 10(-6) and 5.4 x 10(-6) mutations/cell/generation. The mutation rates were more than 4-fold decreased in both of the MSH6-transfected DLD-1 clones examined, while they were not significantly decreased in three of four POLD1-transfected DLD-1 clones. Thus, it was indicated that mutations in the MSH6 gene, and not in the POLD1 gene, are primarily responsible for the elevated mutation rates in DLD-1 cells.

Alleles↗

PubMed2006

Minisatellite germline mutation rate in the Techa River population.

Germline mutation at eight minisatellite loci has been studied among the irradiated families from the Techa River population and non-exposed families from the rural area of the Chelyabinsk and Kurgan Oblasts. The groups were matched by ethnicity, parental age, occupation and smoking habit. A statistically significant 1.7-fold increase in mutation rate was found in the germline of irradiated fathers, whereas maternal germline mutation rate in the exposed families was not elevated. Most of the minisatellite loci showed an elevated paternal mutation rate in the exposed group, indicating a generalised increase in minisatellite germline mutation rate in the Techa River population. These data suggest that the elevated minisatellite mutation rate can be attributed to radioactive exposure. The spectra of paternal mutation seen in the unexposed and exposed families were indistinguishable.

Female↗

PubMed1988

Determination of the mutation rate of a retrovirus.

The mutation rate of Rous sarcoma virus (RSV) was measured. Progeny descended from a single virion were collected after one replication cycle, and seven regions of the genome were analyzed for mutations by denaturing-gradient gel electrophoresis. In all, 65,250 nucleotides were screened, yielding nine mutations, and the RSV mutation rate was calculated as 1.4 x 10(-4) mutations per nucleotide per replication cycle. These results indicate that RSV is an extremely mutable virus. We speculate that the mutation rate of a virus may correlate inversely with the effectiveness of vaccination against a given virus and suggest that prevention of retrovirus-mediated disease via vaccination may prove difficult.

Animals↗

PubMed2003

Estimation of spontaneous mutation rates.

Spontaneous or randomly occurring mutations play a key role in cancer progression. Estimation of the mutation rate of cancer cells can provide useful information about the disease. To ascertain these mutation rates, we need mathematical models that describe the distribution of mutant cells. In this investigation, we develop a discrete time stochastic model for a mutational birth process. We assume that mutations occur concurrently with mitosis so that when a nonmutant parent cell splits into two progeny, one of these daughter cells could carry a mutation. We propose an estimator for the mutation rate and investigate its statistical properties via theory and simulations. A salient feature of this estimator is the ease with which it can be computed. The methods developed herein are applied to a human colorectal cancer cell line and compared to existing continuous time models.

Biometry↗

PubMed1994

Evolution of mutation rate and virulence among human retroviruses.

High mutation rates are generally considered to be detrimental to the fitness of multicellular organisms because mutations untune finely tuned biological machinery. However, high mutation rates may be favoured by a need to evade an immune system that has been strongly stimulated to recognize those variants that reproduced earlier during the infection. HIV infections conform to this situation because they are characterized by large numbers of viruses that are continually breaking latency and large numbers that are actively replicating throughout a long period of infection. To be transmitted, HIVs are thus generally exposed to an immune system that has been activated to destroy them in response to prior viral replication in the individual. Increases in sexual contact should contribute to this predicament by favouring evolution toward relatively high rates of replication early during infection. Because rapid replication and high mutation rate probably contribute to rapid progression of infections to AIDS, the interplay of sexual activity, replication rate, and mutation rate helps explain why HIV-1 has only recently caused a lethal pandemic, even though molecular data suggest that it may have been present in humans for more than a century. This interplay also offers an explanation for geographic differences in progression to cancer found among infections due to the other major group of human retroviruses, human T-cell lymphotropic viruses (HTLV). Finally, it suggests ways in which we can use natural selection as a tool to control the AIDS pandemic and prevent similar pandemics from arising in the future.

Biological Evolution↗

PubMed2000

The mutation rate in the human mtDNA control region.

The mutation rate of the mitochondrial control region has been widely used to calibrate human population history. However, estimates of the mutation rate in this region have spanned two orders of magnitude. To readdress this rate, we sequenced the mtDNA control region in 272 individuals, who were related by a total of 705 mtDNA transmission events, from 26 large Icelandic pedigrees. Three base substitutions were observed, and the mutation rate across the two hypervariable regions was estimated to be 3/705 =.0043 per generation (95% confidence interval [CI].00088-.013), or.32/site/1 million years (95% CI.065-.97). This study is substantially larger than others published, which have directly assessed mtDNA mutation rates on the basis of pedigrees, and the estimated mutation rate is intermediate among those derived from pedigree-based studies. Our estimated rate remains higher than those based on phylogenetic comparisons. We discuss possible reasons for-and consequences of-this discrepancy. The present study also provides information on rates of insertion/deletion mutations, rates of heteroplasmy, and the reliability of maternal links in the Icelandic genealogy database.

Base Sequence↗

PubMedDate not supplied

Mutation rate of avian intestinal coliform bacteria when pressured with fluoroquinolones.

The purpose of this study was to determine the rate at which resistance developed in avian coliform bacteria when exposed to nalidixic acid, sarafloxacin, or enrofloxacin. In in vitro studies, the rates of mutation of avian isolates of Escherichia coli and Salmonella were determined following nalidixic acid, sarafloxacin, or enrofloxacin pressure. The rates of mutation were similar for nalidixic acid and sarafloxacin, whereas a lower rate of mutation was seen after enrofloxacin pressure. In in vivo studies, the quinolones were administered in the drinking water to broiler chickens at a concentration of 40 ppm for five consecutive days. Samples of feces were inoculated onto appropriate media and the frequency of resistance was determined. The frequency rates of resistance to nalidixic acid and sarafloxacin were similar. Enrofloxacin-medicated birds did not develop enrofloxacin-resistant coliform bacteria. The in vitro and in vivo data appear to correlate.

Animals↗

PubMed2003

Minisatellite DNA mutation rate in dandelions increases with leaf-tissue concentrations of Cr, Fe, Mn, and Ni.

We have examined whether mutation rates at minisatellite DNA loci in dandelions (Taraxacum officinale Weber, sensu lato: Asteraceae) increase with increasing exposure to metal pollution. From 16 sites (Colorado to Pennsylvania, USA) covering a range of airborne particulate-matter exposures, soil metal concentrations, and leaf-tissue metal concentrations, we grew an average of 7.9 offspring from each of 10 parent plants, and we analyzed the parent-offspring transmission of 82,715 minisatellite DNA markers to 1,258 offspring for rates of mutation. The mean number of markers examined per individual (using six minisatellite probes) was 65.8. Detection of mutations is facilitated by agamospermous reproduction (clonal seed production) in dandelions. Across sites, the average single-event, parent-offspring marker transmission mutation rate was 0.0067, ranging from 0.002 to 0.015 (a 7.5-fold difference). No significant correlation was detected between site single-event mutation rates and either airborne particulate-matter or soil concentrations for any of the metals. However, across sites, mutation rates were significantly (p < 0.05) and positively correlated to increasing leaf-tissue concentrations of Cr, Fe, Mn, and Ni (Cd, Cu, Pb, and Zn exhibited no correlation). Multiple-regression analyses suggest that a model including three metals--in order of importance: Cr (p = 0.002), Fe (p = 0.02), and Ni (p = 0.005); overall, p = 0.001--may improve the ability to predict mutation rate relative to leaf metal concentrations in dandelions. Mutations at minisatellite DNA loci in sexually apomictic organisms may thus provide convenient biomarkers by which to assess the mutagen stressor risk in environments.

DNA Damage↗

PubMed1998

Mutation rate of a microsatellite sequence in normal human fibroblasts.

Dinucleotide repeats, because of their repetitive nature, are prone to frameshift mutations, most likely via a DNA-polymerase slippage mechanism. Mutation rates in microsatellite DNA sequences are high in mismatch repair-defective cells. In normal cells, only estimates of maximal rates of mutation in microsatellites have been possible previously, because of the low sensitivity of screening assays for mutations in endogenous sequences. We have measured the spontaneous mutation rate of a dinucleotide repeat in diploid human foreskin fibroblasts. In our system, the mutation target is a (CA)17 repeat contained within a stably integrated plasmid. The repeat disrupts the reading frame of a neomycin (neo) resistance gene within the plasmid. Cells containing frameshift mutations in the CA repeat that correct the reading frame of the neo gene are selected using the neo analogue G418. This system of measuring microsatellite mutation rates is highly sensitive, because there is a specific target within which mutations can be selected. Fluctuation analysis of cells containing the target DNA yielded mutation rates of <3.1 x 10(-8) to 44.8 x 10(-8) mutations/cell/generation. This is the first report of a direct measurement of a spontaneous mutation rate of a microsatellite sequence in normal human cells.

Cells, Cultured↗

PubMed2006

The influence of hitchhiking and deleterious mutation upon asexual mutation rates.

The question of how natural selection affects asexual mutation rates has been considered since the 1930s, yet our understanding continues to deepen. The distribution of mutation rates observed in natural bacteria remains unexplained. It is well known that environmental constancy can favor minimal mutation rates. In contrast, environmental fluctuation (e.g., at period T) can create indirect selective pressure for stronger mutators: genes modifying mutation rate may "hitchhike" to greater frequency along with environmentally favored mutations they produce. This article extends a well-known model of Leigh to consider fitness genes with multiple mutable sites (call the number of such sites alpha). The phenotypic effect of such a gene is enabled if all sites are in a certain state and disabled otherwise. The effects of multiple deleterious loci are also included (call the number of such loci gamma). The analysis calculates the indirect selective effects experienced by a gene inducing various mutation rates for given values of alpha, gamma, and T. Finite-population simulations validate these results and let us examine the interaction of drift with hitchhiking selection. We close by commenting on the importance of other factors, such as spatiotemporal variation, and on the origin of variation in mutation rates.

Models, Genetic↗

PubMed1997

Relative mutation rates at di-, tri-, and tetranucleotide microsatellite loci.

Using the generalized stepwise mutation model, we propose a method of estimating the relative mutation rates of microsatellite loci, grouped by the repeat motif. Applying ANOVA to the distributions of the allele sizes at microsatellite loci from a set of populations, grouped by repeat motif types, we estimated the effect of population size differences and mutation rate differences among loci. This provides an estimate of motif-type-specific mutation rates up to a multiplicative constant. Applications to four different sets of di-, tri-, and tetranucleotide loci from a number of human populations reveal that, on average, the non-disease-causing microsatellite loci have mutation rates inversely related to their motif sizes. The dinucleotides appear to have mutation rates 1.5-2 times higher than the tetranucleotides, and the non-disease-causing trinucleotides have mutation rates intermediate between the di- and tetranucleotides. In contrast, the disease-causing trinucleotides have mutation rates 3.9-6.9 times larger than the tetranucleotides. Comparison of these estimates with the direct observations of mutation rates at microsatellites indicates that the earlier suggestion of higher mutation rates of tetranucleotides in comparison with the dinucleotides may stem from a nonrandom sampling of tetranucleotide loci in direct mutation assays.

Analysis of Variance↗

PubMed2006

Mutations, mutation rates, and evolution at the hypervariable VNTR loci of Yersinia pestis.

VNTRs are able to discriminate among closely related isolates of recently emerged clonal pathogens, including Yersinia pestis the etiologic agent of plague, because of their great diversity. Diversity is driven largely by mutation but little is known about VNTR mutation rates, factors affecting mutation rates, or the mutational mechanisms. The molecular epidemiological utility of VNTRs will be greatly enhanced when this foundational knowledge is available. Here, we measure mutation rates for 43 VNTR loci in Y. pestis using an in vitro generated population encompassing approximately 96,000 generations. We estimate the combined 43-locus rate and individual rates for 14 loci. A comparison of Y. pestis and Escherichia coli O157:H7 VNTR mutation rates and products revealed a similar relationship between diversity and mutation rate in these two species. Likewise, the relationship between repeat copy number and mutation rate is nearly identical between these species, suggesting a generalized relationship that may be applicable to other species. The single- versus multiple-repeat mutation ratios and the insertion versus deletion mutation ratios were also similar, providing support for a general model for the mutations associated with VNTRs. Finally, we use two small sets of Y. pestis isolates to show how this general model and our estimated mutation rates can be used to compare alternate phylogenies, and to evaluate the significance of genotype matches, near-matches, and mismatches found in empirical comparisons with a reference database.

Animals↗

PubMed1997

The high spontaneous mutation rate: is it a health risk?

The human mutation rate for base substitutions is much higher in males than in females and increases with paternal age. This effect is mainly, if not entirely, due to the large number of cell divisions in the male germ line. The mutation-rate increase is considerably greater than expected if the mutation rate were simply proportional to the number of cell divisions. In contrast, those mutations that are small deletions or rearrangements do not show the paternal age effect. The observed increase with the age of the father in the incidence of children with different dominant mutations is variable, presumably the result of different mixtures of base substitutions and deletions. In Drosophila, the rate of mutations causing minor deleterious effects is estimated to be about one new mutation per zygote. Because of a larger number of genes and a much larger amount of DNA, the human rate is presumably higher. Recently, the Drosophila data have been reanalyzed and the mutation-rate estimate questioned, but I believe that the totality of evidence supports the original conclusion. The most reasonable way in which a species can cope with a high mutation rate is by quasi-truncation selection, whereby a number of mutant genes are eliminated by one "genetic death."

Animals↗

PubMed1997

Evidence for a selectively favourable reduction in the mutation rate of the X chromosome.

The equilibrium per-genome mutation rate in sexual species is thought to result from a trade-off between the benefits of reducing the deleterious mutation rate and the costs of increasing fidelity. We propose that selection will often favour a lower mutation rate on the X chromosome than on autosomes, owing to the exposure of deleterious recessive mutations on hemizygous chromosomes. We tested this hypothesis by examining 33 X-linked genes that have been sequenced in both mouse and rat, and compared their rate of evolution against 238 autosomal genes. The X-linked genes were found to have a significantly lower rate of synonymous substitution than the autosomal genes. Neither the supposed higher mutation rate in males nor stronger purifying selection against slightly deleterious mutations on the X chromosome can account for the low value. The most parsimonious explanation is that rodents have a lower mutation rate on the X chromosome than on autosomes. It is therefore likely that previous indirect estimates of the excess male mutation rate are inaccurate. Indeed, after correction we find no evidence for a male-biased mutation rate in rodents. Furthermore, the rate of synonymous substitution in Y-linked genes is not significantly different from that in autosomal ones. The extent to which enhanced male mutation rates are problematic for the mutational deterministic model of the evolution of sex must, in turn, be questioned.

Animals↗

PubMed1986

An approach to monitoring mutation rates using restriction fragment lengths.

Monitoring background mutation rates in normal populations, elevated rates in exposed populations and unusual rates in test systems exposed to mutagens and carcinogens remains an unresolved problem. To date, efforts have focused on measurement of mutation rates by searching for protein sequences that appear in children but were not present in their parents. An initial study to measure mutation rates by using recombinant DNA technology was carried out in Alta, Utah, in 1984, and the results are summarized here. The purpose of this paper is to explore in greater detail the use of restriction fragment lengths for monitoring mutation rates. The report of the meeting at Alta was sceptical about the practicality of this approach. The conclusion of this paper is that it is indeed a practical approach, and details are given of a method for realizing a functional system.

DNA↗

PubMed1996

A modified Luria-Delbrück fluctuation assay for estimating and comparing mutation rates.

We have investigated the accuracy with which mutation rates may be estimated using a modification of the Luria and Delbrück fluctuation experiment protocol. The modification involves growing a larger-than-usual culture, and plating out a small aliquot of it. Monte Carlo simulations of the experiments confirm that the modification leads to a decrease in the coefficient of variation of the estimated mutation rate where this is based on the median number of mutants detected in a number of cultures grown in parallel. If sets of experimental and control cultures are compared using the Mann-Whitney U-test, then fractional increases in mutation rate can be reliably detected using relatively small numbers of cultures. The modified protocols promise better estimates of mutation rates, offer a powerful test of differences in mutation rates, and are easier to implement in practice.

Computer Simulation↗