Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Mutation Rate”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 127 records · Page 7Linked to original sources
PubMed1996

The impact of population expansion and mutation rate heterogeneity on DNA sequence polymorphism.

In order to study the effect of mutation rate heterogeneity on patterns of DNA polymorphism, we simulated samples of DNA sequences with gamma-distributed nucleotide substitution rates in stationary and expanding populations. We find that recent population expansions and mutation rate heterogeneity have similar effects on several polymorphism indicators, like the shape and the mean of the observed pairwise difference distribution, or the number of segregating sites. The inferred size of population expansion thus appears overestimated if nucleotides have dissimilar substitution rates. Interestingly, population expansion and uneven mutation rates have contrasting effects on Tajima's D statistic when acting separately, and the consequence on the associated test of selective neutrality is investigated. The patterns of polymorphism of several human populations analyzed for the mitochondrial control region are examined, mainly showing the difficulty in quantifying the respective contribution of past demographic history and uneven mutation rates from a single sampled evolutionary process. However, substitution rates appear more heterogeneous in the second hypervariable segment of the control region than in the first segment.

Animals↗
PubMed2004

Gene expression, synteny, and local similarity in human noncoding mutation rates.

The human genome is organized with regard to many features such as isochores, Giemsa bands, clusters of genes with similar expression patterns, and contiguous regions with shared evolutionary histories (synteny blocks). In addition to these genomic features, it is clear that mutation rates also vary across the human genome. To address how mutation rates and genomic features are related, we analyzed substitution rates at three classes of putatively neutral noncoding sites (nongenic, intronic, and ancestral repeats) in approximately 14 Mb of human-chimpanzee alignments covering human chromosome 7. Patterns of mutation rate variation inferred from substitution rate variation differ among the three site classes. In particular, we find that intronic mutation rates are strongly affected by the breadth of expression of the genes in which they reside, with broadly expressed genes exhibiting low mutation rates, probably as a consequence of the transcription-coupled repair process acting in the germ line. All site classes show significant local similarities in mutation rate at the megabase scale, and regional similarities in nongenic mutation rate covary with blocks of synteny between the human and mouse genomes, indicating that the evolutionary history of a genomic region is an important determinant of mutation rate.

Animals↗
PubMed1996

Estimate of the genomic mutation rate deleterious to overall fitness in E. coli.

Mutations are a double-edged sword: they are the ultimate source of genetic variation upon which evolution depends, yet most mutations affecting fitness (viability and reproductive success) appear to be harmful. Deleterious mutations of small effect can escape natural selection, and should accumulate in small population. Reduced fitness from deleterious-mutation accumulation may be important in the evolution of sex, mate choice, and diploid life-cycles, and in the extinction of small populations. Few empirical data exist, however. Minimum estimates of the genomic deleterious-mutation rate for viability in Drosophila melanogaster are surprisingly high, leading to the conjecture that the rate for total fitness could exceed 1.0 mutation per individual per generation. Here we use Escherichia coli to provide an estimate of the genomic deleterious-mutation rate for total fitness in a microbe. We estimate that the per-microbe rate of deleterious mutations is in excess of 0.0002.

Animals↗
PubMed1995

Modeling and measurement of the spontaneous mutation rate in mammalian cells.

The study of spontaneous mutation rates in mammalian cells has been hampered by the lack of an alternative to the cumbersome Luria and Delbrück fluctuation test. A brief review of mathematical treatments of spontaneous mutagenesis, along with some of the limitations of the fluctuation test, is presented. A new experimental method and a simple mathematical model for deriving the spontaneous mutation rate are described. Data from the transgenic Chinese hamster G12 cell line growing at two different rates is analyzed according to this model. The results support the concept that, at least for growing cells, the spontaneous mutation rate is independent of the growth rate, and the mutant fraction increases in a linear fashion with the number of generations.

Animals↗
PubMed2003

Mutation rate and novel tt mutants of Arabidopsis thaliana induced by carbon ions.

Irradiation of Arabidopsis thaliana by carbon ions was carried out to investigate the mutational effect of ion particles in higher plants. Frequencies of embryonic lethals and chlorophyll-deficient mutants were found to be significantly higher after carbon-ion irradiation than after electron irradiation (11-fold and 7.8-fold per unit dose, respectively). To estimate the mutation rate of carbon ions, mutants with no pigments on leaves and stems (tt) and no trichomes on leaves (gl) were isolated at the M2 generation and subjected to analysis. Averaged segregation rate of the backcrossed mutants was 0.25, which suggested that large deletions reducing the viability of the gametophytes were not transmitted, if generated, in most cases. During the isolation of mutants, two new classes of flavonoid mutants (tt18, tt19) were isolated from carbon-ion-mutagenized M2 plants. From PCR and sequence analysis, two of the three tt18 mutant alleles were found to have a small deletion within the LDOX gene and the other was revealed to contain a rearrangement. Using the segregation rates, the mutation rate of carbon ions was estimated to be 17-fold higher than that of electrons. The isolation of novel mutants and the high mutation rate suggest that ion particles can be used as a valuable mutagen for plant genetics.

Arabidopsis↗
PubMed1993

Accounting for plating efficiency when estimating spontaneous mutation rates.

When the spontaneous mutation rate mu in mammalian cell cultures is estimated using Luria-Delbrück fluctuation analysis, many factors contribute to the unreliability of the estimate. Some of these have been documented by Featherstone et al. (1987) and by Kendal and Frost (1988). In particular, the plating efficiencies for mammalian cells are often much less than 100%, and this can be taken into account. A derivation of a generalized P0 estimator, mg, based on the classical P0 estimator of Luria and Delbrück (1943) is offered. In an experiment involving C cultures, of which z exhibit no mutant colonies, and in which the plating efficiency is p, (0 < p < 1), the estimated mean number of mutations per culture is given by [formula: see text] The classical P0 estimator is shown to be the limiting case of mg as plating efficiency tends to 100%.

Animals↗
PubMed1991

Null mutants of Saccharomyces cerevisiae Cu,Zn superoxide dismutase: characterization and spontaneous mutation rates.

Deletion-replacement mutations of the Saccharomyces cerevisiae Cu,Zn superoxide dismutase gene were constructed. They were exquisitely sensitive to redox cycling drugs and showed slight sensitivity to other agents. The aerobic spontaneous mutation rate was three- to fourfold higher in sod1 delta 1 mutants, while the anaerobic rate was similar to that of the wild type.

Aerobiosis↗
PubMed2004

A new cell-based assay for measuring the forward mutation rate of HIV-1.

Over 20 years into the ever-worsening AIDS pandemic, genetic variation remains the greatest obstacle for treating and preventing HIV-1 infection. Mutation rate assays for HIV-1 have been reported; however, none measure directly the forward mutation rate during replication of the virus in cell culture while still retaining the ability to propagate and further study mutant proviruses. Therefore, the objective of the current study was to develop such a phenotypic cell-based assay for measuring the forward mutation rate of HIV-1. Conventional recombinant DNA techniques and polymerase chain reaction were used to create a replication defective HIV-1 vector, pNL4-3Delta+cass, which is based on the NL4-3 strain and contains the thymidine kinase gene from human herpes virus type 1 as the mutational target. A series of transfection and infection steps were used to introduce the vector into 143B cells, which are negative for thymidine kinase function, and produce vector virus for a single cycle of replication. Viral titers were measured by counting the number of drug resistant colonies on the assay plates, and forward mutation rates were calculated from the viral titers. Mutant proviruses were sequenced to determine the types of genetic alterations that occurred. The average forward mutation rate for HIV-1 was 2.2 x 10(-5)mutations/base/cycle. The majority of mutations were base substitutions, including high frequencies of C-->U and G-->A transitions. Single adenosine insertions were also observed frequently. The new assay is economical and provides a direct measurement of the mutation rate during a single cycle of viral replication. Target cells containing mutant proviruses survive the drug selection process and may be propagated for further analysis. The new assay is novel and has many advantages over previous mutation rate assays and thus will be very useful in future studies on genetic variation of HIV-1.

Cell Line↗
PubMed2002

Optimal mutation rates in dynamic environments.

In this paper, we study the evolution of the mutation rate for simple organisms in dynamic environments. A model based on explicit population dynamics at the gene sequence level, with multiple fitness coding loci tracking a moving fitness peak in a random fitness background, is developed and an analytical expression for the optimal mutation rate is derived. The optimal mutation rate per genome is approximately independent of genome length, something that has been observed in nature. Furthermore, the optimal mutation rate is a function of the absolute, not relative, replication rate of the superior gene sequences. Simulations confirm the theoretical predictions.

Computer Simulation↗
PubMed1986

Measurement of the mutation rates of animal viruses: influenza A virus and poliovirus type 1.

Epidemiologic and genetic evidence suggests that influenza A viruses evolve more rapidly than other viruses in humans. Although the high mutation rate of the virus is often cited as the cause of the extensive variation, direct measurement of this parameter has not been obtained in vivo. In this study, the rate of mutation in tissue culture for the nonstructural (NS) gene of influenza A virus and for the VP1 gene in poliovirus type 1 was assayed by direct sequence analysis. Each gene was repeatedly sequenced in over 100 viral clones which were descended from a single virion in one plaque generation. A total of 108 NS genes of influenza virus were sequenced, and in the 91,708 nucleotides analyzed, seven point changes were observed. A total of 105 VP1 genes of poliovirus were sequenced, and in the 95,688 nucleotides analyzed, no mutations were observed. We then calculated mutation rates of 1.5 X 10(-5) and less than 2.1 X 10(-6) mutations per nucleotide per infectious cycle for influenza virus and poliovirus, respectively. We suggest that the higher mutation rate of influenza A virus may promote the rapid evolution of this virus in nature.

Base Sequence↗
PubMed1986

On three methods for estimating mutation rates indirectly.

Methods for estimating a mutation rate mu has been proposed by Kimura and Ohta; Nei; and Rothman and Adams. It is shown here that all three methods are best applied to rare alleles and that they are all based upon the assumption that all alleles ultimately become extinct. If there is a neutral allele in a growing population, there is conditioning on ultimate extinction, which implies that the underlying stochastic process can be approximated by a branching process for which the mean number of offspring is less than 1. The low numerical values of t0, the mean time to extinction of a line descended from a single mutant, found in two simulation studies, can be attributed to two features. First, the data on which these studies were based came from a fairly rapidly growing population. In such a population, we would expect that extinction, if it does occur, takes place quickly. A second factor is that the effective population size is somewhat lower than the actual number of adults. Population subdivision and migration does not seem to play a significant role. Conservative high and low estimates of mutation rates are computed, and an estimate is obtained for the standard deviation of the estimate of mu. These allow a rough estimate of a 95% confidence interval, which contains estimates of mu found by Neel and Rothman.

Gene Frequency↗
PubMed2006

Elevated mutation rates in the germline of Polkappa mutant male mice.

Mutation rates at two expanded simple tandem repeat (ESTR) loci were studied in the germline of DNA polymerase kappa (Polkappa(-/-)) deficient mice. The spontaneous mutation rate in homozygous Polkappa(-/-) males was significantly higher than in isogenic wild-type mice (Polkappa(+/+)), but the ESTR mutation spectrum in Polkappa(-/-) animals did not differ from that in Polkappa(+/+) males. We suggest that compromised translesion synthesis in Polkappa(-/-) mice may result in replication fork pausing which, in turn, may affect ESTR mutation rate.

Animals↗
PubMed2004

On the rate and linearity of viability declines in Drosophila mutation-accumulation experiments: genomic mutation rates and synergistic epistasis revisited.

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.

Animals↗
PubMed1997

Further evidence for elevated human minisatellite mutation rate in Belarus eight years after the Chernobyl accident.

Analysis of germline mutation rate at human minisatellites among children born in areas of the Mogilev district of Belarus heavily polluted after the Chernobyl accident has been extended, both by recruiting more families from the affected region and by using five additional minisatellite probes, including multi-locus probe 33.6 and four hypervariable single-locus probes. These additional data confirmed a twofold higher mutation rate in exposed families compared with non-irradiated families from the United Kingdom. An elevated rate was seen at all three independent sets of minisatellites (detected separately by multi-locus probes 33.15, 33.6 and six single-locus probes), indicating a generalised increase in minisatellite germline mutation rate in the Belarus families. Within the Belarus cohort, mutation rate was significantly greater in families with higher parental radiation dose estimated for chronic external and internal exposure to caesium-137, consistent with radiation induction of germline mutation. The spectra of mutation seen in the unexposed and exposed families were indistinguishable, suggesting that increased mutation observed over multiple loci arises indirectly by some mechanism that enhances spontaneous minisatellite mutation.

Adult↗
PubMed1997

Low mutation rates of microsatellite loci in Drosophila melanogaster.

Analysis of variation at microsatellite DNA loci is widely used in studies of parentage, linkage and evolutionary history. The utility of microsatellites is primarily due to high levels of allelic diversity, believed to reflect mutation rates orders of magnitude higher than base pair substitutions at single-copy genes. For humans, mice, rats and pigs, microsatellite mutation rates have been estimated at 10(-3)-10(-5). However, a recent study comparing microsatellite variation in humans with non-human primates suggests that microsatellite mutation rates may vary considerably across taxa. We measured mutation rates of 24 microsatellite loci in mutation accumulation lines of Drosophila melanogaster. Surprisingly, only a single mutation was detected after screening 157,680 allele-generations, yielding an estimated average mutation rate per locus of 6.3 x 10(-6), a mutation rate considerably lower than reported for various mammals. We propose that the comparatively low mutation rate is primarily a function of short microsatellite repeat lengths in the D. melanogaster genome.

Animals↗
PubMed2006

Estimation of the species-specific mutation rates at the DRB1 locus in humans and chimpanzee.

To estimate the species-specific mutation rates at the DRB1 locus in humans and chimpanzee, we analyzed the nucleotide sequence of a 37.6-kb chimpanzee chromosomal segment containing the entire Patr-DRB1*0701 allele and the flanking nongenic region and we compared it with two corresponding human sequences containing the HLA-DRB1*070101 allele using the sequence of HLA-DRB1*04011 as an outgroup. Because the allelic pair of HLA-DRB1*070101 and Patr-DRB1*0701 shows the lowest number of substitutions between the two species, it appears that these sequences diverged close to the time of the humans-chimpanzee divergence (6 million years ago). Alignment of the nucleotide sequences for HLA-DRB1*070101 and Patr-DRB1*0701 alleles showed that they share a high degree of similarity, suggesting that the studied chromosomal segments with these sequences have not been subjected to recombination since the humans-chimpanzee divergence. Comparison of the flanking 10.6 kb of nongenic sequences revealed an average of 41.5 and 83 single nucleotide substitutions in humans and chimpanzee, respectively. Thus, the species-specific nucleotide substitution rates in the flanking nongenic region were estimated to be 6.53 x 10(-10) and 1.31 x 10(-9) per site per year in humans and chimpanzee, respectively. Unexpectedly, the estimated rate in humans was twofold lower than in chimpanzee (P < 10(-3), Tajima's relative rate test) and lower than the average substitution rate in the human genome. Because the nucleotide substitution rate in nongenic regions free from selection is expected to be equal to the mutation rate, the estimated substitution rate should correspond to the species-specific mutation rate at the DRB1 locus. Our results strongly suggest that the mutation rate at DRB1 locus differs among species.

Alleles↗
PubMed1981

The effect of a change in mutation rate on the incidence of dominant and X-linked recessive disorders in man.

In order to assess the impact on man of a sustained change in mutation rate that might be caused by ionizing radiation or a chemical mutagen in the environment, it is important to determine the current incidence of genetic disease, the rate at which deleterious mutations arise and the number of generations that mutations persist before eliminated by selection. From these data it should be possible to estimate both the increase in genetic disease in the first generation following the increase in mutation rate, and the rate at which a new equilibrium between mutation and selection would occur. In this paper the results of a survey to determine birth frequency, mutation rate and reproductive fitness for each of the important dominant and X-linked recessive disorders are described. It is estimated that these disorders affect about 0.6% of live-born individuals, including 0.1% of live-borns who carry a newly-arising mutation. These figures are approx. 50% lower than those used by the various committees that have assessed the genetic risk to man from ionizing radiation. If the mutation rate were to permanently double, the frequency of these disorders would be expected in increase in the first generation by 15%, to 0.7% of live-births. The increase in the first 2 generations would be 24% and a 50% increase would occur by the 9th generation. A calculation of the possible increase in dominant and X-linked recessive disorders due to exposure of a population to ionizing radiation indicates that the estimate made in 1977 by the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) may be too high by a factor of 2-6 fold.

Female↗
PubMed2003

The relationship between microsatellite slippage mutation rate and the number of repeat units.

Microsatellite markers are widely used for genetic studies, but the relationship between microsatellite slippage mutation rate and the number of repeat units remains unclear. In this study, microsatellite distributions in the human genome are collected from public sequence databases. We observe that there is a threshold size for slippage mutations. We consider a model of microsatellite mutation consisting of point mutations and single stepwise slippage mutations. From two sets of equations based on two stochastic processes and equilibrium assumptions, we estimate microsatellite slippage mutation rates without assuming any relationship between microsatellite slippage mutation rate and the number of repeat units. We use the least squares method with constraints to estimate expansion and contraction mutation rates. The estimated slippage mutation rate increases exponentially as the number of repeat units increases. When slippage mutations happen, expansion occurs more frequently for short microsatellites and contraction occurs more frequently for long microsatellites. Our results agree with the length-dependent mutation pattern observed from experimental data, and they explain the scarcity of long microsatellites.

Algorithms↗