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 73 records · Page 4Linked to original sources
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↗
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↗
PubMed1996

A new method for estimating high mutation rates in cultured cells.

Fluctuation analysis allows for the determination of mutation rates in cell cultures in vitro. As originally described by Luria and Delbruck and extended by Lea and Coulson and by Capizzi and Jameson, this analysis has been useful in estimating mutation rates in cultured cells where the frequency of mutational events is low. However. in cultures where high mutation rates and multiple independent mutation events occur, leading to the accumulation of many mutant cells, these standard methods may not apply. Here, we present a new method for the estimation of mutation rates based on the assumption that multiple events may contribute to the accumulation of mutant cells. We compared mutation rates determined by Lea and Coulson's and by Capizzi and Jameson's methods with those determined by our method using experimental and stimulated data from our studies of immunoglobulin gene mutation and isotype switching in B lymphocyte cultures. The three methods resulted in very different calculated rates when many mutants were present in the culture, such as when mutation rates were high, while only small differences in calculated rates were found when mutants were rare. Unlike previous fluctuation analysis calculations, our method is applicable for the estimation of both low and high rates.

Animals↗
PubMed2003

Genic mutation rates in mammals: local similarity, chromosomal heterogeneity, and X-versus-autosome disparity.

The reduction of mutation rates on the mammalian X chromosome relative to autosomes is most often explained in the literature as evidence of male-driven evolution. This hypothesis attributes lowered mutation rates on the X chromosome to the fact that this chromosome spends less time in the germline of males than in the germline of females. In contrast to this majority view, two articles argued that the patterns of mutation rates across chromosomes are inconsistent with male-driven evolution. One article reported a 40% reduction in synonymous substitution rates (Ks) for X-linked genes relative to autosomes in the mouse-rat lineage. The authors argued that this reduction is too dramatic to be explained by male-driven evolution and concluded that selection has systematically reduced mutation rate on the X chromosome to a level optimal for this male-hemizygous chromosome. More recently, a second article found that chromosomal mutation rates in both the human-mouse and mouse-rat lineages were so heterogeneous that the X chromosome was not an outlier. Here again, the authors argued that this is at odds with male-driven evolution and suggested that selection has modulated chromosomal mutation rates to locally optimal levels, thus extending the argument of the first mentioned article to include autosomes. Here, we reexamine these conclusions using mouse-rat and human-mouse coding-region data. We find a more modest reduction of Ks on the X chromosome, but our results contradict the finding that the X chromosome is not distinct from autosomes. Multiple statistical tests show that Ks rates on the X chromosome differ systematically from the autosomes in both lineages. We conclude that the moderate reduction of mutation rate on the X chromosome of both lineages is consistent with male-driven evolution; however, the large variance in mutation rates across chromosomes suggests that mutation rates are affected by additional factors besides male-driven evolution. Investigation of mutation rates by synteny reveals that synteny blocks, rather than entire chromosomes, might represent the unit of mutation rate variation.

Animals↗
PubMedDate not supplied

Estimation of the mutation rate during error-prone polymerase chain reaction.

Error-prone polymerase chain reaction (PCR) is widely used to introduce point mutations during in vitro evolution experiments. Accurate estimation of the mutation rate during error-prone PCR is important in studying the diversity of error-prone PCR product. Although many methods for estimating the mutation rate during PCR are available, all the existing methods depend on the assumption that the mutation rate is low and mutations occur at different places whenever they occur. The available methods may not be applicable to estimate the mutation rate during error-prone PCR. We develop a mathematical model for error-prone PCR and present methods to estimate the mutation rate during error-prone PCR without assuming low mutation rate. We also develop a computer program to simulate error-prone PCR. Using the program, we compare the newly developed methods with two other methods. We show that when the mutation rate is relatively low (< 10(-3) per base per PCR cycle), the newly developed methods give roughly the same results as previous methods. When the mutation rate is relatively high (> 5 x 10(-3) per base per PCR cycle, the mutation rate for most error-prone PCR experiments), the previous methods underestimate the mutation rate and the newly developed methods approximate the true mutation rate.

Biometry↗
PubMed2003

Sexual selection, germline mutation rate and sperm competition.

BACKGROUND: An important component of sexual selection arises because females obtain viability benefits for their offspring from their mate choice. Females choosing extra-pair fertilization generally favor males with exaggerated secondary sexual characters, and extra-pair paternity increases the variance in male reproductive success. Furthermore, females are assumed to benefit from 'good genes' from extra-pair sires. How additive genetic variance in such viability genes is maintained despite strong directional selection remains an evolutionary enigma. We propose that sexual selection is associated with elevated mutation rates, changing the balance between mutation and selection, thereby increasing variance in fitness and hence the benefits to be obtained from good genes sexual selection. Two hypotheses may account for such elevated mutation: (1) Increased sperm production associated with sperm competition may increase mutation rate. (2) Mutator alleles increase mutation rates that are revealed by the expression of condition-dependent secondary sexual characters used by choosy females during their mate choice. M Petrie has independently developed the idea that mutator alleles may account for the maintenance of genetic variation in viability despite strong directional selection. RESULTS: A comparative study of birds revealed a positive correlation between mutation rate at minisatellite loci and extra-pair paternity, but not between mutation rate and relative testes mass which is a measure of relative sperm production. Minisatellite mutation rates were not related to longevity, suggesting a meiotic rather than a mitotic origin of mutations. CONCLUSION: We found evidence of increased mutation rate in species with more intense sexual selection. Increased mutation was not associated with increased sperm production, and we suggest that species with intense sexual selection may maintain elevated mutation rates because sexual selection continuously benefits viability alleles expressed in condition-dependent characters. Sexual selection may increase mutational input, which in turn feeds back on sexual selection because of increased variance in viability traits.

Animals↗
PubMed1987

Adaptation of Drosophila melanogaster populations to high mutation pressure: evolutionary adjustment of mutation rates.

Evolutionary aspects of high mutation pressure were studied in laboratory populations of Drosophila melanogaster that have irradiation histories up to 600 generations. Dose-response regressions for the x-ray induction of various types of mutation were obtained from six of these populations. The sensitivity of these irradiated populations relative to an unirradiated control population was characterized by dose reduction factors. Sensitivity decreased stepwise with the stepwise increase in irradiation levels to which the populations had been exposed every generation (0 R, 2 kR, 4 kR, 8 kR; 1 R = 0.258 mC/kg) but remained the same over hundreds of generations when the irradiation levels were constant. Resistance is controlled by single genetic factors. Additional factors evolved in subpopulations exposed to increased irradiation levels, and different factors evolved in populations that were kept separate from the beginning of their irradiation histories. Two of three factors persisted in subpopulations no longer irradiated, but one factor disappeared; this last one behaved like a transposon. Factors of relative radio-resistance are stage specific (immature oocytes) and some of them are assumed to modify or control mutation-rate genes. The resistance factors enable populations to achieve an equilibrium between the amounts of environmental mutagens and intrinsic mutation rates.

Adaptation, Physiological↗
PubMed2000

Determining mutation rates in bacterial populations.

When properly determined, spontaneous mutation rates are a more accurate and biologically meaningful reflection of underlying mutagenic mechanisms than are mutant frequencies. Because bacteria grow exponentially and mutations arise stochastically, methods to estimate mutation rates depend on theoretical models that describe the distribution of mutant numbers among parallel cultures, as in the original Luria-Delbr]uck fluctuation analysis. An accurate determination of mutation rate depends on understanding the strengths and limitations of these methods, and how to design fluctuation assays to optimize a given method. In this paper we describe a number of methods to estimate mutation rates, give brief accounts of their derivations, and discuss how they behave under various experimental conditions.

Bacteria↗
PubMed2002

Mutation at minisatellite locus DYF155S1: allele length mutation rate is affected by age of progenitor.

A father/son material consisting of 1071 pairs was screened for de novo allele length mutation in locus DYF155S1. Six hundred of these pairs were also analyzed in locus DYF155S1 to detect de novo mutations in the minisatellite variant repeat (MVR)-code not resulting in a length change ("boundary switch" mutations). A modified MVR-polymerase chain reaction (PCR) method was used for this purpose. Twenty-seven de novo allele length mutations and eight "boundary switch" mutations were detected indicating mutation frequencies of approximately 2.5% and 1.3%, respectively. The combined mutation rate for MVR-code mutation is approximately 3.8%. There is a significant increase in mutation rate with paternal age (p = 0.049) in allele length mutations. In the present material, the mutation rate in the oldest age group is three times that of the youngest age group. A similar age relationship is not observed in "boundary switch" mutations. A comparison between progenitors and the other fathers in the material revealed no obvious association between mutation rate and allele length or modular structure (variation in repeat sequence). More than 75% of the length mutations involved the gain or loss of one repeat only. This finding as well as the observed paternal age influence on mutation rate, suggests replication slippage to be the major mutation mechanism in length mutations. However, in one particular case, an allele length mutant revealed rearrangements with direct duplication of repeats at distant sites within the repeat array, and with both loss and gain of repeats. Such complex structural changes could indicate that some of the mutants might arise from sister chromatide exchange. The mutation rate of "boundary switch" mutations is by far higher than would be expected if these mutations are two independent one-step allele length mutations. A different age distribution of "boundary switch" mutations than of allele length mutations also argue against such a hypothesis. Together this could indicate that "boundary switches" are products of another mutation mechanism than the one-step allele length mutations.

Adult↗
PubMed1999

Beneficial mutations, hitchhiking and the evolution of mutation rates in sexual populations.

Natural selection acts in three ways on heritable variation for mutation rates. A modifier allele that increases the mutation rate is (i) disfavored due to association with deleterious mutations, but is also favored due to (ii) association with beneficial mutations and (iii) the reduced costs of lower fidelity replication. When a unique beneficial mutation arises and sweeps to fixation, genetic hitchhiking may cause a substantial change in the frequency of a modifier of mutation rate. In previous studies of the evolution of mutation rates in sexual populations, this effect has been underestimated. This article models the long-term effect of a series of such hitchhiking events and determines the resulting strength of indirect selection on the modifier. This is compared to the indirect selection due to deleterious mutations, when both types of mutations are randomly scattered over a given genetic map. Relative to an asexual population, increased levels of recombination reduce the effects of beneficial mutations more rapidly than those of deleterious mutations. However, the role of beneficial mutations in determining the evolutionarily stable mutation rate may still be significant if the function describing the cost of high-fidelity replication has a shallow gradient.

Alleles↗
PubMed1994

How variable is a spontaneous mutation rate in cultured mammalian cells?

The Luria-Delbrück fluctuation analysis provides a method to estimate mutation rates and is commonly applied in somatic cell genetics and in cancer biology. We developed an assay for a Luria-Delbrück fluctuation analysis using the mouse lymphoma cell line, GRSL13. As these cells grow in suspension, one can handle hundreds of parallel cultures using multiwell dishes and dispensers. This assay thereby allows not only an accurate determination of the mutation rate per cell generation but also makes it possible to determine at which time after seeding mutations take place. Using approx. 8000 parallel cultures it has been possible to test whether the mutation rate is constant during the assay. It has been found that the spontaneous mutation rate of GRSL13 cells decreases in the course of a fluctuation test from 2 x 10(-6) to about 2 x 10(-7)/cell/generation. It was shown that this increased replication fidelity may partly be caused by cell density: maintenance of cells at high cell density resulted in a spontaneous mutation rate of 0.7 +/- 4.0 x 10(-7) compared to 4.0 +/- 3.1 x 10(-7) for the standard protocol. In contrast, growing the cells at extremely low cell density resulted in an enhanced mutation rate of 7.7 +/- 1.3 x 10(-7). Thus altogether the mutation rate can vary from 2 x 10(-6) to 0.7 x 10(-7) (approx. 30-fold). These results show that the spontaneous mutation rate is not constant, but highly dependent on experimental conditions. As incomplete expression and metabolic cooperation cannot explain the findings, the data suggest that the fidelity of DNA replication is not fixed but open to variation. Hence, determination of replication infidelity in cultured cells needs rigorous standardization or/and application of controlled variation in culture conditions.

Animals↗
PubMed1992

5-Azacytidine and RNA secondary structure increase the retrovirus mutation rate.

A broad spectrum of mutations occurs at a high rate during a single round of retrovirus replication (V.K. Pathak and H. M. Temin, Proc. Natl. Acad. Sci. USA 87:6019-6023, 1990). We have now determined that this high rate of spontaneous mutation can be further increased by 5-azacytidine (AZC) treatment or by regions of potential RNA secondary structure. We found a 13-fold increase in the mutation rate after AZC treatment of retrovirus-producing cells and target cells. The AZC-induced substitutions were located at the same target sites as previously identified spontaneous substitutions. The concordance of the AZC-induced and spontaneous substitutions indicates the presence of reverse transcription "pause sites," where the growing point is error prone. An analysis of nucleotides that neighbored substitutions revealed that transversions occur primarily by transient template misalignment, whereas transitions occur primarily by misincorporation. We also introduced a 34-bp potential stem-loop structure as an in-frame insertion within a lacZ alpha gene that was inserted in the long terminal repeat (LTR) U3 region and determined whether this potential secondary structure increased the rate of retrovirus mutations. We found a threefold increase in the retrovirus mutation rate. Fifty-seven of 96 mutations were deletions associated with the potential stem-loop. We also determined that these deletion mutations occurred primarily during minus-strand DNA synthesis by comparing the frequencies of mutations in recovered provirus plasmids containing both LTRs and in provirus plasmids containing only one LTR.

Animals↗
PubMed1981

Mutation rates of structural chromosome rearrangements in man.

The gametic mutation rates of human structural chromosome rearrangements have been estimated from rearrangements ascertained from systematic surveys of live births and spontaneous abortions. The mutation rates for rearrangements that survive long enough to give rise to clinically recognized pregnancies are 2.20 X 10(-4) for balanced rearrangements, 3.54 X 10(-4) for unbalanced Robertsonian translocations, and 3.42 X 10(-4) for unbalanced non-Robertsonian rearrangements. These estimates give a mutation rate for all detectable structural chromosome rearrangements of approximately 1 X 10(-3). The most common single rearrangement, the Robertsonian translocation involving chromosomes 13 and 14, has a mutation rate of 1.5 X 10(-4).

Abortion, Spontaneous↗
PubMed2000

Determinants of substitution rates in mammalian genes: expression pattern affects selection intensity but not mutation rate.

To determine whether gene expression patterns affect mutation rates and/or selection intensity in mammalian genes, we studied the relationships between substitution rates and tissue distribution of gene expression. For this purpose, we analyzed 2,400 human/rodent and 834 mouse/rat orthologous genes, and we measured (using expressed sequence tag data) their expression patterns in 19 tissues from three development states. We show that substitution rates at nonsynonymous sites are strongly negatively correlated with tissue distribution breadth: almost threefold lower in ubiquitous than in tissue-specific genes. Nonsynonymous substitution rates also vary considerably according to the tissues: the average rate is twofold lower in brain-, muscle-, retina- and neuron-specific genes than in lymphocyte-, lung-, and liver-specific genes. Interestingly, 5' and 3' untranslated regions (UTRs) show exactly the same trend. These results demonstrate that the expression pattern is an essential factor in determining the selective pressure on functional sites in both coding and noncoding regions. Conversely, silent substitution rates do not vary with expression pattern, even in ubiquitously expressed genes. This latter result thus suggests that synonymous codon usage is not constrained by selection in mammals. Furthermore, this result also indicates that there is no reduction of mutation rates in genes expressed in the germ line, contrary to what had been hypothesized based on the fact that transcribed DNA is more efficiently repaired than nontranscribed DNA.

Animals↗
PubMed2000

3'-Azido-3'-deoxythymidine (AZT) and AZT-resistant reverse transcriptase can increase the in vivo mutation rate of human immunodeficiency virus type 1.

How antiretroviral drug resistance influences human immunodeficiency virus type 1 (HIV-1) evolution is not clear. This study tested the hypothesis that antiretroviral drugs such as 3'-azido-3'-deoxythymidine (AZT) can influence the in vivo mutation rate of HIV-1. It was observed that AZT can increase the rate of HIV-1 mutation by a factor of 7 in a single round of replication. In addition, (-)2',3'-dideoxy-3'-thiacytidine (3TC) was also found to increase the mutation rate of HIV-1 by a factor of 3. It was also found that HIV-1 drug-resistant reverse transcriptase (RT) variants can influence the in vivo mutation rate. Replication of HIV-1 with AZT-resistant RTs increased the mutation rate by as much as a factor of 3, while replication of HIV-1 with a 3TC-resistant RT (M184V) had no significant effect on the mutation rate. It was observed that only high-level, AZT-resistant RT variants could influence the in vivo mutation rate (i.e., M41L/T215Y and M41L/D67N/K70R/T215Y). In total, these observations indicate that both antiretroviral drugs and drug resistance mutations can influence the in vivo mutation rate of HIV-1.

Animals↗