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At least 379 records · Page 21Linked to original sources
PubMed1977

Spontaneous mutation rates at enzyme loci in Drosophila melanogaster.

In a marked-inversion-balanced lethal system mutations were accumulated at a minimum pressure of natural selection on 2000 second chromosomes of Drosophila melanogaster that originated from 4 stem chromosomes. Five enzyme loci were tested: alpha-glycerol-3-phosphate dehydrogenase (EC 1.1.1.8), malate dehydrogenase (Mdh, EC 1.1.1.37), alcohol dehydrogenase (EC 1.1.1.1), hexokinase-C (Hex-C tentative name), and alpha-amylase (Amy, EC 3.2.1.1). Three band-morph mutants, one at the Mdh locus, one at the Hex-C locus, and one at the Amy locus, were detected out of 1,658,308 allele replications. In addition, 17 null mutants were found. Accepting that the number of structural genes is the same as that of bands in the salivary gland chromosomes, the total mutation rate per generation for all the structural genes in the second chromosomes is estimated to be 0.008-0.040, which is much smaller than that estimated for viability polygenes (0.12-0.17). Thus, it is speculated that most viability and other fitness polygenes are located in controlling regions outside the structural genes.

Alcohol Oxidoreductases↗
PubMed1991

Transient mutators: a semiquantitative analysis of the influence of translation and transcription errors on mutation rates.

A population of bacteria growing in a nonlimiting medium includes mutator bacteria and transient mutators defined as wild-type bacteria which, due to occasional transcription or translation errors, display a mutator phenotype. A semiquantitative theoretical analysis of the steady-state composition of an Escherichia coli population suggests that true strong genotypic mutators produce about 3 x 10(-3) of the single mutations arising in the population, while transient mutators produce at least 10% of the single mutations and more than 95% of the simultaneous double mutations. Numbers of mismatch repair proteins inherited by the offspring, proportions of lethal mutations and mortality rates are among the main parameters that influence the steady-state composition of the population. These results have implications for the experimental manipulation of mutation rates and the evolutionary fixation of frequent but nearly neutral mutations (e.g., synonymous codon substitutions).

Bacteria↗
PubMed1990

Spontaneous mutation rates in mammalian cells: effect of differential growth rates and phenotypic lag.

We calculated a spontaneous rate of 26-37 x 10(-6) mutations per cell division for L5178Y MOLY (mouse lymphoma) cells at the thymidine kinase locus (tk+/(-)----tk-/-) using a procedure that isolated and segregated cells during expression. This rate was 50 times higher than when cells expressed the mutant phenotype in suspension. The higher mutation rates obtained with the in situ procedure suggest that many of the mutants, whether expressed or unexpressed, grew more slowly than wild-type cells prior to selection with trifluorothymidine (TFT), implying that the slow growth phenotype is expressed earlier than the TFTr (TFT-resistant) phenotype. The loss of mutants was not restricted to cells forming small colonies; the mutation rate for cells forming large colonies was more than ten times higher using the in situ procedure. In this new procedure, the cells expressed spontaneous mutations while growing in semisolid medium for up to 3 days without TFT. Mutants were then selected in situ by adding an overlay of TFT and the visible colonies were analyzed after 11 days. Cells with spontaneous mutations at the tk locus required approximately 30 hr for the more rapidly expressing cells with new mutations to be detected. Most of the TFTr colonies selected after 60 hr of growth in semisolid medium represented independent mutations that had accumulated during the first 30 hr.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1979

The CAN1 locus of Saccharomyces cerevisiae: fine-structure analysis and forward mutation rates.

A system of strains and growth media was developed to allow efficient detection of forward mutation, reversion, complementation, and suppression at the canavanine-resistance (CAN1) locus of Saccharomyces cerevisiae. Genetic fine-structure analysis revealed that the map length is at least 40, and possibly as much as 60 X-ray map units; this is the longest gene map yet reported in S. cerevisiae. Allelic complementation was not observed, despite testing of a large number of allele pairs, and alleles suppressible by the ochre suppressor SUP11 were absent from a sample of 48 spontaneous mutants and occurred infrequently (7%) among a sample of ultraviolet-induced mutants. Infrequent mutant types included canavanine-resistant mutants capable of arginine uptake and alleles thought to represent deletions or inversions. In contrast to previous reports in the literature, the spontaneous forward mutation rate at CAN1 did not increase during meiosis.

Alleles↗
PubMed1991

Variations in polymer fitness at elevated mutation rates.

Two series expressions were obtained that give the first and second order rates of change in population fitness during competitive replication at elevated mutation rates. At their zero-error limit, the respective power series reduces to the second (Fisher's theorem) and third moments of the fitness distribution. The first series maximized the variation in mean polymer fitness, for a given amount of population covariance. From experimental results reported by Spiegelman's group on evolution in vitro among Q beta RNA variants, it was demonstrated: (i) terms in the (second) series fall-off at a rate broadly equal to the replicase error (epsilon congruent to 10(-4); (ii) the rate of change in mean RNA fitness (polymer formation rate constant) corresponds to the variance in fitness; and (iii) agreement exists between second order rate changes in fitness and the third moment (skewness) regression line, extending over 20 successive replication reactions. The impact of these findings on the standard model of evolution has been discussed.

Biological Evolution↗
PubMed2006

Robustness of coalescent estimators to between-lineage mutation rate variation.

Data from HIV and from human neoplastic cells can show substantial between-lineage mutation rate variation even within a single population. Such variation may affect estimators of population quantities such as Theta = 4N(e)mu. Using simulated DNA data, I measured the effect of rate variation on recovery of Theta by the summary-statistic estimator of Watterson (Watterson GA. 1975. On the number of segregating sites in genetical systems without recombination. Theor Popul Biol. 7:256-276) and the coalescent maximum likelihood algorithm LAMARC (Kuhner MK. 2006. LAMARC 2.0: maximum likelihood and Bayesian estimation of population parameters. Bioinformatics. Advance Access doi: 10.1093/bioinformatics/btk051). Watterson's estimator showed a downward bias, as expected, with high values of Theta. LAMARC's mean estimate was accurate for all tested values of Theta and rate variation except for a downward bias when rate variation was maximal (i.e., the slow rate was zero). LAMARC had consistently narrower confidence intervals (CIs) than Watterson's estimator. Both methods tended to reject the truth too often when rate variation was 8x or greater and independent among branches, as well as when variation was 4x or greater and correlated among branches. In the case of Watterson's estimate, this excess rejection was fully attributable to variation among genealogies in the amount of total branch length associated with the fast and slow rates. However, in the case of LAMARC, some excess rejection was still observed even when between-genealogy variation was taken into account. Both estimators are robust to modest rate variation; however, their use should be coupled with a statistical test to rule out extreme rate variation as the resulting CIs may not be reliable.

Algorithms↗
PubMed1996

Effects of track structure and cell inactivation on the calculation of heavy ion mutation rates in mammalian cells.

It has long been suggested that inactivation severely effects the probability of mutation by heavy ions in mammalian cells. Heavy ions have observed cross sections of inactivation that approach and sometimes exceed the geometric size of the cell nucleus in mammalian cells. In the track structure model of Katz the inactivation cross section is found by summing an inactivation probability over all impact parameters from the ion to the sensitive sites within the cell nucleus. The inactivation probability is evaluated using the dose-response of the system to gamma-rays and the radial dose of the ions and may be equal to unity at small impact parameters for some ions. We show how the effects of inactivation may be taken into account in the evaluation of the mutation cross sections from heavy ions in the track structure model through correlation of sites for gene mutation and cell inactivation. The model is fit to available data for HPRT mutations in Chinese hamster cells and good agreement is found. The resulting calculations qualitatively show that mutation cross sections for heavy ions display minima at velocities where inactivation cross sections display maxima. Also, calculations show the high probability of mutation by relativistic heavy ions due to the radial extension of ions track from delta-rays in agreement with the microlesion concept. The effects of inactivation on mutations rates make it very unlikely that a single parameter such as LET or Z*2/beta(2) can be used to specify radiation quality for heavy ion bombardment.

Animals↗
PubMed2004

Mutation rate at commonly used forensic STR loci: paternity testing experience.

Paternity tests are carried out by the analysis of hypervariable short tandem repeat DNA loci. These microsatellite sequences mutate at a higher rate than that of bulk DNA. The occurrence of germline mutations at STR loci posses problems in interpretation of resulting genetic profiles. We recently analyzed 59-159 parent/child allele transfers at 13 microsatellite loci. We identified 12 mutations in 7 microsatellite loci. No mutations were occurred in other 6 loci. The highest mutation rate was observed with 5 mutations at D8S1179 locus at different alleles. The event was always single repeat related. The mutation rate was between 0 and 1.5 x 10(-2) per locus per gamete per generation. The mutation event is very crucial for forensic DNA testing and accumulation of STR mutation data is extremely important for genetic profile interpretation.

Alleles↗
PubMed2006

Difference between evolutionarily effective and germ line mutation rate due to stochastically varying haplogroup size.

Within a Y-chromosome haplogroup defined by unique event mutations, variation in microsatellites can accumulate due to their rapid mutation. Estimates based on pedigrees for the Y-chromosome microsatellite mutation rate are 3 or more times greater than the same estimates from evolutionary considerations. We show by simulation that the haplogroups that survive the stochastic processes of drift and extinction accumulate microsatellite variation at a lower rate than predicted from corresponding pedigree estimates; in particular, under constant total population size, the accumulated variance is on average 3-4 times smaller.

Chromosomes, Human, Y↗
PubMed2001

Microsatellite mutation rates are equivalent in normal and telomerase-immortalized human fibroblasts.

Telomerase-expressing human fibroblasts generally have the same properties as normal cells, except that they have an indefinite life span in culture. We have introduced a dinucleotide repeat sequence into the telomerase-expressing hTERT-1604 cell line and characterized the rates and types of frameshift mutations within this microsatellite. These data have been compared with those in diploid fibroblasts with a finite life span. The rates of mutation were found to be similar in the two cell types, indicating that DNA mismatch repair and other cellular processes responsible for maintenance of mutational stability are not disrupted by telomerase immortalization.

Cell Line, Transformed↗
PubMed1997

The effect of cryopreservation on the lethal mutation rate in Drosophila melanogaster.

Although cryopreservation is routinely used for the storage of a range of biological organisms, few studies have been conducted to determine whether cryopreservation increases the frequency of mutation. A procedure for the cryopreservation of Drosophila melanogaster embryos has recently been developed. Cryopreservation of D. melanogaster is of special interest to geneticists and evolutionary biologists because it would make it possible to assay control and experimental populations simultaneously during long-term studies. Before cryopreserved embryos can be used for such studies, it is first necessary to show that cryopreservation is not mutagenic. We tested for mutagenic effects or cryopreservation in D. melanogaster embryos with an X-linked, recessive lethal assay. The mutation rates of cryopreserved and control flies were not significantly different. We can be 95% certain that cryopreservation does not increase mutation by a factor greater than 2.39. This is the first quantitative estimate of the mutagenic effect of cryopreservation on the germ line of a metazoan. The results are reassuring when considering the genetic impact of cryopreservation on mammalian gametes and embryos.

Animals↗
PubMed1977

A new estimate of the achondroplasia mutation rate.

An estimate is derived of the mutation of achondroplasia based upon the accumulated data of recent newborn studies in four cities. In a total of 242,257 births, seven infants had mutant achondroplasia, the diagnosis being confirmed radiologically in all but one. From this, the rate of mutation of the normal to the achondroplasia allele is calculated to be 1.4 x 10(-5) +/- standard error 0.5 x 10(-5). Certain shortcomings of this estimate are discussed.

Achondroplasia↗
PubMed2001

Measurement of mutational flow implies both a high new-mutation rate for Huntington disease and substantial underascertainment of late-onset cases.

We describe a new approach for analysis of the epidemiology of progressive genetic disorders that quantifies the rate of progression of the disease in the population by measuring the mutational flow. The framework is applied to Huntington disease (HD), a dominant neurological disorder caused by the expansion of a CAG-trinucleotide sequence to >35 repeats. The disease is 100% penetrant in individuals with > or = 42 repeats. Measurement of the flow from disease alleles provides a minimum estimate of the flow in the whole population and implies that the new mutation rate for HD in each generation is > or = 10% of currently known cases (95% confidence limits 6%-14%). Analysis of the pattern of flow demonstrates systematic underascertainment for repeat lengths <44. Ascertainment falls to <50% for individuals with 40 repeats and to <5% for individuals with 36-38 repeats. Clinicians should not assume that HD is rare outside known pedigrees or that most cases have onset at age <50 years.

Adolescent↗
PubMed2000

Virulence and mutation rates of Salmonella typhimurium strains with increased mutagenic strength in a mouse model.

Two strains of Salmonella typhimurium presenting increased mutation rates, either spontaneous or mediated by DNA damage, have been constructed. One of the strains carries a null mutS mutation, while the other harbors plasmid pRW30, which contains the Escherichia coli umuDC operon. The virulence of these strains has been determined by inoculating BALB/c or Swiss mice. The 50% lethal dose of both strains is identical to that obtained for the wild-type. Likewise, the two strains and the wild-type contribute equally to animal death in mixed infections. The frequency of Nal(R) mutants recovered from animals inoculated with either wild-type or MutS(-) cells was not affected by the presence of pRW30. These results indicate that the DNA damage which S. typhimurium cells can suffer during the infectious process by host cell metabolites does not cause induction of the SOS response at levels able to trigger the error-prone DNA repair pathway.

Adenosine Triphosphatases↗
PubMed1981

DNA polymerase accuracy and spontaneous mutation rates: frequencies of purine.purine, purine.pyrimidine, and pyrimidine.pyrimidine mismatches during DNA replication.

DNA from the am16 mutant of bacteriophage phi X174 may be replicated in vitro and expressed in vivo to give five classes of revertants. Each class may be specifically induced by the appropriate biasing of the concentrations of deoxynucleoside triphosphates in a predictable manner. The frequency of each reversion follows a kinetic rate equation relating it to the concentrations of the triphosphates involved in the substitution. The reversions corresponding to TAG leads to GAG, AAG, CAG, TGG, and TCG are calculated to occur with frequencies of 5 X 10(-7), 4 X 10(-7), 4 X 10(-7), approximately 2 X 10(-7), and approximately 5 X 10(-9), respectively, at the concentration of triphosphates found in vivo. The frequencies are in the range found for the reversion of the phage in vivo and so are consistent with errors in nucleotide selection by DNA polymerase (deoxynucleosidetriphosphate:DNA deoxynucleotidyltransferase, EC 2.7.7.7) III being largely responsible for the rate of spontaneous mutation in vivo. The relative frequency of mispairing leading to misincorporation is: purine.purine approximately purine.pyrimidine much greater than pyrimidine.pyrimidine, confirming predictions from model-building studies that transversions arise through purine.purine mismatches.

Bacteriophage phi X 174↗
PubMed1981

Mutation rates for unbalanced Robertsonian translocations associated with Down syndrome. Evidence for a temporal change in New York State live births 1968--1977.

The mutation rate for translocation Down syndrome was investigated for New York State live births for each of the years 1968--1977 using data from the New York State Chromosome Registry. The overall rate was 2.5 X 10(-5) per gamete (1.4 X 10(-5) for G/21 and 1.0 X 10(-5) for D/21 rearrangements), about 20% higher than rates previously reported by two other studies. For the first 5-year period, 1968--1972, the rate was 1.8 X 10(-5), and for the second 5-year period, 3.1 X 10(-5); there was an abrupt change in 1973 and 1974 to rates more than twice that in the 3 preceding years. These rates were derived by applying completeness estimates for all cases of Down syndrome, mostly 47,trisomy 21, in the jurisdiction to cases with translocation Down syndrome mutations. If completeness corrections are ignored and only the minimum boundaries of rates are considered, however, the increase in 1973 and 1974 was even greater compared with the previous 3 years. The trends, if not attributable to an undetected artifact, may have been caused by an increased frequency of mutant zygotes and/or enhanced intrauterine survival of mutant translocations.

Down Syndrome↗