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PubMed1982

Histocompatibility gene mutation rates, spontaneous and induced by the chemical mutagen procarbazine.

The use of histocompatibility mutations in mice for the development of a mutagenicity test has been proposed by several immunologists. The aim of our work was to find a basis for the establishment of the H-test as a mutagenicity test. We therefore determined the spontaneous mutation rates of H-genes in the two inbred mouse strains C3H and C57Bl. Furthermore, we tried to increase the mutation rate by the well-known chemical mutagen procarbazine. The spontaneous mutation rates of H-genes of both strains were identical at about 1.2 x 10(-3). After long-term mutagen treatment with 100 mg procarbazine/kg per week, the mutant frequency increased to about 7% and decreased again when the total dose had reached more than 9 x 100 mg/kg in C57Bl mice and more than 14 x 100 mg/kg in C3H mice. These results are discussed in comparison with procarbazine experiments with other mutagenicity test systems. The feasibility of the H-test for mutagenicity testing remains to be verified by further experiments with other germ-line mutagens.

Animals↗
PubMed1999

Synonymous nucleotide divergence and saturation: effects of site-specific variations in codon bias and mutation rates.

The synonymous divergence between Escherichia coli and Salmonella typhimurium is explained in a model where there is a large variation between mutation rates at different nucleotide sites in the genome. The model is based on the experimental observation that spontaneous mutation rates can vary over several orders of magnitude at different sites in a gene. Such site-specific variation must be taken into account when studying synonymous divergence and will result in an apparent saturation below the level expected from an assumption of uniform rates. Recently, it has been suggested that codon preference in enterobacteria has a very large site-specific variation and that the synonymous divergence between different species, e.g., E. coli and Salmonella, is saturated. In the present communication it is shown that when site-specific variation in mutation rates is introduced, there is no need to invoke assumptions of saturation and a large variability in codon preference. The same rate variation will also bring average mutation rates as estimated from synonymous sequence divergence into numerical agreement with experimental values.

Codon↗
PubMed1978

Mutation rates from rare variants of proteins in Indian tribes.

Recent attempts to estimate mutation rates in man have resulted in some theoretical developments. Recently, Nei (1977) provided a new formula for estimating mutation rates from electrophoretically detected rare protein variants. His formula is applied here to estimated mutation rates from such variants among the Kadars of Kerala and five tribes of Andhra Pradesh in India. The estimates seem to differ from Nei's estimate on South American Indians by an order of magnitude, although the standard errors associated with such estimates are rather large.

Ethnicity↗
PubMed1990

Spontaneous mutation rate in retinoblastoma.

A novel approach was used to estimate the in vivo mutation rate of the retinoblastoma gene. A mathematical formula can be used to calculate the probability of neoplasia induced by one or more mutations in a population of dividing cells. This formula can then be applied to epidemiological data on hereditary and sporadic retinoblastoma. The analysis yields an estimate of the in vivo mutation rate of 8 x 10(-8)/gene/cell division (range 5.5 x 10(-8) to 1.3 x 10(-7]. The estimated non-replication association in vivo mutation rate is 2.4 x 10(-8)/gene/year (range 0 to 6.8 x 10(-8]. The formula is an improvement on previous attempts to produce a model of the process of mutation during cell generation. It can be applied to neoplastic disease in both children and adults.

Adult↗
PubMed2000

Estimation of microsatellite mutation rates in Drosophila melanogaster.

Microsatellite mutations were studied in a set of 175 mutation accumulation lines, all of them independently derived from a completely homozygous population of Drosophila melanogaster and maintained under strong inbreeding during 80 generations. We assayed 28 microsatellites and detected two mutations. One mutation consisted of a single addition of a dinucleotide repeat and the other was a deletion of five trinucleotide repeats. The average mutation rate was 5.1 x 10(-6), in full agreement with previous estimates from two different sets of mutation accumulation lines.

Animals↗
PubMed1988

Somatic and germ-line reverse mutation rates of the retrovirus-induced dilute coat-color mutation of DBA mice.

At present, the dilute (dv) coat-color mutation of DBA mice provides the only simple means for measuring the relative somatic and germ-line reverse mutation rates of retrovirus-induced mutations in mammals. The dv mutation was generated by the spontaneous integration of an ecotropic murine leukemia virus into noncoding sequences of the dilute locus. Reversion of the dv mutation occurs by provirus excision and is mediated by homologous recombination events involving the viral long terminal repeat sequences. Although numerous independent germ-line d+ revertants have been identified, somatic d+ revertants have not been reported previously. During the past 5 years, we have screened more than one million mice homozygous for the dv mutation to determine whether we could identify somatic d+ revertants. This survey has resulted in the identification of a somatic d+ revertant and has provided a data base from which we can estimate the relative somatic and germ-line excision frequencies of retroviruses in mice and speculate about the nature of homologous recombination events producing d+ revertant alleles.

Animals↗
PubMed1976

Infinite allele model with varying mutation rate.

Available data suggest that the variation in mutation rate among protein loci follows the gamma distribution. Thus, taking into account this variation, formulae are developed for the distribution of allele frequencies, mean and variance of heterozygosity, expected number of alleles, proportion of polymorphic loci, and genetic distance. These formulae should be more appropriate for the analysis of gene frequency data for protein loci than equivalent formulae with constant mutation rate.

Alleles↗
PubMed2006

Low abundance of Escherichia coli microsatellites is associated with an extremely low mutation rate.

It is widely assumed that microsatellites are generated by replication slippage, a mutation process specific to repetitive DNA. Consistent with their high mutation rate, microsatellites are highly abundant in most eukaryotic genomes. In Escherichia coli, however, microsatellites are rare and short despite the fact that a high microsatellite mutation rate was described. We show that this high microsatellite instability depends on the presence of the F-plasmid. E. coli cells lacking the F-plasmid have extremely low microsatellite mutation rates. This result provides a possible explanation for the genome-wide low density of microsatellites in E. coli. Furthermore, we show that the F-plasmid induced microsatellite instability is independent of the mismatch repair pathway.

Conjugation, Genetic↗
PubMed2001

Somatic mutation rate of the APC gene.

BACKGROUND: Somatic inactivation of the wild-type APC gene is involved in the development of adenoma of familial adenomatous polyposis. This situation is also true in sporadic adenomas. It is of biological interest to know the somatic mutation rate of the APC gene. METHODS: The number of stem cells of the colon (N) and somatic mutation rate of the APC gene in a stem cell in a year (m) can induce age-specific incidence of adenomas. The number of stem cells was estimated as 10(8) according to previous reports. In the general population, expected adenomas at the end of age n years will be approximately Nm2n2/4. In patients with polyposis, the expected number of adenomas will be Nmn/2. By setting several figures for m, the expected incidence of adenomas was compared with the actual occurrences. RESULTS: If the mutation rate was set between 2/10(6) and 3/10(6) mutations/stem cell/year, the calculated numbers were well fitted to the actual data. Expected adenomas in polyposis patients at the age of 20 and 40 years were 2000 and 4000 and these were within actual experiences. CONCLUSIONS: This is the first study to estimate the somatic mutation rate of the APC gene. The estimated somatic mutation rate of the APC gene was between 2/10(6) and 3/10(6) mutations/stem cell/year.

Adenoma↗
PubMed1999

High genomic deleterious mutation rates in hominids.

It has been suggested that humans may suffer a high genomic deleterious mutation rate. Here we test this hypothesis by applying a variant of a molecular approach to estimate the deleterious mutation rate in hominids from the level of selective constraint in DNA sequences. Under conservative assumptions, we estimate that an average of 4.2 amino-acid-altering mutations per diploid per generation have occurred in the human lineage since humans separated from chimpanzees. Of these mutations, we estimate that at least 38% have been eliminated by natural selection, indicating that there have been more than 1.6 new deleterious mutations per diploid genome per generation. Thus, the deleterious mutation rate specific to protein-coding sequences alone is close to the upper limit tolerable by a species such as humans that has a low reproductive rate, indicating that the effects of deleterious mutations may have combined synergistically. Furthermore, the level of selective constraint in hominid protein-coding sequences is atypically low. A large number of slightly deleterious mutations may therefore have become fixed in hominid lineages.

Animals↗
PubMed1979

Mutation rates, population sizes and amounts of electrophoretic variation of enzyme loci in natural populations.

A method is presented for estimating relative mutation rates or relative effective population sizes, under the hypothesis of adaptively neutral allelic variation. This method was applied to seven surveys of electrophoretic variation. It was observed that electrophoretic mutation rates so obtained follow the gamma distribution and, in Drosophila, are positively correlated with the molecular weights of the enzymes subunits. The variance in mutation rate is larger under the step-wise model of electrophoretic mutation than under the infinite-alleles model. Rates for the most variable loci may exceed rates for less variable loci by a factor of 500. For completely invariant loci, this factor may be as high as 4 X 10(4), an observation suggesting that these loci are subject to purifying selection. In contrast to mutation rates, effective population sizes may vary at the most by a factor of ten. These results support the hypothesis that differences in the amount of electrophoretic variability among polymorphic loci may reflect differences in the rate by which electrophoretically detectable variation is generated in population.

Animals↗
PubMed2002

Coevolution of quasispecies: B-cell mutation rates maximize viral error catastrophes.

Coevolution of two coupled quasispecies is studied, motivated by the competition between viral evolution and adapting immune response. In this coadaptive model, besides the classical error catastrophe for high virus mutation rates, a second "adaptation" catastrophe occurs, when virus mutation rates are too small to escape immune attack. Maximizing both regimes of viral error catastrophes is a possible strategy for an optimal immune response, reducing the range of allowed viral mutation rates to a minimum. From this requirement, one obtains constraints on B-cell mutation rates and receptor lengths, yielding an estimate of somatic hypermutation rates in the germinal center in accordance with observation.

Animals↗
PubMed1996

Estimation of mutation rates from parentage exclusion data: applications to STR and VNTR loci.

Nonpaternity is a common source of bias in estimating mutation rates when they are obtained from family data showing discordance of parental and children's genotypes. With the availability of hypervariable DNA markers, this source of bias can be largely eliminated. However, the proportion of cases where parentage exclusion is caused by presumed mutation(s) of parental alleles must be adjusted to obtain a valid mutation rate estimate. The present work derives the basis of this adjustment factor, called the proportional bias. This proportional bias depends upon the allele frequency distribution at the locus. The maximum and minimum bounds of the proportional bias depend on the number of alleles at the locus. Using data from Caucasian populations at tandem repeat loci commonly used for parentage testing and forensic identification purposes, we show that when mutation rates are estimated at these loci, the proportional bias is generally very close to the maximum possible value for the observed number of alleles (or binned fragment sizes) at each locus. The expected proportional bias decreases with increasing mutation rate at a locus. For the short tandem repeat loci, without bias correction, the direct count method can result in an underestimation of up to 60% of their true value. In contrast, for the minisatellite VNTR loci, even with crude measurements on allele sizes, we show that the absolute proportional bias is generally below the coefficient of variation of the direct estimates.

Chromosome Mapping↗
PubMed2001

Mutation rates in the dihydrofolate reductase gene of Plasmodium falciparum.

A new method has been established to define the limits on a spontaneous mutation rate for a gene in Plasmodium falciparum. The method combines mathematical modelling and large-scale in vitro culturing and calculates the difference in mutant frequencies at 2 separate time-points. We measured the mutation rate at 2 positions in the dihydrofolate reductase (DHFR) gene of 3D7, a pyrimethamine-sensitive line of P. falciparum. This line was re-cloned and an effectively large population was treated with a selective pyrimethamine concentration of 40 nM. We detected point mutations at codon-46 (TTA to TCA) and codon-108 (AGC to AAC), resulting in serine replacing leucine and asparagine replacing serine respectively in the corresponding gene product. The substitutions caused a decrease in pyrimethamine sensitivity. By mathematical modelling we determined that the mutation rate at a given position in DHFR was low and occurred at less than 2.5 x 10(-9) mutations/DHFR gene/replication. This result has important implications for Plasmodium genetic diversity and antimalarial drug therapy by demonstrating that even with low mutation rates anti-malarial resistance will inevitably arise when mutant alleles are selected under drug pressure.

Amino Acid Substitution↗
PubMed2005

Conditional coalescent trees with two mutation rates and their application to genomic instability.

Humans have invested several genes in DNA repair and fidelity replication. To account for the disparity between the rarity of mutations in normal cells and the large number of mutations present in cancer, an hypothesis is that cancer cells must exhibit a mutator phenotype (genomic instability) during tumor progression, with the initiation of abnormal mutation rates caused by the loss of mismatch repair. In this study we introduce a stochastic model of mutation in tumor cells with the aim of estimating the amount of genomic instability due to the alteration of DNA repair genes. Our approach took into account the difficulties generated by sampling within tumoral clones and the fact that these clones must be difficult to isolate. We provide corrections to two classical statistics to obtain unbiased estimators of the raised mutation rate, and we show that large statistical errors may be associated with such estimators. The power of these new statistics to reject genomic instability is assessed and proved to increase with the intensity of mutation rates. In addition, we show that genomic instability cannot be detected unless the raised mutation rates exceed the normal rates by a factor of at least 1000.

Computational Biology↗
PubMed1984

Specific-locus mutation rates in the mouse following inhalation of ethylene oxide, and application of the results to estimation of human genetic risk.

Male (101 X C3H)F1 mice were exposed in an inhalation chamber to ethylene oxide (EtO) in air at a concentration of (generally) 255 ppm. After accumulating total exposures of 101 000 or 150 000 ppm.h in 16-23 weeks, the males were mated to T-stock females for a standard specific-locus mutation-rate study in which 71387 offspring were observed. The spermatogonial stem-cell mutation rate at each exposure level, as well as the combined result, does not differ significantly from the historical control frequency. At the lower and higher exposure levels, the results rule out (at the 5% significance level) an induced frequency that is, respectively, 0.97 and 6.33 times the spontaneous rate; the combined results rule out a multiple of 1.64. The relationship between mouse spermatogonial stem-cell mutation rates and EtO-induced testis ethylations was compared with the relationship between Drosophila post-stem-cell mutation rates and sperm ethylations (Lee, 1980). The comparison does not rule out equal mutability per ethylation; but it cannot prove parallelism. An assessment of the mouse-Drosophila relationship will require a more efficient alkylator than EtO and the use of comparable germ-cell stages. More meaningful conclusions may be drawn by utilizing the data for direct estimation of human risk by expressing the induced mutation frequency that is ruled out (at the 5% significance level) as a multiple of control rate and extrapolating to human exposure levels. The probable absence of major stem-cell killing (and thus, possibly, cell selection) by EtO indicates that such extrapolation probably does not produce an underestimate. For a human exposure concentration of 0.1 ppm on working days during the reproductive lifespan, the mouse experimental results rule out (at the 5% significance level) an induced spermatogonial stem-cell gene mutation rate greater than 8% of the spontaneous rate; for 1.0 ppm, they rule out an induced rate roughly equal to the spontaneous rate. The induced rate for any one poststem-cell stage would have to be about 3 orders of magnitude higher than that for stem cells to constitute an equivalent risk.

Animals↗
PubMed1998

The mutation rates of di-, tri- and tetranucleotide repeats in Drosophila melanogaster.

In a recent study, we reported that the combined average mutation rate of 10 di-, 6 tri-, and 8 tetranucleotide repeats in Drosophila melanogaster was 6.3 x 10(-6) mutations per locus per generation, a rate substantially below that of microsatellite repeat units in mammals studied to date (range = 10(-2)-10(-5) per locus per generation). To obtain a more precise estimate of mutation rate for dinucleotide repeat motifs alone, we assayed 39 new dinucleotide repeat microsatellite loci in the mutation accumulation lines from our earlier study. Our estimate of mutation rate for a total of 49 dinucleotide repeats is 9.3 x 10(-6) per locus per generation, only slightly higher than the estimate from our earlier study. We also estimated the relative difference in microsatellite mutation rate among di-, tri-, and tetranucleotide repeats in the genome of D. melanogaster using a method based on population variation, and we found that tri- and tetranucleotide repeats mutate at rates 6.4 and 8.4 times slower than that of dinucleotide repeats, respectively. The slower mutation rates of tri- and tetranucleotide repeats appear to be associated with a relatively short repeat unit length of these repeat motifs in the genome of D. melanogaster. A positive correlation between repeat unit length and allelic variation suggests that mutation rate increases as the repeat unit lengths of microsatellites increase.

Africa↗