Showing papers on "Mutation rate published in 1979"

A mathematic model for relating the drug sensitivity of tumors to their spontaneous mutation rate.

Abstract: A mathematic model has been developed relating the drug sensitivity of a tumor to its own spontaneous mutation rate towards phenotypic drug resistance. The proportion as well as the absolute numbers of resistant cells will increase with time and the fraction of resistant cells within tumor colonies of the same size with vary depending on whether mutation occurs as an early or late event. Analysis of the model indicates that the probability of the appearance of a resistant phenotype increases with the mutation rate. Furthermore, for any population of tumors with a non-zero mutation rate the likelihood of there being at least one resistant cell will go from a condition of low to high probability over a very short interval in the tumor's biologic history.

Model of effectively neutral mutations in which selective constraint is incorporated

Abstract: Based on the idea that selective neutrality is the limit when the selective disadvantage becomes indefinitely small, a model of neutral (and nearly neutral) mutations is proposed that assumes that the selection coefficient (s′) against the mutant at various sites within a cistron (gene) follows a Γ distribution; f(s′) = αβe-αs′s′β-1/Γ(β), in which α = β/¯s′ and ¯s′ is the mean selection coefficient against the mutants (¯s′ > 0; 1 [unk] β > 0). The mutation rate for alleles whose selection coefficients s′ lie in the range between 0 and 1/(2Ne), in which Ne is the effective population size, is termed the effectively neutral mutation rate (denoted by ve). Using the model of “infinite sites” in population genetics, formulas are derived giving the average heterozygosity (¯he) and evolutionary rate per generation (kg) in terms of mutant substitutions. It is shown that, with parameter values such as β = 0.5 and ¯s′ = 0.001, the average heterozygosity increases much more slowly as Ne increases, compared with the case in which a constant fraction of mutations are neutral. Furthermore, the rate of evolution per year (k1) becomes constant among various organisms, if the generation span (g) in years is inversely proportional to √Ne among them and if the mutation rate per generation is constant. Also, it is shown that we have roughly kg = ve. The situation becomes quite different if slightly advantageous mutations occur at a constant rate independent of environmental conditions. In this case, the evolutionary rate can become enormously higher in a species with a very large population size than in a species with a small population size, contrary to the observed pattern of evolution at the molecular level.

Efficiency of truncation selection.

Abstract: Truncation selection is known to be the most efficient form of directional selection. When this is modified so that the fitness increases linearly over a range of one or two standard deviations of the value of the selected character, the efficiency is reduced, but not greatly. When truncation selection is compared to a system in which fitness is strictly proportional to the character value, the relative efficiency of truncation selection is given by f(c)/σ, in which f(c) is the ordinate of the frequency distribution at the truncation point and σ is the standard deviation of the character. It is shown, for mutations affecting viability in Drosophila, that truncation selection or reasonable departures therefrom can reduce the mutation load greatly. This may be one way to reconcile the very high mutation rate of such genes with a small mutation load. The truncation model with directional selection is appropriate for this situation because of the approximate additivity of these mutations. On the other hand, it is doubtful that this simple model can be applied to all genes affecting fitness, for which there are intermediate optima and antagonistic selection among components with negative correlations. Whether nature ranks and truncates, or approximates this behavior, is an empirical question, yet to be answered.

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

Abstract: 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.

Fixation of a deleterious allele at one of two "duplicate" loci by mutation pressure and random drift.

Abstract: We consider a diploid population and assume two gene loci with two alleles each, A and a at one locus and B and b at the second locus. Mutation from wild-type alleles A and B to deleterious alleles a and b occurs with mutation rates va and vb, respectively. We assume that alleles are completely recessive and that only the double recessive genotype aabb shows a deleterious effect with relative fitness 1-epsilon. Then, it can be shown that if va greater than vb mutant a becomes fixed in the population by mutation pressure and a mutation-selection balance is ultimately attained with respect to the B/b locus alone. The main aim of this paper is to investigate the situation in which va = vb exactly. In this case a neutral equilibrium is attained and either locus can drift to fixation for the mutant allele. Diffusion models are developed to treat the stochastic process involved whereby the deleterious mutant eventually becomes fixed in one of the two duplicated loci by random sampling drift in finite populations. In particular, the equation for the average time until fixation of mutant a or b is derived, and this is solved numerically for some combinations of parameters 4Nev and 4Ne epsilon, where v is the mutation rate (va = vb = v) and Ne is the effective size of the population. Monte Carlo experiments have been performed (using a device termed "pseudo sampling variable") to supplement the numerical analysis.

A transition density expansion for a multi-allele diffusion model

Abstract: An expansion in orthogonal polynomials is found for the transition density in a neutral multi-allele diffusion model where the mutation rates of allele types A i → A j are assumed to be u j (≥ O). The density is found when the mutation rate is positive for all allele types, and when some or all have zero mutation. The asymptotic conditional density is found for a mixture of positive and zero mutation rates. The infinite alleles limit with equal mutation is studied. Eigenfunctions of the process are derived and the frequency spectrum found. An important result is that the first eigenfunction depends only on the homozygosity. A density for the time to fixation with zero mutation is found for the K allele, and infinite alleles model.

The estimation of mutation rates when premeiotic events are involved.

Abstract: When mutation or recombination events occur premeiotically, the distribution of exceptional individuals among the offspring will be "clustered" as opposed to binomial. Even though the exact nature of the clustering is usually unknown, unbiased methods for measuring mutation rate and determining the precision of these measurements are given to replace a biased method now frequently used. When clustering is pronounced, the unweighted average mutation rate is found to be a more efficient estimator than the usual average weighted by family size. Methods of statistical inference and optimal experimental design in the absence of specific knowledge of the mechanism of clustering are also discussed.

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

Abstract: 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.

Characterization of the mutator mutation mut5-1.

Abstract: The mutator mutation mut5-1 has been characterized with respect to a range of parameters which have been used to describe DNA repair mutants of yeast. No marked effect of the mutation on UV-mutability at lower doses was apparent. Diploids homozygous for the mutation are deficient in UV-induced recombination between the alleles his1-1 and hist1-315, mutation being sufficient to account for all the UV-induced histidine prototrophs. Complementation and mapping studies indicate that mut5-1 is allelic to rad51-1, supporting the conclusion of Hastings et al. (1976) that a mutator may increase spontaneous mutation by modifying repair parameters. Both mut5-1 homozygous and heterozygous diploids give rise to spontaneous or UV-induced segregants which appear to be the products of nondisjunction events. The levels of parameiotic recombination (see Sherman and Roman, 1963; Esposito and Esposito, 1974), sporulation and spore viability observed in mut5-1/mut5-1 diploids indicate that the function encoded by RAD51 is required at 2 times during meiosis. An essential role of the function encoded by RAD51 in mitotic and meiotic recombination is indicated.

Genetic variability maintained in a finite population under mutation and autocorrelated random fluctuation of selection intensity

Abstract: By using the diffusion equation method, the level of genetic variability maintained under mutation pressure in a finite population is investigated, assuming autocorrelated random fluctuation of selection intensity. An appropriate mathematical model was formulated to treat the change of gene frequencies, incorporating mutation pressure and fluctuating selection. Extensive Monte Carlo simulation experiments were also performed to supplement the theoretical treatments. Excellent agreement between the two results suggests the validity of the present diffusion model for the autocorrelated selection. One of the most important findings from the simulation studies is that mutations and random sampling drift largely determine the level of genetic variability, and that the presence of autocorrelated selection can significantly lower genetic variability only when its strength, as measured by the cumulative variance of selection intensity, is larger than about 103 times the mutation rate. It is pointed out that the effects of both mutations and random sampling drift have to be incorporated in order to assess the role of various factors for the maintenance of genetic variability in natural populations.

Increased mutation rates in doubly viral transformed Chinese hamster cells.

Abstract: An untransformed parental Chinese hamster cell line, one polyoma transformed clone, and two clones containing both SV40 and polyoma DNA were tested for the appearance of variants resistant to 6-thioguanine or oubain. The frequency of such variants was found to be highest in doubly transformed cells. The mutation rate at these loci was correlated with the level of transformation. The mutants observed were stable and had low reversion frequencies with no gross cytogenetic changes. These results establish a quantitative basis for the evaluation of phenotypic variability observed in transformed cell populations.

Is intragenic recombination a factor in the maintenance of genetic variation in natural populations

Abstract: INTRAGENIC recombination between two different existing alleles in a population can create new alleles. The role of this process in maintaining variation in a natural population has been investigated1 by assuming that a gene consists of two sites, each of which can mutate to an infinite number of unique ‘alleles’ (the infinite allele model of Kimura and Crow2). Using this model it was shown that if the product of the population size, N, and the mutation rate, μ, is ⩾1, and the recombination rate, r, is the same order of magnitude as the mutation rate, then intragenic recombination significantly increases the number of alleles maintained in a finite population. Moreover, this is not equivalent to an increase in the mutation rate as the variance of homozygosity and the variance of the number of alleles are larger. This implies that the sampling theory of neutral alleles developed by Ewens3 does not apply to the situation where intragenic recombination is important in maintaining variation4. Application of these results to the study of intragenic recombination in natural populations would require a large number of independent samples in order to estimate the variance of homozygosity and the variance of the number of alleles. However, data from natural populations usually consist of the number of alleles and their frequencies in a single sample. Therefore, for the effect of intragenic recombination to be observable, there must be a detectable change in the distribution of the allele frequencies in a sample which contains k alleles. We present here the results of Monte Carlo simulation which show that intragenic recombination in the equilibrium population increases the frequency of the most common allele, increases the number of alleles which occur only once in the sample, and increases the homozygosity.

A model for the evolution of translocation heterozygosity

Abstract: This paper uses algebraic analysis and computer simulation to examine the contribution of homozygote disadvantage created by mutational load to selection for translocation heterozygosity in selfing populations. It is shown first that in structurally homozygous populations mutation pressure can lead to the accumulation of deleterious mutations, as opposed to the establishment of a stable equilibrium between mutational input and selective elimination. The speed of accumulation depends on the mutation rate and inversely on the selection coefficients against deleterious alleles, the population size and the amount of recombination. It is also shown that translocations can be selected, given a sufficiently high rate of mutation per chromosome and provided that crossing-over is suppressed in structural heterozygotes. Incomplete dominance of deleterious mutations lowers the strength of selection for translocations, compared with the case of complete recessivity. In all cases when translocations are selected there is accumulation of deleterious genes in structural heterozygotes, so that the final population consists entirely of structural heterozygotes, the homozygotes behaving effectively as recessive lethals. The model is discussed in relation to what is known about translocation heterozygosity in natural populations, and about mutation rates and selection coefficients for deleterious genes. It is concluded that an unrealistically high mutation rate is probably needed for this mechanism to be the sole factor involved in initiating the evolution of complex heterozygosity in largely self-fertilising plants. It may, however, be an important contributary factor, and we show that it is likely to be more important, the larger the number of interchanges already established in the population.

Production of petites by cell cycle mutants of Saccharomyces cerevisiae defective in DNA synthesis

Abstract: Mutations in two genes (cdc8 and cdc21) required for nuclear and mitochondrial DNA synthesis in Saccharomyces cerevisiae result in a 6- to 11-fold increase in the rate of mitotic segregation of petites at the permissive temperature. The defect in DNA replication and the increased rate of petite production result from the same mutation since the two phenotypes cosegregate and corevert. Most of the petites isolated from strains carrying mutations in cdc8 and cdc21 contain mtDNA. Therefore, the petites do not result simply from an underreplication of mitochondrial DNA. The mutation rates for nuclear and mitochondrial genes are the same in cdc8, cdc21 and their wild-type parent. Therefore the petites are unlikely to result from an increase in the rate of base pair substitution.

Photodynamic effects of dyes on bacteria III. Mutagenesis by acridine orange and 500-nm monochromatic light in strains of Escherichia coli that differ in repair capability

Abstract: In the presence of acridine orange (AO) and monochromatic 500-nm light, the recombination-deficient strain of Escherichia coli, WP10 (recA), showed a 15-fold increase in mutation rate over the wild-type (WP2) strain. Under the same conditions, strain Bs--1 (uvrB lexA lon) showed a 5-fold increase in mutation rate over strain WP2. In contrast, the endonuclease-deficient, strain, WP2s (uvrA), showed a lower AO-500 nm mutation rate than wild-type. The extremely high mutation rate of the recA strain cannot be due to error-prone inducible SOS repair since the inducible recA + function is absent. Repair of the AO-500 nm-induced lesions is likely due to a recA+-dependent, error-free, recombination process. It is concluded that the high mutation rates with AO-500 nm light obtained in chemostat cultures of recA and lexA strains occur as a consequence of errors during semi-conservative DNA replication in the presence of unrepaired DNA lesions.

Genetic control of enhanced mutability of mitochondrial DNA and gamma-ray sensitivity in Saccharomyces cerevisiae

Abstract: Five nuclear mutants enhancing the spontaneous mutation rate of mtDNA have been isolated in Saccharomyces cerevisiae. These mutators fall into five complementation groups and are located at five genetic loci different from rad50 to rad57 loci. Three mutants (gam1, gam2, and gam4), insensitive or weakly sensitive to gamma-rays, exhibit increased frequency of spontaneous production of mutants with large deletions of the mtDNA (p-) and of all tested mitochondrial drug-resistant mutants. Two other mutants (gam3 and gam5), highly sensitive to gamma-rays, increase only the mutation rate of particular alleles of the mtDNA. The mutant gam5 enhances only the production of p- and erythromycin-resistant clones. The mutant gam3 exhibits an enhanced rate of oligomycin-resistant clones as well as a collateral increase of nuclear mutability. The existence of gam3 and gam5 mutants indicates that at least two common steps control both nuclear DNA repair and the mutability of particular alleles of the mtDNA. However, the general spontaneous mutability of the mtDNA includes at least three steps not involved in the repair of nuclear DNA, as revealed by the gam1, gam2, and gam4 mutations.

Is there a proportionality between the spontaneous and the X-ray-induction rates of mutations? Experiments with mutations at 13 X-chromosome loci in Drosophila melanogaster.

Abstract: The X-ray induction of recessive visible specific locus mutations at 14 X-chromosome loci was studied in Drosophila melanogaster using the “Maxy” technique. The X-ray exposure was 3000 R to 5-day-old males and the sampling of germ cells was restricted to mature spermatozoa. Presumptive mutant females recovered in the F1 generation were tested for transmission, allelism, fertility and viability in males. A total of 128 mutations (115 completes and 13 mosaics including those that were male-viable as well as male-lethal) recovered among 38 898 female progeny were found to be transmitted. On the basis of the above frequency, the average mutation rate can be estimated as 7.8 × 10−8/locus/R; for mutations that were viable and fertile in males, the rate is 3.0 × 10−8/locus/R (49 mutations among 38 898 progeny). The frequency of mutations at the different loci encompassed a wide range: while no mutations were recovered at the raspberry and carnation loci, at others, the numbers ranged from 1 at echinus to 31 at garnet; in addition, the proportion of mutations that was male-viable was also different, depending on the locus. Schalet's extensive data on spontaneous mutations at 13 (of the 14 loci employed in the present study) loci permit an estimate of the spontaneous rate which is 6.1 × 10−6/locus (a total of 39 mutations among 490 000 progeny); for mutations that were viable and fertile in males, the rate is 3.0 × 10−6/locus (19 mutations among 490 000 progeny). The mutability of the different loci varied over a 9-fold range. When the different loci are ranked depending on their relative mutability (for spontaneous and induced mutations) it is found that in general, loci that mutate spontaneously relatively more frequently are also those at which more mutations have been recovered in the radiation experiments and likewise, those that are less mutable spontaneously are also those that mutate less after irradiation. Since the data are limited, it is concluded that the above finding is not inconsistent with the assumption of proportionality between spontaneous and induction rates of mutations. On the basis of the above results, a doubling dose of 100 R can be calculated for the X-ray induction of specific-locus mutations in Drosophila spermatozoa.

Radiation-induced dominant skeletal mutations in mice: mutation rate, characteristics, and usefulness in estimating genetic hazard to humans from radiation

Abstract: The work discussed in this paper represents a major advance in the difficult task of trying to estimate the effects that an increase in mutation frequency would have on human health. Male mice were bred to three females prior to being killed and skeleton studies made. Guidelines were instituted for checking progeny mutations. Surprising results showed a mutation frequency of 1.4% per gamete where none would have been expected. It is now clear that mice can be greatly deformed without showing external effects. (PCS)

Comments on mutagenesis risk estimation.

Abstract: Several hypotheses and concepts have tended to oversimplify the problem of mutagenesis and can be misleading when used for genetic risk estimation. These include: (1) the hypothesis that radiation-induced mutation frequency depends primarily on the DNA content per haploid genome, (2) the extension of this concept to chemical mutagenesis, (3) the view that, since DNA is DNA, mutational effects can be expected to be qualitatively similar in all organisms, (4) the REC unit, and (5) the view that mutation rates from chronic irradiation can be theoretically and accurately predicted from acute irradiation data. Therefore, direct determination of frequencies of transmitted mutations in mammals continues to be important for risk estimation, and the specific-locus method in mice is shown to be not as expensive as is commonly supposed for many of the chemical testing requirements.

In vivo somatic mutation systems in the mouse.

Abstract: In an effort to meet the need for a fast and cheap in vivo prescreen for inherited mammalian point mutations, a somatic forward-mutation method, originally developed in an X-ray experiment, has more recently been tested in work with chemical mutagens. The method makes use of coat-color mutations because (a) the gene product is usually locally expressed, (b) mosaics can be detected with minimal effort, and (c) opportunities for making comparison with induction of germinal point mutations are greatest.--Following treatment of embryos that are heterozygous at specific coat-color loci, various induced genetic changes can result in expression of the recessive (RS) in clones derived from "mutant" melanocyte precursor cells. However, other events, such as decrease in the number of precursor cells, or disturbed differentiation, can also result in spots, which with careful classification can usually be distinguished from RS's on the basis of their location and color. When this is done, the relative RS frequencies for a series of compounds at least roughly parallel the relative spermatogonial mutation rates. The fact that easily measurable (though low) RS rates are obtained with compounds that have yielded negative results in spermatogonial tests is not surprising in view of the fact that RS's can be caused by several mechanisms besides point mutation.--In spite of the parallelism observed in one laboratory, the usefulness of the in vivo somatic mutation method as a prescreen could come to be doubted because of major discrepancies between results of similar experiments at different laboratories. However, it appears probable that at least some of these discrepancies are due to failure to discriminate between spots that probably resulted from melanocyte insufficiency and spots that resulted from expression of the recessive.--Reverse somatic mutation systems can potentially avoid some of the pitfalls of forward mutation systems. Such system are still in developmental stages.

CAN1 locus of Saccharomyces cerevisiae: fine-structure analysis and forward mutation rates. [X radiation, uv radiation]

Abstract: 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 infrequency (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

Some sampling properties of selectively neutral alleles:Effects of variability of mutation rates

Abstract: Some sampling properties related with the mean and variance of the number of alleles and single locus heterozygosity are derived to study the effect of variations in mutation rate of selectively neutral alleles. The correlation between single locus heterozygosity and the number of alleles is also derived. Monte Carlo simulation is conducted to examine the effect of stepwise mutations. The relevance of these results in estimating the population parameter, 4 N e ν, is discussed in connexion with neutralist-selectionist controversy over the maintenance of genetic variability in natural populations.

Gene mutations (de novo) found in electrophoretic studies of blood protein of infants with anomalous development.

Abstract: Twelve proteins of enzymic and nonenzymic nature in blood samples of infants that deviate from the average population in physical development (50 premature and 177 full-term infants with rough and multiple developmental defects) were studied by electrophoresis in polyacrylamide and starch gels. The control group consisted of 500 normal newborns. In infants with developmental disorders, the frequency of rare electrophoretic protein variants was found to be about one order of magnitude higher than in the control. It has been shown for at least five cases that such variants are de novo mutations. According to these data the mutation rate is approximately 2 x 10(-3) per locus per generation for the group selected and approximately 6 x 10(-5) for the total population. Despite the fact that further specification of the estimations found is required, we consider the results obtained as evidence in favor of the efficiency of the earlier substantiated monitoring model of gene mutations in the human population [Dubinin, N.P. & Altukhov, Yu. P. (1977) in Genetic Consequences of Environmental Pollution, ed. Dubinin, N.P. (Mysl, Moscow), pp. 14-45]. This approach, which infers electrophoretic screening of blood proteins in a specially selected group of newborns, makes it possible to reduce the size of samples needed for statistically reliable estimations of the alteration of mutation rate.

Some additional considerations on the method of genetical analysis for induced continuous variation of self-fertilising plants

Abstract: Genetic parameters for describing the induced continuous variation of self-fertilising plants have been defined in terms of mutation rate per allele and the additive and dominance effects of the genes concerned. Estimation and interpretation of these parameters are discussed. It is shown that no single generation up to the M3 provides enough statistics to estimate the parameters, unless mutagenic treatment is applied to zygotic cells. As in the case of generations derived from hybridisation between two inbred lines, information on the average degree of dominance and gene association in parental lines can be obtained using these estimates. The mutation rate can be estimated when two parental lines with significantly different phenotypic values are investigated simultaneously.

Some Aspects of the Occurrence of New Mutations in Haemophilia

Abstract: Using the data available on a group of carriers of haemophilia, the mutation rate in the male germ line was compared with that of the female germ line. The mutation rate among the male germ line was about 1-2 times that in the female germ line. An assessment of grandparental ages as a factor in the production of new mutations of haemophilia was also investigated.