Showing papers on "Mutation (genetic algorithm) 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.

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.

Mutation and inactivation of cultured mammalian cells exposed to beams of accelerated heavy ions. III. Human diploid fibroblasts.

Abstract: SummaryThe induction of inactivation and mutation to thioguanine-resistance in cultured human diploid fibroblasts was studied after exposure to ionising radiations with LETs in the range 20–470keV µm−1. Unique r.b.e. values were obtained for inactivation and mutation induction with nine different qualities of radiation. The plot of r.b.e. versus LET gave humped curves for both endpoints; r.b.e. maxima were in the LET range 90–200keV µm−1 but the maximum r.b.e. value for mutation induction was almost twice that for inactivation. The accuracy of estimates of mutation induction are discussed with regard to possible selective effects against mutants during post-irradiation growth.

Site-specific Recombination of Bacteriophage λ: The Role of Host Gene Products

Abstract: Integration of the DNA of bacteriophage A into the chromosome of Escherichia coli occurs by recombination at two unique genetic loci: attP on the phage genome and attB on the bacterial chromosome. This reaction is therefore an example of site-specific recombination. The only phage-encoded protein required for recombination at these art (attachment) sites is Int, the product of the phage int gene. Integration of A generates a prophage that is flanked by two new att sites, attL and attR. Excision, recombination between attL and attR, requires Xis, the product of the phage xis gene, as well as Int (for review, see Weisberg et al. 1977). It has previously been demonstrated that in addition to phage-encoded proteins, the products of one or more host genes are necessary for A site-specific recombination (Miller and Friedman 1977a; Nash et al. 1977; Williams et al. 1977). In this paper, we briefly present the results of experiments that characterize mutant E. coli strains that are unable to carry out A site-specific recombination. Our studies describe the biochemical nature of the integration defect in these strains and define the genetic loci that are responsible. The interest in these newly identified genetic loci promises to extend beyond the study of A site-specific recombination, since the mutants exhibit various other phenotypes, some of which do not appear to be a consequence of a defect in recombination.

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.

Equilibrium Distributions of Continuous Polygenic Traits

Abstract: A model for inheritance of continuous polygenic traits, similar to a model of Lande, is considered. The equilibrium density of gametic types is found approximately, if the forces of mutation and selection are weak compared to recombination.

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.

Mapping Chromosomal Genes of SACCHAROMYCES CEREVISIAE Using an Improved Genetic Mapping Method

Abstract: A triploid (3n) strain of Saccharomyces cereuisiae was constructed carrying a standard marker on each of chromosomes I through XVII in the ——/+J+ configuration. This is called a "supertriploid." Meiotic spores from this strain (n + ∼ n/2) were mated with a haploid (n) carrying an unmapped mutation. Meiotic analysis of each zygote clone (2n + ∼ n/2) produced in this way resulted in elimination of an average of 4.2 chromosomes as the possible location of the unmapped marker. The distribution of extra chromosomes in the 2n + ∼ n/2) strains was nearly random. Meiotic segregrants of these crosses carrying the unmapped mutation in the -/+ configuration were then crossed with multiply marked haploid strains to further narrow the possible location of the unmapped mutation to a single chromosome. Scoring of markers by complemention tests was simplified by mating spore clones with mixtures of a and α strains, each pair carrying the same set of markers. Using this new, more rapid method ("supertriploid mapping"), eight genes required for the maintenance of the killer plasmid were located on the genetic map of S. cerevisiae .

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.

Thalassemia Major: Molecular and Clinical Aspects

Abstract: Thalassemia major is a severe and transfusion-dependent anemia that occurs in persons homozygous for a mutation that affects the capacity for synthesis of the β- globin subunit of hemoglob...

Intraspecific hybridisation and the release of mutator activity.

Abstract: IT has been suggested by Grant1–2 that mutation and hybridisation may not be independent of one another as sources of genetic variation in natural populations. Indeed, it has been shown in both plants and animals3–8 that hybridisation can stimulate the production of new mutations and chromosome breakage events. The possible role of intraspecific hydridisation in inducing genetic change has recently been discussed in various contexts, especially in relation to the action of mutator genes in natural populations1,2,9–11. We have previously suggested that mutator factors, which are known to induce both visible and lethal mutations and chromosome breakage, are commonly present in natural populations of Drosophila melanogaster. Within sub-populations, however, these mutators are genetically suppressed. On hybridisation between subpopulations, genetic suppression breaks down, resulting in the release of mutator activity and, hence, in an explosive increase in genetic variation. Clearly, these explosions of mutation, which have been documented in some natural populations12,13, might have an important role in evolution and speciation. Here, we test this hypothesis of ‘hybrid release’ directly by determining whether intraspecific hybridisation increases the frequency of mutation above that found in the sampled natural population. Our study differs significantly from other assays of mutator gene effect14–16 in that mutation frequencies before and after hybridisation are compared directly. The results show that hybrid release of mutator activity does occur as the result of hybridisation, producing a severalfold increase in the frequency of mutation. Thus, hybrid release may be a major mechanism in the induction of genetic variation in natural populations and so may be a driving force in evolution.

Failure of caffeine to influence induced mutation frequencies and the independence of cell killing and mutation induction in V79 Chinese hamster cells

Abstract: Using V79 Chinese hamster cells and a replating assay, no effect of caffeine post-treatment on spontaneous or UV- or EMS-induced mutation frequencies to 8-azaguanine resistance was demonstrable However, considerable potentiation of cell killing was observed Previous reports that caffeine enhances induced mutation frequencies are explained by an artefact in the situ method used; a similar artefact may also explain the cumulative in situ mutation dose-response curves Furthermore, the relationship between mutation induction and dose has been shown to be qualitatively distinct from that between cell killing and dose These differences suggest that cell killing and mutation induction are mediated via independent mechanisms and that pre-mutational lesions may be qualitatively distinct from pre-lethal lesions

A mutation in Caenorhabditis elegans that increases recombination frequency more than threefold.

Abstract: In higher organisms the rate of recombination between genetic loci is presumably responsive to selective pressure. Recently, selective pressures1 and mutational events2 that influence recombination have been reviewed. Mutational sites and chromosomal rearrangements that enhance or suppress recombination frequency in specific regions are known, but general mechanisms that enhance recombination have not yet been discovered. We describe here the isolation and characterisation of a strain of the hermaphroditic nematode, Caenorhabditis elegans, that has a recombination frequency at least threefold higher than that found in the wild type3,4. In this strain, rec-1, the number of reciprocal recombination events between linked loci is increased. This is true for all pairs of linked loci studied so far. The high recombination strain behaves as if it carries a classical, recessive mutation, although a second mutation exists which can alter the recessive behaviour of rec-1.

Population genetics of multigene family with special reference to decrease of genetic correlation with distance between gene members on a chromosome.

Abstract: A mathematical method is developed which enables us to treat exactly the process of coincidental evolution under mutation, unequal intrachromosomal crossing-over as well as ordinary crossing-over between homologous chromosomes in a finite population of the effective size N. It makes use of finite difference equations involving two quantities denoted by fi and phi i, in which fi is the identity coefficient of two gene members that are i steps apart on the same chromosome and phi i is that of two members i steps apart on two homologous chromosomes. When the number of genes (n) per family is large, the finite difference equations can be approximately by ordinary second-order differential equations which can then be solved analytically. Results obtained by the present method are compared with the corresponding results previously obtained by one of us (T.O.) using conventional diffusion models of gene frequency changes in population genetics. It is shown that the previous results obtained by T.O. regarding second-order statistics are essentially valid, and they give good approximations particularly when N beta is small, where beta is the rate of ordinary interchromosomal crossing-over within the multigene family.

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.

Gene conversion in nonsense suppressors of Schizosaccharomyces pombe. I. The influence of the genetic background and of three mutant genes (rad2, mut1 and mut2) on the frequency of the post-meiotic segregation.

Abstract: The frequency of gene conversion was assessed at the anticodon site of the sup3 gene of Schizosaccharomyces pombe. In order to detect a possible influence of the genetic background on the relative frequency of post-meiotic segregations amongst conversions, three similar crosses were analyzed which differed as follows: In cross I the two parents were derived by spontaneous mutation from one and the same strain. The heterogeneity of the genetic background between these two parent strains is assumed to be at a minimum level. In cross II the crossing partners were strains of the Bernese stock collection and differ probably in their genetic background to some extent. Last, in cross III, one of the parent strains was ten times repeatedly mutagenized with nitrosoguanidine in order to introduce cryptic mutations in the genome. A maximum degree of background heterogeneity between parents is expected for this cross. Neither the total conversion frequency nor the frequency of post-meiotic segregations amongst conversions were found to be significantly different in these three crosses. In addition, no effect of the radiation-sensitive mutation, rad2-44, and of two mutator mutations, mut1-4 and mut2-9, on the conversion pattern could be detected.

Promotion and limitation of genetic exchange.

Abstract: Exchange of genetic material has widely been observed in practically all living organisms. This may suggest that genetic exchange must have been practised since a long time, perhaps ever since life exists. The rules followed by nature in the exchange of genetic information are studied by geneticists. However, as long as the chemical nature of the genetic material remained unknown, genetics had to remain a rather abstract branch of the biological sciences. This began to change gradually after Avery et al. 1 had identified DNA as the carrier of genetic information. Their evidence found an independent support by Hershey and Chase 2 and it was accepted by a majority of biologists by 1953, when Watson and Crick 3 presented their structural model of DNA. Hence it was clear 25 years ago that very long, filamentous macromolecules of DNA contain the genes. As is usual in fundamental research, the knowledge acquired pointed to a number of new important questions. Among them were those on the structure and function of genes, but also those on the molecular mechanisms of exchange of genetic materials. It is at that time, in the fall of 1953, that I joined more or less by chance a small group of investigators animated by Jean Weigle and Eduard Kellenberger. One of their main interests concerned the mechanisms of genetic recombination. Feeling that the time was not ripe to carry out such studies on higher organisms, they had chosen to work with a bacterial virus, the nowadays famous bacteriophage lambda (2). It is interesting to see today how knowledge acquired in work with phage 2 should later strongly influence other research in molecular genetics. In this lecture I would like to trace back the origin of some discoveries made in work with 2 and point to their importance for subsequent investigations. But let me first define in more general terms what I mean with genetic exchange. Bacterial chromosomes and plasmids