Showing papers on "Mutation (genetic algorithm) published in 1988"

Directional mutation pressure and neutral molecular evolution.

Abstract: A quantitative theory of directional mutation pressure proposed in 1962 explained the wide variation of DNA base composition observed among different bacteria and its small heterogeneity within individual bacterial species. The theory was based on the assumption that the effect of mutation on a genome is not random but has a directionality toward higher or lower guanine-plus-cytosine content of DNA, and this pressure generates directional changes more in neutral parts of the genome than in functionally significant parts. Now that DNA sequence data are available, the theory allows the estimation of the extent of neutrality of directional mutation pressure against selection. Newly defined parameters were used in the analysis, and two apparently universal constants were discovered. Analysis of DNA sequence has revealed that practically all organisms are subject to directional mutation pressure. The theory also offers plausible explanations for the large heterogeneity in guanine-plus-cytosine content among different parts of the vertebrate genome.

Spontaneous mutation rates to new length alleles at tandem-repetitive hypervariable loci in human DNA.

Abstract: Tandem-repetitive minisatellite regions in vertebrate DNA frequently show substantial allelic variation in the number of repeat units. This variation is thought to arise through processes such as unequal crossover or replication slippage1–12. We show here that the spontaneous mutation rate to new length alleles at extremely variable human minisatellites is sufficiently high to be directly measurable in human pedigrees. The mutation rate at different loci increases with variability in accord with the neutral mutation/random drift hypothesis, and rises to 5% per gamete for the most unstable human minisatellite isolated. Mutations are sporadic, occur with similar frequencies in sperm and oocytes, and can involve the gain or loss of substantial numbers of repeat units, consistent with length changes arising primarily by unequal exchange at meiosis. Germline instability must therefore be taken into account when using hypervariable loci as genetic markers, particularly in pedigree analysis and parenthood testing.

Molecular quasi-species.

Abstract: 1. The Sequence Space 2. The Kinetic Equations 3. How Realistic is the Kinetic Ansatz? 4. Solutions of the Rate Equations 5. Potential Functions, Optimization, and Guided Evolution 6 . Population Structures Error Threshold For Quasi-species Localization 1. Error Threshold and Selective Advantage 2. Localization Threshold for Statistically Distributed Replication Rates 3. Extreme-Value Theory for Effective Superiority 4. Relaxed Error Threshold and Gene Duplication 5. Analogies to Phase Transitions Examples of Fitness Landscapes and Stationary Populations 1. Error Threshold 2. Degenerate Quasi-species and Neutral Mutants 3. Conformation-dependent Value Functions and Fitness Landscapes 4. Asymmetry of Fitness Landscapes: Apparent Guidance of Evolution

Statistical methods to decide whether mutagenicity test data from Drosophila assays indicate a positive, negative, or inconclusive result

Abstract: Two alternative hypotheses are used to distinguish among the possibilities of a positive, inconclusive, or negative result in Drosophila mutagenicity tests. In the null hypothesis one assumes that there is no difference in the mutation frequency between control and treated series. The alternative hypothesis postulates a priori that the treatment results in an increased mutation frequency that is m times the spontaneous frequency. To test against the hypotheses, the conditional binomial test according to Kastenbaum and Bowman or the chi 2 test for proportions may be applied. These 2 methods are in principle equivalent. An alternative method which is based on determining confidence limits of observed mutation frequencies also leads to the same conclusions. The practical calculations are formulated and an application is shown with a test example demonstrating the genotoxicity of the pyrrolizidine alkaloid 7-acetylintermedine in the somatic wing mosaic test. In the Appendix, the calculus for the 3 testing methods is explained with a numerical example.

The Dynamic Nature of the Antibody Repertoire

Abstract: Antibody production by an animal in response to an immunogen is dictated by the repertoire of B cells at the time of stimulation. The repertoire of B cells, however, is continuously changing. This change is brought about by the dynamic character of the repertoire, and by the antigenic experience of the animal. The naive repertoire is formed by genetic recombination events which are independent of antigenic stimulation. Since the size of the B-cell repertoire only allows the expression of a fraction of the genetic repertoire at any given time, only a random sample of the total potential is available. This constitutes the raw material that must be capable of providing initial recognition to any antigenic challenge to which animals are subjected. This raises the question of how an animal discriminates between self and non-self antigens, an aspect of the response we will not discuss here. We want to restrict ourselves to points in which our experience of the anti-oxazolone response gives informative data. We will therefore concentrate our attention on describing the way in which the antigenic experience influences the available B-cell repertoire. Our general ideas on the subject will be discussed in the context of the model presented in Fig. 1. We will argue that antigensensitive B cells from both the naive and the memory repertoire are modified through hypermutation and selection following each round of antigenic stimulation, so as to continuously refme the pool of memory B cells. One of the important conclusions we draw from otir experiments is that the antigetiic stimulation of memory cells leads to further processes of hypermutation and selection, functioning through a highly organized and purpose-developed procedure, probably operating in the germinal centers (see Fig. 1). We wish to argue that the development of such an elaborate procedure, so far unique to antibody-producing B cells, arose in response to the evolutionary advantage

Mutation, developmental selection, and plant evolution

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The rate of polygenic mutation.

Abstract: By application of the neutral model of phenotypic evolution, quantitative estimates of the rate of input of genetic variance by polygenic mutation can be extracted from divergence experiments as well as from the response of an inbred base population to selection. The analytical methods are illustrated through a survey of data on a diversity of organisms including Drosophila, Tribolium, mice, and several crop species. The mutational rate of introduction of genetic variance (Vm) scaled by the environmental variance (VE) is shown to vary between populations, species, and characters with a range of approximately 10−4 to 5 × 10−2. Vm/VE for Drosophila viability is somewhat below this range, while hybrid dysgenesis may temporarily inflate Vm/VE beyond 10−1. Potential sources of bias and error in the estimation of Vm are discussed, as are the practical implications of the observed limits to Vm/VE for projecting the long-term response to selection and for testing adaptational hypotheses.

Genetic heterogeneity in type 1 Gaucher disease: multiple genotypes in Ashkenazic and non-Ashkenazic individuals.

Abstract: Nucleotide sequence analysis of a genomic clone from an Ashkenazic Jewish patient with type 1 Gaucher disease revealed a single-base mutation (adenosine to guanosine transition) in exon 9 of the glucocerebrosidase gene. This change results in the amino acid substitution of serine for asparagine. Transient expression studies following oligonucleotide-directed mutagenesis of the normal cDNA confirmed that the mutation results in loss of glucocerebrosidase activity. Allele-specific hybridization with oligonucleotide probes demonstrated that this mutation was found exclusively in the type 1 phenotype. None of the 6 type 2 patients, 11 type 3 patients, or 12 normal controls had this allele. In contrast, 15 of 24 type 1 patients had one allele with this mutation, and 3 others were homozygous for the mutation. Furthermore, some of the Ashkenazic Jewish type 1 patients had only one allele with this mutation, suggesting that even in this population there is allelic heterozygosity. These findings indicate that there are multiple allelic mutations responsible for type 1 Gaucher disease in both the Jewish and non-Jewish populations. Allelic-specific hybridization demonstrating this mutation in exon 9, used in conjunction with the Nci I restriction fragment length polymorphism described as a marker for neuronopathic Gaucher disease, provides a tool for diagnosis and genetic counseling that is approximately equal to 80% informative in all Gaucher patients studied.

Determination of the rate of base-pair substitution and insertion mutations in retrovirus replication.

Abstract: We recently described a protocol for determination of retrovirus mutation rates, that is, the mutation frequency in a single cycle of retrovirus replication (J.P. Dougherty and H.M. Temin, Mol. Cell. Biol. 6:4378-4395, 1987; J.P. Dougherty and H.M. Temin, p. 18-23, in J. H. Miller and M. P. Calos, ed., Gene Transfer Vectors for Mammalian Cells, 1987). We used this protocol to determine the mutation rates for defined mutations in a replicating retrovirus by using a spleen necrosis virus-based vector. We determined that the mutation rate for a single base pair substitution during replication of this avian retrovirus is 2 x 10(-5) per base pair per replication cycle and the insertion rate is 10(-7) per base pair per replication cycle. It will be possible to use this protocol to determine mutation rates for other retroviruses.

Rate tests for selection on quantitative characters during macroevolution and microevolution.

Abstract: Evolutionary biologists are increasingly interested in testing alternative models rather than simply presenting plausible explanations for their observations. Although most biologists agree that significant phenotypic changes cannot occur without natural selection, it is useful to have statistical tests that reject alternative mechanisms such as genetic drift and mutation. The first such tests were presented by Lande (1976, 1977). This note reviews previous analyses of neutral phenotypic evolution and concentrates on tests derived from two simple approximations. One describes neutral macroevolution in populations that have achieved an equilibrium level of heritable variation determined by mutation and genetic drift; the other (developed explicitly in Lande [1976, 1977]) describes neutral microevolution in recently established populations whose levels of heritable variation may be far from mutationdrift equilibrium. As our examples below demonstrate, average rates of macroevolutionary change are rarely fast or slow enough to provide sufficient evidence for rejecting neutral models. Although we state our results in terms of statistical tests, the sampling errors for many of the parameters are unknown. Thus our results are best viewed as qualitative assessments of the agreement of evolutionary rates with the expectations from simple neutral models. Lande (1976) applied quantitative-genetics theory to describe two fundamental processes that can change phenotypic means: natural selection and genetic drift. He first estimated the minimum intensity of truncation selection necessary to produce a specific change (see Charlesworth [1984a) for an analysis of another mode of selection); then, he calculated the maximum effective population size, denoted N, *, that would allow genetic drift to produce the same phenotypic change by random sampling. From this stochastic model, Lande (1977) developed a \"rate test\" for the hypothesis that drift alone could account for observed divergence among the mean phenotypes of reproductively isolated populations. Charlesworth (l984b) has developed related tests for the null hypothesis that evolutionary rates remain constant within lineages. All of these tests, including the ones discussed below, assume that changes in mean phenotype are caused by genetic changes rather than direct phenotypic responses to changing environmental conditions. An implication of Lande's (1976) test, which rejects neutrality if N, > Ne*, is that genetic drift changes the mean phenotype more rapidly in small populations than in large ones. This contradicts Kimura's (1968) original neutral theory of molecular evolution, which predicts that the rate of molecular evolution is independent of population size and is governed wholly by the rate at which neutral mutations arise. The reason for this discrepancy is that Lande's (1976) test treats the additive genetic variance as roughly constant and independent of population size. In contrast, Kimura's neutral theory is based on an explicit model of mutation and drift, which leads to the prediction that the equilibrium genetic variance depends on population size while the rate of evolution is independent of population size. Although Lande (1976 p. 326) noted that the equilibrium level of additive variance will generally depend on population size, this was not incorporated into his test for neutral phenotypic evolution. Subsequently, Lande (1979, 1980) gave explicit formulas for the dynamics of phenotypic means and both the equilibria and dynamics of genetic variances and covariances for multiple characters under mutation and drift. As discussed below, these later analyses, like Kimura's neutral theory, lead to the prediction that the longterm rate of neutral phenotypic evolution depends only on mutation parameters and is independent of population size. Lynch and Hill (1986) analyzed the implications of more general genetic assumptions for both the dynamics and equilibria ofa single polygenic character subject to mutation and genetic drift. The purpose of the present note is to clarify the relationships among these results and to emphasize the critical role played by time scales and initial conditions in determining the importance of population size to neutral phenotypic evolution.

Are codon usage patterns in unicellular organisms determined by selection‐mutation balance?

Abstract: Strongly biased codon usage is common in unicellular organisms, particularly in highly expressed genes. The bias is most simply explained as a balance between selection and mutation, with selection favouring those codons which are more efficiently translated. In a review Ikemura (1985) has proposed four rules for predicting which codons will be preferred, based on the properties of the transfer RNAs responsible for translating messenger RNA into protein. In this paper codon usage in E. coli and yeast is re-examined using the recent compilation of Maruyama et al. (1986). The codon adaptation index of Sharp and Li (1986a) is used as a measure of gene expression to investigate the importance of this factor. It is found that Ikemura's rules successfully predict preferred codons for yeast, but that two of them work less well for E. coli, and it is suggested that some of the apparent bias in weakly expressed genes of E. coli may be due to contextual effects on mutation rates.

Splice junction mutation in some Ashkenazi Jews with Tay-Sachs disease: evidence against a single defect within this ethnic group

Abstract: Tay-Sachs disease is an inherited disorder in which the alpha chain of the lysosomal enzyme beta-N-acetylhexosaminidase A bears the mutation. Ashkenazi Jews are found to be carriers for a severe type of Tay-Sachs disease, the classic form, 10 times more frequently than the general population. Ashkenazi Jewish patients with classic Tay-Sachs disease have appeared to be clinically and biochemically identical, and the usual assumption has been that they harbor the same alpha-chain mutation. In this study I have isolated the alpha-chain gene from an Ashkenazi Jewish patient, GM2968, with classic Tay-Sachs disease and compared its nucleotide sequences with that of the normal alpha-chain gene in the promoter region, exon and splice junction regions, and polyadenylylation signal area. Only one difference was observed between these sequences: at the 5' boundary of intron 12, a guanosine in the conserved splice junction dinucleotide sequence G-T had been altered to a cytidine. The alteration is presumed to be functionally significant and to result in aberrant mRNA splicing. Utilizing the polymerase chain reaction to amplify the region encompassing the mutation, I developed an assay to screen patients and heterozygote carriers for this mutation. Surprisingly, in each of two Ashkenazi patients, only one alpha-chain allele harbored the splice junction mutation. Only one parent of each of these patients was positive for the defect. Another Ashkenazi patient did not bear this mutation at all nor did either of the subject's parents. In addition, 30% of obligate heterozygotes tested carried the splice junction mutation, whereas 20 Ashkenazi Jews designated noncarriers by enzymatic assay were negative for this alteration. The data are consistent with the presence of more than one mutation underlying the classic form of Tay-Sachs disease in the Ashkenazi Jewish population.

Genetic load and its causes in long-lived plants

Abstract: Many long-lived plant taxa are characterized by relatively high genetic load levels. This genetic load is manifested as the proportion of offspring that are physiologically handicapped to various degrees. It is proposed that the majority of this load is mutational load and is a consequence of the higher per generation mutation rates that occur in long-lived plants. Higher per generation mutation rates are a result of the chemostat-like accumulation of mutations in the apical initials as the plant grows. Genetic load, therefore, is a function of the postzygotic accumulation of mutations as well as mutations inherited from previous generations.

Spontaneous reversion of novel Lesch-Nyhan mutation by HPRT gene rearrangement.

Abstract: Molecular analysis of an unusual patient with the Lesch-Nyhan syndrome has suggested that the mutation is due to a partial HPRTgene duplication. We now report the cloning and sequencing of the mutant HPRTcDNA which shows the precise duplication of exons 2 and 3. This mutation is the result of an internal duplication of 16–20 kilobases of the gene. The structure of the mutant gene suggests that the duplication was not generated by a single unequal crossing-over event between two normal HPRTalleles. Growth of Epstein-Barr virus-transformed lymphoblasts from this patient in selective medium has permitted isolation of spontaneous HPRT+ revertants of this mutation. The reversion event involves a second major HPRTgene rearrangement where most or all of the duplicated portion of the mutant gene is deleted. The original mutation therefore has the potential for spontaneous somatic reversion. This may explain the relatively mild symptoms of the Lesch-Nyhan syndrome exhibited by this patient.

The Ade6-M26 Mutation of Schizosaccharomyces Pombe Increases the Frequency of Crossing over.

Abstract: The ade6-M26 mutation of Schizosaccharomyces pombe increases conversion frequency in comparison with the nearby mutation ade6-M375. In order to investigate the effect of ade6-M26 on crossover frequency, heteroallelic ade6 duplications were constructed by integration of plasmids carrying the marker gene ura4. One ade6 gene carries either of the mutations M26 or M375 while the other ade6 copy carries the L469 mutation in both duplications. The duplication with ade6-M26 yields Ade(+) recombinants at significantly higher frequencies in meiosis, but not in mitosis. Tetrad analysis and physical characterization of spore clones from recombination tetrads demonstrate that conversions, unequal crossovers and intrachromatid exchanges occur at higher frequencies but with unaltered proportions among them. The conversion events show a pronounced bias when M26 is involved: they take place preferentially at the M26 allele. Thus the ade6-M26 mutation not only enhances conversion frequency as demonstrated before, but also crossover frequency. It displays the properties expected for a preferred site of initiation of general meiotic recombination. The duplications also yielded new information on ectopic recombination in S. pombe: ectopic crossovers occur in the duplications at much higher frequency than among naturally dispersed homologous sequences.

The spectrum of β‐thalassaemia mutations in Sicily

Abstract: To characterize beta-thalassaemia genes among the Sicilian population we have previously determined the DNA haplotypes in the beta-globin gene cluster of 99 beta-thal chromosomes. We found seven haplotypes, although 95 of 99 beta-thal chromosomes contained framework 1 and framework 3 beta genes. We have now determined the mutation in all 99 of these beta-thal genes by the use of oligonucleotide hybridization. PCR-amplification and direct genomic sequencing, and direct restriction analysis. Our results indicate that (1) the beta (0)-39 mutation is most frequent (35%); (2) beta(0)-39, IVS-1 nt 110 and IVS-1 nt 6 mutations account for 90% of beta-thal genes: (3) the IVS-1 nt 6 mutation is more frequent in thalassaemia intermedia (77%) than in Cooley's disease (34%): (4) the association between haplotypes and specific mutations is imperfect, but mutation spread has occurred within haplotypes containing the same beta-gene framework: (5) the beta(0)-39 and the IVS-1 nt 6 mutations, with a mutation spread to two major haplotypes, may be older than the IVS-1 nt 110 mutation: (6) these data make possible first-trimester prenatal diagnosis in many families (85%) in Sicily using only three pairs of oligonucleotides. In addition, a new mutation, a frameshift at codon 76 due to loss of a C residue, was found in a single beta-thal chromosome.

Time for acquiring a new gene by duplication

Abstract: In view of the widespread occurrence of gene families in eukaryotic genomes that suggests the importance of gene duplication in evolution, a population genetic model incorporating unequal crossing-over was formulated By using this model, the time needed for acquiring a new gene is investigated by an approximate analytical method and by computer simulations The model assumes that natural selection favors those chromosomes with more beneficial genes than other chromosomes in the population, as well as random genetic drift, mutation, and unequal crossing-over Starting from a single gene copy, it is found that the time for acquiring another gene with a new function is dependent on the rates of occurrence of unequal crossing-over and mutation Within a realistic range of parameter values, the required time was at least several times 4N generations, where N is the effective population size Interchromosomal unequal crossing-over at meiosis is more effective than intrachromosomal (between sister chromatids) unequal crossing-over for obtaining a new gene, provided that other parameters are the same However, the genetic load for acquiring a gene is larger under the model of interchromosomal crossing-over The relevance of this finding to the advantage of sexual reproduction is discussed

Human adenine phosphoribosyltransferase deficiency. Demonstration of a single mutant allele common to the Japanese.

Abstract: Complete adenine phosphoribosyltransferase (APRT) deficiency causes 2,8-dihydroxyadenine urolithiasis. In previous reports, analysis of the kinetic properties of APRT from APRT-deficient Japanese subjects revealed strikingly similar abnormalities suggesting a distinct "Japanese-type" mutation. In this paper, we report studies of 11 APRT-deficient lymphoblast cell lines. Nucleotide sequence analysis of APRT genomic DNA from WR2, a Japanese-type homozygote, identified a T to C substitution in exon 5, giving rise to the substitution of threonine for methionine at position 136. RNase mapping analysis confirmed this mutation in WR2 and revealed that six other Japanese-type homozygotes carry the same mutation on at least one allele. The remaining Japanese subject, who does not express the Japanese-type phenotype, did not demonstrate this mutation. Southern blot analysis showed that all seven Japanese-type subjects were confined to one TaqI restriction fragment length polymorphism (RFLP) haplotype. These studies provide direct evidence for the nature of the mutation in the Japanese-type APRT deficiency.

Cell division control in Escherichia coli K-12: some properties of the ftsZ84 mutation and suppression of this mutation by the product of a newly identified gene

Abstract: The Fts proteins play an important role in the control of cell division in Escherichia coli. These proteins, which possibly form a functional complex, are encoded by genes that form an operon. In this study, we examined the properties of the temperature-sensitive mutation ftsZ84 harbored by low- or high-copy-number plasmids. Cells of strain AB1157, which had the ftsZ84 mutation, did not form colonies on salt-free L agar at 30 degrees C. When a low-copy-number plasmid containing the ftsZ84 mutation was present in these mutant cells, colony formation was restored on this medium at 30 degrees C, suggesting that FtsZ84 is probably less active than the wild-type protein and is therefore limiting in its capacity to trigger cell divisions. On the other hand, when the ftsZ84 mutation was harbored by the high-copy-number plasmid pBR325, colony formation was prevented on salt-free L agar plates whether the recipients were ftsZ84 mutant or parental cells, suggesting that, at high levels, FtsZ84 acts as a division inhibitor. The fact that colony formation was also prevented at 42 degrees C indicates that the FtsZ84 protein is not inactivated at the nonpermissive temperature. The possibility that FtsZ84 is a more efficient division inhibitor than the wild-type FtsZ is discussed. Evidence is also presented showing that a gene adjacent to mutT codes for a product that, under certain conditions, suppresses the ftsZ84 mutation. Images

The maintenance of single-locus polymorphism. I. Numerical studies of a viability selection model.

Abstract: The ability of viability selection to maintain single-locus polymorphism is investigated with two models in which the population is bombarded with a series of mutations with random fitnesses. In the first model, the population is allowed to reach equilibrium before mutation resumes; in the second the iterations and mutation occur simultaneously. Monte Carlo simulations of these models show that viability selection is easily able to maintain stable 6- or 7-allele polymorphisms and that monomorphisms and diallelic polymorphisms are uncommon. The question of how monomorphisms arise is also discussed.