Showing papers on "Mutation (genetic algorithm) published in 1997"

Evolution of high mutation rates in experimental populations of E. coli

Abstract: Most mutations are likely to be deleterious, and so the spontaneous mutation rate is generally held at a very low value. Nonetheless, evolutionary theory predicts that high mutation rates can evolve under certain circumstances. Empirical observations have previously been limited to short-term studies of the fates of mutator strains deliberately introduced into laboratory populations of Escherichia coli, and to the effects of intense selective events on mutator frequencies in E. coli. Here we report the rise of spontaneously originated mutators in populations of E. coli undergoing long-term adaptation to a new environment. Our results corroborate computer simulations of mutator evolution in adapting clonal populations, and may help to explain observations that associate high mutation rates with emerging pathogens and with certain cancers.

Global prevalence of putative haemochromatosis mutations.

Abstract: Haemochromatosis is a genetic disease associated with progressive iron overload, and is common among populations of northern European origin HLA-H is a recently reported candidate gene for this condition Two mutations have been identified, a substitution of cysteine for tyrosine at amino acid 282 (C282Y, nucleotide 845) and of histidine for aspartate at amino acid 63 (H63D, nucleotide 187) Over 90% of UK haemochromatosis patients are homozygous for the C282Y mutation We have examined 5956 chromosomes (2978 people) for the presence of HLA-H C282Y and H63D by PCR followed by restriction enzyme analysis We have found world wide allele frequencies of 19% for C282Y and 81% for H63D The highest frequencies were 10% for C282Y in 90 Irish chromosomes and 304% for H63D in 56 Basque chromosomes C282Y was most frequent in northern European populations and absent from 1042 African chromosomes, 484 Asian chromosomes, and 644 Australasian chromosomes The distribution of the C282Y mutation coincides with that of populations in which haemochromatosis has been reported and is consistent with the theory of a north European origin for the mutation The H63D polymorphism is more widely distributed and its connection with haemochromatosis remains unclear

Role of mutator alleles in adaptive evolution

Abstract: that the mutation rate has evolved to be as low as possible, limited only by the cost of error-avoidance and error-correction mechanisms. But up to one per cent of natural bacterial isolates are 'mutator' clones that have high mutation rates 4-6 . We consider here whether high mutation rates might play an important role in adaptive evolution. Models of large, asexual, clonal populations adapting to a new environment show that strong mutator genes (such as those that increase mutation rates by 1,000-fold) can accelerate adaptation, even if the mutator gene remains at a very low frequency (for example, 10 2 5 ). Less potent mutators (10 to 100-fold increase) can become fixed in a fraction of finite populations. The parameters of the model have been set to values typical for Escherichia coli cultures, which behave in a manner similar to the model in long-term adaptation experiments 7 . Early models of the evolution of the mutation rate were based on group selection for an optimal compromise between adaptability and adaptedness 2,3 . However, later models, incorporating mutators and antimutators (modifiers of the mutation rate) showed that a mutator can reduce individual fitness while increasing the prob- ability for an adaptive mutation to appear in the population. The prediction of these models was that a minimal mutation rate would be selected in a stable environment (reduction principle 8 ), whereas in an oscillating environment, infinite populations at equilibrium

Fast Evolution Strategies

Abstract: Evolution strategies are a class of general optimisation algorithms which are applicable to functions that are multimodal, non-differentiable, or even discontinuous. Although recombination operators have been introduced into evolution strategies, their primary search operator is still mutation. Classical evolution strategies rely on Gaussian mutations. A new mutation operator based on the Cauchy distribution is proposed in this paper. It is shown empirically that the new evolution strategy based on Cauchy mutation outperforms the classical evolution strategy on most of the 23 benchmark problems tested in this paper. These results, along with those obtained by fast evolutionary programming

The high spontaneous mutation rate: Is it a health risk?

Abstract: The human mutation rate for base substitutions is much higher in males than in females and increases with paternal age. This effect is mainly, if not entirely, due to the large number of cell divisions in the male germ line. The mutation-rate increase is considerably greater than expected if the mutation rate were simply proportional to the number of cell divisions. In contrast, those mutations that are small deletions or rearrangements do not show the paternal age effect. The observed increase with the age of the father in the incidence of children with different dominant mutations is variable, presumably the result of different mixtures of base substitutions and deletions. In Drosophila, the rate of mutations causing minor deleterious effects is estimated to be about one new mutation per zygote. Because of a larger number of genes and a much larger amount of DNA, the human rate is presumably higher. Recently, the Drosophila data have been reanalyzed and the mutation-rate estimate questioned, but I believe that the totality of evidence supports the original conclusion. The most reasonable way in which a species can cope with a high mutation rate is by quasi-truncation selection, whereby a number of mutant genes are eliminated by one “genetic death.”

Align : A program to superimpose protein coordinates, accounting for insertions and deletions

Abstract: The alignment and superposition of protein structures are sometimes complicated by the presence of insertions or deletions in one structure or the other. The program ALIGN [Satow, Cohen, Padlan & Davies (1986). J. Mol. Biol. 190, 593–604] was written to address this problem. The program provides information in its analysis of results to facilitate the understanding of transformations between structurally homologous subunits of protein structures.

Disruption of human limb morphogenesis by a dominant negative mutation in CDMP1

Abstract: Chondrodysplasia Grebe type (CGT) is an autosomal recessive disorder characterized by severe limb shortening and dysmorphogenesis. We have identified a causative point mutation in the gene encoding the bone morphogenetic protein (BMP)–like molecule, cartilage-derived morphogenetic protein–1 (CDMP-1). The mutation substitutes a tyrosine for the first of seven highly conserved cysteine residues in the mature active domain of the protein. We demonstrate that the mutation results in a protein that is not secreted and is inactive in vitro. It produces a dominant negative effect by preventing the secretion of other, related BMP family members. We present evidence that this may occur through the formation of heterodimers. The mutation and its proposed mechanism of action provide the first human genetic indication that composite expression patterns of different BMPs dictate limb and digit morphogenesis.

The genetics of aging.

Abstract: There is no aging program, nor is there an aging gene. Instead, we age because evolution has no reason to protect us against unwelcome actions of multiple genes late in life. Still, every discovery of a harmful mutation or polymorphism raises at least the theoretical possibility of other, beneficial alleles- and offers clues for understanding the biomolecular mechanisms that underlie senescence.

The Genealogy of Samples in Models With Selection

Abstract: We introduce the genealogy of a random sample of genes taken from a large haploid population that evolves according to random reproduction with selection and mutation. Without selection, the genealogy is described by Kingman's well-known coalescent process. In the selective case, the genealogy of the sample is embedded in a graph with a coalescing and branching structure. We describe this graph, called the ancestral selection graph, and point out differences and similarities with Kingman's coalescent. We present simulations for a two-allele model with symmetric mutation in which one of the alleles has a selective advantage over the other. We find that when the allele frequencies in the population are already in equilibrium, then the genealogy does not differ much from the neutral case. This is supported by rigorous results. Furthermore, we describe the ancestral selection graph for other selective models with finitely many selection classes, such as the K-allele models, infinitely-many-alleles models, DNA sequence models, and infinitely-many-sites models, and briefly discuss the diploid case.

Genome-wide hypermutation in a subpopulation of stationary-phase cells underlies recombination-dependent adaptive mutation.

Abstract: Stationary-phase mutation in microbes can produce selected ('adaptive') mutants preferentially. In one system, this occurs via a distinct, recombination-dependent mechanism. Two points of controversy have surrounded these adaptive reversions of an Escherichia coli lac mutation. First, are the mutations directed preferentially to the selected gene in a Lamarckian manner? Second, is the adaptive mutation mechanism specific to the F plasmid replicon carrying lac? We report that lac adaptive mutations are associated with hypermutation in unselected genes, in all replicons in the cell. The associated mutations have a similar sequence spectrum to the adaptive reversions. Thus, the adaptive mutagenesis mechanism is not directed to the lac genes, in a Lamarckian manner, nor to the F' replicon carrying lac. Hypermutation was not found in non-revertants exposed to selection. Therefore, the genome-wide hypermutation underlying adaptive mutation occurs in a differentiated subpopulation. The existence of mutable subpopulations in non-growing cells is important in bacterial evolution and could be relevant to the somatic mutations that give rise to cancers in multicellular organisms.

Formation of neuronal intranuclear inclusions (NII) underlies the neurological dysfunction in mice transgenic for the HD mutation

Abstract: Huntington's disease (HD) is one of an increasing number of human neurodegenerative disorders caused by a CAG/polyglutamine-repeat expansion. The mutation occurs in a gene of unknown function that is expressed in a wide range of tissues. The molecular mechanism responsible for the delayed onset, selective pattern of neuropathology, and cell death observed in HD has not been described. We have observed that mice transgenic for exon 1 of the human HD gene carrying (CAG)115 to (CAG)156 repeat expansions develop pronounced neuronal intranuclear inclusions, containing the proteins huntingtin and ubiquitin, prior to developing a neurological phenotype. The appearance in transgenic mice of these inclusions, followed by characteristic morphological change within neuronal nuclei, is strikingly similar to nuclear abnormalities observed in biopsy material from HD patients.

A Genetic Algorithm for the Multiple-Choice Integer Program

Abstract: We present a genetic algorithm for the multiple-choice integer program that finds an optimal solution with probability one though it is typically used as a heuristic. General constraints are relaxed by a nonlinear penalty function for which the corresponding dual problem has weak and strong duality. The relaxed problem is attacked by a genetic algorithm with solution representation special to the multiple-choice structure. Nontraditional reproduction, crossover and mutation operations are employed. Extensive computational tests for dual degenerate problem instances show that suboptimal solutions can be obtained with the genetic algorithm within running times that are shorter than those of the OSL optimization routine.

Environmental/economic dispatch using fuzzy logic controlled genetic algorithms

Abstract: The paper presents the application of a fuzzy logic controlled genetic algorithm (FCGA) to power system environmental/economic dispatch. The authors first propose an improved genetic algorithm with two fuzzy controllers based on some heuristics to adaptively adjust the crossover probability and mutation rate during the optimisation process. The implementation of the fuzzy crossover and mutation controllers is described. The proposed FCGA can be applied to wide range of optimisation problems. The validity of the proposed algorithm is illustrated on environmental/economic dispatch of a six-generator power system. Its performance is compared with conventional GAs and the Newton-Raphson method. The results are very encouraging.

A New Pathogenic Mutation in the APP Gene (I716V) Increases the Relative Proportion of Aβ42(43)

Abstract: We report a novel mutation in the amyloid precursor protein gene (APP I716V) which probably leads to familial early onset Alzheimer's disease with an onset age in the mid 50s. Cells transfected with cDNAs bearing this mutation produce more A beta 1-42(43) than those transfected with wild-type APP and this effect is additive with that of the previously reported APP V717I mutation thus providing a novel approach for further increasing A beta 1-42(43) in model systems.

Male-driven evolution of DNA sequences in birds.

Abstract: Assuming that new mutations arise mainly during DNA replication, sequence evolution in mammals has been seen as 'male driven' (ref. 1) because of the many more cell divisions in spermatogenesis than in oogenesis. Molecular support for this idea has been obtained from the observation of higher substitution rates in genes on the Y than on the X chromosome of primates and rodents, which are species with male heterogamety, but has not been confirmed by the reciprocal analysis of organisms with female heterogamety. The recent suggestion that an intrinsic reduction in the X-chromosome mutation rate may be confounded with male effects in previous comparisons, and the paradoxical finding of low levels of polymorphism on the primate Y chromosome indicate that the idea of male-biased mutation rate needs to be re-examined. We have analysed the molecular evolution of the gene CHD, which is present on the Z and W sex chromosomes of birds. The substitution rate at synonymous positions, as well as in intron DNA, was considerably higher on the Z chromosome than on the female-specific W chromosome, with an estimated male-to-female bias in mutation rate (alpha m) of 3.9-6.5. Thus, evolution appears to be male driven in birds--a situation that supports a neutral model of molecular evolution.

Unstable minisatellite expansion causing recessively inherited myoclonus epilepsy, EPM1

Abstract: Progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1; MIM 254800) is an autosomal recessive disorder that occurs with a low frequency in many populations but is more common in Finland and the Mediterranean region. It is characterized by stimulus-sensitive myoclonus and tonic-clonic seizures with onset at age 6-15 years, typical electroencephalographic abnormalities and a variable rate of progression between and within families. Following the initial mapping of the EPM1 gene to chromosome 21 (ref. 6) and the refinement of the critical region to a small interval, positional cloning identified the gene encoding cystatin B (CST6), a cysteine protease inhibitor, as the gene underlying EPM1 (ref. 10). Levels of messenger RNA encoded by CST6 were dramatically decreased in patients. A 3' splice site and a stop codon mutation were identified in three families, leaving most mutations uncharacterized. In this study, we report a novel type of disease-causing mutation, an unstable 15- to 18-mer minisatellite repeat expansion in the putative promoter region of the CST6 gene. The mutation accounts for the majority of EPM1 patients worldwide. Haplotype data are compatible with a single ancestral founder mutation. The length of the repeat array differs between chromosomes and families, but changes in repeat number seem to be comparatively rare events.