Showing papers on "Mutation (genetic algorithm) published in 1994"

Adaptive probabilities of crossover and mutation in genetic algorithms

Abstract: In this paper we describe an efficient approach for multimodal function optimization using genetic algorithms (GAs). We recommend the use of adaptive probabilities of crossover and mutation to realize the twin goals of maintaining diversity in the population and sustaining the, convergence capacity of the GA. In the adaptive genetic algorithm (AGA), the probabilities of crossover and mutation, p/sub c/ and p/sub m/, are varied depending on the fitness values of the solutions. High-fitness solutions are 'protected', while solutions with subaverage fitnesses are totally disrupted. By using adaptively varying p/sub c/ and p/sub ,/ we also provide a solution to the problem of deciding the optimal values of p/sub c/ and p/sub m/, i.e., p/sub c/ and p/sub m/ need not be specified at all. The AGA is compared with previous approaches for adapting operator probabilities in genetic algorithms. The Schema theorem is derived for the AGA, and the working of the AGA is analyzed. We compare the performance of the AGA with that of the standard GA (SGA) in optimizing several nontrivial multimodal functions with varying degrees of complexity. >

Convergence analysis of canonical genetic algorithms

Abstract: This paper analyzes the convergence properties of the canonical genetic algorithm (CGA) with mutation, crossover and proportional reproduction applied to static optimization problems. It is proved by means of homogeneous finite Markov chain analysis that a CGA will never converge to the global optimum regardless of the initialization, crossover, operator and objective function. But variants of CGA's that always maintain the best solution in the population, either before or after selection, are shown to converge to the global optimum due to the irreducibility property of the underlying original nonconvergent CGA. These results are discussed with respect to the schema theorem. >

Complex gene conversion events in germline mutation at human minisatellites

Abstract: Mutation at the human minisatellites MS32, MS205 and MS31A has been investigated by characterizing mutant alleles in pedigrees and in the case of MS32 by direct analysis of mutant molecules in single sperm. Most mutations at all three loci are polar, involving the preferential gain of a few repeat units at one end of the tandem repeat array. Incoming repeats can be derived from the same allele or the homologous chromosome, through they are frequently rearranged during mutation. Lack of exchange of flanking markers suggests the involvement of complex conversion-like events in the generation of mutant alleles. At MS32, high frequency mutation processes in sperm appear to be largely germline specific and to occur at a constant rate irrespective of allele size. Together with mutational polarity, this implies that germline instability is controlled by elements outside the tandem repeat array.

Ancestral Inference in Population Genetics

Abstract: Mitochondrial DNA sequence variation is now being used to study the history of our species. In this paper we discuss some aspects of estimation and inference that arise in the study of such variability, focusing in particular on the estimation of substitution rates and their use in calibrating estimates of the time since the most recent common ancestor of a sample of sequences. Observed DNA sequence variation is generated by superimposing the effects of mutation on the ancestral tree of the sequences. For data of the type studied here, this ancestral tree has to be modeled as a random process. Superimposing the effects of mutation produces complicated sampling distributions that form the basis of any statistical model for the data. Using such distributions--for example, for maximum likelihood estimation of rates--poses some difficult computational problems. We describe a Monte Carlo method, a cousin of the popular "Markov chain Monte Carlo," that has proved very useful in addressing some of these issues.

Murine muscular dystrophy caused by a mutation in the laminin alpha 2 (Lama2) gene.

Abstract: The classic murine muscular dystrophy strain, dy, was first described almost 40 years ago. We have identified the molecular basis of an allele of dy, called dy2J, by detecting a mutation in the laminin α2 chain gene — the first identified mutation in laminin-2. The G to A mutation in a splice site consensus sequence causes abnormal splicing and expression of multiple mRNAs. One mRNA is translated into an α2 polypeptide with a deletion in domain VI. The truncated protein apparently lacks important qualities of the wild type protein and is unable to provide sufficient muscle stability.

Parasitism, mutation accumulation and the maintenance of sex.

Abstract: Two classes of models attempt to explain why obligate parthenogenesis only rarely replaces sexual reproduction in natural populations, in spite of the apparent reproductive advantage that parthenogens gain by producing only female offspring1. The mutation-accumulation models suggest that sex is adaptive because it purges the genome of harmful recurrent mutations2,3. The ecological genetic models postulate that sex is adaptive in variable environments, particularly when the relevant variation is generated by revolutionary interactions with parasites4–7. Both of these models have considerable merit, but would seem to have limitations. The mutation-accumulation models require high rates of mutation3,8; the coevolutionary models require that parasites have severe fitness effects on their hosts9. In addition, parasites could select for clonal diversity and thereby erode any advantage that sex gains by producing variable progeny10. Here we consider the interaction between mutation accumulation and host–parasite coevolution. The results suggest that even moderate effects by parasites combined with reasonable rates of mutation could render sex evolutionary stable against repeated invasion by clones.

A ruby in the rubbish: beneficial mutations, deleterious mutations and the evolution of sex.

Abstract: This study presents a mathematical model in which a single beneficial mutation arises in a very large population that is subject to frequent deleterious mutations. The results suggest that, if the population is sexual, then the deleterious mutations will have little effect on the ultimate fate of the beneficial mutation. However, if most offspring are produced asexually, then the probability that the beneficial mutation will be lost from the population may be greatly enhanced by the deleterious mutations. Thus, sexual populations may adapt much more quickly than populations where most reproduction is asexual. Some of the results were produced using computer simulation methods, and a technique was developed that allows treatment of arbitrarily large numbers of individuals in a reasonable amount of computer time. This technique may be of prove useful for the analysis of a wide variety of models, though there are some constraints on its applicability. For example, the technique requires that reproduction can be described by Poisson processes.

A calcium channel mutation causing hypokalemic periodic paralysis

Abstract: The only calcium channel mutation reported to date is a deletion in the gene for the DHP-receptor alpha 1-subunit resulting in neonatal death in muscular dysgenesis mice (1). In humans, this gene maps to chromosome 1q31-32. An autosomal dominant muscle disease, hypokalemic periodic paralysis (HypoPP), has been mapped to the same region (2). Sequencing of cDNA of two patients revealed a G-to-A base exchange of nucleotide 1583 predicting a substitution of histidine for arginine528. This affects the outermost positive charge in the transmembrane segment IIS4 that is considered to participate in voltage sensing. By restriction fragment analysis, the mutation was detected in the affected members of 9 out of 25 HypoPP families. The results indicate that the DHP-receptor alpha 1-subunit mutation causes HypoPP. An altered excitation-contraction coupling may explain the occurrence of muscle weakness.

Variable Selection in QSAR Studies. I. An Evolutionary Algorithm

Abstract: In QSAR studies of large data sets, variable selection and model building is a difficult, time-consuming and ambiguous procedure. While most often stepwise regression procedures are applied for this purpose, other strategies, like neural networks, cluster significance analysis or genetic algorithms have been used. A simple and efficient evolutionary strategy, including iterative mutation and selection, but avoiding crossover of regression models, is described in this work. The MUSEUM (Mutation and Selection Uncover Models) algorithm starts from a model containing any number of randomly chosen variables. Random mutation, first by addition or elimination of only one or very few variables, afterwards by simultaneous random additions, eliminations and/or exchanges of several variables at a time, leads to new models which are evaluated by an appropriate fitness function. In contrast to common genetic algorithm procedures, only the “fittest” model is stored and used for further mutation and selection, leading to better and better models. In the last steps of mutation, all variables inside the model are eliminated and all variables outside the model are added, one by one, to control whether this systematic strategy detects any mutation which still improves the model. After every generation of a better model, a new random mutation procedure starts from this model. In the very last step, variables not significant at the 95% level are eliminated, starting with the least significant variable. In this manner, “stable” models are produced, containing only significant variables. A comparison of the results for the Selwood data set (n = 31 compounds, k = 53 variables) with those obtained by other groups shows that more relevant models are derived by the evolutionary approach than by other methods.

How frequent are correlated changes in families of protein sequences

Abstract: A loss-of-function point mutation in a protein is often rescued by an additional mutation that compensates for the original physical change. According to one hypothesis, such compensation would be most effective in maintaining a structural motif if the two mutated residues were spatial neighbors. If this hypothesis were correct, one would expect that many such compensatory mutations have occurred during evolution and that present-day protein families show some degree of correlation in the occurrence of amino acid residues at positions whose side chains are in contact. Here, a statistical theory is presented which allows evaluation of correlations in a family of aligned protein sequences by assigning a scalar metric (such as charge or side-chain volume) to each type of amino acid and calculating correlation coefficients of these quantities at different positions. For the family of myoglobins it is found that there is a high correlation between fluctuations in neighboring charges. The correlation is close to what would be expected for total conservation of local charge. For the metric side-chain volume, on the other hand, no correlation could be found.

Recombination in Adaptive Mutation

Abstract: The genetic requirements for adaptive mutation in Escherichia coli parallel those for homologous recombination in the RecBCD pathway. Recombination-deficient recA and recB null mutant strains are deficient in adaptive reversion. A hyper-recombinagenic recD strain is hypermutable, and its hypermutation depends on functional recA and recB genes. Genes of subsidiary recombination systems are not required. These results indicate that the molecular mechanism by which adaptive mutation occurs includes recombination. No such association is seen for spontaneous mutation in growing cells.

A novel mitochondrial point mutation in a maternal pedigree with sensorineural deafness

Abstract: We have detected a novel mitochondrial mutation in a maternal pedigree, at least 13 of whose members have sensorineural hearing loss of varying severity, but who exhibit no other pathological features. The mutation, at np 7445, converts the 3' terminal T residue of tRNA-ser(UCN) to a C, and also brings about a silent alteration to the COI stop codon. The mutation destroys an XbaI site, within which a second mutation, at np 7444, has previously been reported in association with Leber's hereditary optic neuropathy. Predominantly mutant mtDNA was found in all 13 family members surveyed, whether or not they are overtly affected by deafness, and some individuals appeared homoplasmic, within the limits of detection. The novel mutation was not found in over 600 normal controls, nor in any of 27 other maternally unrelated individuals with deafness Other mutations found in mitochondrial disorders were also absent from this pedigree.

Regulatory hierarchy of photomorphogenic loci: allele-specific and light-dependent interaction between the HY5 and COP1 loci.

Abstract: Previous studies suggested that the CONSTITUTIVE PHOTOMORPHOGENIC 1 (COP1) gene product represses photomorphogenic development in darkness and that light signals reverse this action. In this report, we used genetic analysis to investigate the regulatory hierarchical relationship of COP1 and the loci encoding the photoreceptors and other signaling components. Our results showed that cop1 mutations are epistatic to the long hypocotyl mutations hy1, hy2, hy3, and hy4, suggesting that COP1 acts downstream of the phytochromes and a blue light receptor. Although epistasis of a putative null cop1-5 mutation over a hy5 mutation implied that COP1 acts downstream of HY5, the same hy5 mutation can suppress the dark photomorphogenic phenotypes (including hypocotyl elongation and cotyledon cellular differentiation) of the weak cop1-6 mutation. This, and other allele-specific interactions between COP1 and HY5, may suggest direct physical contact of their gene products. In addition, the synthetic lethality of the weak deetiolated1 (det1) and cop1 mutations and the fact that the cop1-6 mutation is epistatic to the det1-1 mutation with respect to light control of seed germination and dark-adaptative gene expression suggested that DET1 and COP1 may act in the same pathway, with COP1 being downstream. These results, together with previous epistasis studies, support models in which light signals, once perceived by different photoreceptors, converge downstream and act through a common cascade(s) of regulatory steps, as defined by DET1, HY5, COP1, and likely others, to derepress photomorphogenic development.

The distribution of mutation effects on viability in Drosophila melanogaster.

Abstract: Parameters of continuous distributions of effects and rates of spontaneous mutation for relative viability in Drosophila are estimated by maximum likelihood from data of two published experiments on accumulation of mutations on protected second chromosomes. A model of equal mutant effects gives a poor fit to the data of the two experiments; higher likelihoods are obtained with leptokurtic distributions or for models in which there is more than one class of mutation effect. Minimum estimates of mutation rates (events per generation) at polygenes affecting viability on chromosome 2 are 0.14 and 0.068, but estimates are strongly confounded with other parameters in the model. Separate information on rates of molecular divergence between Drosophila species and from rates of movement of transposable elements is used to infer the overall genomic mutation rate in Drosophila, and the viability data are analyzed with mutation rate as a known parameter. If, for example, a mutation rate for chromosome 2 of 0.4 is assumed, maximum likelihood estimates of mean mutant effect on relative viability are 0.4% and 1%, but the majority of mutations have very much smaller effects than these values as distributions are highly leptokurtic. The methodology is applied to estimate viability effects of single P element insertional mutations. The mean effect per insertion is found to be higher, and their distribution is found to be less leptokurtic than for spontaneous mutations. The equilibrium genetic variance of viability predicted by a mutation-selection balance model with parameters estimated from the mutation accumulation experiments is similar to laboratory estimates of genetic variance of viability from natural populations of Drosophila.

Adaptive Mutation by Deletions in Small Mononucleotide Repeats

Abstract: Adaptive reversion of a +1 frameshift mutation in Escherichia coli, which requires homologous recombination functions, is shown here to occur by -1 deletions in regions of small mononucleotide repeats. This pattern makes improbable recombinational mechanisms for adaptive mutation in which blocks of sequences are transferred into the mutating gene, and it supports mechanisms that use DNA polymerase errors. The pattern appears similar to that of mutations found in yeast cells and in hereditary colon cancer cells that are deficient in mismatch repair. These results suggest a recombinational mechanism for adaptive mutation that functions through polymerase errors that persist as a result of a deficiency in post-synthesis mismatch repair.

Variable Selection in QSAR Studies. II. A Highly Efficient Combination of Systematic Search and Evolution

Abstract: Recently two evolutionary strategies for the derivation of regression models, a genetic function approximation and the mutation/ selection algorithm MUSEUM have been described. The MUSEUM (Mutation and Selection Uncover Models) algorithm starts from a model containing randomly chosen variables. Random mutation, first by addition or elimination of only one or very few variables, afterwards by simultaneous random additions, eliminations and/or exchanges of several variables at a time, leads to new models which are evaluated by an appropriate fitness function. Only the “fittest” model is stored and used for further mutation and selection, leading to better and better models. However, the fitness of all models with up to three X variables can be determined much faster by calculation of the correlation coefficients ry.ij and ry.ijk from the partial correlation coefficients ryi, rij, ryj.j, rjk.i and ryk.ij. Using the Selwood data set (n = 31 compounds, k = 53 variables), it is demonstrated that systematic search is the best strategy for regression models with two or three X variables. The variables contained in the best three-variable models can be selected for further investigation, using the evolutionary approach. With the exception of complex models, containing six and more variables, nearly all relevant regression models are found by this combination of systematic search with the mutation/selection algorithm MUSEUM; the results are obtained in considerably shorter time than by including all variables in the calculations. In addition, systematic search is also a valuable tool for variable selection prior to stepwise regression and PLS analyses.

An empirical evaluation of weak mutation

Abstract: Mutation testing is a fault-based technique for unit-level software testing. Weak mutation was proposed as a way to reduce the expense of mutation testing. Unfortunately, weak mutation is also expected to provide a weaker test of the software than mutation testing does. This paper presents results from an implementation of weak mutation, which we used to evaluate the effectiveness versus the efficiency of weak mutation. Additionally, we examined several options in an attempt to find the most appropriate way to implement weak mutation. Our results indicate that weak mutation can be applied in a manner that is almost as effective as mutation testing, and with significant computational savings. >

Amino acid substitution during functionally constrained divergent evolution of protein sequences.

Abstract: In aligning homologous protein sequences, it is generally assumed that amino acid substitutions subsequent in time occur independently of amino acid substitutions previous in time, i.e. that patterns of mutation are similar at low and high sequence divergence. This assumption is examined here and shown to be incorrect in an interesting way. Separate mutation matrices were constructed for aligned protein sequence pairs at divergences ranging from 5 to 100 PAM units (point accepted mutations per 100 aligned positions). From these, the corresponding log-odds (Dayhoff) matrices, normalized to 250 PAM units, were constructed. The matrices show that the genetic code influences accepted point mutations strongly at early stages of divergence, while the chemical properties of the side chains dominate at more advanced stages.

Transgenic animals harboring app allele having swedish mutation

Abstract: The invention provides transgenic non-human animals and transgenic non-human mammalian cells harboring a transgene encoding an APP polypeptide comprising the Swedish mutation.