Showing papers on "Mutation (genetic algorithm) published in 1992"

The rapid generation of mutation data matrices from protein sequences

Abstract: An efficient means for generating mutation data matrices from large numbers of protein sequences is presented here. By means of an approximate peptide-based sequence comparison algorithm, the set sequences are clustered at the 85% identity level. The closest relating pairs of sequences are aligned, and observed amino acid exchanges tallied in a matrix. The raw mutation frequency matrix is processed in a similar way to that described by Dayhoff et al. (1978), and so the resulting matrices may be easily used in current sequence analysis applications, in place of the standard mutation data matrices, which have not been updated for 13 years. The method is fast enough to process the entire SWISS-PROT databank in 20 h on a Sun SPARCstation 1, and is fast enough to generate a matrix from a specific family or class of proteins in minutes. Differences observed between our 250 PAM mutation data matrix and the matrix calculated by Dayhoff et al. are briefly discussed.

Optimization of laminate stacking sequence for buckling load maximization by genetic algorithm

Abstract: The use of a genetic algorithm to optimize the stacking sequence of a composite laminate for buckling load maximization is studied. Various genetic parameters including the population size, the probability of mutation, and the probability of crossover are optimized by numerical experiments. A new genetic operator - permutation - is proposed and shown to be effective in reducing the cost of the genetic search. Results are obtained for a graphite-epoxy plate, first when only the buckling load is considered, and then when constraints on ply contiguity and strain failure are added. The influence on the genetic search of the penalty parameter enforcing the contiguity constraint is studied. The advantage of the genetic algorithm in producing several near-optimal designs is discussed.

An exonic mutation in the HuP2 paired domain gene causes Waardenburg's syndrome

Abstract: Here we report the identification and characterization of a gene defect causing Waardenburg's syndrome with hearing loss in a large Brazilian family. This demonstrates a mutation causing Waardenburg's syndrome as well as a mutation causing a form of congenital deafness. The mutation was found in the HuP2 gene, a member of the paired domain family of proteins that bind DNA and regulate gene expression. The mutation occurred in 100% of the cases with the disease in this family and was absent in a random sample of 50 unrelated control subjects. Identification of the Waardenburg's syndrome gene and future characterization of its gene product is likely to increase our understanding of the pathogenesis of this disorder and may allow prevention of deafness of this type.

A Null mutation in the rhodopsin gene causes rod photoreceptor dysfunction and autosomal recessive retinitis pigmentosa

Abstract: Mutations within the rhodopsin gene are known to give rise to autosomal dominant retinitis pigmentosa (RP), a common hereditary form of retinal degeneration. We now describe a patient with autosomal recessive RP who is homozygous for a nonsense mutation at codon 249 within exon 4 of the rhodopsin gene. This null mutation, the first gene defect identified in autosomal recessive retinitis pigmentosa, should result in a functionally inactive rhodopsin protein that is missing the sixth and seventh transmembrane domains including the 11-cis-retinal attachment site. We also found a different null mutation carried heterozygously by an unrelated unaffected individual. Heterozygous carriers of either mutation had normal ophthalmologic examinations but their electroretinograms revealed an abnormality in rod photoreceptor function.

How Genetic Algorithms Really Work: Mutation and Hillclimbing.

Abstract: The invention relates to the production of washing powders of stabilized or enhanced appearance which contain a fluorescent whitening agent of the formula or of the formula wherein R1 is hydrogen or chlorine, and M is hydrogen, an alkali metal or ammonium ion. The stabilizing or enhancement of the appearance is effected by first dissolving or dispersing the fluorescent whitening agent in a mixture of water and a polyvinyl alcohol or polyvinyl pyrrolidone which is soluble or is able to swell in water, adding this solution or dispersion to the washing powder slurry and drying the slurry. The solution or dispersion can also be subsequently sprayed onto the dried residual washing powder. The appearance can be further enhanced by employing a polyethylene glycol, a surfactant containing ethyleneoxy and/or propyleneoxy groups, and/or a cellulose ether, in addition to the polymer in the solution or dispersion. The solution or dispersion comprising fluorescent whitening agent and polymer can also alternatively be dried, preferably by spray drying, to produce a preparation which, after it has been suspended in water, can also be added to the washing powder slurry. The slurry is then dried, preferably by spray drying.

The Interaction of Mutation Rate, Selection, and Self-Adaptation Within a Genetic Algorithm.

Abstract: An alkyl alkynyl sulfide can be employed to stabilizer methylchloroform against reaction with the common metals of construction. Stabilization is enhanced by combining with other known stabilizers. Nitroalkanes, alkyl nitrates or alkynols may be employed to eliminate the need of dioxane and alkylene oxides, while the use of the alkyl nitrates or alkynols eliminates the need for a nitroalkane in the stabilizer formulation.

p53 gene mutation spectrum in hepatocellular carcinoma.

Abstract: In order to clarify the significance of mutation of the p53 tumor suppressor gene in the genesis and development of human hepatocellular carcinoma (HCC) in an aflatoxin B1 low-exposure area, the spectrum, i.e., incidence, type, and site, of p53 gene mutations was examined in 169 tissue samples resected mainly from Japanese patients using single-strand conformation polymorphism analysis and direct sequencing. Forty-nine tumors (29%) showed a p53 mutation (39 point mutations and 10 frameshifts). The point mutations comprised 18 transitions, only 4 of which occurred at CpG sites, and 21 transversions. Two evolutionarily conserved domains, IV and V, contained 65% of all mutations and codon 249 was the most frequent mutation site (7/49). The spectrum of p53 mutation did not differ among HCCs in relation to the type of hepatitis virus infection, sex, age, and background liver disease of patients, tumor size, or presence of metastasis, but incidence and site were significantly associated with the degree of differentiation of cancer cells. In poorly differentiated HCC, p53 mutation was frequent (54%) and clustered on domains IV and V, whereas in well or moderately differentiated HCC, the mutation was less frequent (21%) and equally distributed on domains II to V. Restriction fragment length polymorphism analysis revealed loss of heterozygosity on chromosome 17p in 55 (69%) of 80 informative cases and in 34 (95%) of 36 cases with p53 mutation. Therefore, p53 gene mutation is suggested to occur independently of the type of viral infection or status of preexisting liver disease and to occur preferentially in moderately and poorly differentiated HCCs in association with or after loss of another p53 allele as a late event of HCC progression.

Leber's Hereditary Optic Neuropathy: Clinical Manifestations of the 3460 Mutation

Abstract: • Objective. —To define the clinical features of Leber's hereditary optic neuropathy associated with the 14484 mitochondrial DNA mutation and to compare these features with those associated with three other pathogenetic mutations. Design and Patients. —Clinical and historical data were collected from 19 visually symptomatic patients from 17 independent pedigrees with the molecularly confirmed 14484 mutation. Main Outcome Measures. —Demographic features, age of onset of visual loss, nadir of visual acuity, occurrence and timing of visual recovery, family history of visual loss, and associated medical and environmental conditions. Results. —Clinical characteristics associated with the 14484 mutation are similar overall to those of the three other primary mutations. One notable distinguishing feature is the higher incidence of visual recovery among patients with the 14484 mutation. Thirty-seven percent of our patients experienced visual recovery compared with 5% with the 11778 mutation ( P Conclusions. —Leber's hereditary optic neuropathy associated with the 14484 mitochondrial DNA mutation may have a better prognosis for visual recovery. The phenotypic expression of the 14484 mutation may be influenced by concurrent medical and environmental factors. Molecular genetic testing in suspected Leber's hereditary optic neuropathy is useful to confirm the diagnosis and to assess visual prognosis.

Fatal familial insomnia A second kindred with mutation of prion protein gene at codon 178

Abstract: Fatal familial insomnia (FFI), a condition characterized by inability to sleep, dysautonomia, motor disturbances, and selective thalamic atrophy is a prion disease linked to a GAC→C mutation at codon 178 of the prion gene. These data were obtained from one kindred. We now report a second kindred affected by FFI and carrying the same mutation. The finding of the same disease phenotype and genotype in a second family further validates FFI as a distinct disease entity and a phenotype of the GAC→C mutation at codon 178 of the prion gene.

Corrections and Clarifications: Multiple Intestinal Neoplasia Caused By a Mutation in the Murine Homolog of the APC Gene

Abstract: Germ-line mutations of the APC gene are responsible for familial adenomatous polyposis (FAP), an autosomal dominantly inherited disease in humans. Patients with FAP develop multiple benign colorectal tumors. Recently, a mouse lineage that exhibits an autosomal dominantly inherited predisposition to multiple intestinal neoplasia (Min) was described. Linkage analysis showed that the murine homolog of the APC gene (mApc) was tightly linked to the Min locus. Sequence comparison of mApc between normal and Min-affected mice identified a nonsense mutation, which cosegregated with the Min phenotype. This mutation is analogous to those found in FAP kindreds and in sporadic colorectal cancers.

Rapid sampling of model space using genetic algorithms: examples from seismic waveform inversion

Abstract: SUMMARY The seismic waveform inversion problem is usually cast into the framework of Bayesian statistics in which prior information on the model parameters is combined with the data and physics of the forward problem to estimate the a posteriori probability density (PPD) in model space. The PPD is a function of an objective or fitness function computed from the observed and synthetic data. In general, the PPD or the fitness function is multimodal and its shape is unknown. Global optimization methods such as simulated annealing (SA) and genetic algorithms (GA) do not require that the shape of the fitness function be known. In this paper, we investigate GA to rapidly sample the most significant portion or portions of the PPD, when very little prior information is available. First, we use a simple three operator (selection, crossover and mutation) GA acting on a randomly chosen finite population of haploid binary coded models. We use plane wave transformed synthetic seismic data and a normalized cross-correlation function [E(m)] in the frequency domain as a fitness function. A moderate value of crossover probability, a low value of mutation probability, a high value of update probability and a proper population size are required to reach very close to the global maximum of the fitness function. Next, with an attempt to accelerate convergence we show that the concepts from simulated annealing can be used in stretching of the fitness function, i.e., we use exp [E(m)/T] rather than E(m) as the fitness function, where T is a control parameter analogous to temperature in simulated annealing. By a schemata analysis, we show that at low temperatures, schemata with above average fitness values are reproduced in large numbers causing a much more rapid convergence of the algorithm. A high value of temperature T assigns nearly equal selection probability to most of the schemata and thus retains diversity among the members of the population. Thus a GA with a step function type cooling schedule (very high temperature in the beginning followed by rapid cooling to a very low temperature) improves the performance dramatically: high values of the fitness function are obtained rapidly using only half as many models as would be required by a conventional GA. Similar performance could also be achieved by first using a high mutation probability and then decreasing the mutation probability to a very low value, while retaining the same low temperature throughout. We also address the problem of ‘genetic drift’ which causes the finite GAs to converge to one peak or the other when the algorithm is applied to a highly multimodal fitness function with several peaks of nearly the same height. A parallel genetic algorithm based on the concept of ‘punctuated equilibria’ is implemented to circumvent the problem. We run several GAs each with a finite subpopulation in parallel and collect many good models from each one of these runs. These are then used to grasp the most significant portion(s) of the PPD in model space. We then compute the weighted mean model and use the derived good models to estimate uncertainty in the derived model parameters.

Association of a nonsense mutation (W1282X), the most common mutation in the Ashkenazi Jewish cystic fibrosis patients in Israel, with presentation of severe disease.

Abstract: Only about 30% of the cystic fibrosis chromosomes in the Israeli cystic fibrosis patient populations carry the major CF mutation (delta F508). Since different Jewish ethnic groups tended to live as closed isolates until recent times, high frequencies of specific mutations are expected among the remainder cystic fibrosis chromosomes of these ethnic groups. Genetic factors appear to influence the severity of the disease. It is therefore expected that different mutations will be associated with either severe or mild phenotype. Direct genomic sequencing of exons included in the two nucleotide-binding folds of the putative CFTR protein was performed on 119 Israeli cystic fibrosis patients from 97 families. One sequence alteration which is expected to create a termination at residue 1282 (W1282X) was found in 63 chromosomes. Of 95 chromosomes, 57 (60%) are of Ashkenazi origin. Together with the delta F508 (23% in this group), G542X, N1303K, and 1717-1G----A mutations, the identification of 92% of cystic fibrosis chromosomes of Ashkenazi origin becomes possible. Patients homozygous for the W1282X mutation (n = 16) and patients heterozygous for the delta F508 and W1282X mutations (n = 22) had similarly severe disease, reflected by pancreatic insufficiency, high incidence of meconium ileus (37% and 27%, respectively), early age at diagnosis, poor nutritional status, and variable pulmonary function. In conclusion, the W1282X mutation is the most common cystic fibrosis mutation in the Ashkenazi Jewish patient population in Israel. This nonsense mutation is associated with presentation of severe disease.

[Bernard -Soulier syndrome].

Abstract: Bernard-Soulier syndrome is a bleeding disorder associated with abnormal platelets, which are blood cell fragments involved in blood clotting. In affected individuals, platelets are unusually large and fewer in number than usual (a combination known as macrothrombocytopenia). People with Bernard-Soulier syndrome tend to bruise easily and have an increased risk of nosebleeds (epistaxis). They may also experience abnormally heavy or prolonged bleeding following minor injury or surgery or even without trauma (spontaneous bleeding). In some affected individuals, bleeding under the skin causes tiny red or purple spots on the skin called petechiae. Women with Bernard-Soulier syndrome often have heavy or prolonged menstrual periods (menorrhagia).

Evidence of founder chromosomes in fragile X syndrome.

Abstract: The mutation responsible for fragile X syndrome and myotonic dystrophy involves the amplification of a simple trinucleotide repeat sequence, which increases in successive generations of affected pedigrees accounting for increasing penetrance of both disorders. This common molecular basis suggests that the two diseases may share other genetic features, but whereas myotonic dystrophy exhibits a significant founder chromosome effect, fragile X syndrome apparently has a very high mutation frequency. By haplotype analysis of microsatellite markers which flank the fragile X unstable element, we have uncovered evidence of founder chromosomes of the fragile X ‘mutation’. Disorders caused by heritable unstable elements may therefore exhibit common genetic properties including anticipation and founder chromosomes.

Mutation Pattern of the p53 Gene as a Diagnostic Marker for Multiple Hepatocellular Carcinoma

Abstract: Hepatocellular carcinoma, sometimes shows multiple tumor nodules, therefore poses a problem of differential diagnosis between cancers of multifocal and those of metastatic origin. Conventionally, pathological criteria have been used for this purpose, but these are largely subjective. In order to facilitate more objective differential diagnosis of multiple hepatocellular carcinoma, we used the pattern of mutation of the p53 gene as a marker for each tumor nodule. We studied 58 nodules from 26 cases of multiple hepatocellular carcinoma using polymerase chain reaction-single strand conformation polymorphism analysis, a simple method for detecting mutations. p53 gene mutations were detected in 65% (17 of 26) of cases. The internodule mutation patterns were heterogeneous in 11 cases and homogeneous in 6, enabling a multifocal origin to be diagnosed in the former and a metastatic origin in the latter at the genetic level. Moreover, the origin of recurrent tumors was determined from the mutation pattern. It is concluded that analysis of p53 mutations seems to be useful for differentiating the origin of multiple cancers, since the information it yields is essentially objective.

p53 Mutations Cluster at Codon 249 in Hepatitis B Virus-positive Hepatocellular Carcinomas from China

Abstract: DNA samples from 36 hepatocellular carcinoma (HCC) patients from China were screened for a specific mutation affecting codon 249 of the p53 gene, recently identified as a hotspot mutation in some HCCs. We detected the tumor-specific p53 codon 249 mutation in 21 (58%) of 36 HCCs examined. Thirteen patients with the specific codon 249 mutation had lost the remaining allele of p53 , whereas the remaining eight patients appeared to have retained both copies of the gene. These results suggest that alterations of p53 may be important events in the genesis of HCCs and that point mutation may precede allele loss.

Directional mutation pressure, selective constraints, and genetic equilibria.

Abstract: Rates of substitution mutations in two directions, v [from an A-T or T-A nucleotide pair (AT-pair) to a G-C or C-G nucleotide pair (GC-pair)] and u [from a GC-pair to an AT-pair], are usually not the same. The net effect, v/(u + v), has previously been defined as directional mutation pressure (mu D), which explains the wide interspecific variation and narrow intragenomic heterogeneity of DNA G + C content in bacteria. In this article, first, a theory of the evolution of DNA G + C content is presented that is based on the equilibrium among three components: directional mutation pressure, DNA G + C content, and selective constraints. According to this theory, consideration of both u and v as well as selective constraints is essential to explain the molecular evolution of the DNA base composition and sequence. Second, the theory of directional mutation pressure is applied to the analysis of the wide intragenomic heterogeneity of DNA G + C content in multicellular eukaryotes. The theory explains the extensive intragenomic heterogeneity of G + C content of higher eukaryotes primarily as the result of the intragenomic differences of directional mutation pressure and selective constraints rather than the result of positive selections for functional advantages of the DNA G + C content itself.

Missense glucokinase mutation in maturity–onset diabetes of the young and mutation screening in late–onset diabetes

Abstract: We describe a codon 299 mutation in the glucokinase gene in a British pedigree with maturity–onset diabetes of the young (MODY) resulting in a substitution of glycine to arginine. One out of fifty patients diagnosed with classical late–onset type 2 diabetes mellitus was also found to have this mutation. All nine relatives of this patient who have inherited the mutation have type 2 diabetes, although six others without the mutation are also present with diabetes. The discovery that glucokinase mutations can cause MODY and was also found in ten affected members of a pedigree with type 2 diabetes in which MODY had not previously been considered indicates that diagnosis based on molecular pathology will be helpful in understanding the aetiology of type 2 diabetes.

Foot-and-mouth disease virus populations are quasispecies.

Abstract: The term “quasispecies” describes complex distributions of replicating molecules subject to mutation and competitive selection (Eigen 1971; Eigen and Schuster 1979; Eigen and Biebricher 1988). The original theoretical concept of Eigen and colleagues concerned populations of infinite numbers of individual molecules and ideal, steady-state equilibrium conditions (recent review on the theoretical concept in Eigen et al. 1989). It is clear that in spite of their large population size, RNA viruses deviate from such idealized behaviour. However, several key features of RNA viruses such as nucleotide sequence heterogeneity, generally high mutation rates, and potential for very rapid evolution are best understood in the framework of the quasispecies concept (see the chapter by Holland et al.). Viral isolates, either in their natural niche or disturbed by adaptation to growing in cell culture, consist of a multitude of viable and defective mutants termed the “mutant spectrum” of the population. During replication, each genomic distribution is dominated by one (or several) “master sequence (s),” that generally coincides with the average or consensus sequence of the population. With the levels of genetic heterogeneity for foot- and-mouth disease virus (FMDV) documented in the following paragraphs, the master sequence often represents as little as 1% or less of the population of molecules, and it may have a brief life span. Here we review the evidence for the quasispecies structure of FMDV and its biological implications, notably the antigenic diversity of this widespread pathogen.

Identification of a nonsense mutation in the amelogenin gene (AMELX) in a family with X-linked amelogenesis imperfecta (AIH1).

Abstract: A family with X-linked amelogenesis imperfecta (XAI) is described in which the disease is associated with a nonsense mutation in exon 5 of the amelogenin gene. This mutation involves a single base deletion (CCCC-->CCC) in the exon in an affected male, his sister and his mother. The effect of this deletion is to alter the reading frame and to introduce an inappropriate TGA stop codon (an opal mutation) into the exonic sequence of the amelogenin gene immediately 3' of the mutation. The clinical features in the examined members of this family indicate that, in some individuals, the most noticeable defect is of enamel hypoplasia. In others, the hypoplastic changes are subtle and might have been overlooked on cursory examination; the most noticeable change is of enamel colour, indicating a degree of hypomineralisation. We propose that the amelogenin gene is implicated in both the formation of enamel of normal thickness and in the normal mineralisation process.

The genomic mutation rate for fitness in Drosophila

Abstract: The mutation rate per genome for local affecting fitness is crucial in theories of the evolution of sex and recombination and of outbreeding mechanisms. Mutational variation in fitness may also be important in the evolution of mate choice in animals. No information is available on the rate at which spontaneous mutations with small effects on fitness arise, although viability (probability of survival to adulthood) has been studied in Drosophila melanogaster. These experiments involved the accumulation of spontaneous mutations in the virtual absence of natural selection, in a set of independently maintained lines with a common origin. The rates of decline in mean and increase in variance among lines permit estimation of limits to the mean number of new mutations arising per generation (U) and the average homozygous effect of a new mutation of minor effect(s). For the second chromosome of D. melanogaster, the value of U is at least 0.17 (ref. 7), and (1-h)s is less than 0.02, where hs is the average decline in fitness of heterozygotes. As the second chromosome is about 40% of the genome, these data indicate a mutation rate per haploid genome of at least 0.42 for viability. Here we present similar data on the effects of homozygous spontaneous mutations on a measure of fitness in D. melanogaster.

A mutation in adenylosuccinate lyase associated with mental retardation and autistic features.

Abstract: We have examined the molecular basis of three cases of severe mental retardation with autistic features in one family. A point mutation in a purine nucleotide biosynthetic enzyme, adenylosuccinate lyase (ASL), segregates with the disorder. The affected children are homozygous for the point mutation while the parents and all four unaffected children are heterozygous. The point mutation is absent in control subjects. The point mutation results in a Ser413Pro substitution which leads to structural instability of the recombinant mutant enzyme, and this instability lowers ASL levels in lymphocytes. These observations suggest that the instability of ASL underlies the severe developmental disorder in the affected children, and that mutations in the ASL gene may result in other cases of mental retardation and autistic features.

Inherited WT1 mutation in Denys-Drash syndrome.

Abstract: Patients with the Denys-Drash syndrome (Wilms' tumor, genital anomalies, and nephropathy) have been demonstrated to carry de novo constitutional mutations in WT1, the Wilms' tumor gene at chromosome 11p13. We report three new cases, two carrying a previously described WT1 exon 9 mutation and one with a novel WT1 exon 8 mutation. However, unlike patients in previous reports, one of our three patients inherited the affected allele from his phenotypically unaffected father. This observation indicates that the WT1 exon 9 mutation affecting 394Arg demonstrated in over one-half of the patients with the Denys-Drash syndrome may exhibit incomplete penetrance. Consequently, familial studies in patients affected by this syndrome are recommended.