Showing papers on "Mutation (genetic algorithm) published in 2001"

Completely Derandomized Self-Adaptation in Evolution Strategies

Abstract: This paper puts forward two useful methods for self-adaptation of the mutation distribution - the concepts of derandomization and cumulation. Principle shortcomings of the concept of mutative strategy parameter control and two levels of derandomization are reviewed. Basic demands on the self-adaptation of arbitrary (normal) mutation distributions are developed. Applying arbitrary, normal mutation distributions is equivalent to applying a general, linear problem encoding. The underlying objective of mutative strategy parameter control is roughly to favor previously selected mutation steps in the future. If this objective is pursued rigorously, a completely derandomized self-adaptation scheme results, which adapts arbitrary normal mutation distributions. This scheme, called covariance matrix adaptation (CMA), meets the previously stated demands. It can still be considerably improved by cumulation - utilizing an evolution path rather than single search steps. Simulations on various test functions reveal local and global search properties of the evolution strategy with and without covariance matrix adaptation. Their performances are comparable only on perfectly scaled functions. On badly scaled, non-separable functions usually a speed up factor of several orders of magnitude is observed. On moderately mis-scaled functions a speed up factor of three to ten can be expected.

Gene Expression Programming: A New Adaptive Algorithm for Solving Problems.

Abstract: Gene expression programming, a genotype/phenotype genetic algorithm (linear and ramified), is presented here for the first time as a new technique for the creation of computer programs. Gene expression programming uses character linear chromosomes composed of genes structurally organized in a head and a tail. The chromosomes function as a genome and are subjected to modification by means of mutation, transposition, root transposition, gene transposition, gene recombination, and oneand two-point recombination. The chromosomes encode expression trees which are the object of selection. The creation of these separate entities (genome and expression tree) with distinct functions allows the algorithm to perform with high efficiency that greatly surpasses existing adaptive techniques. The suite of problems chosen to illustrate the power and versatility of gene expression programming includes symbolic regression, sequence induction with and without constant creation, block stacking, cellular automata rules for the density-classification problem, and two problems of boolean concept learning: the 11-multiplexer and the GP rule problem.

Are Rare Variants Responsible for Susceptibility to Complex Diseases

Abstract: Little is known about the nature of genetic variation underlying complex diseases in humans. One popular view proposes that mapping efforts should focus on identification of susceptibility mutations that are relatively old and at high frequency. It is generally assumed—at least for modeling purposes—that selection against complex disease mutations is so weak that it can be ignored. In this article, I propose an explicit model for the evolution of complex disease loci, incorporating mutation, random genetic drift, and the possibility of purifying selection against susceptibility mutations. I show that, for the most plausible range of mutation rates, neutral susceptibility alleles are unlikely to be at intermediate frequencies and contribute little to the overall genetic variance for the disease. Instead, it seems likely that the bulk of genetic variance underlying diseases is due to loci where susceptibility mutations are mildly deleterious and where there is a high overall mutation rate to the susceptible class. At such loci, the total frequency of susceptibility mutations may be quite high, but there is likely to be extensive allelic heterogeneity at many of these loci. I discuss some practical implications of these results for gene mapping efforts.

Short Communication Frequent FGFR3 Mutations in Papillary Non-Invasive Bladder (pTa) Tumors

Abstract: (CIS), 50 pTa, 19 pT1, and43 pT2–4. All 48 mutations identified were identical tothe germinal activating mutations that cause thanato-phoric dysplasia, a lethal form of dwarfism. TheS249C mutation, found in 33 of the 48 mutated tu-mors, was the most common. The frequency of mu-tations was higher in pTa tumors (37 of 50, 74%) thanin CIS (0 of 20, 0%;

Evolving responsively: adaptive mutation

Abstract: A basic principle of genetics is that the likelihood that a particular mutation occurs is independent of its phenotypic consequences. The concept of adaptive mutation seemed to challenge this principle with the discoveries of mutations stimulated by stress, some of which allow adaptation to the stress. The emerging mechanisms of adaptive genetic change cast evolution, development and heredity into a new perspective, indicating new models for the genetic changes that fuel these processes.

The Booroola (FecB) phenotype is associated with a mutation in the bone morphogenetic receptor type 1 B (BMPR1B) gene.

Abstract: Genetic variations in ovulation rate which occur in different breeds of sheep provide useful models to explore the mechanisms regulating the development of antral follicles. The Booroola gene, an autosomal mutation that affects ovulation rate, has been known for over two decades and despite intensive research it has not yet been identified. Using resources from human genome mapping and known data about gene linkage and chromosome location in the sheep, we selected the gene encoding the Bone Morphogenetic Protein receptor (BMPR) type 1 B (ALK-6) as a candidate site for the mutation. The BMPR1B gene in the human is located at the region linked with the Booroola mutation, syntenic to chromosome 6 in the sheep. A fragment of the sheep BMPR1B gene was cloned from an ovarian cDNA and the deduced aminoacid (AA) sequence is over 98% homologous to the known mammalian sequences. cDNA and genomic DNA from 20 Booroola genotypes were screened and two point mutation were found in the kinase domain of the receptor, one at base 746 of the coding region (A in the ++ to a G in FF animals) which results in a change from a glutamine in the wild type to a arginine in the Booroola animals. Another point mutation was identified at position 1113, (C to A) but this mutation does not change the coding aminoacid. The first mutation was confirmed in genomic DNA from 10 ewes from an independent Brazilian flock which segregates the Booroola phenotype. In all instances homozygous FecB gene carrier (n=11) had only the 746 A to G mutation, non gene carriers (n=14) had only the wild type sequence and heterozygote gene carriers (n=5) had both sequences. This mutation in the subdomain 3 of the kinase domain could result in an alteration in the expression and/or phosphorylation of SMADs, resulting in the phenotype characteristic of the Booroola animals which is the 'precocious' development of a large number of small antral follicles resulting in increased ovulation rate.

Mutation frequency and biological cost of antibiotic resistance in Helicobacter pylori

Abstract: Among the several factors that affect the appearance and spread of acquired antibiotic resistance, the mutation frequency and the biological cost of resistance are of special importance. Measurements of the mutation frequency to rifampicin resistance in Helicobacter pylori strains isolated from dyspeptic patients showed that approximately 1/4 of the isolates had higher mutation frequencies than Enterobacteriaceae mismatch-repair defective mutants. This high mutation frequency could explain why resistance is so frequently acquired during antibiotic treatment of H. pylori infections. Inactivation of the mutS gene had no substantial effect on the mutation frequency, suggesting that MutS-dependent mismatch repair is absent in this bacterium. Furthermore, clarithromycin resistance conferred a biological cost, as measured by a decreased competitive ability of the resistant mutants in mice. In clinical isolates this cost could be reduced, indicating that compensation is a clinically relevant phenomenon that could act to stabilize resistant bacteria in a population.

Mutation 2000: uniting the orthogonal

Abstract: Mutation testing is a powerful, but computationally expensive, technique for unit testing software. This expense has prevented mutation form becoming widely used in practical situations, but recent engineering advances have given us techniques and algorithms for significantly reducing the cost of mutation testing. These technique include a new algorithmic execution technique include a new algorithmic execution technique called schema-based mutation, a reduction technique called selective mutation, heuristics for detecting equivalent mutants, and algorithms for automatic test data generation. This paper reviews experimentation with these advances and outlines a design for a system that will approximate mutation, but in a way that will be accessible to every day programmers. We envision a system to which a programmer can submit a program unit and get back a set of input/output pairs that are guaranteed to form an effective test of the unit by being close to mutation adequate. We believe this system could be efficient enough to be adopted by leading-edge software developers. Full automation in unit testing has the potential to dramatically change the economic balance between testing and development, by reducing the cost of testing from the major part of the total development cost to a small fraction.

On benchmarking functions for genetic algorithms

Abstract: This paper presents experimental results on the major benchmarking functions used for performance evaluation of Genetic Algorithms (GAs). Parameters considered include the effect of population size, crossover probability, mutation rate and pseudorandom generator. The general computational behavior of two basic GAs models, the Generational Replacement Model (GRM) and the Steady State Replacement Model (SSRM) is evaluated.

Lethal outcome of a patient with a complete dihydropyrimidine dehydrogenase (DPD) deficiency after administration of 5-fluorouracil: frequency of the common IVS14+1G>A mutation causing DPD deficiency.

Abstract: Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-fluorouracil (5FU), and it is suggested that patients with a partial deficiency of this enzyme are at risk from developing a severe 5FU-associated toxicity. In this study, we demonstrated that a lethal toxicity after a treatment with 5FU was attributable to a complete deficiency of DPD. Analysis of the DPD gene for the presence of mutations showed that the patient was homozygous for a G→A mutation in the invariant GT splice donor site flanking exon 14 (IVS14+1G>A). As a consequence, no significant residual activity of DPD was detected in peripheral blood mononuclear cells. To determine the frequency of the IVS14+1G>A mutation in the Dutch population, we developed a novel PCR-based method allowing the rapid analysis of the IVS14+1G>A mutation by RFLP. Screening for the presence of this mutation in 1357 Caucasians showed an allele frequency of 0.91%. In our view, the apparently high prevalence of the IVS14+1G>A mutation in the normal population, with 1.8% heterozygotes, warrants genetic screening for the presence of this mutation in cancer patients before the administration of 5FU.

Mutation induction and tissue culture in improving fruits

Abstract: This review describes in vitro mutation induction methods in fruits and the in vitro selection procedures available for early screening. Results obtained through in vitro mutation techniques, including somaclonal variation, are reviewed and compared with the current achievements and future prospects of transgenic breeding. Plant improvement based on mutations, which change one or a few specific traits of a cultivar, can contribute to fruit improvement without altering the requirements of fruit industry. Induced mutations have well defined limitations in fruit breeding applications, but their possibilities may be expanded by the use of in vitro techniques. Tissue culture increases the efficiency of mutagenic treatments for variation induction, handling of large populations, use of ready selection methods, and rapid cloning of selected variants. Molecular techniques can provide a better understanding of the potential and limitations of mutation breeding e.g. molecular marker-assisted selection, which can lead to the early identification of useful variants. The relatively high number of research reports compared with the low number of cultivars released suggests that mutagenesis in combination with tissue culture is either ineffective or has yet to be exploited in fruits. Positive achievement recorded in other species seem to support the hypothesis that in vitro mutation induction has high potential also for fruit improvement. The possible contribution of a well-pondered and coordinated use of the numerous mutation induction, mutant selection, and field validation procedures available to advances in fruit breeding is discussed.

Novel PRKAG2 Mutation Responsible for the Genetic Syndrome of Ventricular Preexcitation and Conduction System Disease With Childhood Onset and Absence of Cardiac Hypertrophy

Abstract: Background— We recently reported a mutation in the PRKAG2 gene to be responsible for a familial syndrome of ventricular preexcitation, atrial fibrillation, conduction defects, and cardiac hypertrophy. We now report a novel mutation in PRKAG2 causing Wolff-Parkinson-White syndrome and conduction system disease with onset in childhood and the absence of cardiac hypertrophy. Methods and Results— DNA was extracted from white blood cells obtained from family members. PRKAG2 exons were amplified by polymerase chain reaction and were screened for mutations by direct sequencing. The genomic organization of the PRKAG2 gene was determined using inter-exon long-range polymerase chain reaction for cDNA sequence not available in the genome database. A missense mutation, Arg531Gly, was identified in all affected individuals but was absent in 150 unrelated individuals. The PRKAG2 gene was determined to consist of 16 exons and is at least 280 kb in size. Conclusions— We identified a novel mutation (Arg531Gly) in the γ-2 ...

Improvements in genetic algorithms

Abstract: This paper presents an exhaustive study of the Simple Genetic Algorithm (SGA), Steady State Genetic Algorithm (SSGA) and Replacement Genetic Algorithm (RGA). The performance of each method is analyzed in relation to several operators types of crossover, selection and mutation, as well as in relation to the probabilities of crossover and mutation with and without dynamic change of its values during the optimization process. In addition, the space reduction of the design variables and global elitism are analyzed. All GAs are effective when used with its best operations and values of parameters. For each GA, both sets of best operation types and parameters are found. The dynamic change of crossover and mutation probabilities, the space reduction and the global elitism during the evolution process show that great improvement can be achieved for all GA types. These GAs are applied to TEAM benchmark problem 22.

Interface Mutation: an approach for integration testing

Abstract: The need for test adequacy criteria is widely recognized. Several criteria have been proposed for the assessment of adequacy of tests at the unit level. However, there remains a lack of criteria for the assessment of the adequacy of tests generated during integration testing. We present a mutation based interprocedural criterion, named Interface Mutation (IM), suitable for use during integration testing. A case study to evaluate the proposed criterion is reported. In the study, the UNIX sort utility was seeded with errors and Interface Mutation evaluated by measuring the cost of its application and its error revealing effectiveness. Alternative IM criteria using different sets of Interface Mutation operators were also evaluated. While comparing the error revealing effectiveness of these Interface Mutation-based test sets with same size randomly generated test sets, we observed that in most cases Interface Mutation based test sets are superior. The results suggest that Interface Mutation offers a viable test adequacy criteria for use at the integration level.

Genotype and phenotype analysis of 171 patients referred for molecular study of the fibrillin-1 gene FBN1 because of suspected Marfan syndrome.

Abstract: Results: Diagnostic criteria for MFS were fulfilled in 94 patients, 62 (66%) of whom had an FBN1 mutation. A significantly higher incidence of ectopia lentis was found in the patients with MFS with an FBN1 mutation vs those without (P=.04). Among the 77 patients who did not meet the criteria, an FBN1 mutation was found in 9 patients (12%). No correlation was found between the severity of the phenotype and the position and nature of the FBN1 mutation. Conclusions: This study showed a significant difference in the number of FBN1 mutations between patients fulfilling and those not fulfilling the diagnostic criteria for MFS, which seems to be a good predictor of the presence of an FBN1 mutation. A comprehensive clinical evaluation is mandatory before establishing a definitive diagnosis. An FBN1 mutation analysis is helpful to identify individuals at high risk for MFS who need careful follow-up, particularly in families displaying phenotypic variability and in children. Arch Intern Med. 2001;161:2447-2454

A deletion mutation in GJB6 cooperating with a GJB2 mutation in trans in non-syndromic deafness: A novel founder mutation in Ashkenazi Jews.

Abstract: A deletion of at least 140 kb starting approximately 35kb upstream (telomeric) to the GJB2 (CX26) gene was identified in 7 patients from 4 unrelated Jewish Ashkenazi families with non-syndromic hearing loss. These patients were heterozygous for one of the common mutations 167delT or 35delG in the GJB2 gene in trans to the deletion. The deletion started at 5' side of the GJB6 (CX30) gene including the first exon and it did not affect the integrity of the GJB2 gene. The deletion mutation segregated together with the hearing loss, and was not found in a control group of 100 Ashkenazi individuals. We suggest that the deletion is a recessive mutation causing hearing loss in individuals that are double heterozygous for the deletion and for a mutation in the GJB2 gene. The effect of the deletion mutation could be due to a digenic mode of inheritance of GJB2 and GJB6 genes that encode two different connexins; connexin 26 and connexin 30, or it may abolish control elements that are important in the expression of the GJB2 gene in the cochlea. Regardless which of the options is valid, it is apparent that the deletion mutation provides a new insight into connexin function in the auditory system. The deletion mutation was on the same haplotypic background in all the families, and therefore is a founder mutation that increases the impact of GJB2 in the etiology of prelingual recessive non-syndromic hearing loss in the Ashkenazi population.

Further evidence that neurofilament light chain gene mutations can cause Charcot-Marie-Tooth disease type 2E

Abstract: A missense mutation in the neurofilament light chain gene (NEFL, NF-L) at chromosome 8p21 was recently reported in a single Charcot-Marie-Tooth type 2 family (CMT2). This new CMT2 variant is designated CMT2E. The NEFL gene mutation showed co-segregation with the disease phenotype and is thus most likely the disease-causing mutation. However, the possibility that it is a closely linked rare polymorphism can not be ruled out with certainty. We observed a novel NEFL missense mutation in a second CMT family, providing supporting evidence that CMT2E is caused by NEFL gene mutations.

An inherited mutation outside the highly conserved DNA-binding domain of the p53 tumor suppressor protein in children and adults with sporadic adrenocortical tumors.

Abstract: Mutations of the p53 tumor suppressor gene are the single most common genetic alterations in human cancers. Recently, a distinct nucleotide substitution was identified in exon 10 of the p53 gene, leading to an Arg337His mutation in 97% of children with adrenocortical tumors from Southern Brazil. In the present study, we investigated the presence of this mutation in a larger series of 55 patients (37 adults and 18 children) with benign and malignant sporadic adrenocortical tumors. None of the patients had family cancer histories that conformed to the criteria for Li-Fraumeni syndrome. Twenty-one asymptomatic close relatives of patients with p53 mutations and 60 normal unrelated individuals were also studied. The missense Arg337His mutation was identified in 19 patients (14 children and 5 adults), and 8 of 11 cases studied had LOH. Among the 19 patients with the Arg337His mutation, only one boy and three adults showed fatal evolution or recurrent metastases. This mutation was also identified in heterozygous state in asymptomatic first-degree relatives of the patients, indicating that Arg337His mutation was inherited in most cases. In contrast, this mutation was not found in 120 alleles of normal unrelated controls. In conclusion, the germ line Arg337His mutation of p53 protein is present at a high frequency (77.7%) in children with benign or malignant sporadic adrenocortical tumors, but it is not restricted to the pediatric group, since 13.5% of adults with adrenocortical tumors also had this mutation. The presence of this mutation was related to unfavorable prognosis in most of the adults, but not in the children with adrenocortical tumors.

Metapopulation extinction caused by mutation accumulation

Abstract: Theory suggests that the risk of extinction by mutation accumulation can be comparable to that by environmental stochasticity for an isolated population smaller than a few thousand individuals. Here we show that metapopulation structure, habitat loss or fragmentation, and environmental stochasticity can be expected to greatly accelerate the accumulation of mildly deleterious mutations, lowering the genetic effective size to such a degree that even large metapopulations may be at risk of extinction. Because of mutation accumulation, viable metapopulations may need to be far larger and better connected than would be required under just stochastic demography.

Mutation analysis in mitochondrial fatty acid oxidation defects: Exemplified by acyl-CoA dehydrogenase deficiencies, with special focus on genotype-phenotype relationship.

Abstract: Mutation analysis of metabolic disorders, such as the fatty acid oxidation defects, offers an additional, and often superior, tool for specific diagnosis compared to traditional enzymatic assays. With the advancement of the structural part of the Human Genome Project and the creation of mutation databases, procedures for convenient and reliable genetic analyses are being developed. The most straightforward application of mutation analysis is to specific diagnoses in suspected patients, particularly in the context of family studies and for prenatal/preimplantation analysis. In addition, from these practical uses emerges the possibility to study genotype–phenotype relationships and investigate the molecular pathogenesis resulting from specific mutations or groups of mutations. In the present review we summarize current knowledge regarding genotype–phenotype relationships in three disorders of mitochondrial fatty acid oxidation: very-long chain acyl-CoA dehydrogenase (VLCAD, also ACADVL), medium-chain acyl-CoA dehydrogenase (MCAD, also ACADM), and short-chain acyl-CoA dehydrogenase (SCAD, also ACADS) deficiencies. On the basis of this knowledge we discuss current understanding of the structural implications of mutation type, as well as the modulating effect of the mitochondrial protein quality control systems, composed of molecular chaperones and intracellular proteases. We propose that the unraveling of the genetic and cellular determinants of the modulating effects of protein quality control systems may help to assess the balance between genetic and environmental factors in the clinical expression of a given mutation. The realization that the effect of the monogene, such as disease-causing mutations in the VLCAD, MCAD, and SCAD genes, may be modified by variations in other genes presages the need for profile analyses of additional genetic variations. The rapid development of mutation detection systems, such as the chip technologies, makes such profile analyses feasible. However, it remains to be seen to what extent mutation analysis will be used for diagnosis of fatty acid oxidation defects and other metabolic disorders. Hum Mutat 18:169–189, 2001. © 2001 Wiley-Liss, Inc.

Psychological impact of receiving a BRCA1/BRCA2 test result.

Abstract: Mutation analysis for autosomal dominant hereditary breast/ovarian cancer genes (BRCA1/BRCA2) became an important technique for women at risk of carrying these mutations. Healthy female mutation carriers have a high lifetime risk for breast and/or ovarian cancer and may opt for frequent breast and ovary surveillance or prophylactic surgery (mastectomy and/or oophorectomy). Psychological distress was assessed in 78 healthy women at risk of having inherited a BRCA1/BRCA2 mutation opting for genetic testing and 56 partners several weeks prior to (“pre-test”) and after (“post-test”) learning about their DNA test result. Twenty-five women were found to be mutation carriers, and 53 were non-mutation carriers. One goal of the study was to identify individuals at risk for high distress in the weeks following disclosure of the test result. Interview transcripts were used to give a fuller picture of pre- and post-test distress. High post-test anxiety was reported by 20% of the mutation carrier women and by 35% of their partners. Eleven percent of women without the mutation and 13% of their partners reported high post-test anxiety levels. High post-test anxiety in women was significantly related to 1) a high level of pre-test anxiety and 2) being a mutation carrier. Women without a mutation who had a sister identified as a mutation carrier recently had higher post-test levels of depression than the other non-mutation carriers. It is suggested to consider seriously the need for psychological support in mutation carriers who had been anxious at pre-test already. For most non-mutation carriers, psychological follow-up might be of lesser importance, but those having a sister receiving an unfavorable test result should be informed about the possibility that they might not feel relief. © 2001 Wiley-Liss, Inc.

Vanishing Cycles and Mutation

Abstract: Using Floer cohomology, we establish a connection between PicardLefschetz theory and the notion of mutation of exceptional collections in homological algebra.

Random Genetic Drift Determines the Level of Mutant mtDNA in Human Primary Oocytes

Abstract: We measured the proportion of mutant mtDNA (mutation load) in 82 primary oocytes from a woman who harbored the A3243G mtDNA mutation. The frequency distribution of mutation load indicates that random drift is the principal mechanism that determines the level of mutant mtDNA within individual oocytes.

The beta-thalassemia mutation spectrum in the Iranian population.

Abstract: β-Thalassemia is the most common hereditary disease in Iran. More than two million carriers of β-thalassemia live in Iran. Since the Iranian population is a mixture of different ethnic groups, it is necessary to determine the frequency and distribution of mutations in the different parts of the country. For this purpose, we divided Iran in to eight different regions according to the geographic and ethnic distribution of the population. Over a 10-year period 1,217 β-thalassemia chromosomes of 164 affected patients and 889 unrelated carriers were studied using the amplification refractory mutation system-polymerase chain reaction technique. We detected 81% β-thalassemia mutations in the studied chromosomes. IVS-II-I (G → A) was the predominant mutation found in our study (34%). Its relative frequency in the north was much higher than other regions, and it lessened toward the south, where the IVS-I-5(G → C) mutation was more common. IVS-I-5 (G → C) (7.55%), codons 8/9 (+G) (4.76%), and IVS-I-110 (G → A) (4.7...