Showing papers on "Mutation (genetic algorithm) published in 2004"
TL;DR: The development of a genetic association database (GAD) that aims to collect, standardize and archive genetic association study data and to make it easily accessible to the scientific community is described.
Abstract: To the editor: The increasing availability of polymorphism data has allowed more gene association studies to be carried out and the number of published genetic association studies is growing rapidly. Studies done secondarily to successful linkage studies over the last decade have also fueled the increase in published association studies. Although there are single-nucleotide polymorphism and human variation databases 1,2 , there is currently no public repository for genetic association data. It is difficult to query association data in a systematic manner or to integrate association data with other molecular databases. OMIM 3 , the main repository of genetic information for mendelian disorders, is largely text based and is of a historical narrative design, making it difficult to compare large sets of molecular data. Moreover, OMIM archives mature, high-quality data of high significance, the standard in rare mendelian disorders. Although this data is useful, OMIM does not routinely collect findings of lower significance or negative findings. The study of nonmendelian, common complex disorders is often a struggle to find disease relevance with lower significance values, and often conflicting evidence. Negative data are often not reported or are marginalized into obscure and less accessible scientific journals, resulting in a publication bias favoring positive genetic associations 4. Here, we describe the development of a genetic association database (GAD; http://geneticassociationdb.nih.gov) that aims to collect, standardize and archive genetic association study data and to make it easily accessible to the scientific community. There are no standards for designing, implementing, interpreting or reporting association studies (e.g., sample size, replication, significant P values), although guidelines have been suggested 4–7. The literature is filled with alternative, idiosyncratic and arbitrary gene names and gene symbols, as well as a continuum of phenotypic descriptions. Studies using arbitrary nomenclature continue to be published, making cross-comparison and meta-analysis difficult. One goal of GAD is to standardize molecular nomenclature in the archival process by including official HUGO gene symbols. After this assignment, each record is annotated with links to molecular databases (LocusLink, GeneCards, HapMap, etc.) and reference databases (PubMed, CDC), among others. Once they are standardized, integrating association data with other molecular databases, data mining tools, annotation and future sources of molecular data (e.g., gene interactions, quantitative trait loci) can be done systematically. Moreover, cross-comparison and meta-analysis of studies becomes more efficient. There are three main components of GAD: a web interface, Perl modules and the database, which uses the Oracle RDBMS. …
975 citations
TL;DR: The fundamental principles that govern the dynamics of activating oncogenes and inactivating tumour-suppressor genes in populations of reproducing cells are revealed.
Abstract: Evolutionary concepts such as mutation and selection can be best described when formulated as mathematical equations. Cancer arises as a consequence of somatic evolution. Therefore, a mathematical approach can be used to understand the process of cancer initiation and progression. But what are the fundamental principles that govern the dynamics of activating oncogenes and inactivating tumour-suppressor genes in populations of reproducing cells? Also, how does a quantitative theory of somatic mutation and selection help us to evaluate the role of genetic instability?
552 citations
TL;DR: A three‐dimension structure model of AChE is presented, showing that this unique substitution is localized in the oxyanion hole, explaining the insecticide insensitivity and its interference with the enzyme catalytic functions.
Abstract: High insecticide resistance resulting from insensitive acetylcholinesterase (AChE) has emerged in mosquitoes. A single mutation (G119S of the ace-1 gene) explains this high resistance in Culex pipiens and in Anopheles gambiae. In order to provide better documentation of the ace-1 gene and the effect of the G119S mutation, we present a three-dimension structure model of AChE, showing that this unique substitution is localized in the oxyanion hole, explaining the insecticide insensitivity and its interference with the enzyme catalytic functions. As the G119S creates a restriction site, a simple PCR test was devised to detect its presence in both A. gambiae and C. pipiens, two mosquito species belonging to different subfamilies (Culicinae and Anophelinae). It is possibile that this mutation also explains the high resistance found in other mosquitoes, and the present results indicate that the PCR test detects the G119S mutation in the malaria vector A. albimanus. The G119S has thus occurred independently at least four times in mosquitoes and this PCR test is probably of broad applicability within the Culicidae family.
543 citations
TL;DR: The aim of this study was to determine the cumulative risk of developing cancer in a large series of MSH6 mutation carriers, and recommended starting colonoscopic surveillance in female MSH 6 mutation carriers from age 30 years.
460 citations
TL;DR: The evaluation of 28 unrelated Chinese kindreds with AF found an arginine-to-cysteine mutation at position 27 (R27C) of KCNE2, the beta subunit of the KCNQ1-KCNE2 channel responsible for a background potassium current, is a gain-of-function mutation associated with the initiation and/or maintenance of AF.
Abstract: Atrial fibrillation (AF) is the most common cardiac arrhythmia encountered in clinical practice. We first reported an S140G mutation of KCNQ1, an α subunit of potassium channels, in one Chinese kindred with AF. However, the molecular defects and cellular mechanisms in most patients with AF remain to be identified. We evaluated 28 unrelated Chinese kindreds with AF and sequenced eight genes of potassium channels (KCNQ1, HERG, KCNE1, KCNE2, KCNE3, KCNE4, KCNE5, and KCNJ2). An arginine-to-cysteine mutation at position 27 (R27C) of KCNE2, the β subunit of the KCNQ1-KCNE2 channel responsible for a background potassium current, was found in 2 of the 28 probands. The mutation was present in all affected members in the two kindreds and was absent in 462 healthy unrelated Chinese subjects. Similar to KCNQ1 S140G, the mutation had a gain-of-function effect on the KCNQ1-KCNE2 channel; unlike long QT syndrome–associated KCNE2 mutations, it did not alter HERG-KCNE2 current. The mutation did not alter the functions of the HCN channel family either. Thus, KCNE2 R27C is a gain-of-function mutation associated with the initiation and/or maintenance of AF.
432 citations
TL;DR: The convergence speed with the proposed improved genetic algorithm is faster than that with the penalty function method and the forced mutation method, and the result of placement optimization is better.
Abstract: The global optimization of sensor locations for structural health monitoring systems is studied in this paper. First, the performance function based on damage detection is presented. Then, genetic algorithms (GAs) are adopted to search for the optimal locations of sensors. However, the simple GAs can result in infeasible solutions to the problem. Some improved strategies are presented in this paper, such as crossover based on identification code, mutation based on two gene bits, and improved convergence. The analytical results from the improved genetic algorithm are compared with the penalty function method and the forced mutation method. It is concluded that the convergence speed with the proposed improved genetic algorithm is faster than that with the penalty function method and the forced mutation method, and the result of placement optimization is better.
377 citations
TL;DR: The authors described a family in which three members affected by acute myeloid leukemia (AML) had identical, 212delC mutation in CEBPA, the gene encoding the granulocytic differentiation factor C/EBPalpha.
Abstract: We describe a family in whom three members affected by acute myeloid leukemia (AML) had an identical, 212delC mutation in CEBPA, the gene encoding the granulocytic differentiation factor C/EBPalpha. Unaffected family members did not have this mutation. Latent periods of 10, 18, and 30 years elapsed before the onset of overt leukemia in the three patients. One of them had a second CEBPA mutation, but only at the time of diagnosis. All three patients are currently well, with no abnormalities in the bone marrow. CEBPA mutation is apparently the primary event in the development of AML in this family.
332 citations
TL;DR: The observed effects on lipid binding and filament assembly may explain the pathogenic nature of the E46K mutation in α‐synuclein.
283 citations
248 citations
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TL;DR: In this article, a representation theoretic interpretation of matrix mutation, using tilting theory in cluster categories of hereditary algebras, was given, which was used to obtain a representation theoretical interpretation of cluster mutation in case of acyclic CHs of finite type.
Abstract: Matrix mutation appears in the definition of cluster algebras of Fomin and Zelevinsky. We give a representation theoretic interpretation of matrix mutation, using tilting theory in cluster categories of hereditary algebras. Using this, we obtain a representation theoretical interpretation of cluster mutation in case of acyclic cluster algebras of finite type.
173 citations
TL;DR: The evidence about HFE C282Y frequencies, extended haplotypes involving HLA-A and -B alleles, the validity of calculations of mutation age, selective advantage and current views on the relative importance of “demic-diffusion” and “adoption-diffusions” in the neolithic transition in Europe and since then are examined.
Abstract: The mutation responsible for most cases of genetic haemochromatosis in Europe (HFE C282Y) appears to have been originated as a unique event on a chromosome carrying HLA-A3 and -B7. It is often described as a “Celtic mutation”—originating in a Celtic population in central Europe and spreading west and north by population movement. It has also been suggested that Viking migrations were largely responsible for the distribution of this mutation. Two, initial estimates of the age of the mutation are compatible with either of these suggestions. Here we examine the evidence about HFE C282Y frequencies, extended haplotypes involving HLA-A and -B alleles, the validity of calculations of mutation age, selective advantage and current views on the relative importance of “demic-diffusion” (population migration) and “adoption-diffusion” (cultural change) in the neolithic transition in Europe and since then. We conclude that the HFE C282Y mutation occurred in mainland Europe before 4,000 BC.
TL;DR: During extensive sampling in Burkina Faso and other African countries, the Leu‐Phe mutation producing the kdr pyrethroid resistance phenotype was reported in both Anopheles gambiae ss and A. arabiensis.
Abstract: During extensive sampling in Burkina Faso and other African countries, the Leu-Phe mutation producing the kdr pyrethroid resistance phenotype was reported in both Anopheles gambiae ss and A. arabiensis. This mutation was widely distributed at high frequency in the molecular S form of A. gambiae while it has been observed at a very low frequency in both the molecular M form and A. arabiensis in Burkina Faso. While the mutation in the M form is inherited through an introgression from the S form, its occurrence is a new and independent mutation event in A. arabiensis. Three nucleotides in the upstream intron of the kdr mutation differentiated A. arabiensis from A. gambiae ss and these specific nucleotides were associated with kdr mutation in A. arabiensis. Ecological divergences which facilitated the spread of the kdr mutation within the complex of A. gambiae ss in West Africa, are discussed.
TL;DR: The results suggest that frequent occurrence of BRAF mutation is inherently associated with PTC, irrespective of geographic origin, and is apparently not a radiation-susceptible mutation.
Abstract: A high prevalence of activating mutation of the B type Raf kinase (BRAF) gene was recently reported in papillary thyroid cancer (PTC). However, the frequency of this mutation in several other types of thyroid neoplasms was not thoroughly investigated. In the present study, in addition to PTC, we evaluated various thyroid tumor types for the most common BRAF T1796A mutation by direct genomic DNA sequencing. We found a high and similar frequency (45%) of the BRAF T1796A mutation in two geographically distinct PTC patient populations: one composed of sporadic cases from North America, and the other from Kiev, Ukraine, that included individuals who were exposed to the Chernobyl nuclear accident. In contrast, we found BRAF mutation in only 20% of anaplastic thyroid cancers and no mutation in medullary thyroid cancers and benign thyroid hyperplasia. We also confirmed previous reports that the BRAF T1796A mutation did not occur in benign thyroid adenomas and follicular thyroid cancers. Specific analysis of the Ukraine patients with confirmed history of radiation exposure failed to show a higher incidence of BRAF mutation. Our results suggest that frequent occurrence of BRAF mutation is inherently associated with PTC, irrespective of geographic origin, and is apparently not a radiation-susceptible mutation. The lack or low prevalence of BRAF mutation in other thyroid neoplasms is consistent with the notion that other previously defined genetic alterations on the same signaling pathway are sufficient to cause tumorigenesis in most thyroid neoplasms.
TL;DR: In this article, the application of GA for irrigation planning is discussed and the GA technique is used to evolve efficient cropping pattern for maximizing benefits for an irrigation project in India, the results obtained by GA are compared with Linear Programming solution and found to be reasonably close.
Abstract: The present study deals with the application of Genetic Algorithms(GA) for irrigation planning. The GA technique is used to evolve efficient cropping pattern for maximizing benefits for an irrigation project in India. Constraints include continuity equation, land and water requirements, crop diversification and restrictions on storage. Penalty function approach is used to convert constrained problem into an unconstrained one. For fixing GA parameters the model is run for various values of population, generations, cross over and mutation probabilities. It is found that the appropriate parameters for number of generations, population size, crossover probability, and mutation probability are 200, 50, 0.6 and 0.01 respectively for the present study. Results obtained by GA are compared with Linear Programming solution and found to be reasonably close. GA is found to be an effective optimization tool for irrigation planning and the results obtained can be utilized for efficient planning of any irrigation system.
TL;DR: Early detection of Gly170Arg and Phe152Ile mutations in PH1 has important clinical implications because of their association with pyridoxine responsiveness and clinical outcome.
TL;DR: It is shown that the mean fitness decline experienced by larger populations is actually greater than expected on the basis of the estimates of mutational parameters, which could be consistent with the existence of a common class of mutations with small individual effects.
Abstract: The consequences of mutation for population-genetic and evolutionary processes depend on the rate and, especially, the frequency distribution of mutational effects on fitness. We sought to approximate the form of the distribution of mutational effects by conducting divergence experiments in which lines of a DNA repair-deficient strain of Caenorhabditis elegans, msh-2, were maintained at a range of population sizes. Assays of these lines conducted in parallel with the ancestral control suggest that the mutational variance is dominated by contributions from highly detrimental mutations. This was evidenced by the ability of all but the smallest population-size treatments to maintain relatively high levels of mean fitness even under the 100-fold increase in mutational pressure caused by knocking out the msh-2 gene. However, we show that the mean fitness decline experienced by larger populations is actually greater than expected on the basis of our estimates of mutational parameters, which could be consistent with the existence of a common class of mutations with small individual effects. Further, comparison of the total mutation rate estimated from direct sequencing of DNA to that detected from phenotypic analyses implies the existence of a large class of evolutionarily relevant mutations with no measurable effect on laboratory fitness.
TL;DR: This paper presents a publicly available mutation system for Java that supports both traditional statement-level mutants and newer inter-class mutants, and hopes that it will promote the use of mutation analysis for experimental research in software testing.
Abstract: Mutation is a powerful but complicated and computationally expensive testing method. Mutation is also a valuable experimental research technique that has been used in many studies. Mutation has been experimentally compared with other test criteria, and also used to support experimental comparisons of other test criteria, by using mutants as a method to create faults. In effect, mutation is often used as a "gold standard" for experimental evaluations of test methods. This paper presents a publicly available mutation system for Java that supports both traditional statement-level mutants and newer inter-class mutants. MUJAVA can be freely downloaded and installed with relative ease under both Unix and Windows. MUJAVA is offered as a free service to the community and we hope that it will promote the use of mutation analysis for experimental research in software testing.
TL;DR: It is found that two-phase models do not lead to a significantly better fit than their one-phase counterparts and models that allow chimps to have a larger per-repeat unit slippage rate and/or a shorter focal length compared to humans give a better fit to the human-chimp data as well as the human genomic data.
Abstract: Using genomic data from homologous microsatellite loci of pure AC repeats in humans and chimpanzees, several models of microsatellite evolution are tested and compared using likelihood-ratio tests and the Akaike information criterion. A proportional-rate, linear-biased, one-phase model emerges as the best model. A focal length toward which the mutational and/or substitutional process is linearly biased is a crucial feature of microsatellite evolution. We find that two-phase models do not lead to a significantly better fit than their one-phase counterparts. The performance of models based on the fit of their stationary distributions to the empirical distribution of microsatellite lengths in the human genome is consistent with that based on the human-chimp comparison. Microsatellites interrupted by even a single point mutation exhibit a twofold decrease in their mutation rate when compared to pure AC repeats. In general, models that allow chimps to have a larger per-repeat unit slippage rate and/or a shorter focal length compared to humans give a better fit to the human-chimp data as well as the human genomic data.
TL;DR: A real-time allele-specific PCR to detect the V600E mutation in BRAF, which has been described in the majority of cutaneous melanomas, papillary thyroid carcinoma and to a lesser extent in other cancers.
TL;DR: A novel MSX1 mutation (559 C → T, resulting in Gln187Stop) is identified in three individuals of one family with autosomal dominant tooth agenesis.
Abstract: MSX1 mutations have been reported in four unrelated families with autosomal dominant tooth agenesis. In one family, some individuals also had cleft lip and/or palate. We have identified a novel MSX1 mutation (559 C --> T, resulting in Gln187Stop) in three individuals of one family.
TL;DR: Examination of the predictions of correlated mutation algorithms for a number of proteins for which coupling between residues has been determined by analysis of double mutant cycles finds that correlated mutations algorithms can find residue pairs that are physically close and that physically close residue pairs tend to be thermodynamically coupled.
TL;DR: The data support previous studies that show heterogeneity in the frequencies and types of mutations in Cx26 within populations and among ethnicities and that before clinical significance and causality can be attributed to a genetic variant, functional characterization is necessary.
Abstract: Hearing loss is highly prevalent with a worldwide incidence of 1-2 per 1000 newborns. Several previous studies have demonstrated that mutations of connexin 26 (Cx26 or GJB2) are responsible for most cases of the recessive non-syndromic sensorineural hearing loss (NSSHL). Certain mutations have been described frequently among various populations, which include 35delG, 167delT, and 235delC. Recently, a missense mutation, V37I, was reported as a pathogenic change in East Asian affected individuals. To identify genetic variants associated with NSSHL in Thai population, we performed mutation analysis of Cx26 in 166 unrelated probands with NSSHL and 205 controls. We identified seven novel genetic variants in Cx26. We also identified a high prevalence of the V37I mutation among both affected probands (11.1%) and control subjects (8.5%), which suggests that the pathologic role of V37I may be modified by other genes. Our data support previous studies that show heterogeneity in the frequencies and types of mutations in Cx26 within populations and among ethnicities and that before clinical significance and causality can be attributed to a genetic variant, functional characterization is necessary.
TL;DR: The postulated high frequency and continent-wide geographic distribution of a cancer-predisposing founder mutation of the MSH2 gene in a large, outbred population, and the ease with which the mutation can be detected, suggest that the routine testing of individuals at risk for HNPCC in the United States should include an assay for this mutation until more is learned about its occurrence.
Abstract: ContextHereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch
syndrome, is caused by mutations in the mismatch repair genes and confers
an extraordinarily high risk of colorectal, endometrial, and other cancers.
However, while carriers of these mutations should be identified, counseled,
and offered clinical surveillance, at present the mutations are not tested
for in mutation analyses.ObjectiveTo describe the prevalence of a large genomic deletion encompassing
exons 1 to 6 of the MSH2 gene that is widespread
in the US population as a result of a founder effect.Design, Setting, and PatientsOngoing genealogical and historical study conducted to assess the origin
and spread of an MSH2 mutation previously identified
in 9 apparently unrelated families with putative HNPCC and living in widely
different geographic locations in the United States.Main Outcome MeasuresClassification of family members as carriers or noncarriers of the MSH2 mutation; spread of the mutation across the continental
United States.ResultsTo date, 566 family members of the 9 probands have been identified to
be at risk and counseled; 137 of these have been tested, and 61 carry the
founder mutation. Three families have been genealogically shown to descend
from a German immigrant family that arrived and first settled in Pennsylvania
in the early 1700s. Movements of branches of the family from Pennsylvania
through North Carolina, Alabama, Kentucky, Missouri, Iowa, Nebraska, Utah,
Texas, and California have been documented, and carriers of the mutation have
already been diagnosed in 14 states. In contrast, the deletion was not found
among 407 European and Australian families with HNPCC.ConclusionThe postulated high frequency and continent-wide geographic distribution
of a cancer-predisposing founder mutation of the MSH2 gene
in a large, outbred (as opposed to genetically isolated) population, and the
ease with which the mutation can be detected, suggest that the routine testing
of individuals at risk for HNPCC in the United States should include an assay
for this mutation until more is learned about its occurrence.
TL;DR: The genetic variation in 1509 C2-V5 env sequences derived from nine men with chronic HIV-1 infection can be explained by a predominance of random genetic drift of neutral mutations with brief episodes of natural selection that were frequently masked by recombination.
Abstract: Human immunodeficiency virus type 1 (HIV-1) has high replication and mutation rates that generate large census populations and high levels of genetic variation. We examined the roles of natural selection, population growth, random genetic drift, and recombination in shaping the variation in 1509 C2-V5 env sequences derived from nine men with chronic HIV-1 infection. These sequences were obtained from clinical visits that reflect the first 6-13.7 years of infection. Pairwise comparisons of nonsynonymous and synonymous distances, Tajima9s D test, Fu and Li9s D * test, and a test of recurrent mutation revealed evidence for episodes of nonneutral evolution in a total of 22 out of 145 blood samples, representing six of the nine individuals. Using three coalescent-based maximum-likelihood estimators, we found viral effective population sizes in all nine individuals to be ∼10 3 . We also show that a previous estimate of the effective population size of ∼10 5 based on rare haplotype frequencies decreases to ∼10 3 upon correcting a biased sampling procedure. We conclude that the genetic variation in these data sets can be explained by a predominance of random genetic drift of neutral mutations with brief episodes of natural selection that were frequently masked by recombination.
TL;DR: Fractional anisotropy (FA), a measure of axonal integrity and coherence, was reduced in the subgyral white matter of the sensorimotor cortex of DYT1 carriers.
Abstract: We tested the hypothesis that the DYT1 genotype is associated with a disorder of anatomical connectivity involving primarily the sensorimotor cortex. We used diffusion tensor magnetic resonance imaging (DTI) to assess the microstructure of white matter pathways in mutation carriers and control subjects. Fractional anisotropy (FA), a measure of axonal integrity and coherence, was reduced (p < 0.005) in the subgyral white matter of the sensorimotor cortex of DYT1 carriers. Abnormal anatomical connectivity of the supplementary motor area may contribute to the susceptibility of DYT1 carriers to develop clinical manifestations of dystonia.
TL;DR: It is suggested that specific mutations in the epidermal growth factor receptor (EGFR) characterize a subgroup of non–smallcell lung cancers that may be highly responsive to gefitinib therapy, and these mutations predict a greater sensitivity to chemotherapy as well.
Abstract: to the editor: The important study by Dr. Lynch and colleagues (May 20 issue) 1 suggests that specific mutations in the epidermal growth factor receptor (EGFR) characterize a subgroup of non–smallcell lung cancers that may be highly responsive to gefitinib therapy. Do these mutations predict a greater sensitivity to chemotherapy as well? The overall objective response rate to first-line combination chemotherapy for metastatic non–small-cell lung cancer is about 20 percent. 2 Only tumors from a small cohort of patients who had a response to gefitinib were studied for the specific mutations, but all patients except one had also received prior chemotherapy. Although the authors describe Patient 6 as “representative” of the cohort, the percentage of other patients who previously had a response to chemotherapy is not reported. If the rate of response to first-line chemotherapy was high for the other patients in the cohort who had a response to gefitinib, the specific mutations may be predictive of either chemotherapy or gefitinib sensitivity, thus identifying a distinct subgroup of patients with non–smallcell lung cancer.
TL;DR: Here new real royal road functions are presented where crossover leads to a small optimization time, although the GA works with the smallest possible population size--namely 2.5 million people.
TL;DR: Three haplotypes identified are consistent with a single ancestral origin for the mutation R255X, which was detected in two probands originated from a small community in southern Italy and reported on the screening for this mutation in 30% of the village population.
Abstract: Genetic alterations of the FOXN1 transcription factor, selectively expressed in thymic epithelia and skin, are responsible in both mice and humans for the Nude/SCID phenotype. The first described human FOXN1 mutation was a C792T transition in exon 5 resulting in the nonsense mutation R255X, and was detected in two probands originated from a small community in southern Italy. In this community, four additional children affected with congenital alopecia died in early childhood because of severe infections. In this study, we report on the screening for this mutation in 30% of the village population. This analysis led us to identify 55 heterozygous carriers (6.52%) of the R255X mutation out of 843 inhabitants screened. A genealogical study revealed that these subjects, belonging to 39 families, were linked in an extended 7-generational pedigree comprising 483 individuals. Through the archival database a single ancestral couple, born at the beginning of the 19th century, was identified. To confirm the ancestral origin of the mutation we genotyped two microsatellite markers, D17S2187 and D17S1880, flanking the FOXN1 gene on chromosome 17. The three haplotypes identified, 3/R255X/3, 3/R255X/2 and 3/R255X/1, are consistent with a single ancestral origin for the mutation R255X.