Showing papers on "Mutation (genetic algorithm) published in 2004"

The Genetic Association Database

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. …

Dynamics of cancer progression

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?

The unique mutation in ace-1 giving high insecticide resistance is easily detectable in mosquito vectors.

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.

Identification of a KCNE2 Gain-of-Function Mutation in Patients with Familial Atrial Fibrillation

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.

High mutation rate and predominance of insertions in the Caenorhabditis elegans nuclear genome

Abstract: Mutations have pivotal functions in the onset of genetic diseases and are the fundamental substrate for evolution. However, present estimates of the spontaneous mutation rate and spectrum are derived from indirect and biased measurements. For instance, mutation rate estimates for Caenorhabditis elegans are extrapolated from observations on a few genetic loci with visible phenotypes and vary over an order of magnitude1. Alternative approaches in mammals, relying on phylogenetic comparisons of pseudogene loci2 and fourfold degenerate codon positions3, suffer from uncertainties in the actual number of generations separating the compared species and the inability to exclude biases associated with natural selection. Here we provide a direct and unbiased estimate of the nuclear mutation rate and its molecular spectrum with a set of C. elegans mutation-accumulation lines that reveal a mutation rate about tenfold higher than previous indirect estimates and an excess of insertions over deletions. Because deletions dominate patterns of C. elegans pseudogene variation4,5, our observations indicate that natural selection might be significant in promoting small genome size, and challenge the prevalent assumption that pseudogene divergence accurately reflects the spontaneous mutation spectrum.

Mutation of CEBPA in Familial Acute Myeloid Leukemia

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.

Optimal placement of sensors for structural health monitoring using improved genetic algorithms

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.

The Arg451Cys-Neuroligin-3 Mutation Associated with Autism Reveals a Defect in Protein Processing

Abstract: The neuroligins are a family of postsynaptic transmembrane proteins that associate with presynaptic partners, the beta-neurexins. Neurexins and neuroligins play a critical role in initiating formation and differentiation of synaptic junctions. A recent study reported that a mutation of neuroligin-3 (NL3), an X-linked gene, was found in siblings with autistic spectrum disorder in which two affected brothers had a point mutation that substituted a Cys for Arg451. To characterize the mutation at the biochemical level, we analyzed expression and activity of the mutated protein. Mass spectrometry comparison of the disulfide bonding pattern between the native and the mutated proteins indicates the absence of aberrant disulfide bonding, suggesting that the secondary structure of the mutated protein is conserved. However, the mutation separately affects protein expression and activity. The Cys mutation causes defective neuroligin trafficking, leading to retention of the protein in the endoplasmic reticulum. This, in turn, decreases the delivery of NL3 to the cell surface. Also, the small fraction of protein that reaches the cell membrane lacks or has markedly diminished beta-neurexin-1 (NX1beta) binding activity. Other substitutions for Arg451 allow for normal cellular expression but diminished affinity for NX1beta. Our findings reveal a cellular phenotype and loss of function for a congenital mutation associated with autistic spectrum disorders.

Genetic Bottlenecks Reduce Population Variation in an Experimental RNA Virus Population

Abstract: Genetic bottlenecks are stochastic events that limit genetic variation in a population and result in founding populations that can lead to genetic drift. Evidence of past genetic bottlenecks in numerous biological systems, from mammals to viruses, has been described. In this study, we used an artificial population of Cucumber mosaic virus consisting of 12 restriction enzyme marker-bearing mutants. This population was inoculated onto young leaves of tobacco plants and monitored throughout the course of systemic infection. We show here that the genetic variation in a defined population of an RNA virus is significantly, stochastically, and reproducibly reduced during the systemic infection process, providing clear evidence of a genetic bottleneck.

Novel PMS2 Pseudogenes Can Conceal Recessive Mutations Causing a Distinctive Childhood Cancer Syndrome

Abstract: We investigated a family with an autosomal recessive syndrome of cafe-au-lait patches and childhood malignancy, notably supratentorial primitive neuroectodermal tumor. There was no cancer predisposition in heterozygotes; nor was there bowel cancer in any individual. However, autozygosity mapping indicated linkage to a region of 7p22 surrounding the PMS2 mismatch-repair gene. Sequencing of genomic PCR products initially failed to identify a PMS2 mutation. Genome searches then revealed a previously unrecognized PMS2 pseudogene, corresponding to exons 9–15, within a 100-kb inverted duplication situated 600 kb centromeric from PMS2 itself. This information allowed a redesigned sequence analysis, identifying a homozygous mutation (R802X) in PMS2 exon 14. Furthermore, in the family with Turcot syndrome, in which the first inherited PMS2 mutation (R134X) was described, a further truncating mutation was identified on the other allele, in exon 13. Further whole-genome analysis shows that the complexity of PMS2 pseudogenes is greater than appreciated and may have hindered previous mutation studies. Several previously reported PMS2 polymorphisms are, in fact, pseudogene sequence variants. Although PMS2 mutations may be rare in colorectal cancer, they appear, for the most part, to behave as recessive traits. For technical reasons, their involvement in childhood cancer, particularly in primitive neuroectodermal tumor, may have been underestimated.

A neural-network-based method for predicting protein stability changes upon single point mutations

Abstract: Motivation: One important requirement for protein design is to be able to predict changes of protein stability upon mutation. Different methods addressing this task have been described and their performance tested considering global linear correlation between predicted and experimental data. Neither is direct statistical evaluation of their prediction performance available, nor is a direct comparison among different approaches possible. Recently, a significant database of thermodynamic data on protein stability changes upon single point mutation has been generated (ProTherm). This allows the application of machine learning techniques to predicting free energy stability changes upon mutation starting from the protein sequence. Results: In this paper, we present a neural-network-based method to predict if a given mutation increases or decreases the protein thermodynamic stability with respect to the native structure. Using a dataset consisting of 1615 mutations, our predictor correctly classifies >80% of the mutations in the database. On the same task and using the same data, our predictor performs better than other methods available on the Web. Moreover, when our system is coupled with energy-based methods, the joint prediction accuracy increases up to 90%, suggesting that it can be used to increase also the performance of pre-existing methods, and generally to improve protein design strategies. Availability: The server is under construction and will be available at http://www.biocomp.unibo.it

How to Overcome the Equivalent Mutant Problem and Achieve Tailored Selective Mutation Using Co-evolution

Abstract: The use of Genetic Algorithms in evolution of mutants and test cases offers new possibilities in addressing some of the main problems of mutation testing. Most specifically the problem of equivalent mutant detection, and the problem of the large number of mutants produced. In this paper we describe the above problems in detail and introduce a new methodology based on co-evolutionary search techniques using Genetic Algorithms in order to address them effectively. Co-evolution allows the parallel evolution of mutants and test cases. We discuss the advantages of this approach over other existing mutation testing techniques, showing details of some initial experimental results carried out.

Cluster mutation via quiver representations

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.

General stress response regulator RpoS in adaptive mutation and amplification in Escherichia coli.

Abstract: Microbial cells under growth-limiting stress can generate mutations by mechanisms distinct from those in rapidly growing cells. These mechanisms might be specific stress responses that increase mutation rates, potentially altering rates of evolution, or might reflect non-stress-specific processes in rare growing cells. In an Escherichia coli model system, both frameshift reversion mutations and gene amplifications occur as apparent starvation-induced mutations. Whereas frameshift reversion ("point mutation") requires recombination proteins, the SOS response, and error-prone DNA polymerase IV (DinB), amplification requires neither SOS nor pol IV. We report that both point mutation and amplification require the stationary-phase and general stress response transcription factor RpoS (sigmaS). Growth-dependent mutation does not. Alternative interpretations are excluded. The results imply, first, that point mutation and amplification are stress responses that occur in differentiated stationary-phase (not rare growing) cells and, second, that transient genetic instability, producing both point mutation and genome rearrangement, may be a previously unrecognized component of the RpoS-dependent general stress response.

The spread of the Leu-Phe kdr mutation through Anopheles gambiae complex in Burkina Faso: genetic introgression and de novo phenomena

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.

The origin and spread of the HFE-C282Y haemochromatosis mutation.

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.

BRAF T1796A transversion mutation in various thyroid neoplasms.

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.

New insights on the evolution of the SMN1 and SMN2 region: simulation and meta-analysis for allele and haplotype frequency calculations.

Abstract: Most spinal muscular atrophy patients lack both copies of SMN1. Loss of SMN1 ('0-copy alleles') can occur by gene deletion or SMN1-to-SMN2 gene conversion. Despite worldwide efforts to map the segmental duplications within the SMN region, most assemblies do not correctly delineate these genes. A near pericentromeric location provides impetus for the strong evidence that SMN1 and SMN2 arose from a primate-specific paralogous gene duplication. Here we meta-analyzed our recent laboratory results together with available published data, in order to calculate new mutation rates and allele/haplotype frequencies in this recalcitrant and highly unstable region of the human genome. Based on our tested assumption of compliance with Hardy-Weinberg equilibrium, we conclude that the SMN1 allele frequencies are: '0-copy disease alleles,' 0.013; '1-copy normal alleles,' 0.95; '2-copy normal alleles (ie, two copies of SMN1 on one chromosome),' 0.038; and '1(D) disease alleles (SMN1 with a small intragenic mutation),' 0.00024. The SMN1 haplotype ['(SMN1 copy number)-(SMN2 copy number)'] frequencies are: '0-0,' 0.00048; '0-1,' 0.0086; '0-2,' 0.0042; '1-0,' 0.27; '1-1,' 0.66; '1-2,' 0.015; '2-0,' 0.027; and '2-1,' 0.012. Paternal and maternal de novo mutation rates are 2.1 x 10(-4) and 4.2 x 10(-5), respectively. Our data provide the basis for the most accurate genetic risk calculations, as well as new insights on the evolution of the SMN region, with evidence that nucleotide position 840 (where a transition 840C>T functionally distinguishes SMN2 from SMN1) constitutes a mutation hotspot. Our data also suggest selection of the 1-1 haplotype and the presence of rare chromosomes with three copies of SMN1.

DNA detection on transistor arrays following mutation-specific enzymatic amplification

Abstract: An integrated array of silicon field-effect transistor structures is used for electronic detection of label-free DNA Measurements of the dc current–voltage characteristics of the transistors gives us access to reproducible detection of single- and double-stranded DNA, locally adsorbed on the surface of the device We combine this approach with allele-specific polymerase chain reaction, to test for the 35delG mutation, a frequent mutation related to prelingual nonsyndromic deafness

Irrigation planning using Genetic Algorithms

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.

An experimental mutation system for Java

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.

Mutation Accumulation in Populations of Varying Size: The Distribution of Mutational Effects for Fitness Correlates in Caenorhabditis elegans

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.

FMGA: finding motifs by genetic algorithm

Abstract: In the era of post-genomics, almost all the genes have been sequenced and enormous amounts of data have been generated. Hence, to mine useful information from these data is a very important topic. In this paper we propose a new approach for finding potential motifs in the regions located from the -2000 bp upstream to +1000 bp downstream of transcription start site (TSS). This new approach is developed based on the genetic algorithm (GA). The mutation in the GA is performed by using position weight matrices to reserve the completely conserved positions. The crossover is implemented with special-designed gap penalties to produce the optimal child pattern. We also present a rearrangement method based on position weight matrices to avoid the presence of a very stable local minimum, which may make it quite difficult for the other operators to generate the optimal pattern. Our approach shows superior results by comparing with multiple em for motif elicitation (MEME) and Gibbs sampler, which are two popular algorithms for finding motifs.