Showing papers on "Mutation (genetic algorithm) published in 2005"

A standardized genetic differentiation measure

Abstract: Interpretation of genetic differentiation values is often problematic because of their dependence on the level of genetic variation. For example, the maximum level of GST is less than the average within population homozygosity so that for highly variable loci, even when no alleles are shared between subpopulations, GST may be low. To remedy this difficulty, a standardized measure of genetic differentiation is introduced here, one which has the same range, 0–1, for all levels of genetic variation. With this measure, the magnitude is the proportion of the maximum differentiation possible for the level of subpopulation homozygosity observed. This is particularly important for situations in which the mutation rate is of the same magnitude or higher than the rate of gene flow. The standardized measure allows comparison between loci with different levels of genetic variation, such as allozymes and microsatellite loci, or mtDNA and Y-chromosome genes, and for genetic differentiation for organisms with d...

The Concept of Synthetic Lethality in the Context of Anticancer Therapy

Abstract: Two genes are synthetic lethal if mutation of either alone is compatible with viability but mutation of both leads to death. So, targeting a gene that is synthetic lethal to a cancer-relevant mutation should kill only cancer cells and spare normal cells. Synthetic lethality therefore provides a conceptual framework for the development of cancer-specific cytotoxic agents. This paradigm has not been exploited in the past because there were no robust methods for systematically identifying synthetic lethal genes. This is changing as a result of the increased availability of chemical and genetic tools for perturbing gene function in somatic cells.

BRAF mutation in thyroid cancer

Abstract: Genetic alteration is the driving force for thyroid tumorigenesis and progression, based upon which novel approaches to the management of thyroid cancer can be developed. A recent important genetic finding in thyroid cancer is the oncogenic T1799A transversion mutation of BRAF (the gene for the B-type Raf kinase, BRAF). Since the initial report of this mutation in thyroid cancer 2 years ago, rapid advancements have been made. BRAF mutation is the most common genetic alteration in thyroid cancer, occurring in about 45% of sporadic papillary thyroid cancers (PTCs), particularly in the relatively aggressive subtypes, such as the tall-cell PTC. This mutation is mutually exclusive with other common genetic alterations, supporting its independent oncogenic role, as demonstrated by transgenic mouse studies that showed BRAF mutation-initiated development of PTC and its transition to anaplastic thyroid cancer. BRAF mutation is mutually exclusive with RET/PTC rearrangement, and also displays a reciprocal age association with this common genetic alteration in thyroid cancer. The T1799A BRAF mutation occurs exclusively in PTC and PTC-derived anaplastic thyroid cancer and is a specific diagnostic marker for this cancer when identified in cytological and histological specimens. This mutation is associated with a poorer clinicopathological outcome and is a novel independent molecular prognostic marker in the risk evaluation of thyroid cancer. Moreover, preclinical and clinical evaluations of the therapeutic value of novel specific mitogen-activated protein kinase pathway inhibitors in thyroid cancer are anticipated. This newly discovered BRAF mutation may prove to have an important impact on thyroid cancer in the clinic.

Developmental plasticity and the origin of species differences

Abstract: Speciation is the origin of reproductive isolation and divergence between populations, according to the “biological species concept” of Mayr. Studies of reproductive isolation have dominated research on speciation, leaving the origin of species differences relatively poorly understood. Here, I argue that the origin of species differences, and of novel phenotypes in general, involves the reorganization of ancestral phenotypes (developmental recombination) followed by the genetic accommodation of change. Because selection acts on phenotypes, not directly on genotypes or genes, novel traits can originate by environmental induction as well as mutation, then undergo selection and genetic accommodation fueled by standing genetic variation or by subsequent mutation and genetic recombination. Insofar as phenotypic novelties arise from adaptive developmental plasticity, they are not “random” variants, because their initial form reflects adaptive responses with an evolutionary history, even though they are initiated by mutations or novel environmental factors that are random with respect to (future) adaptation. Change in trait frequency involves genetic accommodation of the threshold or liability for expression of a novel trait, a process that follows rather than directs phenotypic change. Contrary to common belief, environmentally initiated novelties may have greater evolutionary potential than mutationally induced ones. Thus, genes are probably more often followers than leaders in evolutionary change. Species differences can originate before reproductive isolation and contribute to the process of speciation itself. Therefore, the genetics of speciation can profit from studies of changes in gene expression as well as changes in gene frequency and genetic isolation.

A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera

Abstract: Myeloproliferative disorders are clonal haematopoietic stem cell malignancies characterized by independency or hypersensitivity of haematopoietic progenitors to numerous cytokines. The molecular basis of most myeloproliferative disorders is unknown. On the basis of the model of chronic myeloid leukaemia, it is expected that a constitutive tyrosine kinase activity could be at the origin of these diseases. Polycythaemia vera is an acquired myeloproliferative disorder, characterized by the presence of polycythaemia diversely associated with thrombocytosis, leukocytosis and splenomegaly. Polycythaemia vera progenitors are hypersensitive to erythropoietin and other cytokines. Here, we describe a clonal and recurrent mutation in the JH2 pseudo-kinase domain of the Janus kinase 2 (JAK2) gene in most (> 80%) polycythaemia vera patients. The mutation, a valine-to-phenylalanine substitution at amino acid position 617, leads to constitutive tyrosine phosphorylation activity that promotes cytokine hypersensitivity and induces erythrocytosis in a mouse model. As this mutation is also found in other myeloproliferative disorders, this unique mutation will permit a new molecular classification of these disorders and novel therapeutical approaches.

Perspective:sign epistasis and genetic constraint on evolutionary trajectories

Abstract: Epistasis for fitness means that the selective effect of a mutation is conditional on the genetic background in which it appears. Although epistasis is widely observed in nature, our understanding of its consequences for evolution by natural selection remains incomplete. In particular, much attention focuses only on its influence on the instantaneous rate of changes in frequency of selected alleles via epistatic contribution to the additive genetic variance for fitness. Thus, in this framework epistasis only has evolutionary importance if the interacting loci are simultaneously segregating in the population. However, the selective accessibility of mutational trajectories to high fitness genotypes may depend on the genetic background in which novel mutations appear, and this effect is independent of population polymorphism at other loci. Here we explore this second influence of epistasis on evolution by natural selection. We show that it is the consequence of a particular form of epistasis, which we designate sign epistasis. Sign epistasis means that the sign of the fitness effect of a mutation is under epistatic control; thus, such a mutation is beneficial on some genetic backgrounds and deleterious on others. Recent experimental innovations in microbial systems now permit assessment of the fitness effects of individual mutations on multiple genetic backgrounds. We review this literature and identify many examples of sign epistasis, and we suggest that the implications of these results may generalize to other organisms. These theoretical and empirical considerations imply that strong genetic constraint on the selective accessibility of trajectories to high fitness genotypes may exist and suggest specific areas of investigation for future research.

Systematic interpretation of genetic interactions using protein networks

Abstract: Genetic interaction analysis,in which two mutations have a combined effect not exhibited by either mutation alone, is a powerful and widespread tool for establishing functional linkages between genes. In the yeast Saccharomyces cerevisiae, ongoing screens have generated >4,800 such genetic interaction data. We demonstrate that by combining these data with information on protein-protein, prote in-DNA or metabolic networks, it is possible to uncover physical mechanisms behind many of the observed genetic effects. Using a probabilistic model, we found that 1,922 genetic interactions are significantly associated with either between- or within-pathway explanations encoded in the physical networks, covering approximately 40% of known genetic interactions. These models predict new functions for 343 proteins and suggest that between-pathway explanations are better than within-pathway explanations at interpreting genetic interactions identified in systematic screens. This study provides a road map for how genetic and physical interactions can be integrated to reveal pathway organization and function.

Sign epistasis and genetic constraint on evolutionary trajectories

Abstract: Epistasis for fitness means that the selective effect of a mutation is conditional on the genetic background in which it appears. Although epistasis is widely observed in nature, our understanding of its consequences for evolution by natural selection remains incomplete. In particular, much attention focuses only on its influence on the instantaneous rate of changes in frequency of selected alleles via epistatic contribution to the additive genetic variance for fitness. Thus, in this framework epistasis only has evolutionary importance if the interacting loci are simultaneously segregating in the population. However, the selective accessibility of mutational trajectories to high fitness genotypes may depend on the genetic background in which novel mutations appear, and this effect is independent of population polymorphism at other loci. Here we explore this second influence of epistasis on evolution by natural selection. We show that it is the consequence of a particular form of epistasis, which we designate sign epistasis. Sign epistasis means that the sign of the fitness effect of a mutation is under epistatic control; thus, such a mutation is beneficial on some genetic backgrounds and deleterious on others. Recent experimental innovations in microbial systems now permit assessment of the fitness effects of individual mutations on multiple genetic backgrounds. We review this literature and identify many examples of sign epistasis, and we suggest that the implications of these results may generalize to other organisms. These theoretical and empirical considerations imply that strong genetic constraint on the selective accessibility of trajectories to high fitness genotypes may exist and suggest specific areas of investigation for future research.

Adaptive Value of High Mutation Rates of RNA Viruses: Separating Causes from Consequences

Abstract: As a consequence of the lack of proofreading activity of RNA virus polymerases, new viral genetic variants are constantly created. RNA viruses readily adapt to changing environmental conditions. Therefore, the high mutation rate of RNA viruses compared with DNA organisms is responsible for their enormous adaptive capacity. The above syllogism, with some variation, is deeply rooted in the thinking of many virologists: RNA viruses mutate at the maximum error rate compatible with maintaining the integrity of genetic information (i.e., the error threshold) because this would allow them to quickly find the beneficial mutations needed for adaptation (12, 14, 23, 32). It is an unquestionable fact that RNA virus populations exist as swarms of mutant genotypes (13). Such enormous variability is an unavoidable consequence of the lack of exonuclease proofreading activity of the virus-encoded RNA polymerases (44) with, in some cases, the added contribution of recombination (20, 29, 33). However, the argument that the more mutations are generated, the faster adaptation proceeds is flawed because it ignores the fact that the vast majority of mutations are deleterious, hence hindering adaptation, as shown by recent theoretical developments (25, 34). Therefore, the adaptive value of the RNA virus extreme mutation rate has to be carefully reconsidered, and new alternative explanations, beyond a purely mechanistic level, should be taken into consideration.

Clinical implications of the JAK2 V617F mutation in essential thrombocythemia

Abstract: istic upmodulation of CD20 and downmodulation of CD10, comparable to the immunophenotypic modulation observed in vivo. In contrast, the viable 7-AAD-negative cells retained their original immunophenotype (Figure 2e, f). For each antibody, the MFI differed between the viable and dead cells, but within these two populations the MFI was not affected by the type and dose of the cytotoxic agents to which the cells were exposed (data not shown). Further analysis of dead and viable cells showed that dead cells had a higher MFI for each isotype control antibody than viable cells. This increase in background staining was comparable to the upmodulation of CD20 on CD20-negative leukemic cells observed in day 15 and 28 samples. Altogether, these data indicate that the immunophenotypic modulation observed in vitro is due to the induction of cell kill, resulting in a higher aspecific staining and a decreased expression of membrane antigens. Our data suggest that in ALL patients undergoing treatment, immunophenotypic modulation is caused by drug-induced cell death, resulting in loss of membrane antigens and higher aspecific staining. Our data are in agreement with a recent study, which showed that the loss of expression of lineage antigens (such as CD19) is a common feature of lymphocytes undergoing apoptosis and that the MFI for different antigens might drop to undetectable levels during different stages of apoptosis. Antigens coexpressed on the same cells showed different degrees of loss in the different stages of apoptosis, suggesting that it is a specific, active process, rather than a general degradation of cell components. Our observation that immunophenotypic modulation is due to apoptotic cells also explains why ALL blast cells in resistant patients show no modulation. In conclusion, our data indicate that immunophenotypic modulation in ALL patients undergoing treatment can (at least in part) be explained by the induction of cell death. As the presence of these dying cells may still be clinically relevant, usage of strict gating procedures, based on the exact immunophenotype of the blast cells at diagnosis, should be avoided for the analysis of MRD.

An evolutionary algorithm with guided mutation for the maximum clique problem

Abstract: Estimation of distribution algorithms sample new solutions (offspring) from a probability model which characterizes the distribution of promising solutions in the search space at each generation. The location information of solutions found so far (i.e., the actual positions of these solutions in the search space) is not directly used for generating offspring in most existing estimation of distribution algorithms. This paper introduces a new operator, called guided mutation. Guided mutation generates offspring through combination of global statistical information and the location information of solutions found so far. An evolutionary algorithm with guided mutation (EA/G) for the maximum clique problem is proposed in this paper. Besides guided mutation, EA/G adopts a strategy for searching different search areas in different search phases. Marchiori's heuristic is applied to each new solution to produce a maximal clique in EA/G. Experimental results show that EA/G outperforms the heuristic genetic algorithm of Marchiori (the best evolutionary algorithm reported so far) and a MIMIC algorithm on DIMACS benchmark graphs.

Clinical features of LRRK2-associated Parkinson's disease in central Norway.

Abstract: Background and objectivesParkinson’s disease (PD) is a common neurodegenerative disorder affecting 1% of the elderly. The disease causes a significant burden of illness and cost to society. The causes of PD have remained unknown, and the influence of genetic factors used to be controversial. In 2004, several mutations were identified in familial PD within two genes: PINK1 and the novel gene LRRK2. The aims of this thesis were to further investigate genetic, clinical and pathological aspects of these genes in PD and other neurodegenerative disorders causing parkinsonism. Five papers based on data from studies of these genes are included in this thesis.Methods- DNA from probands of families with autosomal dominant parkinsonism were sequenced to identify novel mutations in the LRRK2 gene. After the identification of a novel heterozygous LRRK2 mutation, we assessed the frequency of this mutation in a total of 248 families from different populations. We also screened samples of patients with idiopathic PD from three populations (Norway, Ireland, and Poland). Family members of mutation carriers were examined, and analyses of segregation, mutation haplotypes and penetrance were performed (Paper I).- A clinicogenetic study of PD in Central Norway was initiated several years ago at the Department of Neurology, St. Olav’s University Hospital in Trondheim. We screened 435 Norwegian patients diagnosed with PD and 519 control subjects from this study for the presence of seven known LRRK2 mutations. The clinical presentation of disease was studied in patients with mutations (Paper II).-A series of 242 patients from a clinicogenetic study of dementia in Central Norway (Tronderbrain) were screened for the presence of seven known pathogenic mutations previously reported in the LRRK2 gene (Paper III).- We examined several brain banks for cases with clinical or pathological features of parkinsonian disorders. DNA was obtained from frozen brain tissue of cases with parkinsonism, other neurodegenerative disorders and controls (total n=1584) and genotyped for the exon 41 LRRK2 g.6055G>A (G2019S) mutation. Available medical records of mutation carriers were reviewed and neuropathological examination was performed (Paper IV).- Comprehensive PINK1 mutation analysis was performed in a total of 131 patients from Norway with early-onset parkinsonism (onset =50 years) or familial late-onset PD. Mutations identified were examined in 350 Norwegian control individuals (Paper V).Results- We identified a novel heterozygous LRRK2 g.6055G>A mutation (G2019S). Seven of 248 families with autosomal dominant parkinsonism (2.8%) and six of 806 patients with idiopathic PD (0.7%) carried this mutation. All patients with this mutation shared an ancestral haplotype, indicative of a common founder. The mutation segregates with disease (multipoint LOD score 2.41). Penetrance is age dependent, increasing from 17% at age 50 years to 85% at age 70 years (Paper I).- Ten Norwegian PD patients were found to be heterozygote carriers of the Lrrk2 G2019S mutation. The clinical features included asymmetric resting tremor, bradykinesia, and rigidity with a good response to levodopa and could not be distinguished from idiopathic Parkinson’s disease. No Parkinson’s disease patient carried any of the other LRRK2 mutations (Paper II). We did not identify LRRK2 mutations in our series of dementia patients (Paper III).- Lrrk2 G2019S was found in 2% (n=8) of the pathologically confirmed PD/Lewy body disease (LBD) cases (n=405). Neuropathological examination showed typical LBD in all cases (Paper IV).-Heterozygous missense mutations in PINK1 were found in three of 131 patients; homozygous or compound heterozygous mutations were not identified. A parkinsonian phenotype, with asymmetric onset and without atypical features, characterised these patients clinically (Paper V).ConclusionsWe identified a novel mutation in the LRRK2 gene, g.6055G>A (G2019S). This mutation is a relatively common cause of both familial and sporadic PD, and it is found in a number of populations from North America and Europe, including Norway. This specific mutation is today the most prevalent known cause of PD, but seems to be rare in other neurodegenerative disorders.Clinically, patients with the Lrrk2 G2019S substitution present with a levodopa–responsive parkinsonian syndrome with asymmetric resting tremor, bradykinesia, and rigidity. Both clinically and pathologically LRRK2-associated PD appears to be indistinguishable from idiopathic disease.PINK1 mutations were rare in our Norwegian population, but heterozygote mutation carriers might be at increased risk for disease.

Quasispecies Made Simple

Abstract: Quasispecies are clouds of genotypes that appear in a population at mutation-selection balance. This concept has recently attracted the attention of virologists, because many RNA viruses appear to generate high levels of genetic variation that may enhance the evolution of drug resistance and immune escape. The literature on these important evolutionary processes is, however, quite challenging. Here we use simple models to link mutation-selection balance theory to the most novel property of quasispecies: the error threshold-a mutation rate below which populations equilibrate in a traditional mutation-selection balance and above which the population experiences an error catastrophe, that is, the loss of the favored genotype through frequent deleterious mutations. These models show that a single fitness landscape may contain multiple, hierarchically organized error thresholds and that an error threshold is affected by the extent of back mutation and redundancy in the genotype-to-phenotype map. Importantly, an error threshold is distinct from an extinction threshold, which is the complete loss of the population through lethal mutations. Based on this framework, we argue that the lethal mutagenesis of a viral infection by mutation-inducing drugs is not a true error catastophe, but is an extinction catastrophe.

History of genetic disease: The molecular genetics of Huntington disease — a history

Abstract: The Huntington disease gene was mapped to human chromosome 4p in 1983 and 10 years later the pathogenic mutation was identified as a CAG-repeat expansion. Our current understanding of the molecular pathogenesis of Huntington disease could never have been achieved without the recent progress in the field of molecular genetics. We are now equipped with powerful genetic models that continue to uncover new aspects of the pathogenesis of Huntington disease and will be instrumental for the development of therapeutic approaches for this disease.

Characterization of a Recurrent Germ Line Mutation of the E-Cadherin Gene: Implications for Genetic Testing and Clinical Management

Abstract: Purpose: To identify germ line CDH1 mutations in hereditary diffuse gastric cancer (HDGC) families and develop guidelines for management of at risk individuals. Experimental Design: We ascertained 31 HDGC previously unreported families, including 10 isolated early-onset diffuse gastric cancer (DGC) cases. Screening for CDH1 germ line mutations was done by denaturing high-performance liquid chromatography and automated DNA sequencing. Results: We identified eight inactivating and one missense CDH1 germ line mutation. The missense mutation conferred in vitro loss of protein function. Two families had the previously described 1003C>T nonsense mutation. Haplotype analysis revealed this to be a recurrent and not a founder mutation. Thirty-six percent (5 of 14) of the families with a documented DGC diagnosed before the age of 50 and other cases of gastric cancer carried CDH1 germ line mutations. Two of 10 isolated cases of DGC in individuals ages CDH1 germ line mutations. One mutation positive family was ascertained through a family history of lobular breast cancer (LBC) and another through an individual with both DGC and LBC. Occult DGC was identified in five of six prophylactic gastrectomies done on asymptomatic, endoscopically negative 1003C>T mutation carriers. Conclusions: In addition to families with a strong history of early-onset DGC, CDH1 mutation screening should be offered to isolated cases of DGC in individuals ages

The Rate of Compensatory Mutation in the DNA Bacteriophage φX174

Abstract: A compensatory mutation occurs when the fitness loss caused by one mutation is remedied by its epistatic interaction with a second mutation at a different site in the genome. This poorly understood biological phenomenon has important implications, not only for the evolutionary consequences of mutation, but also for the genetic complexity of adaptation. We have carried out the first direct experimental measurement of the average rate of compensatory mutation. An arbitrary selection of 21 missense substitutions with deleterious effects on fitness was introduced by site-directed mutagenesis into the bacteriophage φX174. For each deleterious mutation, we evolved 8–16 replicate populations to determine the frequency at which a compensatory mutation, instead of the back mutation, was acquired to recover fitness. The overall frequency of compensatory mutation was ∼70%. Deleterious mutations that were more severe were significantly more likely to be compensated for. Furthermore, experimental reversion of deleterious mutations revealed that compensatory mutations have deleterious effects in a wild-type background. A large diversity of intragenic compensatory mutations was identified from sequencing fitness-recovering genotypes. Subsequent analyses of intragenic mutation diversity revealed a significant degree of clustering around the deleterious mutation in the linear sequence and also within folded protein structures. Moreover, a likelihood analysis of mutation diversity predicts that, on average, a deleterious mutation can be compensated by about nine different intragenic compensatory mutations. We estimate that about half of all compensatory mutations are located extragenically in this organism.

Hamilton's indicators of the force of selection.

Abstract: To quantify the force of selection, Hamilton [Hamilton, W. D. (1966) J. Theor. Biol. 12, 12-45] derived expressions for the change in fitness with respect to age-specific mutations. Hamilton's indicators are decreasing functions of age. He concluded that senescence is inevitable: survival and fertility decline with age. I show that alternative parameterizations of mutational effects lead to indicators that can increase with age. I then consider the case of deleterious mutations with age-specific effects. In this case, it is the balance between mutation and selection pressure that determines the equilibrium number of mutations in a population. In this balance, the effects of different parameterizations cancel out, but only to a linear approximation. I show that mutation accumulation has little impact at ages when this linear approximation holds. When mutation accumulation matters, nonlinear effects become important, and the parameterizations of mutational effects make a difference. The results also suggest that mutation accumulation may be relatively unimportant over most of the reproductive lifespan of any species.

Mutation rates at Y chromosome specific microsatellites.

Abstract: A collaborative work was carried out by the Spanish and Portuguese ISFG Working Group (GEP-ISFG) to estimate Y-STR mutation rates. Seventeen Y chromosome STR loci (DYS19, DYS385, DYS389I and II, DYS390, DYS391, DYS392, DYS393, DYS437, DYS438, DYS439, DYS460, DYS461, DYS635 [GATA C4], GATA H4, and GATA A10) were analyzed in a sample of 3,026 father/son pairs. Among 27,029 allele transfers, 54 mutations were observed, with an overall mutation rate across the 17 loci of 1.998 x 10(-3) (95% CI, 1.501 x 10(-3) to 2.606 x 10(-3)). With just one exception, all of the mutations were single-step, and they were observed only once per gametogenesis. Repeat gains were more frequent than losses, longer alleles were found to be more mutable, and the mutation rate seemed to increase with the father's age. Hum Mutat 26(6), 520-528, 2005. (c) 2005 Wiley-Liss, Inc.

The probability of parallel evolution

Abstract: How often will natural selection drive parallel evolution at the DNA sequence level? More precisely, what is the probability that selection will cause two populations that live in identical environments to substitute the same beneficial mutation? Here I show that, under fairly general conditions, the answer is simple: if a wild-type sequence can mutate to n different beneficial mutations, replicate populations will on average fix the same mutation with probability P = 2/(n + 1). This probability, which is derived using extreme value theory, is independent of most biological details, including the length of the gene in question and the precise distribution of fitness effects among alleles. I conclude that the probability of parallel evolution under natural selection is nearly twice as large as that under neutrality.

Comparison of Performance between Different Selection Strategies on Simple Genetic Algorithms

Abstract: This paper presents the comparison of performance on a simple genetic algorithm (SGA) using roulette wheel selection and tournament selection A SGA is mainly composed of three genetic operations, which are selection, crossover and mutation With the same crossover and mutation operation, the simulation results are studied by comparing different selection strategies which are discussed in this paper Qualitative analysis of the selection strategies is depicted, and the numerical experiments show that SGA with tournament selection strategy converges much faster than roulette wheel selection