Abstract: Mutations in the fibrillin-1 (FBN1) gene cause Marfan syndrome (MFS) and have been associated with a wide range of overlapping phenotypes. Clinical care is complicated by variable age at onset and the wide range of severity of aortic features. The factors that modulate phenotypical severity, both among and within families, remain to be determined. The availability of international FBN1 mutation Universal Mutation Database (UMD-FBN1) has allowed us to perform the largest collaborative study ever reported, to investigate the correlation between the FBN1 genotype and the nature and severity of the clinical phenotype. A range of qualitative and quantitative clinical parameters (skeletal, cardiovascular, ophthalmologic, skin, pulmonary, and dural) was compared for different classes of mutation (types and locations) in 1,013 probands with a pathogenic FBN1 mutation. A higher probability of ectopia lentis was found for patients with a missense mutation substituting or producing a cysteine, when compared with other missense mutations. Patients with an FBN1 premature termination codon had a more severe skeletal and skin phenotype than did patients with an inframe mutation. Mutations in exons 24-32 were associated with a more severe and complete phenotype, including younger age at diagnosis of type I fibrillinopathy and higher probability of developing ectopia lentis, ascending aortic dilatation, aortic surgery, mitral valve abnormalities, scoliosis, and shorter survival; the majority of these results were replicated even when cases of neonatal MFS were excluded. These correlations, found between different mutation types and clinical manifestations, might be explained by different underlying genetic mechanisms (dominant negative versus haploinsufficiency) and by consideration of the two main physiological functions of fibrillin-1 (structural versus mediator of TGF beta signalling). Exon 24-32 mutations define a high-risk group for cardiac manifestations associated with severe prognosis at all ages.

Abstract: When beneficial mutations are rare, they accumulate by a series of selective sweeps. But when they are common, many beneficial mutations will occur before any can fix, so there will be many different mutant lineages in the population concurrently. In an asexual population, these different mutant lineages interfere and not all can fix simultaneously. In addition, further beneficial mutations can accumulate in mutant lineages while these are still a minority of the population. In this article, we analyze the dynamics of such multiple mutations and the interplay between multiple mutations and interference between clones. These result in substantial variation in fitness accumulating within a single asexual population. The amount of variation is determined by a balance between selection, which destroys variation, and beneficial mutations, which create more. The behavior depends in a subtle way on the population parameters: the population size, the beneficial mutation rate, and the distribution of the fitness increments of the potential beneficial mutations. The mutation–selection balance leads to a continually evolving population with a steady-state fitness variation. This variation increases logarithmically with both population size and mutation rate and sets the rate at which the population accumulates beneficial mutations, which thus also grows only logarithmically with population size and mutation rate. These results imply that mutator phenotypes are less effective in larger asexual populations. They also have consequences for the advantages (or disadvantages) of sex via the Fisher–Muller effect; these are discussed briefly.

Abstract: A basic knowledge about mutation rates is central to our understanding of a myriad of evolutionary phenomena, including the maintenance of sex and rates of molecular evolution. Although there is substantial evidence that mutation rates vary among taxa, relatively little is known about the factors that underlie this variation at an empirical level, particularly in multicellular eukaryotes. Here we integrate several disparate lines of theoretical and empirical inquiry into a unified framework to guide future studies that are aimed at understanding why and how mutation rates evolve in multicellular species.

Abstract: Bacterial cultures in changing environments sometimes accumulate 'mutator' strains, with elevated mutation rates, presumably to enhance their potential for adaptive evolution. This can often happen in clinical situations. If they are to persist, mutators need a consistently changing environment. Coevolution with parasites, such as viruses, is a scenario that can provide that. Experiments with Pseudomonas fluorescens now show that coevolution with a naturally occurring bacteriophage significantly increases bacterial mutation rates — and results in a higher probability of phage extinction. Targeting phage populations might therefore be a way of weakening selection for mutator bacteria in clinical infections. Bacterial cultures experiencing changes in environmental conditions accumulate mutator strains, presumably to enhance their capability for adaptive evolution. The presence of bacterial viruses is demonstrated to have a similar effect, as during co-evolution of Pseudomonas fluorescens and its lytic DNA phage, bacterial mutation rates significantly increase, resulting in a higher probability of phage extinction. Bacteria with greatly elevated mutation rates (mutators) are frequently found in natural1,2,3 and laboratory4,5 populations, and are often associated with clinical infections6,7. Although mutators may increase adaptability to novel environmental conditions, they are also prone to the accumulation of deleterious mutations. The long-term maintenance of high bacterial mutation rates is therefore likely to be driven by rapidly changing selection pressures8,9,10,11,12,13,14, in addition to the possible slow transition rate by point mutation from mutators to non-mutators15. One of the most likely causes of rapidly changing selection pressures is antagonistic coevolution with parasites16,17. Here we show whether coevolution with viral parasites could drive the evolution of bacterial mutation rates in laboratory populations of the bacterium Pseudomonas fluorescens18. After fewer than 200 bacterial generations, 25% of the populations coevolving with phages had evolved 10- to 100-fold increases in mutation rates owing to mutations in mismatch-repair genes; no populations evolving in the absence of phages showed any significant change in mutation rate. Furthermore, mutator populations had a higher probability of driving their phage populations extinct, strongly suggesting that mutators have an advantage against phages in the coevolutionary arms race. Given their ubiquity, bacteriophages may play an important role in the evolution of bacterial mutation rates.

Abstract: Although numerous investigators assume that the global features of genetic networks are moulded by natural selection, there has been no formal demonstration of the adaptive origin of any genetic network. This Analysis shows that many of the qualitative features of known transcriptional networks can arise readily through the non-adaptive processes of genetic drift, mutation and recombination, raising questions about whether natural selection is necessary or even sufficient for the origin of many aspects of gene-network topologies. The widespread reliance on computational procedures that are devoid of population-genetic details to generate hypotheses for the evolution of network configurations seems to be unjustified.

Abstract: Research into adjusting the probabilities of crossover and mutation pm in genetic algorithms (GAs) is one of the most significant and promising areas in evolutionary computation. px and pm greatly determine whether the algorithm will find a near-optimum solution or whether it will find a solution efficiently. Instead of using fixed values of px and pm , this paper presents the use of fuzzy logic to adaptively adjust the values of px and pm in GA. By applying the K-means algorithm, distribution of the population in the search space is clustered in each generation. A fuzzy system is used to adjust the values of px and pm. It is based on considering the relative size of the cluster containing the best chromosome and the one containing the worst chromosome. The proposed method has been applied to optimize a buck regulator that requires satisfying several static and dynamic operational requirements. The optimized circuit component values, the regulator's performance, and the convergence rate in the training are favorably compared with the GA using fixed values of px and pm. The effectiveness of the fuzzy-controlled crossover and mutation probabilities is also demonstrated by optimizing eight multidimensional mathematical functions

Abstract: BACKGROUND. Numerous studies have investigated the clinical significance of BRAF mutation in papillary thyroid carcinoma (PTC). However, there have been conflicting data on the usefulness of BRAF mutation as a prognostic marker of PTC. To address this controversy, the frequency of the BRAF mutation and the associations between BRAF mutation and clinicopathologic parameters in PTC were evaluated by meta-analysis. METHODS. The relevant published studies were reviewed according to the defined selection criteria. The effect sizes of outcome parameters were estimated by odds ratio or weighted mean difference. RESULTS. The current meta-analysis included 12 studies with a total of 1168 patients. The frequency of the BRAF mutation was 49%. The BRAF mutation was associated with histologic subtype, the presence of extrathyroidal extension, and higher clinical stage, but not with age, sex, race, or tumor size. CONCLUSIONS. The effect of the BRAF mutation on the poor prognosis of PTC patients was evident from the current meta-analysis. The detection of the BRAF mutation may be used as an important prognostic marker of patients with PTC. Cancer 2007. © 2007 American Cancer Society.

Abstract: Recent studies of developmental biology have shown that the genes controlling phenotypic characters expressed in the early stage of development are highly conserved and that recent evolutionary changes have occurred primarily in the characters expressed in later stages of development. Even the genes controlling the latter characters are generally conserved, but there is a large component of neutral or nearly neutral genetic variation within and between closely related species. Phenotypic evolution occurs primarily by mutation of genes that interact with one another in the developmental process. The enormous amount of phenotypic diversity among different phyla or classes of organisms is a product of accumulation of novel mutations and their conservation that have facilitated adaptation to different environments. Novel mutations may be incorporated into the genome by natural selection (elimination of preexisting genotypes) or by random processes such as genetic and genomic drift. However, once the mutations are incorporated into the genome, they may generate developmental constraints that will affect the future direction of phenotypic evolution. It appears that the driving force of phenotypic evolution is mutation, and natural selection is of secondary importance.

Abstract: Resistance to QoI fungicides in Pyrenophora teres (Dreschsler) and P. tritici-repentis (Died.) Dreschsler was detected in 2003 in France and in Sweden and Denmark respectively. Molecular analysis revealed the presence of the F129L mutation in resistant isolates of both pathogens. In 2004, the frequency of the F129L mutation in populations of both pathogens further increased. The G143A mutation was also detected in a few isolates of P. tritici-repentis from Denmark and Germany. In 2005, the F129L mutation in P. teres increased in frequency and geographical distribution in France and the UK but remained below 2% in Germany, Switzerland, Belgium and Ireland. In P. tritici-repentis, both mutations were found in a significant proportion of the isolates from Sweden, Denmark and Germany. The G143A mutation conferred a significantly higher level of resistance (higher EC50 values) to Qo inhibitors (QoIs) than did the F129L mutation. In greenhouse trials, resistant isolates with G143A were not well controlled on plants sprayed with recommended field rates, whereas satisfactory control of isolates with F129L was achieved. For the F129L mutation, three different single nucleotide polymorphisms (SNPs), TTA, TTG and CTC, can code for L (leucine) in P. teres, whereas only the CTC codon was detected in P. tritici-repentis isolates. In two out of 250 isolates of P. tritici-repentis from 2005, a mutation at position 137 (G137R) was detected at very low frequency. This mutation conferred similar resistance levels to F129L. The structure of the cytochrome b gene of P. tritici-repentis is significantly different from that of P. teres: an intron directly after amino acid position 143 was detected in P. teres which is not present in P. tritici-repentis. This gene structure suggests that resistance based on the G143A mutation may not occur in P. teres because it is lethal. No G143A isolates were found in any P. teres populations. Although different mutations may evolve in P. tritici-repentis, the G143A mutation will have the strongest impact on field performance of QoI fungicides.

Abstract: HbVar (http://globin.bx.psu.edu/hbvar) is a locus-specific database (LSDB) developed in 2001 by a multi-center academic effort to provide timely information on the genomic sequence changes leading to hemoglobin variants and all types of thalassemia and hemoglobinopathies. Database records include extensive phenotypic descriptions, biochemical and hematological effects, associated pathology, and ethnic occurrence, accompanied by mutation frequencies and references. In addition to the regular updates to entries, we report significant advances and updates, which can be useful not only for HbVar users but also for other LSDB development and curation in general. The query page provides more functionality but in a simpler, more user-friendly format and known single nucleotide polymorphisms in the human alpha- and beta-globin loci are provided automatically. Population-specific beta-thalassemia mutation frequencies for 31 population groups have been added and/or modified and the previously reported delta- and alpha-thalassemia mutation frequency data from 10 population groups have also been incorporated. In addition, an independent flat-file database, named XPRbase (http://www.goldenhelix.org/xprbase), has been developed and linked to the main HbVar web page to provide a succinct listing of 51 experimental protocols available for globin gene mutation screening. These updates significantly augment the database profile and quality of information provided, which should increase the already high impact of the HbVar database, while its combination with the UCSC powerful genome browser and the ITHANET web portal paves the way for drawing connections of clinical importance, that is from genome to function to phenotype.

Abstract: Identification of the selective forces contributing to the origin and maintenance of sex is a fundamental problem in biology. The Fisher–Muller model proposes that sex is advantageous because it allows beneficial mutations that arise in different lineages to recombine, thereby reducing clonal interference and speeding adaptation. I used the F plasmid to mediate recombination in the bacterium Escherichia coli and measured its effect on adaptation at high and low mutation rates. Recombination increased the rate of adaptation ∼3-fold more in the high mutation rate treatment, where beneficial mutations had to compete for fixation. Sequencing of candidate loci revealed the presence of a beneficial mutation in six high mutation rate lines. In the absence of recombination, this mutation took longer to fix and, over the course of its substitution, conferred a reduced competitive advantage, indicating interference between competing beneficial mutations. Together, these results provide experimental support for the Fisher–Muller model and demonstrate that plasmid-mediated gene transfer can accelerate bacterial adaptation.

Abstract: Huntington disease is caused by the expansion of a CAG repeat encoding an extended glutamine tract in a protein called huntingtin. Here, we provide evidence supporting the hypothesis that somatic increases of mutation length play a role in the progressive nature and cell-selective aspects of HD pathogenesis. Results from micro-dissected tissue and individual laser-dissected cells obtained from human HD cases and knock-in HD mice indicate that the CAG repeat is unstable in all cell types tested although neurons tend to have longer mutation length gains than glia. Mutation length gains occur early in the disease process and continue to accumulate as the disease progresses. In keeping with observed patterns of cell loss, neuronal mutation length gains tend to be more prominent in the striatum than in the cortex of low-grade human HD cases, less so in more advanced cases. Interestingly, neuronal sub-populations of HD mice appear to have different propensities for mutation length gains; in particular, smaller mutation length gains occur in nitric oxide synthase-positive striatal interneurons (a relatively spared cell type in HD) compared with the pan-striatal neuronal population. More generally, the data demonstrate that neuronal changes in HD repeat length can be at least as great, if not greater, than those observed in the germline. The fact that significant CAG repeat length gains occur in non-replicating cells also argues that processes such as inappropriate mismatch repair rather than DNA replication are involved in generating mutation instability in HD brain tissue.

Abstract: Mutation has traditionally been considered a random process, but this paradigm is challenged by recent evidence of divergence rate heterogeneity in different genomic regions. One facet of mutation rate variation is the propensity for genetic change to correlate with the number of germ cell divisions, reflecting the replication-dependent origin of many mutations. Haldane was the first to connect this association of replication and mutation to the difference in the number of cell divisions in oogenesis (low) and spermatogenesis (usually high), and the resulting sex difference in the rate of mutation. The concept of male-biased mutation has been thoroughly analysed in recent years using an evolutionary approach, in which sequence divergence of autosomes and/or sex chromosomes are compared to allow inference about the relative contribution of mothers and fathers in the accumulation of mutations. For instance, assuming that a neutral sequence is analysed, that rate heterogeneity owing to other factors is cancelled out by the investigation of many loci and that the effect of ancestral polymorphism is properly taken into account, the male-to-female mutation rate ratio, αm, can be solved from the observed difference in rate of X and Y chromosome divergence. The male mutation bias is positively correlated with the relative excess of cell divisions in the male compared to the female germ line, as evidenced by a generation time effect: in mammals, αm is estimated at approximately 4–6 in primates, approximately 3 in carnivores and approximately 2 in small rodents. Another life-history correlate is sexual selection: when there is intense sperm competition among males, increased sperm production will be associated with a larger number of mitotic cell divisions in spermatogenesis and hence an increase in αm. Male-biased mutation has implications for important aspects of evolutionary biology such as mate choice in relation to mutation load, sexual selection and the maintenance of genetic diversity despite strong directional selection, the tendency for a disproportionate large role of the X (Z) chromosome in post-zygotic isolation, and the evolution of sex.

Abstract: The JAK2 V617F mutation is a frequent genetic event in the three classical Philadelphia-chromosome negative chronic myeloproliferative disorders (Ph(neg.)-CMPD), polycythemia vera (PV), essential thrombocythemia (ET) and idiopathic myelofibrosis (IMF). Its occurrence varies in frequency in regards to phenotype. The mutation is found in the majority of patients with PV and about half of the patients with ET and IMF. These diseases are clonal stem cell disorders arising in an early stem cell progenitor. The level in the stem cell hierarchy on which the initiating genetic events and the JAK2 V617F mutation occurs is not known. The mutation has so far been detected in all cells of the myeloid lineage, whereas the potential clonal involvement of the lymphoid lineage is controversial. In this study, we detected the JAK2 V617F mutation by real-time quantitative PCR (qPCR) in both B-lymphocytes and T-lymphocytes in a subgroup of patients with Ph(neg.)-CMPDs. These results demonstrate the origin of the JAK2 V617F positive disorders in an early stem cell with both lymphoid and myeloid differentiation potential.

Abstract: This paper shows the existence of independent random matching of a large (continuum) population in both static and dynamic systems, which has been popular in the economics and genetics literatures. We construct a joint agent-probability space, and randomized mutation, partial matching and match-induced type-changing functions that satisfy appropriate independence conditions. The proofs are achieved via nonstandard analysis. The proof for the dynamic setting relies on a new Fubini-type theorem for an infinite product of Loeb transition probabilities, based on which a continuum of independent Markov chains is derived from random mutation, random partial matching and random type changing.

Abstract: In this paper, we review recent advances in evolutionary programming (EP) and its implementation in various antenna, microwave, frequency selective surfaces and RF circuit optimization problems. EP, unlike the other two paradigms of evolutionary computational techniques, namely, genetic algorithms (GA) and evolution strategies (ES), uses a mutation only variation operator where adaptive and/or self-adaptive techniques exist, or can easily be designed, for adapting the parameters of mutation operator during the evolution process. We present the so-called meta-EP and design of its mutation operator, using Gaussian, Cauchy and Poisson mutations as well as a hybrid of these mutations, for continuous, discrete and mixed parameter electromagnetic optimization problems. In addition, an efficient hybrid use of EP, gradient search methods and cluster analysis, as well as a novel hybrid EP-GA algorithm are discussed. Examples presented include optimizations of corrugated horn antennas, multilayered stacked microstrip antennas, Yagi-Uda arrays, partially reflective surfaces, dielectric filters, meander-line polarizer and RF duplexers

Abstract: The PI3K-AKT pathway is activated in a variety of human cancers, resulting in disturbance of cell growth, proliferation and survival. Among the factors affecting the pathway, the K-Ras mutation and PIK3CA mutation are the most common oncogenic alterations in colorectal cancer. We hypothesized that these two mutations are important in activation of the PI3K pathway and colorectal carcinogenesis. In this study, we aimed to examine the influence of PIK3CA mutation and K-Ras mutation on AKT activation, and to clarify whether PIK3CA mutation, K-Ras mutation and p-AKT expression may be used as parameters for predicting prognosis in colorectal cancer. Tissue samples from 158 colorectal cancer patients who underwent surgical resection were examined. The sequences of exon 1 of K-Ras and exons 9 and 20 of PIK3CA were determined by direct sequencing using genomic DNA extracted from paraffin-embedded blocks. Activation status of AKT was evaluated by immunohistochemical staining using phospho-specific AKT antibody (Ser473). Correlation between these factors and clinicopathologic findings/patient survival were examined. As a result, PIK3CA mutation was significantly associated with shorter relapse-free survival (RFS) in stage II/III patients (p = 0.0216) and shorter disease-specific survival in all patients (p = 0.0357). In the multivariate analysis, PIK3CA mutation was the only independent and significant prognostic factor for RFS in stage II/III patients (p = 0.0433, HR 2.478). This study revealed the prognostic value of PIK3CA mutation in colorectal cancer patients. Patients with PIK3CA mutation should be followed up carefully. Moreover, our result suggests that inhibition of PIK3CA mutant may be a new molecular target therapy.

Abstract: A set of mutation operators for SQL queries that retrieve information from a database is developed and tested against a set of queries drawn from the NIST SQL Conformance Test Suite. The mutation operators cover a wide spectrum of SQL features, including the handling of null values. Additional experiments are performed to explore whether the cost of executing mutants can be reduced using selective mutation or the test suite size can be reduced by using an appropriate ordering of the mutants. The SQL mutation approach can be helpful in assessing the adequacy of database test cases and their development, and as a tool for systematically injecting faults in order to compare different database testing techniques.

Abstract: Mitochondrial disorders are frequently caused by mutations in mitochondrial genes and usually present as multisystem disease. One of the most frequent mitochondrial mutations is the A3243G transition in the tRNALeu(UUR) gene. The phenotypic expression of the mutation is variable and comprises syndromic or non-syndromic mitochondrial disorders. Among the syndromic manifestations the mitochondrial encephalopathy, lactacidosis, and stroke-like episode (MELAS) syndrome is the most frequent. In single cases the A3243G mutation may be associated with maternally inherited diabetes and deafness syndrome, myoclonic epilepsy and ragged-red fibers (MERRF) syndrome, MELAS/MERRF overlap syndrome, maternally inherited Leigh syndrome, chronic external ophthalmoplegia, or Kearns-Sayre syndrome. The wide phenotypic variability of the mutation is explained by the peculiarities of the mitochondrial DNA, such as heteroplasmy and mitotic segregation, resulting in different mutation loads in different tissues and family members. Moreover, there is some evidence that additional mtDNA sequence variations (polymorphisms, haplotypes) influence the phenotype of the A3243G mutation. This review aims to give an overview on the actual knowledge about the genetic, pathogenetic, and phenotypic implications of the A3243G mtDNA mutation.

Abstract: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. This tumor typically expresses KIT, and has KIT or PDGFRA activating mutation. In this study we evaluated 89 GISTs diagnosed in Northern Norway during a 30‐year period. KIT exons 8, 9, 11, 13, and 17 were analyzed by PCR amplification and direct sequencing. Subsequently PDGRA exons 12, 14, and 18 were evaluated in KIT wild‐type cases. KIT mutations were found in 66 cases (75%), and PDGFRA mutations in 9 cases (10%). Most common were KIT exon 11 mutations, with 58 cases. Tumors with Kit exon 11 point mutations had a significantly better prognosis than those with deletions. There were five KIT exon 9 duplications, three exon 13 point mutations, and one point mutation in exon 17. There were nine PDGFGRA mutations: seven in exon 18 and two in exon 12. All but one PDGFRA mutant GISTs were gastric tumors with epithelioid morphology, and these tumors were on average smaller than those with KIT mutations. KIT and PDGFRA wild type was found in 15% of cases. Analysis of KIT and PDGFRA mutations is of significance for treatment with tyrosine kinase inhibitors, and may also have value when assessing the biological potential of GIST.

Abstract: A genome wide scan in a consanguineous family of Indian origin with autosomal recessive developmental cataracts was performed by two-point linkage analysis with 382 microsatellite markers. It showed linkage to markers on chromosome 20q, between D20S852 and D20S912, with a maximum lod score of 5.4 obtained with D20S860. This region encompasses the beaded filament structural protein 1 (BFSP1) gene. Direct sequencing revealed a 3343 bp deletion including exon 6 (c.736-1384_c.957-66 del) predicted to result in a shift of the open reading frame. This mutation was absent in 50 control individuals from south India. This is the first report of a mutation in the BFSP1 gene associated with human inherited cataracts. This further increases the genetic heterogeneity of inherited cataracts and provides clues as to the importance of BFSP1 in the cell biology of intermediate filaments and their role in the eye lens.

Abstract: Mutations in the FBN1 gene have been characterised in patients affected by Marfan syndrome and Marfan-related disorders. Starting with genomic DNA, we analysed the FBN1 gene using PCR, SSCP and/or dHPLC analysis, and automatic sequencing of abnormal bands/peaks, in a consecutive series of 508 patients, of which 22 were children less than 5 years old. Our results are comparable with those reported by other groups. In this study we observed 193 mutations, 126 of which previously unreported. A total of 331 relatives (including 51 infants) of 120 probands for whom a family mutation had been identified here or elsewhere, were tested for the presence of that particular mutation. In addition, 4 prenatal tests were carried out. The identification of a mutation allows for early diagnosis, prognosis, genetic counselling, preventive management of carriers and reassurance for unaffected relatives. The importance of knowing in advance the location of the putative family mutation is highlighted by its straightforward application to prenatal and postnatal screening. © 2007 Wiley-Liss, Inc.