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Mutation Rate (mutation + rate)
Kinds of Mutation Rate Selected AbstractsOral lichen planus has a high rate of TP53 mutations.EUROPEAN JOURNAL OF ORAL SCIENCES, Issue 3 2002A study of oral mucosa in Iceland Oral squamous cell carcinoma (OSCC) is a world-wide health problem. In addition to external exposure (smoking and alcohol), certain oral lesions may increase the risk of oral cancer (e.g. leukoplakia, erythroplakia, and oral lichen planus). TP53 has been implicated in OSCC, but there are limited studies of mutations in premalignant oral lesions. In this study, 55 samples from OSCC, 47 from hyperkeratotic (HK) oral mucosa, clinically diagnosed as white patches, 48 samples from oral lichen planus (OLP), and 12 biopsies from normal oral mucosa were studied immunohistochemically for expression of TP53 protein. From all the carcinoma samples and selected non-malignant samples showing moderate or strong TP53 protein expression, malignant cells or TP53-positive nuclei were microdissected and screened for mutations in exons 5,8 by constant denaturation gel electrophoresis. Moderate to strong TP53 protein staining was seen in 56% of OSCC, 32% of OLP but only in 13% of HK. All OLP samples showed a characteristic pattern of positive nuclei confined to the basal layer, whereas TP53 staining was seen in suprabasal nuclei in HK. Mutation rate was 11 out of 52 for OSCC, three out of 20 tested for HK and, remarkably, nine out 27 tested for OLP. There was no correlation between TP53 protein staining and TP53 mutations. No associations were found with anatomical sites or disease progression. The unexpectedly high mutation rate of OLP might explain the premalignant potential of this lesion. [source] Mutation rate of MAP2K4/MKK4 in breast carcinoma ,,HUMAN MUTATION, Issue 1 2002Gloria H. Su Abstract The stress-activated protein kinase (SAPK) pathways represent phosphorylation cascades that convey pro-apoptotic signals. The relevant inputs include Ras proteins as well as exposure of cells to ultraviolet light, tumor-necrosis factor, and other stress-related inputs. The mitogen-activated protein kinase kinase (MAPKK) homolog MAP2K4 (MKK4, SEK, JNKK1) is a centrally-placed mediator of the SAPK pathways. MAP2K4 mutations or homozygous deletions are reported in about 5% of a wide variety of tumor types. The exception is breast cancer, where genetic inactivation in 3 of 22 (15%) cell lines had suggested that the mutational involvement of MAP2K4 might be accentuated in this tumor type. This finding might have represented an important difference, or solely a chance numerical variation. To address this question, we studied an independent panel of 20 breast cancer cell lines and xenografts for MAP2K4 alterations. We found a splice acceptor mutation accompanied by loss of the other allele in the cell line MPE600. This was the sole alteration in this panel (5% of tumors). These data seem to re-establish a rather consistent rate of genetic inactivation of MAP2K4 among most tumor types, including breast cancer. The genetic evaluation of other mediators of the SAPK pathways might offer insight into a promising, but as yet poorly defined, tumor-suppressive system. © 2001 Wiley-Liss, Inc. [source] Hepatitis B virus X mutations occurring naturally associated with clinical severity of liver disease among Korean patients with chronic genotype C infection,JOURNAL OF MEDICAL VIROLOGY, Issue 8 2008Hyun-Ju Kim Abstract Few reports have detailed mutation frequencies and mutation patterns in the entire X region according to clinical status. The aims of this study were to elucidate the relationships between mutation patterns and their frequencies in the X region and clinical status in a Korean cohort and determine specific X mutation types, related closely with liver disease progression. All X mutations were determined by direct sequencing in 184 patients with different clinical features. Mutation rates in the X region in patients with more severe liver disease, hepatocellular carcinoma (HCC) (3.6%) or liver cirrhosis (4%) were always significantly higher than in patients with corresponding less severe forms, chronic hepatitis (2.9%) or asymptomatic carriers (2.1%), but no significant difference in mutation rates was found in terms of HBeAg serostatus. All five mutation types (V5M/L, P38S, H94Y, I127T/N, and K130M and V131I) affecting the six codons were found to be related significantly to clinical severity. Among these, two mutation types (V5M/L and K130M and V131I) were observed more frequently in HBeAg negative patients than in HBeAg positive patients. In conclusion, the results suggest that an accumulation of mutations in the X region contributes to disease progression in chronic patients, at least Korean patients with genotype C. Specific mutation types appears to be related more to severe liver diseases such as HCC or liver cirrhosis. In particular, a novel mutation type (V5M/L) discovered firstly during the present study was found to be associated significantly with HCC. J. Med. Virol. 80:1337,1343, 2008. © 2008 Wiley-Liss, Inc. [source] Bioenergetics and the epigenome: Interface between the environment and genes in common diseasesDEVELOPMENTAL DISABILITIES RESEARCH REVIEW, Issue 2 2010Douglas C. Wallace Abstract Extensive efforts have been directed at using genome-wide association studies (GWAS) to identify the genes responsible for common metabolic and degenerative diseases, cancer, and aging, but with limited success. While environmental factors have been evoked to explain this conundrum, the nature of these environmental factors remains unexplained. The availability of and demands for energy constitute one of the most important aspects of the environment. The flow of energy through the cell is primarily mediated by the mitochondrion, which oxidizes reducing equivalents from hydrocarbons via acetyl-CoA, NADH + H+, and FADH2 to generate ATP through oxidative phosphorylation (OXPHOS). The mitochondrial genome encompasses hundreds of nuclear DNA (nDNA)-encoded genes plus 37 mitochondrial DNA (mtDNA)-encoded genes. Although the mtDNA has a high mutation rate, only milder, potentially adaptive mutations are introduced into the population through female oocytes. In contrast, nDNA-encoded bioenergetic genes have a low mutation rate. However, their expression is modulated by histone phosphorylation and acetylation using mitochondrially-generated ATP and acetyl-CoA, which permits increased gene expression, growth, and reproduction when calories are abundant. Phosphorylation, acetylaton, and cellular redox state also regulate most signal transduction pathways and activities of multiple transcription factors. Thus, mtDNA mutations provide heritable and stable adaptation to regional differences while mitochondrially-mediated changes in the epigenome permit reversible modulation of gene expression in response to fluctuations in the energy environment. The most common genomic changes that interface with the environment and cause complex disease must, therefore, be mitochondrial and epigenomic in origin. © 2010 Wiley-Liss, Inc. Dev Disabil Res Rev 2010;16:114,119. [source] Advancing the metabolic theory of biodiversityECOLOGY LETTERS, Issue 10 2009James C. Stegen Abstract A component of metabolic scaling theory has worked towards understanding the influence of metabolism over the generation and maintenance of biodiversity. Specific models within this ,metabolic theory of biodiversity' (MTB) have addressed temperature gradients in speciation rate and species richness, but the scope of MTB has been questioned because of empirical departures from model predictions. In this study, we first show that a generalized MTB is not inconsistent with empirical patterns and subsequently implement an eco-evolutionary MTB which has thus far only been discussed qualitatively. More specifically, we combine a functional trait (body mass) approach and an environmental gradient (temperature) with a dynamic eco-evolutionary model that builds on the current MTB. Our approach uniquely accounts for feedbacks between ecological interactions (size-dependent competition and predation) and evolutionary rates (speciation and extinction). We investigate a simple example in which temperature influences mutation rate, and show that this single effect leads to dynamic temperature gradients in macroevolutionary rates and community structure. Early in community evolution, temperature strongly influences speciation and both speciation and extinction strongly influence species richness. Through time, niche structure evolves, speciation and extinction rates fall, and species richness becomes increasingly independent of temperature. However, significant temperature-richness gradients may persist within emergent functional (trophic) groups, especially when niche breadths are wide. Thus, there is a strong signal of both history and ecological interactions on patterns of species richness across temperature gradients. More generally, the successful implementation of an eco-evolutionary MTB opens the perspective that a process-based MTB can continue to emerge through further development of metabolic models that are explicit in terms of functional traits and environmental gradients. [source] Stationary phase mutagenesis: mechanisms that accelerate adaptation of microbial populations under environmental stressENVIRONMENTAL MICROBIOLOGY, Issue 10 2003Maia Kivisaar Summary Microorganisms are exposed to constantly changing environmental conditions. In a growth-restricting environment (e.g. during starvation), mutants arise that are able to take over the population by a process known as stationary phase mutation. Genetic adaptation of a microbial population under environmental stress involves mechanisms that lead to an elevated mutation rate. Under stressful conditions, DNA synthesis may become more erroneous because of the induction of error-prone DNA polymerases, resulting in a situation in which DNA repair systems are unable to cope with increasing amounts of DNA lesions. Transposition may also increase genetic variation. One may ask whether the rate of mutation under stressful conditions is elevated as a result of malfunctioning of systems responsible for accuracy or are there specific mechanisms that regulate the rate of mutations under stress. Evidence for the presence of mutagenic pathways that have probably been evolved to control the mutation rate in a cell will be discussed. [source] Variation in mitochondrial DNA control region haplotypes in populations of the bank vole, Clethrionomys glareolus, living in the Chernobyl environment, UkraineENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 2 2006Jeffrey K. Wickliffe Abstract Bank vole, Clethrionomys glareolus, specimens have been annually sampled from the radioactive Chernobyl, Ukraine, environment and nonradioactive reference sites since 1997. Exposed voles continually exhibit increased mitochondrial DNA hap-lotype (h) and nucleotide diversity (ND), observed in the hypervariable control region (1997,1999). Increased maternal mutation rates, source,sink relationships, or both are proposed as hypotheses for these differences. Samples from additional years (2000 and 2001) have been incorporated into this temporal study. To evaluate the hypothesis that an increased mutation rate is associated with increased h, DNA sequences were examined in a phylogenetic context for novel substitutions not observed in haplotypes from bank voles from outside Ukraine or in other species of Clethrionomys. Such novel substitutions might result from in situ mutation events and, if largely restricted to samples from radioactive environments, support an increased maternal mutation rate in these areas. The only unique substitution meeting this criterion was found in an uncontaminated reference site. All other substitutions are found in other haplotypes of the bank vole or in other species. Increased maternal mutation rates do not appear to explain trends in h and ND observed in northern Ukraine. Studies examining ecological dynamics will clarify the reasons behind, and significance of, increased levels of h in contaminated areas. [source] Oral lichen planus has a high rate of TP53 mutations.EUROPEAN JOURNAL OF ORAL SCIENCES, Issue 3 2002A study of oral mucosa in Iceland Oral squamous cell carcinoma (OSCC) is a world-wide health problem. In addition to external exposure (smoking and alcohol), certain oral lesions may increase the risk of oral cancer (e.g. leukoplakia, erythroplakia, and oral lichen planus). TP53 has been implicated in OSCC, but there are limited studies of mutations in premalignant oral lesions. In this study, 55 samples from OSCC, 47 from hyperkeratotic (HK) oral mucosa, clinically diagnosed as white patches, 48 samples from oral lichen planus (OLP), and 12 biopsies from normal oral mucosa were studied immunohistochemically for expression of TP53 protein. From all the carcinoma samples and selected non-malignant samples showing moderate or strong TP53 protein expression, malignant cells or TP53-positive nuclei were microdissected and screened for mutations in exons 5,8 by constant denaturation gel electrophoresis. Moderate to strong TP53 protein staining was seen in 56% of OSCC, 32% of OLP but only in 13% of HK. All OLP samples showed a characteristic pattern of positive nuclei confined to the basal layer, whereas TP53 staining was seen in suprabasal nuclei in HK. Mutation rate was 11 out of 52 for OSCC, three out of 20 tested for HK and, remarkably, nine out 27 tested for OLP. There was no correlation between TP53 protein staining and TP53 mutations. No associations were found with anatomical sites or disease progression. The unexpectedly high mutation rate of OLP might explain the premalignant potential of this lesion. [source] GENES WITH SOCIAL EFFECTS ARE EXPECTED TO HARBOR MORE SEQUENCE VARIATION WITHIN AND BETWEEN SPECIESEVOLUTION, Issue 7 2009Timothy A. Linksvayer The equilibrium sequence diversity of genes within a population and the rate of sequence divergence between populations or species depends on a variety of factors, including expression pattern, mutation rate, nature of selection, random drift, and mating system. Here, we extend population genetic theory developed for maternal-effect genes to predict the equilibrium polymorphism within species and sequence divergence among species for genes with social effects on fitness. We show how the fitness effects of genes, mating system, and genetic system affect predicted gene polymorphism. We find that, because genes with indirect social effects on fitness effectively experience weaker selection, they are expected to harbor higher levels of polymorphism relative to genes with direct fitness effects. The relative increase in polymorphism is proportional to the inverse of the genetic relatedness between individuals expressing the gene and their social partners that experience the fitness effects of the gene. We find a similar pattern of more rapid divergence between populations or species for genes with indirect social effects relative to genes with direct effects. We focus our discussion on the social insects, organisms with diverse indirect genetic effects, mating and genetic systems, and we suggest specific examples for testing our predictions with emerging sociogenomic tools. [source] PURGING THE GENOME WITH SEXUAL SELECTION: REDUCING MUTATION LOAD THROUGH SELECTION ON MALESEVOLUTION, Issue 3 2009Michael C. Whitlock Healthy males are likely to have higher mating success than unhealthy males because of differential expression of condition-dependent traits such as mate searching intensity, fighting ability, display vigor, and some types of exaggerated morphological characters. We therefore expect that most new mutations that are deleterious for overall fitness may also be deleterious for male mating success. From this perspective, sexual selection is not limited to influencing those genes directly involved in exaggerated morphological traits but rather affects most, if not all, genes in the genome. If true, sexual selection can be an important force acting to reduce the frequency of deleterious mutations and, as a result, mutation load. We review the literature and find various forms of indirect evidence that sexual selection helps to eliminate deleterious mutations. However, direct evidence is scant, and there are almost no data available to address a key issue: is selection in males stronger than selection in females? In addition, the total effect of sexual selection on mutation load is complicated by possible increases in mutation rate that may be attributable to sexual selection. Finally, sexual selection affects population fitness not only through mutation load but also through sexual conflict, making it difficult to empirically measure how sexual selection affects load. Several lines of enquiry are suggested to better fill large gaps in our understanding of sexual selection and its effect on genetic load. [source] ASSORTATIVE MATING FOR FITNESS AND THE EVOLUTION OF RECOMBINATIONEVOLUTION, Issue 7 2006Alistair Blachford Abstract To understand selection on recombination, we need to consider how linkage disequilibria develop and how recombination alters these disequilibria. Any factors that development of disequilbria, including nonrandom mating, can potentially change selectio on recombination. Assortative mating is known to affect linkage disequilbria but its effect on the evolution of recombination have not been previously studied. Given that assortative arise indirectly via a number of biologically realistic scenarios, it is plausible that weak assortative mating occurs across a diverse set of taxa. Using a modifier model, we examine how assortative mating for fitness affects the evolution of recombination under two evolutionary scenarios: selective sweeps and mutation-selection balance. We find there is no net effect of assortative mating during a selective sweep. In contrast, assortative mating could have a large effect on recombination when deleterious alleles are maintained at mutation-selection balance but only if assortative mating is sufficiently strong. Upon considering reasonable values for the number of loci affecting fitness components, the strength of selection, and the mutation rate, we conclude that the correlation in fitness between mates is unlikely to be sufficiently high for assortative mating to affect the evolution of recombination in most species. [source] THE PHENOTYPIC VARIANCE WITHIN PLASTIC TRAITS UNDER MIGRATION-MUTATION-SELECTION BALANCEEVOLUTION, Issue 6 2006Xu-Sheng Zhang Abstract How phenotypic variances of quantitative traits are influenced by the heterogeneity in environment is an important problem in evolutionary biology. In this study, both genetic and environmental variances in a plastic trait under migration-mutation-stabilizing selection are investigated. For this, a linear reaction norm is used to approximate the mapping from genotype to phenotype, and a population of clonal inheritance is assumed to live in a habitat consisting of many patches in which environmental conditions vary among patches and generations. The life cycle is assumed to be selection-reproduction-mutation-migration. Analysis shows that phenotypic plasticity is adaptive if correlations between the optimal phenotype and environment have become established in both space and/or time, and it is thus possible to maintain environmental variance (VE) in the plastic trait. Under the special situation of no mutation but maximum migration such that separate patches form an effective single-site habitat, the genotype that maximizes the geometric mean fitness will come to fixation and thus genetic variance (VG) cannot be maintained. With mutation and/or restricted migration, VG can be maintained and it increases with mutation rate but decreases with migration rate; whereas VE is little affected by them. Temporal variation in environmental quality increases VG while its spatial variance decreases VG. Variation in environmental conditions may decrease the environmental variance in the plastic trait. [source] ADAPTIVE REPTILE COLOR VARIATION AND THE EVOLUTION OF THE MCIR GENEEVOLUTION, Issue 8 2004Erica Bree Rosenblum Abstract The wealth of information on the genetics of pigmentation and the clear fitness consequences of many pigmentation phenotypes provide an opportunity to study the molecular basis of an ecologically important trait. The melanocortin-1 receptor (Mc1r) is responsible for intraspecific color variation in mammals and birds. Here, we study the molecular evolution of Mc1r and investigate its role in adaptive intraspecific color differences in reptiles. We sequenced the complete Mc1r locus in seven phylogenetically diverse squamate species with melanic or blanched forms associated with different colored substrates or thermal environments. We found that patterns of amino acid substitution across different regions of the receptor are similar to the patterns seen in mammals, suggesting comparable levels of constraint and probably a conserved function for Mc1r in mammals and reptiles. We also found high levels of silent-site heterozygosity in all species, consistent with a high mutation rate or large long-term effective population size. Mc1r polymorphisms were strongly associated with color differences in Holbrookia maculata and Aspidoscelis inornata. In A. inornata, several observations suggest that Mc1r mutations may contribute to differences in color: (1) a strong association is observed between one Mc1r amino acid substitution and dorsal color; (2) no significant population structure was detected among individuals from these populations at the mitochondrial ND4 gene; (3) the distribution of allele frequencies at Mc1r deviates from neutral expectations; and (4) patterns of linkage disequilibrium at Mc1r are consistent with recent selection. This study provides comparative data on a nuclear gene in reptiles and highlights the utility of a candidate-gene approach for understanding the evolution of genes involved in vertebrate adaptation. [source] CALIBRATING A MOLECULAR CLOCK FROM PHYLOGEOGRAPHIC DATA: MOMENTS AND LIKELIHOOD ESTIMATORSEVOLUTION, Issue 10 2003Michael J. Hickerson Abstract We present moments and likelihood methods that estimate a DNA substitution rate from a group of closely related sister species pairs separated at an assumed time, and we test these methods with simulations. The methods also estimate ancestral population size and can test whether there is a significant difference among the ancestral population sizes of the sister species pairs. Estimates presented in the literature often ignore the ancestral coalescent prior to speciation and therefore should be biased upward. The simulations show that both methods yield accurate estimates given sample sizes of five or more species pairs and that better likelihood estimates are obtained if there is no significant difference among ancestral population sizes. The model presented here indicates that the larger than expected variation found in multitaxa datasets can be explained by variation in the ancestral coalescence and the Poisson mutation process. In this context, observed variation can often be accounted for by variation in ancestral population sizes rather than invoking variation in other parameters, such as divergence time or mutation rate. The methods are applied to data from two groups of species pairs (sea urchins and Alpheus snapping shrimp) that are thought to have separated by the rise of Panama three million years ago. [source] DELETERIOUS MUTATION AND THE EVOLUTION OF EUSOCIALITYEVOLUTION, Issue 12 2002Joshua L. Cherry Abstract., Certain arguments concerning the evolution of eusociality form a classic example of the application of the principles of kin selection. These arguments center on the different degrees of relatedness of potential beneficiaries of an individual's efforts, for example a female's higher relatedness to her sisters than to her daughters in a haplodiploid system. This type of reasoning is insufficient to account for the evolution and maintainence of sexual reproduction, because parthenogenic females produce offspring that are more closely related to them than are offspring produced sexually. Among the forces invoked to explain sexual reproduction is deleterious mutation. This factor can be shown to favor eusociality as well, because siblings produced by helping carry fewer deleterious alleles on average than would offspring. The strength of this effect depends on the genomewide deleterious mutation rate, U, and on the selection coefficient, s, associated with deleterious alleles. For small s, the effect depends approximately on the product Us. This phenomenon illustrates that an assumption implicit in some analyses,that the relatedness of an individual to an actor is all that matters to its value to that actor,can fail for the evolution of eusociality as it does for the evolution of sex. [source] THE FITNESS EFFECTS OF SPONTANEOUS MUTATIONS IN CAENORHABDITIS ELEGANSEVOLUTION, Issue 4 2000Larissa L. Vassilieva Abstract. Spontaneous mutation to mildly deleterious alleles has emerged as a potentially unifying component of a variety of observations in evolutionary genetics and molecular evolution. However, the biological significance of hypotheses based on mildly deleterious mutation depends critically on the rate at which new mutations arise and on their average effects. A long-term mutation-accumulation experiment with replicate lines of the nematode Caenorhabditis elegans maintained by single-progeny descent indicates that recurrent spontaneous mutation causes approximately 0.1% decline in fitness per generation, which is about an order of magnitude less than that suggested by previous studies with Drosophila. Two rather different approaches, Bateman-Mukai and maximum likelihood, suggest that this observation, along with the observed rate of increase in the variance of fitness among lines, is consistent with a genomic deleterious mutation rate for fitness of approximately 0.03 per generation and with an average homozygous effect of approximately 12%. The distribution of mutational effects for fitness appears to have a relatively low coefficient of variation, being no more extreme than expected for a negative exponential, and for one composite fitness measure (total progeny production) approaches constancy of effects. These results are derived from assays in a benign environment. At stressful temperatures, estimates of the genomic deleterious mutation rate (for genes expressed at such temperatures) is sixfold lower, whereas those for the average homozygous effect is approximately eightfold higher. Our results are reasonably compatible with existing estimates for flies, when one considers the differences between these species in the number of germ-line cell divisions per generation and the magnitude of transposable element activity. [source] STABILITY AND EVOLUTION OF OVERLAPPING GENESEVOLUTION, Issue 3 2000David C. Krakauer Abstract., When the same sequence of nucleotides codes for regions of more than one functional polypeptide, this sequence contains overlapping genes. Overlap is most common in rapidly evolving genomes with high mutation rates such as viruses, bacteria, and mitochondria. Overlap is thought to be important as: (1) a means of compressing a maximum amount of information into short sequences of structural genes; and (2) as a mechanism for regulating gene expression through translational coupling of functionally related polypeptides. The stability of overlapping codes is examined in relation to the information cost of overlap and the mutation rate of the genome. The degree of overlap in a given population will tend to become monomorphic. Evolution toward partial overlap of genes is shown to depend on a convex cost function of overlap. Overlap does not evolve when expression of overlapping genes is mutually exclusive and produced by rare mutations to the wild-type genome. Assuming overlap increases coupling between functionally related genes, the conditions favoring overlap are explored in relation to the kinetics of gene activation and decay. Coupling is most effective for genes in which the gene overlapping at its 5'end (leading gene) decays rapidly, while the gene overlapping at the 3'end (induced gene) decays slowly. If gene expression can feedback on itself (autocatalysis), then high rates of activation favor overlap. [source] Protection of DNA during early development: adaptations and evolutionary consequencesEVOLUTION AND DEVELOPMENT, Issue 1 2003David Epel SUMMARY The rapidly dividing cleavage stages of embryos do not have the typical responses to cell damage, such as induction of the heat shock response, use of mitotic checkpoints, or use of apoptosis to eliminate severely damaged cells. This could create problems with integrity of DNA, but the solution in these embryos appears to be a "be prepared" approach, in which specific adaptations are used to minimize DNA damage during cleavage and the use of apoptosis at the mid-blastula transition to remove any cells that were nevertheless damaged. It has been assumed that this approach has evolved because of the advantage of rapid production of a motile larvae. Alternatively, this particular approach may have the selective advantage of increasing mutation rate when there are greater environmental stresses. This could provide more variants on which selective pressures could act and thus accelerate evolution during environmentally stressful periods. [source] Somatic NF1 mutation spectra in a family with neurofibromatosis type 1: Toward a theory of genetic modifiers,HUMAN MUTATION, Issue 6 2003Verena Wiest Abstract Neurofibromatosis type 1 (NF1), an autosomal dominantly-inherited disorder, is mainly characterized by the occurrence of multiple dermal neurofibromas and is caused by mutations in the NF1 gene, a tumor suppressor gene. The variable expressivity of the disease and the lack of a genotype/phenotype correlation prevents any prediction of patient outcome and points to the action of genetic factors in addition to stochastic factors modifying the severity of the disease. The analysis of somatic NF1 gene mutations in neurofibromas from NF1 patients revealed that each neurofibroma results from an individual second hit mutation, indicating that factors that influence somatic mutation rates may be regarded as potential modifiers of NF1. A mutational screen of numerous neurofibromas from two NF1 patients presented here revealed a predominance of point mutations, small deletions, and insertions as second hit mutations in both patients. Seven novel mutations are reported. Together with the results of studies that showed LOH as the predominant second hit in neurofibromas of other patients, our results suggest that in different patients different factors may influence the somatic mutation rate and thereby the severity of the disease. Hum Mutat 22:423,427, 2003. © 2003 Wiley-Liss, Inc. [source] Frequency of and variables associated with the EGFR mutation and its subtypesINTERNATIONAL JOURNAL OF CANCER, Issue 3 2010Tomoaki Tanaka Mutation in the epidermal growth factor receptor (EGFR) is frequently seen in non-small cell lung cancers (NSCLCs), especially in Asian females with adenocarcinoma. The frequency of mutation and the factors associated requires to be elucidated by analyzing a large number of consecutive clinical samples. We summarized the result of the EGFR mutation analysis for 1,176 patients performed at the time of diagnosis or relapse. The PNA-LNA PCR clamp, a highly sensitive detection method for the EGFR mutation, was employed. For fresh cases a portion of samples isolated to establish the diagnosis of lung cancer was used. For cases with a relapsed disease archival tissue were tested. The variables associated with the EGFR mutation after removing the confound factors were investigated by the logistic analysis using the samples collected in our university (n = 308) where detailed information on patients were available. The frequency of the EGFR mutation and its subtypes were investigated using all samples (n = 1,176). The EGFR mutation was significantly associated with adenocarcinoma (p = 0.006) and light-smoking (p < 0.0001), but not gender. The deletions in exon 19 were more frequently associated with male gender while exon 21 deletions were with female gender (p = 0.0011). The overall frequency of the EGFR mutation was 31%. Our result suggests that the female predominance in the EGFR mutation rate is a reflection of a higher frequency of adenocarcinoma in females. The gender difference in the mutation subtypes may provide a clue for the mechanism of the occurrence of the EGFR mutation. [source] Satellite image segmentation using hybrid variable genetic algorithmINTERNATIONAL JOURNAL OF IMAGING SYSTEMS AND TECHNOLOGY, Issue 3 2009Mohamad M. Awad Abstract Image segmentation is an important task in image processing and analysis. Many segmentation methods have been used to segment satellite images. The success of each method depends on the characteristics of the acquired image such as resolution limitations and on the percentage of imperfections in the process of image acquisition due to noise. Many of these methods require a priori knowledge which is difficult to obtain. Some of them are parametric statistical methods that use many parameters which are dependent on image property. In this article, a new unsupervised nonparametric method is developed to segment satellite images into homogeneous regions without any a priori knowledge. The new method is called hybrid variable genetic algorithm (HVGA). The variability is found in the variable number of cluster centers and in the changeable mutation rate. In addition, this new method uses different heuristic processes to increase the efficiency of genetic algorithm in avoiding local optimal solutions. Experiments performed on two different satellite images (Landsat and Spot) proved the high accuracy and efficiency of HVGA compared with another two unsupervised and nonparametric segmentation methods genetic algorithm (GA) and self-organizing map (SOM). The verification of the results included stability and accuracy measurements using an evaluation method implemented from the functional model (FM) and field surveys. © 2009 Wiley Periodicals, Inc. Int J Imaging Syst Technol, 19, 199,207, 2009 [source] Identification of monozygous twins and microsatellite mutation rate in pigs from QTL linkage analysis dataJOURNAL OF ANIMAL BREEDING AND GENETICS, Issue 5 2001L. Grapes In previous work, microsatellite markers have primarily been tools for genome studies. However, the use of marker data can be extended beyond its original intent to maximize the amount of information obtained. There have been few studies to determine the occurrence of monozygous (MZ) twins in pigs. The advent of DNA marker technology, and microsatellites in particular, allows MZ twins to be identified based on their genotype data. To determine if MZ twin births occur in pigs, genotypes for F2 individuals, n=525, from 65 Berkshire × Yorkshire families were examined. One pair of female twins was found to have matching genotype data (95% CI: 0,2.94 twins). This is a unique result since there have been no published reports to date of twin pigs that survived until birth. Additionally, three dinucleotide microsatellite mutations were found after screening 134 565 meioses of 125 loci spanning the entire genome and the X chromosome. The average mutation rate for the population, n=570, was 2.23 × 10,5 (95% CI: 6.17 × 10,6,6.51 × 10,5). A mutation rate similar to this was published earlier for dinucleotide repeat microsatellite mutations in swine. Identification de jumeaux monozygotes et taux de mutation des microsatellites à partir de données d, analyse de liaison avec des caractères quantitatifs Jusqu'à présent, les marqueurs microsatelittes ont été principalement utilisés comme outils pour étudier le génome. Cependant, l'utilisation des données de marquage peut être étendue au delà de ce but initial et permet d'obtenir d'autres types d'informations. Au cours des dernières années, il n'y a eu que peu d'études visant à determiner l'existence de jumeaux monozygotes (MZ) chez le porc. L'avènement des techniques de marquage de l'ADN, et plus particulièrement des microsatelittes, permet l'identification de jumeaux MZ sur la base de leur génotype aux marqueurs. Afin de déterminer s'il existe des jumeaux MZ chez le porc, nous avons examiné les génotypes d'individus F2 (n=525) issus de 65 familles Berkshire × Yorkshire. La recherche d'individus ayant un genotype identique a permis d'identifer un couple de jumeaux femelles (95% CI: 0,2.94). Il s'agit d'un résultat unique car jusqu'à ce jour, il n'y avait aucun cas publié de jumeaux ayant survécus après la naissance chez le porc. Par ailleurs, après analyse de 134 565 méioses pour 125 loci répartis sur l'ensemble du génome et sur le chromosome X, 3 mutations ont été trouvées au niveau de microsatelittes dinucleotidiques. Le taux moyen de mutation dans la population (n=570) a été estiméà 2.23 × 10,5 (95% IC: 6.17 × 10,6à 6.51 × 10,5). Un taux de mutation similaire à celui-ci a été publié précédemment pour des marqueurs microsatelittes dinucleotidiques chez le porc. [source] Condition-dependent mutation rates and sexual selectionJOURNAL OF EVOLUTIONARY BIOLOGY, Issue 4 2009S. COTTON Abstract ,Good genes' models of sexual selection show that females can gain indirect benefits for their offspring if male ornaments are condition-dependent signals of genetic quality. Recurrent deleterious mutation is viewed as a major contributor to variance in genetic quality, and previous theoretical treatments of ,good genes' processes have assumed that the influx of new mutations is constant. I propose that this assumption is too simplistic, and that mutation rates vary in ways that are important for sexual selection. Recent data have shown that individuals in poor condition can have higher mutation rates, and I argue that if both male sexual ornaments and mutation rates are condition-dependent, then females can use male ornamentation to evaluate their mate's mutation rate. As most mutations are deleterious, females benefit from choosing well-ornamented mates, as they are less likely to contribute germline-derived mutations to offspring. I discuss some of the evolutionary ramifications of condition-dependent mutation rates and sexual selection. [source] The influence of environmental factors, the pollen : ovule ratio and seed bank persistence on molecular evolutionary rates in plantsJOURNAL OF EVOLUTIONARY BIOLOGY, Issue 1 2006C.-A. WHITTLE Abstract One of the main goals of molecular evolutionary biology is to determine the factors that influence the evolutionary rate of selectively neutral DNA, but much remains unknown, especially for plants. Key factors that could alter the mutation rate include environmental tolerances (because they reflect a plants vulnerability to changes in habitat), the pollen : ovule ratio (as it is associated with the number of mitotic divisions) and seed longevity (because this influences the number of generations per unit time in plants). This is the first study to demonstrate that seed bank persistence and drought tolerance are positively associated with molecular evolutionary rates in plants and that pollen : ovule ratio, shade tolerance and salinity tolerance have no detectable relationship. The implications of the findings to our understanding of the impact of environmental agents, the number of cell divisions and cell aging on neutral DNA sequence evolution are discussed. [source] Finding a (pine) needle in a haystack: chloroplast genome sequence divergence in rare and widespread pinesMOLECULAR ECOLOGY, Issue 2010J. B. WHITTALL Abstract Critical to conservation efforts and other investigations at low taxonomic levels, DNA sequence data offer important insights into the distinctiveness, biogeographic partitioning and evolutionary histories of species. The resolving power of DNA sequences is often limited by insufficient variability at the intraspecific level. This is particularly true of studies involving plant organelles, as the conservative mutation rate of chloroplasts and mitochondria makes it difficult to detect polymorphisms necessary to track genealogical relationships among individuals, populations and closely related taxa, through space and time. Massively parallel sequencing (MPS) makes it possible to acquire entire organelle genome sequences to identify cryptic variation that would be difficult to detect otherwise. We are using MPS to evaluate intraspecific chloroplast-level divergence across biogeographic boundaries in narrowly endemic and widespread species of Pinus. We focus on one of the world's rarest pines , Torrey pine (Pinus torreyana) , due to its conservation interest and because it provides a marked contrast to more widespread pine species. Detailed analysis of nearly 90% (,105 000 bp each) of these chloroplast genomes shows that mainland and island populations of Torrey pine differ at five sites in their plastome, with the differences fixed between populations. This is an exceptionally low level of divergence (1 polymorphism/,21 kb), yet it is comparable to intraspecific divergence present in widespread pine species and species complexes. Population-level organelle genome sequencing offers new vistas into the timing and magnitude of divergence within species, and is certain to provide greater insight into pollen dispersal, migration patterns and evolutionary dynamics in plants. [source] An AFLP clock for the absolute dating of shallow-time evolutionary history based on the intraspecific divergence of southwestern European alpine plant speciesMOLECULAR ECOLOGY, Issue 4 2009MATTHIAS KROPF Abstract The dating of recent events in the history of organisms needs divergence rates based on molecular fingerprint markers. Here, we used amplified fragment length polymorphisms (AFLPs) of three distantly related alpine plant species co-occurring in the Spanish Sierra Nevada, the Pyrenees and the southwestern Alps/Massif Central to establish divergence rates. Within each of these species (Gentiana alpina, Kernera saxatilis and Silene rupestris), we found that the degree of AFLP divergence (DN72) between mountain phylogroups was significantly correlated with their time of divergence (as inferred from palaeoclimatic/palynological data), indicating constant AFLP divergence rates. As these rates did not differ significantly among species, a regression analysis based on the pooled data was utilized to generate a general AFLP rate. The application of this latter rate to AFLP data from other herbaceous plant species (Minuartia biflora: Schönswetter et al. 2006; Nigella degenii: Comes et al. 2008) resulted in a plausible timing of the recolonization of the Svalbard Islands and the separation of populations from the Alps and Scandinavia (Minuartia), and of island population separation in the Aegean Archipelago (Nigella). Furthermore, the AFLP mutation rate obtained in our study is of the same magnitude as AFLP mutation rates published previously. The temporal limits of our AFLP rate, which is based on intraspecific vicariance events at shallow (i.e. late glacial/Early Holocene) time scales, remains to be tested. [source] Revealing the hidden complexities of mtDNA inheritanceMOLECULAR ECOLOGY, Issue 23 2008DANIEL JAMES WHITE Abstract Mitochondrial DNA (mtDNA) is a pivotal tool in molecular ecology, evolutionary and population genetics. The power of mtDNA analyses derives from a relatively high mutation rate and the apparent simplicity of mitochondrial inheritance (maternal, without recombination), which has simplified modelling population history compared to the analysis of nuclear DNA. However, in biology things are seldom simple, and advances in DNA sequencing and polymorphism detection technology have documented a growing list of exceptions to the central tenets of mitochondrial inheritance, with paternal leakage, heteroplasmy and recombination now all documented in multiple systems. The presence of paternal leakage, recombination and heteroplasmy can have substantial impact on analyses based on mtDNA, affecting phylogenetic and population genetic analyses, estimates of the coalescent and the myriad of other parameters that are dependent on such estimates. Here, we review our understanding of mtDNA inheritance, discuss how recent findings mean that established ideas may need to be re-evaluated, and we assess the implications of these new-found complications for molecular ecologists who have relied for decades on the assumption of a simpler mode of inheritance. We show how it is possible to account for recombination and heteroplasmy in evolutionary and population analyses, but that accurate estimates of the frequencies of biparental inheritance and recombination are needed. We also suggest how nonclonal inheritance of mtDNA could be exploited, to increase the ways in which mtDNA can be used in analyses. [source] Can clone size serve as a proxy for clone age?An exploration using microsatellite divergence in Populus tremuloidesMOLECULAR ECOLOGY, Issue 22 2008D. ALLY Abstract In long-lived clonal plants, the overall size of a clone is often used to estimate clone age. The size of a clone, however, might be largely determined by physical or biotic interactions, obscuring the relationship between clone size and age. Here, we use the accumulation of mutations at 14 microsatellite loci to estimate clone age in trembling aspen (Populus tremuloides) from southwestern Canada. We show that the observed patterns of genetic divergence are consistent with a model of increasing ramet population size, allowing us to use pairwise genetic divergence as an estimator of clone age. In the populations studied, clone size did not exhibit a significant relationship with microsatellite divergence, indicating that clone size is not a good proxy for clone age. In P. tremuloides, the per-locus per-year neutral somatic mutation rate across 14 microsatellite loci was estimated to lie between 6 × 10,7 (lower bound) and 4 × 10,5 (upper bound). [source] Phylogeography and postglacial expansion of Mus musculus domesticus inferred from mitochondrial DNA coalescent, from Iran to EuropeMOLECULAR ECOLOGY, Issue 2 2008HASSAN RAJABI-MAHAM Abstract Few genetic data document the postglacial history of the western house mouse, Mus musculus domesticus. We address this by studying a sample from the southeastern tip of the Fertile Crescent in the Iranian province of Ahvaz. Including other published and unpublished data from France, Germany, Italy, Bulgaria, Turkey and other places in Iran, altogether 321 mitochondrial D-loop sequences are simultaneously analysed. The patterns of coalescence obtained corroborate the classical proposal according to which the Fertile Crescent is where commensalism with humans has started in the Western Hemisphere, and from where the subspecies has expanded further west. Our data also clearly show that despite multiple colonisations and long-range transportation, there is still a rather high ,ST of 0.39. The original expansion signal is still recognisable, with two well-separated derived clades, allowing us to propose a hypothetical scenario in which expansion toward Europe and Asia Minor took at least two routes, tentatively termed the Mediterranean and the Bosphorus/Black Sea routes. This scenario resembles that of another domesticated species, the goat, and fits with the known progression of Neolithic culture. Given the concomitance of both phenomena around 12 000 years ago, we propose a recalibration of the D-loop mutation rate to a much faster tick of ~40% per site per million years (Myr). This value should be used for intrasubspecific polymorphism, while the interspecific rate in Mus is presently estimated at 6,10%/site/Myr. This is in keeping with the now well recognised fact that only a subfraction of segregating mutations go to fixation. [source] Effects of recent population bottlenecks on reconstructing the demographic history of prairie-chickensMOLECULAR ECOLOGY, Issue 11 2007JEFF A. JOHNSON Abstract Current methods of DNA sequence analysis attempt to reconstruct historical patterns of population structure and growth from contemporary samples. However, these techniques may be influenced by recent population bottlenecks, which have the potential to eliminate lineages that reveal past changes in demography. One way to examine the performance of these demographic methods is to compare samples from populations before and after recent bottlenecks. We compared estimates of demographic history from populations of greater prairie-chickens (Tympanuchus cupido) before and after recent bottlenecks using four common methods (nested clade analysis [NCA], Tajima's D, mismatch distribution, and mdiv). We found that NCA did not perform well in the presence of bottleneck events, although it did recover some genetic signals associated with increased isolation and the extinction of intermediate populations. The majority of estimates for Tajima's D, including those from bottlenecked populations, were not significantly different from zero, suggesting our data conformed to neutral expectations. In contrast, mismatch distributions including the raggedness index were more likely to identify recently bottlenecked populations with this data set. Estimates of population mutation rate (,), population divergence time (t), and time to the most recent common ancestor (TMRCA) from mdiv were similar before and after bottlenecks; however, estimates of gene flow (M) were significantly lower in a few cases following a bottleneck. These results suggest that caution should be used when assessing demographic history from contemporary data sets, as recently fragmented and bottlenecked populations may have lost lineages that affect inferences of their demographic history. [source] | |||||||||||||||||||||||||||||||||||||