Science.gov

Sample records for imposed mutation rate

  1. Evolution at a high imposed mutation rate: adaptation obscures the load in phage T7.

    PubMed

    Springman, R; Keller, T; Molineux, I J; Bull, J J

    2010-01-01

    Evolution at high mutation rates is expected to reduce population fitness deterministically by the accumulation of deleterious mutations. A high enough rate should even cause extinction (lethal mutagenesis), a principle motivating the clinical use of mutagenic drugs to treat viral infections. The impact of a high mutation rate on long-term viral fitness was tested here. A large population of the DNA bacteriophage T7 was grown with a mutagen, producing a genomic rate of 4 nonlethal mutations per generation, two to three orders of magnitude above the baseline rate. Fitness-viral growth rate in the mutagenic environment-was predicted to decline substantially; after 200 generations, fitness had increased, rejecting the model. A high mutation load was nonetheless evident from (i) many low- to moderate-frequency mutations in the population (averaging 245 per genome) and (ii) an 80% drop in average burst size. Twenty-eight mutations reached high frequency and were thus presumably adaptive, clustered mostly in DNA metabolism genes, chiefly DNA polymerase. Yet blocking DNA polymerase evolution failed to yield a fitness decrease after 100 generations. Although mutagenic drugs have caused viral extinction in vitro under some conditions, this study is the first to match theory and fitness evolution at a high mutation rate. Failure of the theory challenges the quantitative basis of lethal mutagenesis and highlights the potential for adaptive evolution at high mutation rates. PMID:19858285

  2. Mutation rates as adaptations.

    PubMed

    Maley, C

    1997-06-01

    In order to better understand life, it is helpful to look beyond the envelop of life as we know it. A simple model of coevolution was implemented with the addition of a gene for the mutation rate of the individual. This allowed the mutation rate itself to evolve in a lineage. The model shows that when the individuals interact in a sort of zero-sum game, the lineages maintain relatively high mutation rates. However, when individuals engage in interactions that have greater consequences for one individual in the interaction than the other, lineages tend to evolve relatively low mutation rates. This model suggests that one possible cause for differential mutation rates across genes may be the coevolutionary pressure of the various forms of interactions with other genes. PMID:9219670

  3. Estimating mutation rate: how to count mutations?

    PubMed Central

    Fu, Yun-Xin; Huai, Haying

    2003-01-01

    Mutation rate is an essential parameter in genetic research. Counting the number of mutant individuals provides information for a direct estimate of mutation rate. However, mutant individuals in the same family can share the same mutations due to premeiotic mutation events, so that the number of mutant individuals can be significantly larger than the number of mutation events observed. Since mutation rate is more closely related to the number of mutation events, whether one should count only independent mutation events or the number of mutants remains controversial. We show in this article that counting mutant individuals is a correct approach for estimating mutation rate, while counting only mutation events will result in underestimation. We also derived the variance of the mutation-rate estimate, which allows us to examine a number of important issues about the design of such experiments. The general strategy of such an experiment should be to sample as many families as possible and not to sample much more offspring per family than the reciprocal of the pairwise correlation coefficient within each family. To obtain a reasonably accurate estimate of mutation rate, the number of sampled families needs to be in the same or higher order of magnitude as the reciprocal of the mutation rate. PMID:12807798

  4. Burning rate response of liquid monopropellants to imposed pressure oscillations

    NASA Technical Reports Server (NTRS)

    Allison, C. B.

    1974-01-01

    The combustion characteristics of hydrazine strands were studied under both steady state and oscillatory conditions. A steady strand burner was used to measure steady strand burning rates, liquid temperature distributions and surface temperatures as a function of pressure in the pressure range of 0.32 to 42 atm. It was found that for subatmospheric pressures the burning rate varied as the square root of pressure; for pressures greater than atmospheric the burning rate varied linearly with pressure. A theoretical model of the strand combustion system was developed and matched to the steady burning rates by assuming a reaction order of one for subatmospheric pressures and a reaction order of two for pressures greater than atmospheric. The model was also found to be in good agreement with measurements of liquid temperature distributions and surface temperatures. The results show an increse in the response of the combustion process as interaction occurs with transient liquid phase effects, yielding a band of frequencies where the combustion process exerts sufficient amplifying power to provide a mechanism for driving combustion instability.

  5. Compensatory Evolution of pbp Mutations Restores the Fitness Cost Imposed by β-Lactam Resistance in Streptococcus pneumoniae

    PubMed Central

    Albarracín Orio, Andrea G.; Piñas, Germán E.; Cortes, Paulo R.; Cian, Melina B.; Echenique, José

    2011-01-01

    The prevalence of antibiotic resistance genes in pathogenic bacteria is a major challenge to treating many infectious diseases. The spread of these genes is driven by the strong selection imposed by the use of antibacterial drugs. However, in the absence of drug selection, antibiotic resistance genes impose a fitness cost, which can be ameliorated by compensatory mutations. In Streptococcus pneumoniae, β-lactam resistance is caused by mutations in three penicillin-binding proteins, PBP1a, PBP2x, and PBP2b, all of which are implicated in cell wall synthesis and the cell division cycle. We found that the fitness cost and cell division defects conferred by pbp2b mutations (as determined by fitness competitive assays in vitro and in vivo and fluorescence microscopy) were fully compensated by the acquisition of pbp2x and pbp1a mutations, apparently by means of an increased stability and a consequent mislocalization of these protein mutants. Thus, these compensatory combinations of pbp mutant alleles resulted in an increase in the level and spectrum of β-lactam resistance. This report describes a direct correlation between antibiotic resistance increase and fitness cost compensation, both caused by the same gene mutations acquired by horizontal transfer. The clinical origin of the pbp mutations suggests that this intergenic compensatory process is involved in the persistence of β-lactam resistance among circulating strains. We propose that this compensatory mechanism is relevant for β-lactam resistance evolution in Streptococcus pneumoniae. PMID:21379570

  6. Evolution of Mutation Rate in Asexual Populations

    NASA Astrophysics Data System (ADS)

    Wylie, Scott; Levine, Herbert; Kessler, David

    2007-03-01

    Several evolution experiments with E. coli document the spontaneous emergence and eventual fixation of so called ``mutator'' alleles that increase the genomic mutation rate by the order of 100-fold. Variations in mutation rates are due to polymorphisms in the molecular machinery that copies and checks the genome for errors. These polymorphisms are coded in the genome and thus heritable. Like any heritable trait, elevated mutation rates are subject to natural selection and evolution. However, unlike other traits, mutation rate does not directly affect the rate at which an organism reproduces, i.e. its fitness. Rather, it affects the statistical distribution of the offspring's fitness. This fitness distribution, in turn, leads via ``hitchhiking'' to a change in the frequency of the mutator allele, i.e. evolution of the mutation rate itself. In our work we simulate a birth-death process that approximates simple asexual populations and we measure the fixation probability of rare mutators. We then develop an approximate analytic model of the population dynamics, the results of which agree reasonably well with simulation. In particular, we are able to analytically predict the ``effective fitness'' of mutators and the conditions under which they are expected to emerge.

  7. Elevated germline mutation rate in teenage fathers.

    PubMed

    Forster, Peter; Hohoff, Carsten; Dunkelmann, Bettina; Schürenkamp, Marianne; Pfeiffer, Heidi; Neuhuber, Franz; Brinkmann, Bernd

    2015-03-22

    Men age and die, while cells in their germline are programmed to be immortal. To elucidate how germ cells maintain viable DNA despite increasing parental age, we analysed DNA from 24 097 parents and their children, from Europe, the Middle East and Africa. We chose repetitive microsatellite DNA that mutates (unlike point mutations) only as a result of cellular replication, providing us with a natural 'cell-cycle counter'. We observe, as expected, that the overall mutation rate for fathers is seven times higher than for mothers. Also as expected, mothers have a low and lifelong constant DNA mutation rate. Surprisingly, however, we discover that (i) teenage fathers already set out from a much higher mutation rate than teenage mothers (potentially equivalent to 77-196 male germline cell divisions by puberty); and (ii) ageing men maintain sperm DNA quality similar to that of teenagers, presumably by using fresh batches of stem cells known as 'A-dark spermatogonia'. PMID:25694621

  8. Studies of human mutation rates

    SciTech Connect

    Neel, J.V.

    1990-01-01

    November 1989, marked the beginning of a new three-year cycle of DOE grant support, in connection with which the program underwent a major reorganization. This document presents the progress on the three objectives of the present program which are: to isolate by the technique of two-dimensional polyacrylamide gel electrophoresis (2-D PAGE), proteins of special interest because of the relative mutability of the corresponding gene, establish the identity of the protein, and, for selected proteins, move to a characterization of the corresponding gene; to develop a more efficient approach, based on 2-D PAGE, for the detection of variants in DNA, with special reference to the identification of mutations in the parents of the individual whose DNA is being examined; and, to continue an effective interface with the genetic studies on the children of atomic bomb survivors in Japan, with reference to both the planning and implementation of new studies at the molecular level.

  9. Studies of human mutation rates

    SciTech Connect

    Neel, J.V.

    1991-07-15

    The three objectives of the program are: To isolate by the technique of two-dimensional polyacrylamide gel electrophoresis (2-D PAGE), proteins of special interest because of the relative mutability of the corresponding gene, establish the identity of the protein, and, for selected proteins, move to a characterization of the corresponding gene; To develop a more efficient approach, based on 2-D PAGE, for the detection of variants in DNA, with special reference to the identification of a variant in a child not present in either parent of the child (i.e., a mutation); and, To continue an effective interface with the genetic studies on the children of atomic bomb survivors in Japan, with reference to both the planning and implementation of new studies at the molecular level. For administrative purposes, the program is subdivided into four sections, each under the direction of one of the four co-PIs; the progress during the past year will be summarized in accordance with this sectional structure. 1 tab.

  10. Effects of Imposed Variable Rates of Lateral Subsidence on a Deltaic System

    NASA Astrophysics Data System (ADS)

    Kim, W.; Kopp, J.

    2012-12-01

    Fluviodeltaic systems exist on Earth often under complex tectonic conditions, thus creating a myriad of motivations to understand the deltaic landscape evolution associated with tectonic activity. We present results from a series of six experiments conducted in the Sediment Transport and Earth-surface Processes (STEP) basin facility at the University of Texas at Austin. The STEP basin has a dimension of 4-m long, 5-m wide, and 1.5-m deep, and contains a hinged table that acts as a subsiding basin basement, which can be raised or lowered to create many different subsidence patterns in combination with placement of the sediment source. We utilized the table to impose lateral basement tilting to examine the effects of spatially varying rates of subsidence on an evolving fluviodeltaic system. The hinge axis at the center of the basin maintained constant base level at the location and thus created a bisection of the evolving delta such that relative base level fall occurred on one side of the delta (uplift), while a relative base level rise occurred on the other side of the delta (subsidence). The differential relative base-level changes on both sides of the rotation axis were applied to each experiment with a different rate, and thus causing variations in the overall asymmetrical shoreline planform pattern. The slow-tilting runs resulted in stronger shoreline progradation in the relatively uplifted side of the basin due to the shallow water depth in front of the delta, and thus caused asymmetrical shoreline pattern. However during the fast-tilting runs, the dominant section of prograding shoreline shifted to the subsiding side of the basin because rapid tilting prevents progradation on the uplifted side and instead steer the channels in the direction of subsidence. The tectonically influenced fluvial processes organize into the unique deltaic coastal pattern, providing insight into the integration of small-scale processes and large-scale landform.

  11. Academic response rate as a function of teacher- and self-imposed contingencies1

    PubMed Central

    Lovitt, Thomas C.; Curtiss, Karen A.

    1969-01-01

    The purpose of this study was to assess the effects of the contingency manager (teacher or pupil) on a pupil's academic response rate. The results of two such experiments disclosed that higher academic rates occurred when the pupil arranged the contingency requirements than when the teacher specified them. A third study manipulated only reinforcement magnitude to ascertain whether amount of reinforcement had interacted with pupil-specified contingencies to produce the increase in academic response rate. The latter findings revealed that the contingency manager, not reinforcement magnitude, accounted for this subject's gain in performance. PMID:16795202

  12. Precise estimates of mutation rate and spectrum in yeast

    PubMed Central

    Zhu, Yuan O.; Siegal, Mark L.; Hall, David W.; Petrov, Dmitri A.

    2014-01-01

    Mutation is the ultimate source of genetic variation. The most direct and unbiased method of studying spontaneous mutations is via mutation accumulation (MA) lines. Until recently, MA experiments were limited by the cost of sequencing and thus provided us with small numbers of mutational events and therefore imprecise estimates of rates and patterns of mutation. We used whole-genome sequencing to identify nearly 1,000 spontaneous mutation events accumulated over ∼311,000 generations in 145 diploid MA lines of the budding yeast Saccharomyces cerevisiae. MA experiments are usually assumed to have negligible levels of selection, but even mild selection will remove strongly deleterious events. We take advantage of such patterns of selection and show that mutation classes such as indels and aneuploidies (especially monosomies) are proportionately much more likely to contribute mutations of large effect. We also provide conservative estimates of indel, aneuploidy, environment-dependent dominant lethal, and recessive lethal mutation rates. To our knowledge, for the first time in yeast MA data, we identified a sufficiently large number of single-nucleotide mutations to measure context-dependent mutation rates and were able to (i) confirm strong AT bias of mutation in yeast driven by high rate of mutations from C/G to T/A and (ii) detect a higher rate of mutation at C/G nucleotides in two specific contexts consistent with cytosine methylation in S. cerevisiae. PMID:24847077

  13. Mutations, mutation rates, and evolution at the hypervariable VNTR loci of Yersinia pestis.

    PubMed

    Vogler, Amy J; Keys, Christine E; Allender, Christopher; Bailey, Ira; Girard, Jessica; Pearson, Talima; Smith, Kimothy L; Wagner, David M; Keim, Paul

    2007-03-01

    VNTRs are able to discriminate among closely related isolates of recently emerged clonal pathogens, including Yersinia pestis the etiologic agent of plague, because of their great diversity. Diversity is driven largely by mutation but little is known about VNTR mutation rates, factors affecting mutation rates, or the mutational mechanisms. The molecular epidemiological utility of VNTRs will be greatly enhanced when this foundational knowledge is available. Here, we measure mutation rates for 43 VNTR loci in Y. pestis using an in vitro generated population encompassing approximately 96,000 generations. We estimate the combined 43-locus rate and individual rates for 14 loci. A comparison of Y. pestis and Escherichia coli O157:H7 VNTR mutation rates and products revealed a similar relationship between diversity and mutation rate in these two species. Likewise, the relationship between repeat copy number and mutation rate is nearly identical between these species, suggesting a generalized relationship that may be applicable to other species. The single- versus multiple-repeat mutation ratios and the insertion versus deletion mutation ratios were also similar, providing support for a general model for the mutations associated with VNTRs. Finally, we use two small sets of Y. pestis isolates to show how this general model and our estimated mutation rates can be used to compare alternate phylogenies, and to evaluate the significance of genotype matches, near-matches, and mismatches found in empirical comparisons with a reference database. PMID:17161849

  14. Timing, rates and spectra of human germline mutation

    PubMed Central

    Lindsay, Sarah J.; Hardwick, Robert J.; Alexandrov, Ludmil B.; Turki, Saeed Al; Dominiczak, Anna; Morris, Andrew; Porteous, David; Smith, Blair; Stratton, Michael R.; Hurles, Matthew E.

    2015-01-01

    Germline mutations are a driving force behind genome evolution and genetic disease. We investigated genome-wide mutation rates and spectra in multi-sibling families. Mutation rate increased with paternal age in all families, but the number of additional mutations per year differed more than two-fold between families. Meta-analysis of 6,570 mutations showed that germline methylation influences mutation rates. In contrast to somatic mutations, we found remarkable consistency of germline mutation spectra between the sexes and at different paternal ages. 3.8% of mutations were mosaic in the parental germline, resulting in 1.3% of mutations being shared between siblings. The number of these shared mutations varied significantly between families. Our data suggest that the mutation rate per cell division is higher during both early embryogenesis and differentiation of primordial germ cells, but is reduced substantially during post-pubertal spermatogenesis. These findings have important consequences for the recurrence risks of disorders caused by de novo mutations. PMID:26656846

  15. Timing, rates and spectra of human germline mutation.

    PubMed

    Rahbari, Raheleh; Wuster, Arthur; Lindsay, Sarah J; Hardwick, Robert J; Alexandrov, Ludmil B; Al Turki, Saeed; Dominiczak, Anna; Morris, Andrew; Porteous, David; Smith, Blair; Stratton, Michael R; Hurles, Matthew E

    2016-02-01

    Germline mutations are a driving force behind genome evolution and genetic disease. We investigated genome-wide mutation rates and spectra in multi-sibling families. The mutation rate increased with paternal age in all families, but the number of additional mutations per year differed by more than twofold between families. Meta-analysis of 6,570 mutations showed that germline methylation influences mutation rates. In contrast to somatic mutations, we found remarkable consistency in germline mutation spectra between the sexes and at different paternal ages. In parental germ line, 3.8% of mutations were mosaic, resulting in 1.3% of mutations being shared by siblings. The number of these shared mutations varied significantly between families. Our data suggest that the mutation rate per cell division is higher during both early embryogenesis and differentiation of primordial germ cells but is reduced substantially during post-pubertal spermatogenesis. These findings have important consequences for the recurrence risks of disorders caused by de novo mutations. PMID:26656846

  16. Perceptual and Cognitive Factors Imposing "Speed Limits" on Reading Rate: A Study with the Rapid Serial Visual Presentation.

    PubMed

    Primativo, Silvia; Spinelli, Donatella; Zoccolotti, Pierluigi; De Luca, Maria; Martelli, Marialuisa

    2016-01-01

    Adults read at high speed, but estimates of their reading rate vary greatly, i.e., from 100 to 1500 words per minute (wpm). This discrepancy is likely due to different recording methods and to the different perceptual and cognitive processes involved in specific test conditions. The present study investigated the origins of these notable differences in RSVP reading rate (RR). In six experiments we investigated the role of many different perceptual and cognitive variables. The presence of a mask caused a steep decline in reading rate, with an estimated masking cost of about 200 wpm. When the decoding process was isolated, RR approached values of 1200 wpm. When the number of stimuli exceeded the short-term memory span, RR decreased to 800 wpm. The semantic context contributed to reading speed only by a factor of 1.4. Finally, eye movements imposed an upper limit on RR (around 300 wpm). Overall, data indicate a speed limit of 300 wpm, which corresponds to the time needed for eye movement execution, i.e., the most time consuming mechanism. Results reconcile differences in reading rates reported by different laboratories and thus provide suggestions for targeting different components of reading rate. PMID:27088226

  17. Perceptual and Cognitive Factors Imposing “Speed Limits” on Reading Rate: A Study with the Rapid Serial Visual Presentation

    PubMed Central

    Spinelli, Donatella; Zoccolotti, Pierluigi; De Luca, Maria; Martelli, Marialuisa

    2016-01-01

    Adults read at high speed, but estimates of their reading rate vary greatly, i.e., from 100 to 1500 words per minute (wpm). This discrepancy is likely due to different recording methods and to the different perceptual and cognitive processes involved in specific test conditions. The present study investigated the origins of these notable differences in RSVP reading rate (RR). In six experiments we investigated the role of many different perceptual and cognitive variables. The presence of a mask caused a steep decline in reading rate, with an estimated masking cost of about 200 wpm. When the decoding process was isolated, RR approached values of 1200 wpm. When the number of stimuli exceeded the short-term memory span, RR decreased to 800 wpm. The semantic context contributed to reading speed only by a factor of 1.4. Finally, eye movements imposed an upper limit on RR (around 300 wpm). Overall, data indicate a speed limit of 300 wpm, which corresponds to the time needed for eye movement execution, i.e., the most time consuming mechanism. Results reconcile differences in reading rates reported by different laboratories and thus provide suggestions for targeting different components of reading rate. PMID:27088226

  18. Condition-dependent mutation rates and sexual selection.

    PubMed

    Cotton, S

    2009-04-01

    '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. PMID:19210586

  19. The study of human mutation rates

    SciTech Connect

    Neel, J.V.

    1992-01-01

    We will describe recent developments regarding the question of induced mutations in the survivors of the atomic bombings of Hiroshima and Nagasaki. As part of that work we, describe some developments with respect to the Amerindian blood samples collected under DoE sponsorship between 1964 and 1982. Then developments regarding the application of two-dimensional polyacrylamide gel electrophoresis (2-D PAGE) to the study of genetic variation and mutation affecting protein characteristics. In particular, we will report on the identification and isolation of genes of especial interest as reflected in the behavior of the proteins which they encode.

  20. Rate of fixation of beneficial mutations in sexual populations

    NASA Astrophysics Data System (ADS)

    Gouveia, Joseilme F.; de Oliveira, Viviane M.; Sátiro, Caio; Campos, Paulo R. A.

    2009-06-01

    We have investigated the rate of substitution of advantageous mutations in populations of haploid organisms where the rate of recombination can be controlled. We have verified that in all the situations recombination speeds up adaptation through recombination of beneficial mutations from distinct lineages in a single individual, and so reducing the intensity of clonal interference. The advantage of sex for adaptation is even stronger when deleterious mutations occur since now recombination can also restore genetic background free of deleterious mutations. However, our simulation results demonstrate that evidence of clonal interference, as increased mean selective effect of fixed mutations and reduced likelihood of fixation of small-effect mutations, are also present in sexual populations. What we see is that this evidence is delayed when compared to asexual populations.

  1. Evolution of evolvability via adaptation of mutation rates.

    PubMed

    Bedau, Mark A; Packard, Norman H

    2003-05-01

    We examine a simple form of the evolution of evolvability-the evolution of mutation rates-in a simple model system. The system is composed of many agents moving, reproducing, and dying in a two-dimensional resource-limited world. We first examine various macroscopic quantities (three types of genetic diversity, a measure of population fitness, and a measure of evolutionary activity) as a function of fixed mutation rates. The results suggest that (i) mutation rate is a control parameter that governs a transition between two qualitatively different phases of evolution, an ordered phase characterized by punctuated equilibria of diversity, and a disordered phase of characterized by noisy fluctuations around an equilibrium diversity, and (ii) the ability of evolution to create adaptive structure is maximized when the mutation rate is just below the transition between these two phases of evolution. We hypothesize that this transition occurs when the demands for evolutionary memory and evolutionary novelty are typically balanced. We next allow the mutation rate itself to evolve, and we observe that evolving mutation rates adapt to values at this transition. Furthermore, the mutation rates adapt up (or down) as the evolutionary demands for novelty (or memory) increase, thus supporting the balance hypothesis. PMID:12689727

  2. The Spontaneous Mutation Rate in the Fission Yeast Schizosaccharomyces pombe.

    PubMed

    Farlow, Ashley; Long, Hongan; Arnoux, Stéphanie; Sung, Way; Doak, Thomas G; Nordborg, Magnus; Lynch, Michael

    2015-10-01

    The rate at which new mutations arise in the genome is a key factor in the evolution and adaptation of species. Here we describe the rate and spectrum of spontaneous mutations for the fission yeast Schizosaccharomyces pombe, a key model organism with many similarities to higher eukaryotes. We undertook an ∼1700-generation mutation accumulation (MA) experiment with a haploid S. pombe, generating 422 single-base substitutions and 119 insertion-deletion mutations (indels) across the 96 replicates. This equates to a base-substitution mutation rate of 2.00 × 10(-10) mutations per site per generation, similar to that reported for the distantly related budding yeast Saccharomyces cerevisiae. However, these two yeast species differ dramatically in their spectrum of base substitutions, the types of indels (S. pombe is more prone to insertions), and the pattern of selection required to counteract a strong AT-biased mutation rate. Overall, our results indicate that GC-biased gene conversion does not play a major role in shaping the nucleotide composition of the S. pombe genome and suggest that the mechanisms of DNA maintenance may have diverged significantly between fission and budding yeasts. Unexpectedly, CpG sites appear to be excessively liable to mutation in both species despite the likely absence of DNA methylation. PMID:26265703

  3. How much do we know about spontaneous human mutation rates

    SciTech Connect

    Crow, J.F. )

    1993-01-01

    The much larger number of cell divisions between zygote and sperm than between zygote and egg, the increased age of fathers of children with new dominant mutations, and the greater evolution rate of pseudogenes on the Y chromosome than of those on autosomes all point to a much higher mutation rate in human males than in females, as first pointed out by Haldane in his classical study of X-linked hemophilia. The age of the father is the main factor determining the human spontaneous mutation rate, and probably the total mutation rate. The total mutation rate in Drosophila males of genes causing minor reduction in viability is at least 0.4 per sperm and may be considerably higher. The great mutation load implied by a rate of [approx] 1 per zygote can be greatly ameliorated by quasi-transition selection. Corresponding data are not available for the human population. The evolution rate of pseudogenes in primates suggests some 10[sup 2] new mutations per zygote. Presumably the overwhelming majority of these are neutral, but even the approximate fraction is not known. Statistical evidence in Drosophilia shows that mutations with minor effects cause about the same heterozygous impairment of fitness as those that are lethal when homozygous. The magnitude of heterozygous effect is such that almost all mutant genes are eliminated as heterozygotes before ever becoming homozygous. Although quantitative data in the human species are lacking, anecdotal information supports the conclusion that partial dominance is the rule here as well. This suggests that if the human mutation rate were increased or decreased, the effects would be spread over a period of 50-100 generations. 31 refs., 3 figs., 2 tabs.

  4. Male mutation rates and the cost of sex for females

    NASA Astrophysics Data System (ADS)

    Redfield, Rosemary J.

    1994-05-01

    ALTHOUGH we do not know why sex evolved, the twofold cost of meiosis for females provides a standard against which postulated benefits of sex can be evaluated1. The most reliable benefit is sex's ability to reduce the impact of deleterious mutations2,3. But deleterious mutations may themselves generate a large and previously overlooked female-specific cost of sex. DNA sequence comparisons have confirmed Haldane's suggestion that most mutations arise in the male germ line4,5; recent estimates of α, the ratio of male to female mutation rates, are ten, six and two in humans, primates and rodents, respectively6-8. Consequently, male gametes may give progeny more mutations than the associated sexual recombination eliminates. Here I describe computer simulations showing that the cost of male mutations can easily exceed the benefits of recombination, causing females to produce fitter progeny by parthenogenesis than by mating. The persistence of sexual reproduction by females thus becomes even more problematic.

  5. Interpreting the Dependence of Mutation Rates on Age and Time

    PubMed Central

    Gao, Ziyue; Wyman, Minyoung J.; Sella, Guy; Przeworski, Molly

    2016-01-01

    Mutations can originate from the chance misincorporation of nucleotides during DNA replication or from DNA lesions that arise between replication cycles and are not repaired correctly. We introduce a model that relates the source of mutations to their accumulation with cell divisions, providing a framework for understanding how mutation rates depend on sex, age, and cell division rate. We show that the accrual of mutations should track cell divisions not only when mutations are replicative in origin but also when they are non-replicative and repaired efficiently. One implication is that observations from diverse fields that to date have been interpreted as pointing to a replicative origin of most mutations could instead reflect the accumulation of mutations arising from endogenous reactions or exogenous mutagens. We further find that only mutations that arise from inefficiently repaired lesions will accrue according to absolute time; thus, unless life history traits co-vary, the phylogenetic “molecular clock” should not be expected to run steadily across species. PMID:26761240

  6. Mutation rates, spectra, and genome-wide distribution of spontaneous mutations in mismatch repair deficient yeast.

    PubMed

    Lang, Gregory I; Parsons, Lance; Gammie, Alison E

    2013-09-01

    DNA mismatch repair is a highly conserved DNA repair pathway. In humans, germline mutations in hMSH2 or hMLH1, key components of mismatch repair, have been associated with Lynch syndrome, a leading cause of inherited cancer mortality. Current estimates of the mutation rate and the mutational spectra in mismatch repair defective cells are primarily limited to a small number of individual reporter loci. Here we use the yeast Saccharomyces cerevisiae to generate a genome-wide view of the rates, spectra, and distribution of mutation in the absence of mismatch repair. We performed mutation accumulation assays and next generation sequencing on 19 strains, including 16 msh2 missense variants implicated in Lynch cancer syndrome. The mutation rate for DNA mismatch repair null strains was approximately 1 mutation per genome per generation, 225-fold greater than the wild-type rate. The mutations were distributed randomly throughout the genome, independent of replication timing. The mutation spectra included insertions/deletions at homopolymeric runs (87.7%) and at larger microsatellites (5.9%), as well as transitions (4.5%) and transversions (1.9%). Additionally, repeat regions with proximal repeats are more likely to be mutated. A bias toward deletions at homopolymers and insertions at (AT)n microsatellites suggests a different mechanism for mismatch generation at these sites. Interestingly, 5% of the single base pair substitutions might represent double-slippage events that occurred at the junction of immediately adjacent repeats, resulting in a shift in the repeat boundary. These data suggest a closer scrutiny of tumor suppressors with homopolymeric runs with proximal repeats as the potential drivers of oncogenesis in mismatch repair defective cells. PMID:23821616

  7. Microsatellite Mutation Rate during Allohexaploidization of Newly Resynthesized Wheat

    PubMed Central

    Luo, Jiangtao; Hao, Ming; Zhang, Li; Chen, Jixiang; Zhang, Lianquan; Yuan, Zhongwei; Yan, Zehong; Zheng, Youliang; Zhang, Huaigang; Yen, Yang; Liu, Dengcai

    2012-01-01

    Simple sequence repeats (SSRs, also known as microsatellites) are known to be mutational hotspots in genomes. DNA rearrangements have also been reported to accompany allopolyploidization. A study of the effect of allopolyploidization on SSR mutation is therefore important for understanding the origin and evolutionary dynamics of SSRs in allopolyploids. Three synthesized double haploid (SynDH) populations were made from 241 interspecific F1 haploid hybrids between Triticum turgidum L. and Aegilops tauschii (Coss.) through spontaneous chromosome doubling via unreduced gametes. Mutation events were studied at 160 SSR loci in the S1 generation (the first generation after chromosome doubling) of the three SynDH populations. Of the 148260 SSR alleles investigated in S1 generation, only one mutation (changed number of repeats) was confirmed with a mutation rate of 6.74 × 10−6. This mutation most likely occurred in the respective F1 hybrid. In comparison with previously reported data, our results suggested that allohexaploidization of wheat did not increase SSR mutation rate. PMID:23202911

  8. Mutation rates and the evolution of germline structure

    PubMed Central

    2016-01-01

    Genome sequencing studies of de novo mutations in humans have revealed surprising incongruities in our understanding of human germline mutation. In particular, the mutation rate observed in modern humans is substantially lower than that estimated from calibration against the fossil record, and the paternal age effect in mutations transmitted to offspring is much weaker than expected from our long-standing model of spermatogenesis. I consider possible explanations for these discrepancies, including evolutionary changes in life-history parameters such as generation time and the age of puberty, a possible contribution from undetected post-zygotic mutations early in embryo development, and changes in cellular mutation processes at different stages of the germline. I suggest a revised model of stem-cell state transitions during spermatogenesis, in which ‘dark’ gonial stem cells play a more active role than hitherto envisaged, with a long cycle time undetected in experimental observations. More generally, I argue that the mutation rate and its evolution depend intimately on the structure of the germline in humans and other primates. This article is part of the themed issue ‘Dating species divergences using rocks and clocks'. PMID:27325834

  9. Mutation rates and the evolution of germline structure.

    PubMed

    Scally, Aylwyn

    2016-07-19

    Genome sequencing studies of de novo mutations in humans have revealed surprising incongruities in our understanding of human germline mutation. In particular, the mutation rate observed in modern humans is substantially lower than that estimated from calibration against the fossil record, and the paternal age effect in mutations transmitted to offspring is much weaker than expected from our long-standing model of spermatogenesis. I consider possible explanations for these discrepancies, including evolutionary changes in life-history parameters such as generation time and the age of puberty, a possible contribution from undetected post-zygotic mutations early in embryo development, and changes in cellular mutation processes at different stages of the germline. I suggest a revised model of stem-cell state transitions during spermatogenesis, in which 'dark' gonial stem cells play a more active role than hitherto envisaged, with a long cycle time undetected in experimental observations. More generally, I argue that the mutation rate and its evolution depend intimately on the structure of the germline in humans and other primates.This article is part of the themed issue 'Dating species divergences using rocks and clocks'. PMID:27325834

  10. The Y-chromosome point mutation rate in humans.

    PubMed

    Helgason, Agnar; Einarsson, Axel W; Guðmundsdóttir, Valdís B; Sigurðsson, Ásgeir; Gunnarsdóttir, Ellen D; Jagadeesan, Anuradha; Ebenesersdóttir, S Sunna; Kong, Augustine; Stefánsson, Kári

    2015-05-01

    Mutations are the fundamental source of biological variation, and their rate is a crucial parameter for evolutionary and medical studies. Here we used whole-genome sequence data from 753 Icelandic males, grouped into 274 patrilines, to estimate the point mutation rate for 21.3 Mb of male-specific Y chromosome (MSY) sequence, on the basis of 1,365 meioses (47,123 years). The combined mutation rate for 15.2 Mb of X-degenerate (XDG), X-transposed (XTR) and ampliconic excluding palindromes (rAMP) sequence was 8.71 × 10(-10) mutations per position per year (PPPY). We observed a lower rate (P = 0.04) of 7.37 × 10(-10) PPPY for 6.1 Mb of sequence from palindromes (PAL), which was not statistically different from the rate of 7.2 × 10(-10) PPPY for paternally transmitted autosomes. We postulate that the difference between PAL and the other MSY regions may provide an indication of the rate at which nascent autosomal and PAL de novo mutations are repaired as a result of gene conversion. PMID:25807285

  11. Deterministic Mutation Rate Variation in the Human Genome

    PubMed Central

    Smith, Nick G.C.; Webster, Matthew T.; Ellegren, Hans

    2002-01-01

    Several studies of substitution rate variation have indicated that the local mutation rate varies over the mammalian genome. In the present study, we show significant variation in substitution rates within the noncoding part of the human genome using 4.7 Mb of human-chimpanzee pairwise comparisons. Moreover, we find a significant positive covariation of lineage-specific chimpanzee and human local substitution rates, and very similar mean substitution rates down the two lineages. The substitution rate variation is probably not caused by selection or biased gene conversion, and so we conclude that mutation rates vary deterministically across the noncoding nonrepetitive regions of the human genome. We also show that noncoding substitution rates are significantly affected by G+C base composition, partly because the base composition is not at equilibrium. PMID:12213772

  12. Unbiased estimation of mutation rates under fluctuating final counts.

    PubMed

    Ycart, Bernard; Veziris, Nicolas

    2014-01-01

    Estimation methods for mutation rates (or probabilities) in Luria-Delbrück fluctuation analysis usually assume that the final number of cells remains constant from one culture to another. We show that this leads to systematically underestimate the mutation rate. Two levels of information on final numbers are considered: either the coefficient of variation has been independently estimated, or the final number of cells in each culture is known. In both cases, unbiased estimation methods are proposed. Their statistical properties are assessed both theoretically and through Monte-Carlo simulation. As an application, the data from two well known fluctuation analysis studies on Mycobacterium tuberculosis are reexamined. PMID:24988217

  13. Rates of spontaneous mutation in an archaeon from geothermal environments.

    PubMed Central

    Jacobs, K L; Grogan, D W

    1997-01-01

    To estimate the efficacy of mechanisms which may prevent or repair thermal damage to DNA in thermophilic archaea, a quantitative assay of forward mutation at extremely high temperature was developed for Sulfolobus acidocaldarius, based on the selection of pyrimidine-requiring mutants resistant to 5-fluoro-orotic acid. Maximum-likelihood analysis of spontaneous mutant distributions in wild-type cultures yielded maximal estimates of (2.8 +/- 0.7) x 10(-7) and (1.5 +/- 0.6) x 10(-7) mutational events per cell per division cycle for the pyrE and pyrF loci, respectively. To our knowledge, these results provide the first accurate measurement of the genetic fidelity maintained by archaea that populate geothermal environments. The measured rates of forward mutation at the pyrE and pyrF loci in S. acidocaldarius are close to corresponding rates reported for protein-encoding genes of Escherichia coli. The normal rate of spontaneous mutation in E. coli at 37 degrees C is known to require the functioning of several enzyme systems that repair spontaneous damage in DNA. Our results provide indirect evidence that S. acidocaldarius has cellular mechanisms, as yet unidentified, which effectively compensate for the higher chemical instability of DNA at the temperatures and pHs that prevail within growing Sulfolobus cells. PMID:9150227

  14. Strong effects of ionizing radiation from Chernobyl on mutation rates.

    PubMed

    Møller, Anders Pape; Mousseau, Timothy A

    2015-01-01

    In this paper we use a meta-analysis to examine the relationship between radiation and mutation rates in Chernobyl across 45 published studies, covering 30 species. Overall effect size of radiation on mutation rates estimated as Pearson's product-moment correlation coefficient was very large (E = 0.67; 95% confidence intervals (CI) 0.59 to 0.73), accounting for 44.3% of the total variance in an unstructured random-effects model. Fail-safe calculations reflecting the number of unpublished null results needed to eliminate this average effect size showed the extreme robustness of this finding (Rosenberg's method: 4135 at p = 0.05). Indirect tests did not provide any evidence of publication bias. The effect of radiation on mutations varied among taxa, with plants showing a larger effect than animals. Humans were shown to have intermediate sensitivity of mutations to radiation compared to other species. Effect size did not decrease over time, providing no evidence for an improvement in environmental conditions. The surprisingly high mean effect size suggests a strong impact of radioactive contamination on individual fitness in current and future generations, with potentially significant population-level consequences, even beyond the area contaminated with radioactive material. PMID:25666381

  15. Strong effects of ionizing radiation from Chernobyl on mutation rates

    PubMed Central

    Møller, Anders Pape; Mousseau, Timothy A.

    2015-01-01

    In this paper we use a meta-analysis to examine the relationship between radiation and mutation rates in Chernobyl across 45 published studies, covering 30 species. Overall effect size of radiation on mutation rates estimated as Pearson's product-moment correlation coefficient was very large (E = 0.67; 95% confidence intervals (CI) 0.59 to 0.73), accounting for 44.3% of the total variance in an unstructured random-effects model. Fail-safe calculations reflecting the number of unpublished null results needed to eliminate this average effect size showed the extreme robustness of this finding (Rosenberg's method: 4135 at p = 0.05). Indirect tests did not provide any evidence of publication bias. The effect of radiation on mutations varied among taxa, with plants showing a larger effect than animals. Humans were shown to have intermediate sensitivity of mutations to radiation compared to other species. Effect size did not decrease over time, providing no evidence for an improvement in environmental conditions. The surprisingly high mean effect size suggests a strong impact of radioactive contamination on individual fitness in current and future generations, with potentially significant population-level consequences, even beyond the area contaminated with radioactive material. PMID:25666381

  16. Strong effects of ionizing radiation from Chernobyl on mutation rates

    NASA Astrophysics Data System (ADS)

    Møller, Anders Pape; Mousseau, Timothy A.

    2015-02-01

    In this paper we use a meta-analysis to examine the relationship between radiation and mutation rates in Chernobyl across 45 published studies, covering 30 species. Overall effect size of radiation on mutation rates estimated as Pearson's product-moment correlation coefficient was very large (E = 0.67; 95% confidence intervals (CI) 0.59 to 0.73), accounting for 44.3% of the total variance in an unstructured random-effects model. Fail-safe calculations reflecting the number of unpublished null results needed to eliminate this average effect size showed the extreme robustness of this finding (Rosenberg's method: 4135 at p = 0.05). Indirect tests did not provide any evidence of publication bias. The effect of radiation on mutations varied among taxa, with plants showing a larger effect than animals. Humans were shown to have intermediate sensitivity of mutations to radiation compared to other species. Effect size did not decrease over time, providing no evidence for an improvement in environmental conditions. The surprisingly high mean effect size suggests a strong impact of radioactive contamination on individual fitness in current and future generations, with potentially significant population-level consequences, even beyond the area contaminated with radioactive material.

  17. Highly heterogeneous mutation rates in the hepatitis C virus genome.

    PubMed

    Geller, Ron; Estada, Úrsula; Peris, Joan B; Andreu, Iván; Bou, Juan-Vicente; Garijo, Raquel; Cuevas, José M; Sabariegos, Rosario; Mas, Antonio; Sanjuán, Rafael

    2016-01-01

    Spontaneous mutations are the ultimate source of genetic variation and have a prominent role in evolution. RNA viruses such as hepatitis C virus (HCV) have extremely high mutation rates, but these rates have been inferred from a minute fraction of genome sites, limiting our view of how RNA viruses create diversity. Here, by applying high-fidelity ultradeep sequencing to a modified replicon system, we scored >15,000 spontaneous mutations, encompassing more than 90% of the HCV genome. This revealed >1,000-fold differences in mutability across genome sites, with extreme variations even between adjacent nucleotides. We identify base composition, the presence of high- and low-mutation clusters and transition/transversion biases as the main factors driving this heterogeneity. Furthermore, we find that mutability correlates with the ability of HCV to diversify in patients. These data provide a site-wise baseline for interrogating natural selection, genetic load and evolvability in HCV, as well as for evaluating drug resistance and immune evasion risks. PMID:27572964

  18. bz-rates: A Web Tool to Estimate Mutation Rates from Fluctuation Analysis.

    PubMed

    Gillet-Markowska, Alexandre; Louvel, Guillaume; Fischer, Gilles

    2015-11-01

    Fluctuation analysis is the standard experimental method for measuring mutation rates in micro-organisms. The appearance of mutants is classically described by a Luria-Delbrück distribution composed of two parameters: the number of mutations per culture (m) and the differential growth rate between mutant and wild-type cells (b). A precise estimation of these two parameters is a prerequisite to the calculation of the mutation rate. Here, we developed bz-rates, a Web tool to calculate mutation rates that provides three useful advances over existing Web tools. First, it allows taking into account b, the differential growth rate between mutant and wild-type cells, in the estimation of m with the generating function. Second, bz-rates allows the user to take into account a deviation from the Luria-Delbrück distribution called z, the plating efficiency, in the estimation of m. Finally, the Web site provides a graphical visualization of the goodness-of-fit between the experimental data and the model. bz-rates is accessible at http://www.lcqb.upmc.fr/bzrates. PMID:26338660

  19. bz-rates: A Web Tool to Estimate Mutation Rates from Fluctuation Analysis

    PubMed Central

    Gillet-Markowska, Alexandre; Louvel, Guillaume; Fischer, Gilles

    2015-01-01

    Fluctuation analysis is the standard experimental method for measuring mutation rates in micro-organisms. The appearance of mutants is classically described by a Luria-Delbrück distribution composed of two parameters: the number of mutations per culture (m) and the differential growth rate between mutant and wild-type cells (b). A precise estimation of these two parameters is a prerequisite to the calculation of the mutation rate. Here, we developed bz-rates, a Web tool to calculate mutation rates that provides three useful advances over existing Web tools. First, it allows taking into account b, the differential growth rate between mutant and wild-type cells, in the estimation of m with the generating function. Second, bz-rates allows the user to take into account a deviation from the Luria-Delbrück distribution called z, the plating efficiency, in the estimation of m. Finally, the Web site provides a graphical visualization of the goodness-of-fit between the experimental data and the model. bz-rates is accessible at http://www.lcqb.upmc.fr/bzrates. PMID:26338660

  20. Extensive de novo mutation rate variation between individuals and across the genome of Chlamydomonas reinhardtii

    PubMed Central

    Ness, Rob W.; Morgan, Andrew D.; Vasanthakrishnan, Radhakrishnan B.; Colegrave, Nick; Keightley, Peter D.

    2015-01-01

    Describing the process of spontaneous mutation is fundamental for understanding the genetic basis of disease, the threat posed by declining population size in conservation biology, and much of evolutionary biology. Directly studying spontaneous mutation has been difficult, however, because new mutations are rare. Mutation accumulation (MA) experiments overcome this by allowing mutations to build up over many generations in the near absence of natural selection. Here, we sequenced the genomes of 85 MA lines derived from six genetically diverse strains of the green alga Chlamydomonas reinhardtii. We identified 6843 new mutations, more than any other study of spontaneous mutation. We observed sevenfold variation in the mutation rate among strains and that mutator genotypes arose, increasing the mutation rate approximately eightfold in some replicates. We also found evidence for fine-scale heterogeneity in the mutation rate, with certain sequence motifs mutating at much higher rates, and clusters of multiple mutations occurring at closely linked sites. There was little evidence, however, for mutation rate heterogeneity between chromosomes or over large genomic regions of 200 kbp. We generated a predictive model of the mutability of sites based on their genomic properties, including local GC content, gene expression level, and local sequence context. Our model accurately predicted the average mutation rate and natural levels of genetic diversity of sites across the genome. Notably, trinucleotides vary 17-fold in rate between the most and least mutable sites. Our results uncover a rich heterogeneity in the process of spontaneous mutation both among individuals and across the genome. PMID:26260971

  1. Natural selection fails to optimize mutation rates for long-term adaptation on rugged fitness landscapes.

    PubMed

    Clune, Jeff; Misevic, Dusan; Ofria, Charles; Lenski, Richard E; Elena, Santiago F; Sanjuán, Rafael

    2008-01-01

    The rate of mutation is central to evolution. Mutations are required for adaptation, yet most mutations with phenotypic effects are deleterious. As a consequence, the mutation rate that maximizes adaptation will be some intermediate value. Here, we used digital organisms to investigate the ability of natural selection to adjust and optimize mutation rates. We assessed the optimal mutation rate by empirically determining what mutation rate produced the highest rate of adaptation. Then, we allowed mutation rates to evolve, and we evaluated the proximity to the optimum. Although we chose conditions favorable for mutation rate optimization, the evolved rates were invariably far below the optimum across a wide range of experimental parameter settings. We hypothesized that the reason that mutation rates evolved to be suboptimal was the ruggedness of fitness landscapes. To test this hypothesis, we created a simplified landscape without any fitness valleys and found that, in such conditions, populations evolved near-optimal mutation rates. In contrast, when fitness valleys were added to this simple landscape, the ability of evolving populations to find the optimal mutation rate was lost. We conclude that rugged fitness landscapes can prevent the evolution of mutation rates that are optimal for long-term adaptation. This finding has important implications for applied evolutionary research in both biological and computational realms. PMID:18818724

  2. Natural Selection Fails to Optimize Mutation Rates for Long-Term Adaptation on Rugged Fitness Landscapes

    PubMed Central

    Clune, Jeff; Misevic, Dusan; Ofria, Charles; Lenski, Richard E.; Elena, Santiago F.; Sanjuán, Rafael

    2008-01-01

    The rate of mutation is central to evolution. Mutations are required for adaptation, yet most mutations with phenotypic effects are deleterious. As a consequence, the mutation rate that maximizes adaptation will be some intermediate value. Here, we used digital organisms to investigate the ability of natural selection to adjust and optimize mutation rates. We assessed the optimal mutation rate by empirically determining what mutation rate produced the highest rate of adaptation. Then, we allowed mutation rates to evolve, and we evaluated the proximity to the optimum. Although we chose conditions favorable for mutation rate optimization, the evolved rates were invariably far below the optimum across a wide range of experimental parameter settings. We hypothesized that the reason that mutation rates evolved to be suboptimal was the ruggedness of fitness landscapes. To test this hypothesis, we created a simplified landscape without any fitness valleys and found that, in such conditions, populations evolved near-optimal mutation rates. In contrast, when fitness valleys were added to this simple landscape, the ability of evolving populations to find the optimal mutation rate was lost. We conclude that rugged fitness landscapes can prevent the evolution of mutation rates that are optimal for long-term adaptation. This finding has important implications for applied evolutionary research in both biological and computational realms. PMID:18818724

  3. Genomic background and generation time influence deleterious mutation rates in Daphnia.

    PubMed

    Latta, Leigh C; Morgan, Kendall K; Weaver, Casse S; Allen, Desiree; Schaack, Sarah; Lynch, Michael

    2013-02-01

    Understanding how genetic variation is generated and how selection shapes mutation rates over evolutionary time requires knowledge of the factors influencing mutation and its effects on quantitative traits. We explore the impact of two factors, genomic background and generation time, on deleterious mutation in Daphnia pulicaria, a cyclically parthenogenic aquatic microcrustacean, using parallel mutation-accumulation experiments. The deleterious mutational properties of life-history characters for individuals from two different populations, and for individuals maintained at two different generation times, were quantified and compared. Mutational properties varied between populations, especially for clutch size, suggesting that genomic background influences mutational properties for some characters. Generation time was found to have a greater effect on mutational properties, with higher per-generation deleterious mutation rates in lines with longer generation times. These results suggest that differences in genetic architecture among populations and species may be explained in part by demographic features that significantly influence generation time and therefore the rate of mutation. PMID:23183667

  4. Exact Phase Diagram of a Quasispecies Model with a Mutation Rate Modifier

    NASA Astrophysics Data System (ADS)

    Nagar, Apoorva; Jain, Kavita

    2009-01-01

    We consider an infinite asexual population with a mutator allele which can elevate mutation rates. With probability f, a transition from nonmutator to mutator state occurs but the reverse transition is forbidden. We find that at f=0, the population is in the state with minimum mutation rate, and at f=fc, a phase transition occurs between a mixed phase with both nonmutators and mutators and a pure mutator phase. We calculate the critical probability fc and the total mutator fraction Q in the mixed phase exactly. Our predictions for Q are in agreement with those seen in microbial populations in static environments.

  5. Exact phase diagram of a quasispecies model with a mutation rate modifier.

    PubMed

    Nagar, Apoorva; Jain, Kavita

    2009-01-23

    We consider an infinite asexual population with a mutator allele which can elevate mutation rates. With probability f, a transition from nonmutator to mutator state occurs but the reverse transition is forbidden. We find that at f=0, the population is in the state with minimum mutation rate, and at f=fc, a phase transition occurs between a mixed phase with both nonmutators and mutators and a pure mutator phase. We calculate the critical probability fc and the total mutator fraction Q in the mixed phase exactly. Our predictions for Q are in agreement with those seen in microbial populations in static environments. PMID:19257397

  6. Mutation biases and mutation rate variation around very short human microsatellites revealed by human-chimpanzee-orangutan genomic sequence alignments.

    PubMed

    Amos, William

    2010-09-01

    I have studied mutation patterns around very short microsatellites, focusing mainly on sequences carrying only two repeat units. By using human-chimpanzee-orangutan alignments, inferences can be made about both the relative rates of mutations and which bases have mutated. I find remarkable non-randomness, with mutation rate depending on a base's position relative to the microsatellite, the identity of the base itself and the motif in the microsatellite. Comparing the patterns around AC2 with those around other four-base combinations reveals that AC2 does not stand out as being special in the sense that non-repetitive tetramers also generate strong mutation biases. However, comparing AC2 and AC3 with AC4 reveals a step change in both the rate and nature of mutations occurring, suggesting a transition state, AC4 exhibiting an alternating high-low mutation rate pattern consistent with the sequence patterning seen around longer microsatellites. Surprisingly, most changes in repeat number occur through base substitutions rather than slippage, and the relative probability of gaining versus losing a repeat in this way varies greatly with repeat number. Slippage mutations reveal rather similar patterns of mutability compared with point mutations, being rare at two repeats where most cause the loss of a repeat, with both mutation rate and the proportion of expansion mutations increasing up to 6-8 repeats. Inferences about longer repeat tracts are hampered by uncertainties about the proportion of multi-species alignments that fail due to multi-repeat mutations and other rearrangements. PMID:20700734

  7. Mutation rate estimation for 15 autosomal STR loci in a large population from Mainland China

    PubMed Central

    Zhao, Zhuo; Zhang, Jie; Wang, Hua; Liu, Zhi-Peng; Liu, Ming; Zhang, Yuan; Sun, Li; Zhang, Hui

    2015-01-01

    STR, short tandem repeats, are well known as a type of powerful genetic marker and widely used in studying human population genetics. Compared with the conventional genetic markers, the mutation rate of STR is higher. Additionally, the mutations of STR loci do not lead to genetic inconsistencies between the genotypes of parents and children; therefore, the analysis of STR mutation is more suited to assess the population mutation. In this study, we focused on 15 autosomal STR loci. DNA samples from a total of 42,416 unrelated healthy individuals (19,037 trios) from the population of Mainland China collected between Jan 2012 and May 2014 were successfully investigated. In our study, the allele frequencies, paternal mutation rates, maternal mutation rates and average mutation rates were detected. Furthermore, we also investigated the relationship between paternal ages, maternal ages, area, the time of pregnancy and average mutation rate. We found that the paternal mutation rate was higher than the maternal mutation rate and the paternal, maternal, and average mutation rates had a positive correlation with paternal age, maternal age and the time of pregnancy respectively. Additionally, the average mutation rate of coastal areas was higher than that of inland areas. PMID:26273562

  8. Studies of human mutation rates, December 1, 1985--November 30, 1986

    SciTech Connect

    Neel, J.V.

    1985-05-01

    This program seeks to quantify native human mutation rates and to determine how man's activities may affect these rates. The program is divided into six tasks, i.e. The American Indian mutation rate, monitoring populations for frequency of mutation by electrophoresis of blood proteins, application of molecular biological approaches to the detection and study of mutational events in human populations, development of two-dimensional electrophoresis for identification of mutant proteins, co-operative program with the Radiation Effects Research Foundation in Hiroshima and Nagasaki, Japan, and statistical problems associated with the estimation of mutation rates. Progress of each of the above tasks is related in detail. (DT)

  9. Direct Estimation of the Mitochondrial DNA Mutation Rate in Drosophila melanogaster

    PubMed Central

    Haag-Liautard, Cathy; Coffey, Nicole; Houle, David; Lynch, Michael; Charlesworth, Brian; Keightley, Peter D

    2008-01-01

    Mitochondrial DNA (mtDNA) variants are widely used in evolutionary genetics as markers for population history and to estimate divergence times among taxa. Inferences of species history are generally based on phylogenetic comparisons, which assume that molecular evolution is clock-like. Between-species comparisons have also been used to estimate the mutation rate, using sites that are thought to evolve neutrally. We directly estimated the mtDNA mutation rate by scanning the mitochondrial genome of Drosophila melanogaster lines that had undergone approximately 200 generations of spontaneous mutation accumulation (MA). We detected a total of 28 point mutations and eight insertion-deletion (indel) mutations, yielding an estimate for the single-nucleotide mutation rate of 6.2 × 10−8 per site per fly generation. Most mutations were heteroplasmic within a line, and their frequency distribution suggests that the effective number of mitochondrial genomes transmitted per female per generation is about 30. We observed repeated occurrences of some indel mutations, suggesting that indel mutational hotspots are common. Among the point mutations, there is a large excess of G→A mutations on the major strand (the sense strand for the majority of mitochondrial genes). These mutations tend to occur at nonsynonymous sites of protein-coding genes, and they are expected to be deleterious, so do not become fixed between species. The overall mtDNA mutation rate per base pair per fly generation in Drosophila is estimated to be about 10× higher than the nuclear mutation rate, but the mitochondrial major strand G→A mutation rate is about 70× higher than the nuclear rate. Silent sites are substantially more strongly biased towards A and T than nonsynonymous sites, consistent with the extreme mutation bias towards A+T. Strand-asymmetric mutation bias, coupled with selection to maintain specific nonsynonymous bases, therefore provides an explanation for the extreme base composition of

  10. Costs and Benefits of High Mutation Rates: Adaptive Evolution of Bacteria in the Mouse Gut

    NASA Astrophysics Data System (ADS)

    Giraud, Antoine; Matic, Ivan; Tenaillon, Olivier; Clara, Antonio; Radman, Miroslav; Fons, Michel; Taddei, François

    2001-03-01

    We have shown that bacterial mutation rates change during the experimental colonization of the mouse gut. A high mutation rate was initially beneficial because it allowed faster adaptation, but this benefit disappeared once adaptation was achieved. Mutator bacteria accumulated mutations that, although neutral in the mouse gut, are often deleterious in secondary environments. Consistently, the competitiveness of mutator bacteria is reduced during transmission to and re-colonization of similar hosts. The short-term advantages and long-term disadvantages of mutator bacteria could account for their frequency in nature.

  11. Adaptive evolution by recombination is not associated with increased mutation rates in Maize streak virus

    PubMed Central

    2012-01-01

    Background Single-stranded (ss) DNA viruses in the family Geminiviridae are proving to be very useful in real-time evolution studies. The high mutation rate of geminiviruses and other ssDNA viruses is somewhat mysterious in that their DNA genomes are replicated in host nuclei by high fidelity host polymerases. Although strand specific mutation biases observed in virus species from the geminivirus genus Mastrevirus indicate that the high mutation rates in viruses in this genus may be due to mutational processes that operate specifically on ssDNA, it is currently unknown whether viruses from other genera display similar strand specific mutation biases. Also, geminivirus genomes frequently recombine with one another and an alternative cause of their high mutation rates could be that the recombination process is either directly mutagenic or produces a selective environment in which the survival of mutants is favoured. To investigate whether there is an association between recombination and increased basal mutation rates or increased degrees of selection favoring the survival of mutations, we compared the mutation dynamics of the MSV-MatA and MSV-VW field isolates of Maize streak virus (MSV; Mastrevirus), with both a laboratory constructed MSV recombinant, and MSV recombinants closely resembling MSV-MatA. To determine whether strand specific mutation biases are a general characteristic of geminivirus evolution we compared mutation spectra arising during these MSV experiments with those arising during similar experiments involving the geminivirus Tomato yellow leaf curl virus (Begomovirus genus). Results Although both the genomic distribution of mutations and the occurrence of various convergent mutations at specific genomic sites indicated that either mutation hotspots or selection for adaptive mutations might elevate observed mutation rates in MSV, we found no association between recombination and mutation rates. Importantly, when comparing the mutation spectra of MSV

  12. The Rate and Spectrum of Spontaneous Mutations in a Plant RNA Virus

    PubMed Central

    Tromas, Nicolas; Elena, Santiago F.

    2010-01-01

    Knowing mutation rates and the molecular spectrum of spontaneous mutations is important to understanding how the genetic composition of viral populations evolves. Previous studies have shown that the rate of spontaneous mutations for RNA viruses widely varies between 0.01 and 2 mutations per genome and generation, with plant RNA viruses always occupying the lower side of this range. However, this peculiarity of plant RNA viruses is based on a very limited number of studies. Here we analyze the spontaneous mutational spectrum and the mutation rate of Tobacco etch potyvirus, a model system of positive sense RNA viruses. Our experimental setup minimizes the action of purifying selection on the mutational spectrum, thus giving a picture of what types of mutations are produced by the viral replicase. As expected for a neutral target, we found that transitions and nonsynonymous (including a few stop codons and small deletions) mutations were the most abundant type. This spectrum was notably different from the one previously described for another plant virus. We have estimated that the spontaneous mutation rate for this virus was in the range 10−6−10−5 mutations per site and generation. Our estimates are in the same biological ballpark that previous values reported for plant RNA viruses. This finding gives further support to the idea that plant RNA viruses may have lower mutation rates than their animal counterparts. PMID:20439778

  13. Longevity Is Linked to Mitochondrial Mutation Rates in Rockfish: A Test Using Poisson Regression.

    PubMed

    Hua, Xia; Cowman, Peter; Warren, Dan; Bromham, Lindell

    2015-10-01

    The mitochondrial theory of ageing proposes that the cumulative effect of biochemical damage in mitochondria causes mitochondrial mutations and plays a key role in ageing. Numerous studies have applied comparative approaches to test one of the predictions of the theory: That the rate of mitochondrial mutations is negatively correlated with longevity. Comparative studies face three challenges in detecting correlates of mutation rate: Covariation of mutation rates between species due to ancestry, covariation between life-history traits, and difficulty obtaining accurate estimates of mutation rate. We address these challenges using a novel Poisson regression method to examine the link between mutation rate and lifespan in rockfish (Sebastes). This method has better performance than traditional sister-species comparisons when sister species are too recently diverged to give reliable estimates of mutation rate. Rockfish are an ideal model system: They have long life spans with indeterminate growth and little evidence of senescence, which minimizes the confounding tradeoffs between lifespan and fecundity. We show that lifespan in rockfish is negatively correlated to rate of mitochondrial mutation, but not the rate of nuclear mutation. The life history of rockfish allows us to conclude that this relationship is unlikely to be driven by the tradeoffs between longevity and fecundity, or by the frequency of DNA replications in the germline. Instead, the relationship is compatible with the hypothesis that mutation rates are reduced by selection in long-lived taxa to reduce the chance of mitochondrial damage over its lifespan, consistent with the mitochondrial theory of ageing. PMID:26048547

  14. The R21C Mutation in Cardiac Troponin I Imposes Differences in Contractile Force Generation between the Left and Right Ventricles of Knock-In Mice.

    PubMed

    Liang, Jingsheng; Kazmierczak, Katarzyna; Rojas, Ana I; Wang, Yingcai; Szczesna-Cordary, Danuta

    2015-01-01

    We investigated the effect of the hypertrophic cardiomyopathy-linked R21C (arginine to cysteine) mutation in human cardiac troponin I (cTnI) on the contractile properties and myofilament protein phosphorylation in papillary muscle preparations from left (LV) and right (RV) ventricles of homozygous R21C(+/+) knock-in mice. The maximal steady-state force was significantly reduced in skinned papillary muscle strips from the LV compared to RV, with the latter displaying the level of force observed in LV or RV from wild-type (WT) mice. There were no differences in the Ca(2+) sensitivity between the RV and LV of R21C(+/+) mice; however, the Ca(2+) sensitivity of force was higher in RV-R21C(+/+) compared with RV-WT and lower in LV- R21C(+/+) compared with LV-WT. We also observed partial loss of Ca(2+) regulation at low [Ca(2+)]. In addition, R21C(+/+)-KI hearts showed no Ser23/24-cTnI phosphorylation compared to LV or RV of WT mice. However, phosphorylation of the myosin regulatory light chain (RLC) was significantly higher in the RV versus LV of R21C(+/+) mice and versus LV and RV of WT mice. The difference in RLC phosphorylation between the ventricles of R21C(+/+) mice likely contributes to observed differences in contractile force and the lower tension monitored in the LV of HCM mice. PMID:25961037

  15. Extensive Variation in the Mutation Rate Between and Within Human Genes Associated with Mendelian Disease.

    PubMed

    Smith, Thomas; Ho, Gladys; Christodoulou, John; Price, Elizabeth Ann; Onadim, Zerrin; Gauthier-Villars, Marion; Dehainault, Catherine; Houdayer, Claude; Parfait, Beatrice; van Minkelen, Rick; Lohman, Dietmar; Eyre-Walker, Adam

    2016-05-01

    We have investigated whether the mutation rate varies between genes and sites using de novo mutations (DNMs) from three genes associated with Mendelian diseases (RB1, NF1, and MECP2). We show that the relative frequency of mutations at CpG dinucleotides relative to non-CpG sites varies between genes and relative to the genomic average. In particular we show that the rate of transition mutation at CpG sites relative to the rate of non-CpG transversion is substantially higher in our disease genes than amongst DNMs in general; the rate of CpG transition can be several hundred-fold greater than the rate of non-CpG transversion. We also show that the mutation rate varies significantly between sites of a particular mutational type, such as non-CpG transversion, within a gene. We estimate that for all categories of sites, except CpG transitions, there is at least a 30-fold difference in the mutation rate between the 10% of sites with the highest and lowest mutation rates. However, our best estimate is that the mutation rate varies by several hundred-fold variation. We suggest that the presence of hypermutable sites may be one reason certain genes are associated with disease. PMID:26857394

  16. Differential DNA mismatch repair underlies mutation rate variation across the human genome

    PubMed Central

    Supek, Fran; Lehner, Ben

    2015-01-01

    Cancer genome sequencing has revealed considerable variation in somatic mutation rates across the human genome, with mutation rates elevated in heterochromatic late replicating regions and reduced in early replicating euchromatin1-5. Multiple mechanisms have been suggested to underlie this2,6-10, but the actual cause is unknown. Here we identify variable DNA mismatch repair (MMR) as the basis of this variation. Analysing ~17 million single nucleotide variants from the genomes of 652 tumours, we show that regional autosomal mutation rates at megabase resolution are largely stable across cancer types, with differences related to changes in replication timing and gene expression. However, mutations arising after the inactivation of MMR are no longer enriched in early replicating euchromatin relative to late replicating heterochromatin. Thus, differential DNA repair and not differential mutation supply is the primary cause of the large-scale regional mutation rate variation across the human genome. PMID:25707793

  17. Population-Scale Sequencing Data Enable Precise Estimates of Y-STR Mutation Rates.

    PubMed

    Willems, Thomas; Gymrek, Melissa; Poznik, G David; Tyler-Smith, Chris; Erlich, Yaniv

    2016-05-01

    Short tandem repeats (STRs) are mutation-prone loci that span nearly 1% of the human genome. Previous studies have estimated the mutation rates of highly polymorphic STRs by using capillary electrophoresis and pedigree-based designs. Although this work has provided insights into the mutational dynamics of highly mutable STRs, the mutation rates of most others remain unknown. Here, we harnessed whole-genome sequencing data to estimate the mutation rates of Y chromosome STRs (Y-STRs) with 2-6 bp repeat units that are accessible to Illumina sequencing. We genotyped 4,500 Y-STRs by using data from the 1000 Genomes Project and the Simons Genome Diversity Project. Next, we developed MUTEA, an algorithm that infers STR mutation rates from population-scale data by using a high-resolution SNP-based phylogeny. After extensive intrinsic and extrinsic validations, we harnessed MUTEA to derive mutation-rate estimates for 702 polymorphic STRs by tracing each locus over 222,000 meioses, resulting in the largest collection of Y-STR mutation rates to date. Using our estimates, we identified determinants of STR mutation rates and built a model to predict rates for STRs across the genome. These predictions indicate that the load of de novo STR mutations is at least 75 mutations per generation, rivaling the load of all other known variant types. Finally, we identified Y-STRs with potential applications in forensics and genetic genealogy, assessed the ability to differentiate between the Y chromosomes of father-son pairs, and imputed Y-STR genotypes. PMID:27126583

  18. Estimates of the rate and distribution of fitness effects of spontaneous mutation in Saccharomyces cerevisiae.

    PubMed Central

    Zeyl, C; DeVisser, J A

    2001-01-01

    The per-genome, per-generation rate of spontaneous mutation affecting fitness (U) and the mean fitness cost per mutation (s) are important parameters in evolutionary genetics, but have been estimated for few species. We estimated U and sh (the heterozygous effect of mutations) for two diploid yeast strains differing only in the DNA mismatch-repair deficiency used to elevate the mutation rate in one (mutator) strain. Mutations were allowed to accumulate in 50 replicate lines of each strain, during 36 transfers of randomly chosen single colonies (approximately 600 generations). Among wild-type lines, fitnesses were bimodal, with one mode showing no change in mean fitness. The other mode showed a mean 29.6% fitness decline and the petite phenotype, usually caused by partial deletion of the mitochondrial genome. Excluding petites, maximum-likelihood estimates adjusted for the effect of selection were U = 9.5 x 10(-5) and sh = 0.217 for the wild type. Among the mutator lines, the best fit was obtained with 0.005 < or = U < or = 0.94 and 0.049 > or = sh > or = 0.0003. Like other recently tested model organisms, wild-type yeast have low mutation rates, with high mean fitness costs per mutation. Inactivation of mismatch repair increases the frequency of slightly deleterious mutations by approximately two orders of magnitude. PMID:11139491

  19. Evolution of digital organisms at high mutation rates leads to survival of the flattest

    NASA Astrophysics Data System (ADS)

    Wilke, Claus O.; Wang, Jia Lan; Ofria, Charles; Lenski, Richard E.; Adami, Christoph

    2001-07-01

    Darwinian evolution favours genotypes with high replication rates, a process called `survival of the fittest'. However, knowing the replication rate of each individual genotype may not suffice to predict the eventual survivor, even in an asexual population. According to quasi-species theory, selection favours the cloud of genotypes, interconnected by mutation, whose average replication rate is highest. Here we confirm this prediction using digital organisms that self-replicate, mutate and evolve. Forty pairs of populations were derived from 40 different ancestors in identical selective environments, except that one of each pair experienced a 4-fold higher mutation rate. In 12 cases, the dominant genotype that evolved at the lower mutation rate achieved a replication rate >1.5-fold faster than its counterpart. We allowed each of these disparate pairs to compete across a range of mutation rates. In each case, as mutation rate was increased, the outcome of competition switched to favour the genotype with the lower replication rate. These genotypes, although they occupied lower fitness peaks, were located in flatter regions of the fitness surface and were therefore more robust with respect to mutations.

  20. Upper-limit mutation rate estimation for a plant RNA virus

    PubMed Central

    Sanjuán, Rafael; Agudelo-Romero, Patricia; Elena, Santiago F.

    2009-01-01

    It is generally accepted that mutation rates of RNA viruses are inherently high due to the lack of proofreading mechanisms. However, direct estimates of mutation rate are surprisingly scarce, in particular for plant viruses. Here, based on the analysis of in vivo mutation frequencies in tobacco etch virus, we calculate an upper-bound mutation rate estimation of 3×10−5 per site and per round of replication; a value which turns out to be undistinguishable from the methodological error. Nonetheless, the value is barely on the lower side of the range accepted for RNA viruses, although in good agreement with the only direct estimate obtained for other plant viruses. These observations suggest that, perhaps, differences in the selective pressures operating during plant virus evolution may have driven their mutation rates towards values lower than those characteristic of other RNA viruses infecting bacteria or animals. PMID:19324646

  1. Direct determination of the point mutation rate of a murine retrovirus.

    PubMed Central

    Monk, R J; Malik, F G; Stokesberry, D; Evans, L H

    1992-01-01

    The point mutation rate of a murine leukemia virus (MuLV) genome (AKV) was determined under conditions in which the number of replicative cycles was carefully controlled and the point mutation rate was determined by direct examination of the RNA genomes of progeny viruses. A clonal cell line infected at a low multiplicity of infection (2 x 10(-3)) was derived to provide a source of virus with high genetic homogeneity. Virus stocks from this cell line were used to infect cells at a low multiplicity of infection, and the cells were seeded soon after infection to obtain secondary clonal cell lines. RNase T1-oligonucleotide fingerprinting analyses of virion RNAs from 93 secondary lines revealed only 3 base changes in nearly 130,000 bases analyzed. To obtain an independent assessment of the mutation rate, we directly sequenced virion RNAs by using a series of DNA oligonucleotide primers distributed across the genome. RNA sequencing detected no mutations in over 21,000 bases analyzed. The combined fingerprinting and sequencing analyses yielded a mutation rate for infectious progeny viruses of one base change per 50,000 (2 x 10(-5)) bases per replication cycle. Our results suggest that over 80% of infectious progeny MuLVs may be replicated with complete fidelity and that only a low percentage undergo more than one point mutation during a replication cycle. Previous estimates of retroviral mutation rates suggest that the majority of infectious progeny viruses have undergone one or more point mutations. Recent studies of the mutation rates of marker genes in spleen necrosis virus-based vectors estimate a base substitution rate lower than estimates for infectious avian retroviruses and nearly identical to our determinations with AKV. The differences between mutation rates observed in studies of retroviruses may reflect the imposition of different selective conditions. Images PMID:1316475

  2. Critical Mutation Rate Has an Exponential Dependence on Population Size in Haploid and Diploid Populations

    PubMed Central

    Aston, Elizabeth; Channon, Alastair; Day, Charles; Knight, Christopher G.

    2013-01-01

    Understanding the effect of population size on the key parameters of evolution is particularly important for populations nearing extinction. There are evolutionary pressures to evolve sequences that are both fit and robust. At high mutation rates, individuals with greater mutational robustness can outcompete those with higher fitness. This is survival-of-the-flattest, and has been observed in digital organisms, theoretically, in simulated RNA evolution, and in RNA viruses. We introduce an algorithmic method capable of determining the relationship between population size, the critical mutation rate at which individuals with greater robustness to mutation are favoured over individuals with greater fitness, and the error threshold. Verification for this method is provided against analytical models for the error threshold. We show that the critical mutation rate for increasing haploid population sizes can be approximated by an exponential function, with much lower mutation rates tolerated by small populations. This is in contrast to previous studies which identified that critical mutation rate was independent of population size. The algorithm is extended to diploid populations in a system modelled on the biological process of meiosis. The results confirm that the relationship remains exponential, but show that both the critical mutation rate and error threshold are lower for diploids, rather than higher as might have been expected. Analyzing the transition from critical mutation rate to error threshold provides an improved definition of critical mutation rate. Natural populations with their numbers in decline can be expected to lose genetic material in line with the exponential model, accelerating and potentially irreversibly advancing their decline, and this could potentially affect extinction, recovery and population management strategy. The effect of population size is particularly strong in small populations with 100 individuals or less; the exponential model has

  3. The mutation rate of the human mtDNA deletion mtDNA{sup 4977}

    SciTech Connect

    Shenkar, R.; Navidi, W.; Tavare, S.

    1996-10-01

    The human mitochondrial mutation mtDNA{sup 4977} is a 4,977-bp deletion that originates between two 13-bp direct repeats. We grew 220 colonies of cells, each from a single human cell. For each colony, we counted the number of cells and amplified the DNA by PCR to test for the presence of a deletion. To estimate the mutation rate, we used a model that describes the relationship between the mutation rate and the probability that a colony of a given size will contain no mutants, taking into account such factors as possible mitochondrial turnover and mistyping due to PCR error. We estimate that the mutation rate for mtDNA{sup 4977} in cultured human cells is 5.95 x 10{sup {minus}8} per mitochondrial genome replication. This method can be applied to specific chromosomal, as well as mitochondrial, mutations. 17 refs., 1 fig., 1 tab.

  4. Estimate of the genomic mutation rate deleterious to overall fitness in E. coll

    NASA Astrophysics Data System (ADS)

    Kibota, Travis T.; Lynch, Michael

    1996-06-01

    MUTATIONS are a double-edged sword: they are the ultimate source of genetic variation upon which evolution depends, yet most mutations affecting fitness (viability and reproductive success) appear to be harmful1. Deleterious mutations of small effect can escape natural selection, and should accumulate in small populations2-4. Reduced fitness from deleterious-mutation accumulation may be important in the evolution of sex5-7, mate choice8,9, and diploid life-cycles10, and in the extinction of small populations11,12. Few empirical data exist, however. Minimum estimates of the genomic deleterious-mutation rate for viability in Drosophila melanogaster are surprisingly high1,13,14, leading to the conjecture that the rate for total fitness could exceed 1.0 mutation per individual per generation5,6. Here we use Escherichia coli to provide an estimate of the genomic deleterious-mutation rate for total fitness in a microbe. We estimate that the per-microbe rate of deleterious mutations is in excess of 0.0002.

  5. Parental age affects somatic mutation rates in the progeny of flowering plants.

    PubMed

    Singh, Amit Kumar; Bashir, Tufail; Sailer, Christian; Gurumoorthy, Viswanathan; Ramakrishnan, Anantha Maharasi; Dhanapal, Shanmuhapreya; Grossniklaus, Ueli; Baskar, Ramamurthy

    2015-05-01

    In humans, it is well known that the parental reproductive age has a strong influence on mutations transmitted to their progeny. Meiotic nondisjunction is known to increase in older mothers, and base substitutions tend to go up with paternal reproductive age. Hence, it is clear that the germinal mutation rates are a function of both maternal and paternal ages in humans. In contrast, it is unknown whether the parental reproductive age has an effect on somatic mutation rates in the progeny, because these are rare and difficult to detect. To address this question, we took advantage of the plant model system Arabidopsis (Arabidopsis thaliana), where mutation detector lines allow for an easy quantitation of somatic mutations, to test the effect of parental age on somatic mutation rates in the progeny. Although we found no significant effect of parental age on base substitutions, we found that frameshift mutations and transposition events increased in the progeny of older parents, an effect that is stronger through the maternal line. In contrast, intrachromosomal recombination events in the progeny decrease with the age of the parents in a parent-of-origin-dependent manner. Our results clearly show that parental reproductive age affects somatic mutation rates in the progeny and, thus, that some form of age-dependent information, which affects the frequency of double-strand breaks and possibly other processes involved in maintaining genome integrity, is transmitted through the gametes. PMID:25810093

  6. Parental Age Affects Somatic Mutation Rates in the Progeny of Flowering Plants1

    PubMed Central

    Singh, Amit Kumar; Bashir, Tufail; Sailer, Christian; Gurumoorthy, Viswanathan; Ramakrishnan, Anantha Maharasi; Dhanapal, Shanmuhapreya; Grossniklaus, Ueli; Baskar, Ramamurthy

    2015-01-01

    In humans, it is well known that the parental reproductive age has a strong influence on mutations transmitted to their progeny. Meiotic nondisjunction is known to increase in older mothers, and base substitutions tend to go up with paternal reproductive age. Hence, it is clear that the germinal mutation rates are a function of both maternal and paternal ages in humans. In contrast, it is unknown whether the parental reproductive age has an effect on somatic mutation rates in the progeny, because these are rare and difficult to detect. To address this question, we took advantage of the plant model system Arabidopsis (Arabidopsis thaliana), where mutation detector lines allow for an easy quantitation of somatic mutations, to test the effect of parental age on somatic mutation rates in the progeny. Although we found no significant effect of parental age on base substitutions, we found that frameshift mutations and transposition events increased in the progeny of older parents, an effect that is stronger through the maternal line. In contrast, intrachromosomal recombination events in the progeny decrease with the age of the parents in a parent-of-origin-dependent manner. Our results clearly show that parental reproductive age affects somatic mutation rates in the progeny and, thus, that some form of age-dependent information, which affects the frequency of double-strand breaks and possibly other processes involved in maintaining genome integrity, is transmitted through the gametes. PMID:25810093

  7. Mutation rates at Y chromosome short tandem repeats in Texas populations.

    PubMed

    Ge, Jianye; Budowle, Bruce; Aranda, Xavier G; Planz, John V; Eisenberg, Arthur J; Chakraborty, Ranajit

    2009-06-01

    Father-son pairs from three populations (African American, Caucasian, and Hispanic) of Texas were typed for the 17 Y STR markers DYS19, DYS385, DYS389I, DYS389II, DYS390, DYS391, DYS392, DYS393, DYS437, DYS438, DYS439, DYS456, DYS458, DYS635, DYS448, and Y GATA H4 using the AmpFlSTR YfilerTM kit. With 49,578 allele transfers, 102 mutations were detected. One three-step and four two-step mutations were found, and all others (95.1%) were one-step mutations. The number of gains (48) and losses (54) of repeats were nearly similar. The average mutation rate in the total population is 2.1 x 10(-3) per locus (95% CI (1.7-2.5)x10(-3)). African Americans showed a higher mutation rate (3.0 x 10(-3); 95% CI (2.4-4.0)x10(-3)) than the Caucasians (1.7 x 10(-3); 95% CI (1.1-2.5)x10(-3)) and Hispanics (1.5 x 10(-3); 95% CI (1.0-2.2)x10(-3)), but grouped by repeat-lengths, such differences were not significant. Mutation is correlated with relative length of alleles, i.e., longer alleles are more likely to mutate compared with the shorter ones at the same locus. Mutation rates are also correlated with the absolute number of repeats, namely, alleles with higher number of repeats are more likely to mutate than the shorter ones (p-value=0.030). Finally, occurrences of none, one, and two mutations over the father-son transmission of alleles were consistent with the assumption of independence of mutation rates across loci. PMID:19414166

  8. Association of Intron Loss with High Mutation Rate in Arabidopsis: Implications for Genome Size Evolution

    PubMed Central

    Yang, Yu-Fei; Zhu, Tao; Niu, Deng-Ke

    2013-01-01

    Despite the prevalence of intron losses during eukaryotic evolution, the selective forces acting on them have not been extensively explored. Arabidopsis thaliana lost half of its genome and experienced an elevated rate of intron loss after diverging from A. lyrata. The selective force for genome reduction was suggested to have driven the intron loss. However, the evolutionary mechanism of genome reduction is still a matter of debate. In this study, we found that intron-lost genes have high synonymous substitution rates. Assuming that differences in mutability among different introns are conserved among closely related species, we used the nucleotide substitution rate between orthologous introns in other species as the proxy of the mutation rate of Arabidopsis introns, either lost or extant. The lost introns were found to have higher mutation rates than extant introns. At the genome-wide level, A. thaliana has a higher mutation rate than A. lyrata, which correlates with the higher rate of intron loss and rapid genome reduction of A. thaliana. Our results indicate that selection to minimize mutational hazards might be the selective force for intron loss, and possibly also for genome reduction, in the evolution of A. thaliana. Small genome size and lower genome-wide intron density were widely reported to be correlated with phenotypic features, such as high metabolic rates and rapid growth. We argue that the mutational-hazard hypothesis is compatible with these correlations, by suggesting that selection for rapid growth might indirectly increase mutational hazards. PMID:23516254

  9. Distinct mutation accumulation rates among tissues determine the variation in cancer risk

    PubMed Central

    Hao, Dapeng; Wang, Li; Di, Li-jun

    2016-01-01

    Cancer is believed to be a result of accumulated mutations. However, this concept has not been fully confirmed owing to the impossibility of tracking down the ancestral somatic cell. We sought to verify the concept by exploring the correlation between cancer risk and mutation accumulation among different tissues. We hypothesized that the detected mutations through bulk tumor sequencing are commonly shared in majority, if not all, of tumor cells and are therefore largely a reflection of the mutations accumulated in the ancestral cell that gives rise to tumor. We collected a comprehensive list of mutation frequencies revealed by bulk tumor sequencing, and investigated its correlation with cancer risk to mirror the correlation between mutation accumulation and cancer risk. This revealed an approximate 1:1 relationship between mutation frequency and cancer risk in 41 different cancer types based on the sequencing data of 5,542 patients. The correlation strongly suggests that variation in cancer risk among tissues is mainly attributable to distinct mutation accumulation rates. Moreover, the correlation establishes a baseline to evaluate the effect of non-mutagenic carcinogens on cancer risk. Finally, our mathematic modeling provides a reasonable explanation to reinforce that cancer risk is predominantly determined by the first rate-limiting mutation. PMID:26785814

  10. Distinct mutation accumulation rates among tissues determine the variation in cancer risk.

    PubMed

    Hao, Dapeng; Wang, Li; Di, Li-jun

    2016-01-01

    Cancer is believed to be a result of accumulated mutations. However, this concept has not been fully confirmed owing to the impossibility of tracking down the ancestral somatic cell. We sought to verify the concept by exploring the correlation between cancer risk and mutation accumulation among different tissues. We hypothesized that the detected mutations through bulk tumor sequencing are commonly shared in majority, if not all, of tumor cells and are therefore largely a reflection of the mutations accumulated in the ancestral cell that gives rise to tumor. We collected a comprehensive list of mutation frequencies revealed by bulk tumor sequencing, and investigated its correlation with cancer risk to mirror the correlation between mutation accumulation and cancer risk. This revealed an approximate 1:1 relationship between mutation frequency and cancer risk in 41 different cancer types based on the sequencing data of 5,542 patients. The correlation strongly suggests that variation in cancer risk among tissues is mainly attributable to distinct mutation accumulation rates. Moreover, the correlation establishes a baseline to evaluate the effect of non-mutagenic carcinogens on cancer risk. Finally, our mathematic modeling provides a reasonable explanation to reinforce that cancer risk is predominantly determined by the first rate-limiting mutation. PMID:26785814

  11. Quantification of designer nuclease induced mutation rates: a direct comparison of different methods

    PubMed Central

    Ehrke-Schulz, Eric; Bergmann, Thorsten; Schiwon, Maren; Doerner, Johannes; Saydaminova, Kamola; Lieber, Andre; Ehrhardt, Anja

    2016-01-01

    Designer nucleases are broadly applied to induce site-specific DNA double-strand breaks (DSB) in genomic DNA. These are repaired by nonhomologous end joining leading to insertions or deletions (in/dels) at the respective DNA-locus. To detect in/del mutations, the heteroduplex based T7-endonuclease I -assay is widely used. However, it only provides semi-quantitative evidence regarding the number of mutated alleles. Here we compared T7-endonuclease I- and heteroduplex mobility assays, with a quantitative polymerase chain reaction mutation detection method. A zinc finger nuclease pair specific for the human adeno-associated virus integration site 1 (AAVS1), a transcription activator-like effector nuclease pair specific for the human DMD gene, and a zinc finger nuclease- and a transcription activator-like effector nuclease pair specific for the human CCR5 gene were explored. We found that the heteroduplex mobility assays and T7-endonuclease I - assays detected mutations but the relative number of mutated cells/alleles can only be estimated. In contrast, the quantitative polymerase chain reaction based method provided quantitative results which allow calculating mutation and homologous recombination rates in different eukaryotic cell types including human peripheral blood mononuclear cells. In conclusion, our quantitative polymerase chain reaction based mutation detection method expands the array of methods for in/del mutation detection and facilitates quantification of introduced in/del mutations for a genomic locus containing a mixture of mutated and unmutated DNA. PMID:27419195

  12. Evolution of the Insertion-Deletion Mutation Rate Across the Tree of Life.

    PubMed

    Sung, Way; Ackerman, Matthew S; Dillon, Marcus M; Platt, Thomas G; Fuqua, Clay; Cooper, Vaughn S; Lynch, Michael

    2016-01-01

    Mutations are the ultimate source of variation used for evolutionary adaptation, while also being predominantly deleterious and a source of genetic disorders. Understanding the rate of insertion-deletion mutations (indels) is essential to understanding evolutionary processes, especially in coding regions, where such mutations can disrupt production of essential proteins. Using direct estimates of indel rates from 14 phylogenetically diverse eukaryotic and bacterial species, along with measures of standing variation in such species, we obtain results that imply an inverse relationship of mutation rate and effective population size. These results, which corroborate earlier observations on the base-substitution mutation rate, appear most compatible with the hypothesis that natural selection reduces mutation rates per effective genome to the point at which the power of random genetic drift (approximated by the inverse of effective population size) becomes overwhelming. Given the substantial differences in DNA metabolism pathways that give rise to these two types of mutations, this consistency of results raises the possibility that refinement of other molecular and cellular traits may be inversely related to species-specific levels of random genetic drift. PMID:27317782

  13. Evolution of the Insertion-Deletion Mutation Rate Across the Tree of Life

    PubMed Central

    Sung, Way; Ackerman, Matthew S.; Dillon, Marcus M.; Platt, Thomas G.; Fuqua, Clay; Cooper, Vaughn S.; Lynch, Michael

    2016-01-01

    Mutations are the ultimate source of variation used for evolutionary adaptation, while also being predominantly deleterious and a source of genetic disorders. Understanding the rate of insertion-deletion mutations (indels) is essential to understanding evolutionary processes, especially in coding regions, where such mutations can disrupt production of essential proteins. Using direct estimates of indel rates from 14 phylogenetically diverse eukaryotic and bacterial species, along with measures of standing variation in such species, we obtain results that imply an inverse relationship of mutation rate and effective population size. These results, which corroborate earlier observations on the base-substitution mutation rate, appear most compatible with the hypothesis that natural selection reduces mutation rates per effective genome to the point at which the power of random genetic drift (approximated by the inverse of effective population size) becomes overwhelming. Given the substantial differences in DNA metabolism pathways that give rise to these two types of mutations, this consistency of results raises the possibility that refinement of other molecular and cellular traits may be inversely related to species-specific levels of random genetic drift. PMID:27317782

  14. Fungal Infection Increases the Rate of Somatic Mutation in Scots Pine (Pinus sylvestris L.).

    PubMed

    Ranade, Sonali Sachin; Ganea, Laura-Stefana; Razzak, Abdur M; García Gil, M R

    2015-01-01

    Somatic mutations are transmitted during mitosis in developing somatic tissue. Somatic cells bearing the mutations can develop into reproductive (germ) cells and the somatic mutations are then passed on to the next generation of plants. Somatic mutations are a source of variation essential to evolve new defense strategies and adapt to the environment. Stem rust disease in Scots pine has a negative effect on wood quality, and thus adversely affects the economy. It is caused by the 2 most destructive fungal species in Scandinavia: Peridermium pini and Cronartium flaccidum. We studied nuclear genome stability in Scots pine under biotic stress (fungus-infected, 22 trees) compared to a control population (plantation, 20 trees). Stability was assessed as accumulation of new somatic mutations in 10 microsatellite loci selected for genotyping. Microsatellites are widely used as molecular markers in population genetics studies of plants, and are particularly used for detection of somatic mutations as their rate of mutation is of a much higher magnitude when compared with other DNA markers. We report double the rate of somatic mutation per locus in the fungus-infected trees (4.8×10(-3) mutations per locus), as compared to the controls (2.0×10(-3) mutations per locus) when individual samples were analyzed at 10 different microsatellite markers. Pearson's chi-squared test indicated a significant effect of the fungal infection which increased the number of mutations in the fungus-infected trees (χ(2) = 12.9883, df = 1, P = 0.0003134). PMID:25890976

  15. Mutational Biases Drive Elevated Rates of Substitution at Regulatory Sites across Cancer Types.

    PubMed

    Kaiser, Vera B; Taylor, Martin S; Semple, Colin A

    2016-08-01

    Disruption of gene regulation is known to play major roles in carcinogenesis and tumour progression. Here, we comprehensively characterize the mutational profiles of diverse transcription factor binding sites (TFBSs) across 1,574 completely sequenced cancer genomes encompassing 11 tumour types. We assess the relative rates and impact of the mutational burden at the binding sites of 81 transcription factors (TFs), by comparing the abundance and patterns of single base substitutions within putatively functional binding sites to control sites with matched sequence composition. There is a strong (1.43-fold) and significant excess of mutations at functional binding sites across TFs, and the mutations that accumulate in cancers are typically more disruptive than variants tolerated in extant human populations at the same sites. CTCF binding sites suffer an exceptionally high mutational load in cancer (3.31-fold excess) relative to control sites, and we demonstrate for the first time that this effect is seen in essentially all cancer types with sufficient data. The sub-set of CTCF sites involved in higher order chromatin structures has the highest mutational burden, suggesting a widespread breakdown of chromatin organization. However, we find no evidence for selection driving these distinctive patterns of mutation. The mutational load at CTCF-binding sites is substantially determined by replication timing and the mutational signature of the tumor in question, suggesting that selectively neutral processes underlie the unusual mutation patterns. Pervasive hyper-mutation within transcription factor binding sites rewires the regulatory landscape of the cancer genome, but it is dominated by mutational processes rather than selection. PMID:27490693

  16. Mutational Biases Drive Elevated Rates of Substitution at Regulatory Sites across Cancer Types

    PubMed Central

    Semple, Colin A.

    2016-01-01

    Disruption of gene regulation is known to play major roles in carcinogenesis and tumour progression. Here, we comprehensively characterize the mutational profiles of diverse transcription factor binding sites (TFBSs) across 1,574 completely sequenced cancer genomes encompassing 11 tumour types. We assess the relative rates and impact of the mutational burden at the binding sites of 81 transcription factors (TFs), by comparing the abundance and patterns of single base substitutions within putatively functional binding sites to control sites with matched sequence composition. There is a strong (1.43-fold) and significant excess of mutations at functional binding sites across TFs, and the mutations that accumulate in cancers are typically more disruptive than variants tolerated in extant human populations at the same sites. CTCF binding sites suffer an exceptionally high mutational load in cancer (3.31-fold excess) relative to control sites, and we demonstrate for the first time that this effect is seen in essentially all cancer types with sufficient data. The sub-set of CTCF sites involved in higher order chromatin structures has the highest mutational burden, suggesting a widespread breakdown of chromatin organization. However, we find no evidence for selection driving these distinctive patterns of mutation. The mutational load at CTCF-binding sites is substantially determined by replication timing and the mutational signature of the tumor in question, suggesting that selectively neutral processes underlie the unusual mutation patterns. Pervasive hyper-mutation within transcription factor binding sites rewires the regulatory landscape of the cancer genome, but it is dominated by mutational processes rather than selection. PMID:27490693

  17. Variation in genome-wide mutation rates within and between human families.

    PubMed

    Conrad, Donald F; Keebler, Jonathan E M; DePristo, Mark A; Lindsay, Sarah J; Zhang, Yujun; Casals, Ferran; Idaghdour, Youssef; Hartl, Chris L; Torroja, Carlos; Garimella, Kiran V; Zilversmit, Martine; Cartwright, Reed; Rouleau, Guy A; Daly, Mark; Stone, Eric A; Hurles, Matthew E; Awadalla, Philip

    2011-07-01

    J.B.S. Haldane proposed in 1947 that the male germline may be more mutagenic than the female germline. Diverse studies have supported Haldane's contention of a higher average mutation rate in the male germline in a variety of mammals, including humans. Here we present, to our knowledge, the first direct comparative analysis of male and female germline mutation rates from the complete genome sequences of two parent-offspring trios. Through extensive validation, we identified 49 and 35 germline de novo mutations (DNMs) in two trio offspring, as well as 1,586 non-germline DNMs arising either somatically or in the cell lines from which the DNA was derived. Most strikingly, in one family, we observed that 92% of germline DNMs were from the paternal germline, whereas, in contrast, in the other family, 64% of DNMs were from the maternal germline. These observations suggest considerable variation in mutation rates within and between families. PMID:21666693

  18. Transcription restores DNA repair to heterochromatin, determining regional mutation rates in cancer genomes.

    PubMed

    Zheng, Christina L; Wang, Nicholas J; Chung, Jongsuk; Moslehi, Homayoun; Sanborn, J Zachary; Hur, Joseph S; Collisson, Eric A; Vemula, Swapna S; Naujokas, Agne; Chiotti, Kami E; Cheng, Jeffrey B; Fassihi, Hiva; Blumberg, Andrew J; Bailey, Celeste V; Fudem, Gary M; Mihm, Frederick G; Cunningham, Bari B; Neuhaus, Isaac M; Liao, Wilson; Oh, Dennis H; Cleaver, James E; LeBoit, Philip E; Costello, Joseph F; Lehmann, Alan R; Gray, Joe W; Spellman, Paul T; Arron, Sarah T; Huh, Nam; Purdom, Elizabeth; Cho, Raymond J

    2014-11-20

    Somatic mutations in cancer are more frequent in heterochromatic and late-replicating regions of the genome. We report that regional disparities in mutation density are virtually abolished within transcriptionally silent genomic regions of cutaneous squamous cell carcinomas (cSCCs) arising in an XPC(-/-) background. XPC(-/-) cells lack global genome nucleotide excision repair (GG-NER), thus establishing differential access of DNA repair machinery within chromatin-rich regions of the genome as the primary cause for the regional disparity. Strikingly, we find that increasing levels of transcription reduce mutation prevalence on both strands of gene bodies embedded within H3K9me3-dense regions, and only to those levels observed in H3K9me3-sparse regions, also in an XPC-dependent manner. Therefore, transcription appears to reduce mutation prevalence specifically by relieving the constraints imposed by chromatin structure on DNA repair. We model this relationship among transcription, chromatin state, and DNA repair, revealing a new, personalized determinant of cancer risk. PMID:25456125

  19. Microsatellite evolutionary rate and pattern in Schistocerca gregaria inferred from direct observation of germline mutations.

    PubMed

    Chapuis, M-P; Plantamp, C; Streiff, R; Blondin, L; Piou, C

    2015-12-01

    Unravelling variation among taxonomic orders regarding the rate of evolution in microsatellites is crucial for evolutionary biology and population genetics research. The mean mutation rate of microsatellites tends to be lower in arthropods than in vertebrates, but data are scarce and mostly concern accumulation of mutations in model species. Based on parent-offspring segregations and a hierarchical Bayesian model, the mean rate of mutation in the orthopteran insect Schistocerca gregaria was estimated at 2.1e(-4) per generation per untranscribed dinucleotide locus. This is close to vertebrate estimates and one order of magnitude higher than estimates from species of other arthropod orders, such as Drosophila melanogaster and Daphnia pulex. We also found evidence of a directional bias towards expansions even for long alleles and exceptionally large ranges of allele sizes. Finally, at transcribed microsatellites, the mean rate of mutation was half the rate found at untranscribed loci and the mutational model deviated from that usually considered, with most mutations involving multistep changes that avoid disrupting the reading frame. Our direct estimates of mutation rate were discussed in the light of peculiar biological and genomic features of S. gregaria, including specificities in mismatch repair and the dependence of its activity to allele length. Shedding new light on the mutational dynamics of grasshopper microsatellites is of critical importance for a number of research fields. As an illustration, we showed how our findings improve microsatellite application in population genetics, by obtaining a more precise estimation of S. gregaria effective population size from a published data set based on the same microsatellites. PMID:26562076

  20. Similar relative mutation rates in the three genetic compartments of Mesostigma and Chlamydomonas.

    PubMed

    Hua, Jimeng; Smith, David Roy; Borza, Tudor; Lee, Robert W

    2012-01-01

    Levels of nucleotide substitution at silent sites in organelle versus nuclear DNAs have been used to estimate relative mutation rates among these compartments and explain lineage-specific features of genome evolution. Synonymous substitution divergence values in animals suggest that the rate of mutation in the mitochondrial DNA is 10-50 times higher than that of the nuclear DNA, whereas overall data for most seed plants support relative mutation rates in mitochondrial, plastid, and nuclear DNAs of 1:3:10. Little is known about relative mutation rates in green algae, as substitution rate data is limited to only the mitochondrial and nuclear genomes of the chlorophyte Chlamydomonas. Here, we measure silent-site substitution rates in the plastid DNA of Chlamydomonas and the three genetic compartments of the streptophyte green alga Mesostigma. In contrast to the situation in animals and land plants, our results support similar relative mutation rates among the three genetic compartments of both Chlamydomonas and Mesostigma. These data are discussed in relation to published intra-species genetic diversity data for the three genetic compartments of Chlamydomonas and are ultimately used to address contemporary hypotheses on the organelle genome evolution. To guide future work, we describe evolutionary divergence data of all publically available Mesostigma viride strains and identify, for the first time, three distinct lineages of Mesostigma. PMID:21621456

  1. 5-Azacytidine and RNA secondary structure increase the retrovirus mutation rate.

    PubMed Central

    Pathak, V K; Temin, H M

    1992-01-01

    A broad spectrum of mutations occurs at a high rate during a single round of retrovirus replication (V.K. Pathak and H. M. Temin, Proc. Natl. Acad. Sci. USA 87:6019-6023, 1990). We have now determined that this high rate of spontaneous mutation can be further increased by 5-azacytidine (AZC) treatment or by regions of potential RNA secondary structure. We found a 13-fold increase in the mutation rate after AZC treatment of retrovirus-producing cells and target cells. The AZC-induced substitutions were located at the same target sites as previously identified spontaneous substitutions. The concordance of the AZC-induced and spontaneous substitutions indicates the presence of reverse transcription "pause sites," where the growing point is error prone. An analysis of nucleotides that neighbored substitutions revealed that transversions occur primarily by transient template misalignment, whereas transitions occur primarily by misincorporation. We also introduced a 34-bp potential stem-loop structure as an in-frame insertion within a lacZ alpha gene that was inserted in the long terminal repeat (LTR) U3 region and determined whether this potential secondary structure increased the rate of retrovirus mutations. We found a threefold increase in the retrovirus mutation rate. Fifty-seven of 96 mutations were deletions associated with the potential stem-loop. We also determined that these deletion mutations occurred primarily during minus-strand DNA synthesis by comparing the frequencies of mutations in recovered provirus plasmids containing both LTRs and in provirus plasmids containing only one LTR. PMID:1373201

  2. The repeatability of genome-wide mutation rate and spectrum estimates.

    PubMed

    Behringer, Megan G; Hall, David W

    2016-08-01

    Over the last decade, mutation studies have grown in popularity due to the affordability and accessibility of whole genome sequencing. As the number of species in which spontaneous mutation has been directly estimated approaches 20 across two domains of life, questions arise over the repeatability of results in such experiments. Five species were identified in which duplicate mutation studies have been performed. Across these studies the difference in estimated spontaneous mutation rate is at most, weakly significant (p < 0.01). However, a highly significant (p < 10(-5)), threefold difference in the rate of insertions/deletions (indels) exists between two recent studies in Schizosaccharomyces pombe. Upon investigation of the ancestral genome sequence for both studies, a possible anti-mutator allele was identified. The observed variation in indel rate may imply that the use of indel markers, such as microsatellites, for the investigation of genetic diversity within and among populations may be inappropriate because of the assumption of uniform mutation rate within a species. PMID:26919990

  3. Mutation rate at 17 Y-STR loci in "Father/Son" pairs from moroccan population.

    PubMed

    Laouina, Adil; Nadifi, Sellama; Boulouiz, Redouane; El Arji, Marzouk; Talbi, Jalal; El Houate, Brahim; Yahia, Hakima; Chbel, Faiza

    2013-09-01

    Precise knowledge of mutation rate at Y-STRs loci is essential for a correct evaluation of typing results in forensic casework and specially kinship genetic studies. In this study, we have examined 252 confirmed and unrelated father/son sample pairs from Moroccan population using the 17 Y-STR markers DYS19, DYS389I, DYS389II, DYS390, DYS391, DYS392, DYS393, DYS385a, DYS385b, DYS437, DYS438, DYS439, DYS448, DYS456, DYS458, DYS635, and Y-GATA-H4 of the AmpFlSTR Yfiler™ kit used in routine casework. We observed a total of 15 single repeat mutations between fathers and sons as mutational events. Nine mutations resulted in the gain of a repeat in the son and six resulted in a loss of a repeat. The average mutation rate in the studied sample is 3.5×10(-3) (95% CI 2-5.8×10(-3)). Furthermore, Y-STRs mutation occurrence seems to be 4 times more frequent than autosomal STRs mutation in this sample. PMID:23623014

  4. Somatic deleterious mutation rate in a woody plant: estimation from phenotypic data

    PubMed Central

    Bobiwash, K; Schultz, S T; Schoen, D J

    2013-01-01

    We conducted controlled crosses in populations of the long-lived clonal shrub, Vaccinium angustifolium (lowbush blueberry) to estimate inbreeding depression and mutation parameters associated with somatic deleterious mutation. Inbreeding depression level was high, with many plants failing to set fruit after self-pollination. We also compared fruit set from autogamous pollinations (pollen collected from within the same inflorescence) with fruit set from geitonogamous pollinations (pollen collected from the same plant but from inflorescences separated by several meters of branch growth). The difference between geitonogamous versus autogamous fitness within single plants is referred to as ‘autogamy depression' (AD). AD can be caused by somatic deleterious mutation. AD was significantly different from zero for fruit set. We developed a maximum-likelihood procedure to estimate somatic mutation parameters from AD, and applied it to geitonogamous and autogamous fruit set data from this experiment. We infer that, on average, approximately three sublethal, partially dominant somatic mutations exist within the crowns of the plants studied. We conclude that somatic mutation in this woody plant results in an overall genomic deleterious mutation rate that exceeds the rate measured to date for annual plants. Some implications of this result for evolutionary biology and agriculture are discussed. PMID:23778990

  5. Leveraging Distant Relatedness to Quantify Human Mutation and Gene-Conversion Rates

    PubMed Central

    Palamara, Pier Francesco; Francioli, Laurent C.; Wilton, Peter R.; Genovese, Giulio; Gusev, Alexander; Finucane, Hilary K.; Sankararaman, Sriram; Sunyaev, Shamil R.; de Bakker, Paul I.W.; Wakeley, John; Pe’er, Itsik; Price, Alkes L.

    2015-01-01

    The rate at which human genomes mutate is a central biological parameter that has many implications for our ability to understand demographic and evolutionary phenomena. We present a method for inferring mutation and gene-conversion rates by using the number of sequence differences observed in identical-by-descent (IBD) segments together with a reconstructed model of recent population-size history. This approach is robust to, and can quantify, the presence of substantial genotyping error, as validated in coalescent simulations. We applied the method to 498 trio-phased sequenced Dutch individuals and inferred a point mutation rate of 1.66 × 10−8 per base per generation and a rate of 1.26 × 10−9 for <20 bp indels. By quantifying how estimates varied as a function of allele frequency, we inferred the probability that a site is involved in non-crossover gene conversion as 5.99 × 10−6. We found that recombination does not have observable mutagenic effects after gene conversion is accounted for and that local gene-conversion rates reflect recombination rates. We detected a strong enrichment of recent deleterious variation among mismatching variants found within IBD regions and observed summary statistics of local sharing of IBD segments to closely match previously proposed metrics of background selection; however, we found no significant effects of selection on our mutation-rate estimates. We detected no evidence of strong variation of mutation rates in a number of genomic annotations obtained from several recent studies. Our analysis suggests that a mutation-rate estimate higher than that reported by recent pedigree-based studies should be adopted in the context of DNA-based demographic reconstruction. PMID:26581902

  6. Leveraging Distant Relatedness to Quantify Human Mutation and Gene-Conversion Rates.

    PubMed

    Palamara, Pier Francesco; Francioli, Laurent C; Wilton, Peter R; Genovese, Giulio; Gusev, Alexander; Finucane, Hilary K; Sankararaman, Sriram; Sunyaev, Shamil R; de Bakker, Paul I W; Wakeley, John; Pe'er, Itsik; Price, Alkes L

    2015-12-01

    The rate at which human genomes mutate is a central biological parameter that has many implications for our ability to understand demographic and evolutionary phenomena. We present a method for inferring mutation and gene-conversion rates by using the number of sequence differences observed in identical-by-descent (IBD) segments together with a reconstructed model of recent population-size history. This approach is robust to, and can quantify, the presence of substantial genotyping error, as validated in coalescent simulations. We applied the method to 498 trio-phased sequenced Dutch individuals and inferred a point mutation rate of 1.66 × 10(-8) per base per generation and a rate of 1.26 × 10(-9) for <20 bp indels. By quantifying how estimates varied as a function of allele frequency, we inferred the probability that a site is involved in non-crossover gene conversion as 5.99 × 10(-6). We found that recombination does not have observable mutagenic effects after gene conversion is accounted for and that local gene-conversion rates reflect recombination rates. We detected a strong enrichment of recent deleterious variation among mismatching variants found within IBD regions and observed summary statistics of local sharing of IBD segments to closely match previously proposed metrics of background selection; however, we found no significant effects of selection on our mutation-rate estimates. We detected no evidence of strong variation of mutation rates in a number of genomic annotations obtained from several recent studies. Our analysis suggests that a mutation-rate estimate higher than that reported by recent pedigree-based studies should be adopted in the context of DNA-based demographic reconstruction. PMID:26581902

  7. HIV-1 Mutation and Recombination Rates Are Different in Macrophages and T-cells

    PubMed Central

    Cromer, Deborah; Schlub, Timothy E.; Smyth, Redmond P.; Grimm, Andrew J.; Chopra, Abha; Mallal, Simon; Davenport, Miles P.; Mak, Johnson

    2016-01-01

    High rates of mutation and recombination help human immunodeficiency virus (HIV) to evade the immune system and develop resistance to antiretroviral therapy. Macrophages and T-cells are the natural target cells of HIV-1 infection. A consensus has not been reached as to whether HIV replication results in differential recombination between primary T-cells and macrophages. Here, we used HIV with silent mutation markers along with next generation sequencing to compare the mutation and the recombination rates of HIV directly in T lymphocytes and macrophages. We observed a more than four-fold higher recombination rate of HIV in macrophages compared to T-cells (p < 0.001) and demonstrated that this difference is not due to different reliance on C-X-C chemokine receptor type 4 (CXCR4) and C-C chemokine receptor type 5 (CCR5) co-receptors between T-cells and macrophages. We also found that the pattern of recombination across the HIV genome (hot and cold spots) remains constant between T-cells and macrophages despite a three-fold increase in the overall recombination rate. This indicates that the difference in rates is a general feature of HIV DNA synthesis during macrophage infection. In contrast to HIV recombination, we found that T-cells have a 30% higher mutation rate than macrophages (p < 0.001) and that the mutational profile is similar between these cell types. Unexpectedly, we found no association between mutation and recombination in macrophages, in contrast to T-cells. Our data highlights some of the fundamental difference of HIV recombination and mutation amongst these two major target cells of infection. Understanding these differences will provide invaluable insights toward HIV evolution and how the virus evades immune surveillance and anti-retroviral therapeutics. PMID:27110814

  8. HIV-1 Mutation and Recombination Rates Are Different in Macrophages and T-cells.

    PubMed

    Cromer, Deborah; Schlub, Timothy E; Smyth, Redmond P; Grimm, Andrew J; Chopra, Abha; Mallal, Simon; Davenport, Miles P; Mak, Johnson

    2016-01-01

    High rates of mutation and recombination help human immunodeficiency virus (HIV) to evade the immune system and develop resistance to antiretroviral therapy. Macrophages and T-cells are the natural target cells of HIV-1 infection. A consensus has not been reached as to whether HIV replication results in differential recombination between primary T-cells and macrophages. Here, we used HIV with silent mutation markers along with next generation sequencing to compare the mutation and the recombination rates of HIV directly in T lymphocytes and macrophages. We observed a more than four-fold higher recombination rate of HIV in macrophages compared to T-cells (p < 0.001) and demonstrated that this difference is not due to different reliance on C-X-C chemokine receptor type 4 (CXCR4) and C-C chemokine receptor type 5 (CCR5) co-receptors between T-cells and macrophages. We also found that the pattern of recombination across the HIV genome (hot and cold spots) remains constant between T-cells and macrophages despite a three-fold increase in the overall recombination rate. This indicates that the difference in rates is a general feature of HIV DNA synthesis during macrophage infection. In contrast to HIV recombination, we found that T-cells have a 30% higher mutation rate than macrophages (p < 0.001) and that the mutational profile is similar between these cell types. Unexpectedly, we found no association between mutation and recombination in macrophages, in contrast to T-cells. Our data highlights some of the fundamental difference of HIV recombination and mutation amongst these two major target cells of infection. Understanding these differences will provide invaluable insights toward HIV evolution and how the virus evades immune surveillance and anti-retroviral therapeutics. PMID:27110814

  9. Whole genome sequencing of Mycobacterium tuberculosis reveals slow growth and low mutation rates during latent infections in humans.

    PubMed

    Colangeli, Roberto; Arcus, Vic L; Cursons, Ray T; Ruthe, Ali; Karalus, Noel; Coley, Kathy; Manning, Shannon D; Kim, Soyeon; Marchiano, Emily; Alland, David

    2014-01-01

    Very little is known about the growth and mutation rates of Mycobacterium tuberculosis during latent infection in humans. However, studies in rhesus macaques have suggested that latent infections have mutation rates that are higher than that observed during active tuberculosis disease. Elevated mutation rates are presumed risk factors for the development of drug resistance. Therefore, the investigation of mutation rates during human latency is of high importance. We performed whole genome mutation analysis of M. tuberculosis isolates from a multi-decade tuberculosis outbreak of the New Zealand Rangipo strain. We used epidemiological and phylogenetic analysis to identify four cases of tuberculosis acquired from the same index case. Two of the tuberculosis cases occurred within two years of exposure and were classified as recently transmitted tuberculosis. Two other cases occurred more than 20 years after exposure and were classified as reactivation of latent M. tuberculosis infections. Mutation rates were compared between the two recently transmitted pairs versus the two latent pairs. Mean mutation rates assuming 20 hour generation times were 5.5 X 10(-10) mutations/bp/generation for recently transmitted tuberculosis and 7.3 X 10(-11) mutations/bp/generation for latent tuberculosis. Generation time versus mutation rate curves were also significantly higher for recently transmitted tuberculosis across all replication rates (p = 0.006). Assuming identical replication and mutation rates among all isolates in the final two years before disease reactivation, the u 20 hr mutation rate attributable to the remaining latent period was 1.6 × 10(-11) mutations/bp/generation, or approximately 30 fold less than that calculated during the two years immediately before disease. Mutations attributable to oxidative stress as might be caused by bacterial exposure to the host immune system were not increased in latent infections. In conclusion, we did not find any evidence to suggest

  10. Whole Genome Sequencing of Mycobacterium tuberculosis Reveals Slow Growth and Low Mutation Rates during Latent Infections in Humans

    PubMed Central

    Colangeli, Roberto; Arcus, Vic L.; Cursons, Ray T.; Ruthe, Ali; Karalus, Noel; Coley, Kathy; Manning, Shannon D.; Kim, Soyeon; Marchiano, Emily; Alland, David

    2014-01-01

    Very little is known about the growth and mutation rates of Mycobacterium tuberculosis during latent infection in humans. However, studies in rhesus macaques have suggested that latent infections have mutation rates that are higher than that observed during active tuberculosis disease. Elevated mutation rates are presumed risk factors for the development of drug resistance. Therefore, the investigation of mutation rates during human latency is of high importance. We performed whole genome mutation analysis of M. tuberculosis isolates from a multi-decade tuberculosis outbreak of the New Zealand Rangipo strain. We used epidemiological and phylogenetic analysis to identify four cases of tuberculosis acquired from the same index case. Two of the tuberculosis cases occurred within two years of exposure and were classified as recently transmitted tuberculosis. Two other cases occurred more than 20 years after exposure and were classified as reactivation of latent M. tuberculosis infections. Mutation rates were compared between the two recently transmitted pairs versus the two latent pairs. Mean mutation rates assuming 20 hour generation times were 5.5X10−10 mutations/bp/generation for recently transmitted tuberculosis and 7.3X10−11 mutations/bp/generation for latent tuberculosis. Generation time versus mutation rate curves were also significantly higher for recently transmitted tuberculosis across all replication rates (p = 0.006). Assuming identical replication and mutation rates among all isolates in the final two years before disease reactivation, the u20hr mutation rate attributable to the remaining latent period was 1.6×10−11 mutations/bp/generation, or approximately 30 fold less than that calculated during the two years immediately before disease. Mutations attributable to oxidative stress as might be caused by bacterial exposure to the host immune system were not increased in latent infections. In conclusion, we did not find any evidence to suggest

  11. The evolution of mutation rate in an antagonistic coevolutionary model with maternal transmission of parasites

    PubMed Central

    Greenspoon, Philip B.; M'Gonigle, Leithen K.

    2013-01-01

    By constantly selecting for novel genotypes, coevolution between hosts and parasites can favour elevated mutation rates. Models of this process typically assume random encounters. However, offspring are often more likely to encounter their mother's parasites. Because parents and offspring are genetically similar, they may be susceptible to the same parasite strains and thus, in hosts, maternal transmission should select for mechanisms that decrease intergenerational genetic similarity. In parasites, however, maternal transmission should select for genetic similarity. We develop and analyse a model of host and parasite mutation rate evolution when parasites are maternally inherited. In hosts, we find that maternal transmission has two opposing effects. First, it eliminates coevolutionary cycles that previous work shows select for higher mutation. Second, it independently selects for higher mutation rates, because offspring that differ from their mothers are more likely to avoid infection. In parasites, however, the two effects of maternal transmission act in the same direction. As for hosts, maternal transmission eliminates coevolutionary cycles, thereby reducing selection for increased mutation. Unlike for hosts, however, maternal transmission additionally selects against higher mutation by favouring parasite offspring that are the same as their mothers. PMID:23760645

  12. Calibrating the Human Mutation Rate via Ancestral Recombination Density in Diploid Genomes

    PubMed Central

    Lipson, Mark; Loh, Po-Ru; Sankararaman, Sriram; Patterson, Nick; Berger, Bonnie; Reich, David

    2015-01-01

    The human mutation rate is an essential parameter for studying the evolution of our species, interpreting present-day genetic variation, and understanding the incidence of genetic disease. Nevertheless, our current estimates of the rate are uncertain. Most notably, recent approaches based on counting de novo mutations in family pedigrees have yielded significantly smaller values than classical methods based on sequence divergence. Here, we propose a new method that uses the fine-scale human recombination map to calibrate the rate of accumulation of mutations. By comparing local heterozygosity levels in diploid genomes to the genetic distance scale over which these levels change, we are able to estimate a long-term mutation rate averaged over hundreds or thousands of generations. We infer a rate of 1.61 ± 0.13 × 10−8 mutations per base per generation, which falls in between phylogenetic and pedigree-based estimates, and we suggest possible mechanisms to reconcile our estimate with previous studies. Our results support intermediate-age divergences among human populations and between humans and other great apes. PMID:26562831

  13. Numerical solution of the Penna model of biological aging with age-modified mutation rate.

    PubMed

    Magdoń-Maksymowicz, M S; Maksymowicz, A Z

    2009-06-01

    In this paper we present results of numerical calculation of the Penna bit-string model of biological aging, modified for the case of a -dependent mutation rate m(a), where a is the parent's age. The mutation rate m(a) is the probability per bit of an extra bad mutation introduced in offspring inherited genome. We assume that m(a) increases with age a. As compared with the reference case of the standard Penna model based on a constant mutation rate m , the dynamics of the population growth shows distinct changes in age distribution of the population. Here we concentrate on mortality q(a), a fraction of items eliminated from the population when we go from age (a) to (a+1) in simulated transition from time (t) to next time (t+1). The experimentally observed q(a) dependence essentially follows the Gompertz exponential law for a above the minimum reproduction age. Deviation from the Gompertz law is however observed for the very old items, close to the maximal age. This effect may also result from an increase in mutation rate m with age a discussed in this paper. The numerical calculations are based on analytical solution of the Penna model, presented in a series of papers by Coe et al. [J. B. Coe, Y. Mao, and M. E. Cates, Phys. Rev. Lett. 89, 288103 (2002)]. Results of the numerical calculations are supported by the data obtained from computer simulation based on the solution by Coe et al. PMID:19658536

  14. High mutational rates of large-scale duplication and deletion in Daphnia pulex.

    PubMed

    Keith, Nathan; Tucker, Abraham E; Jackson, Craig E; Sung, Way; Lucas Lledó, José Ignacio; Schrider, Daniel R; Schaack, Sarah; Dudycha, Jeffry L; Ackerman, Matthew; Younge, Andrew J; Shaw, Joseph R; Lynch, Michael

    2016-01-01

    Knowledge of the genome-wide rate and spectrum of mutations is necessary to understand the origin of disease and the genetic variation driving all evolutionary processes. Here, we provide a genome-wide analysis of the rate and spectrum of mutations obtained in two Daphnia pulex genotypes via separate mutation-accumulation (MA) experiments. Unlike most MA studies that utilize haploid, homozygous, or self-fertilizing lines, D. pulex can be propagated ameiotically while maintaining a naturally heterozygous, diploid genome, allowing the capture of the full spectrum of genomic changes that arise in a heterozygous state. While base-substitution mutation rates are similar to those in other multicellular eukaryotes (about 4 × 10(-9) per site per generation), we find that the rates of large-scale (>100 kb) de novo copy-number variants (CNVs) are significantly elevated relative to those seen in previous MA studies. The heterozygosity maintained in this experiment allowed for estimates of gene-conversion processes. While most of the conversion tract lengths we report are similar to those generated by meiotic processes, we also find larger tract lengths that are indicative of mitotic processes. Comparison of MA lines to natural isolates reveals that a majority of large-scale CNVs in natural populations are removed by purifying selection. The mutations observed here share similarities with disease-causing, complex, large-scale CNVs, thereby demonstrating that MA studies in D. pulex serve as a system for studying the processes leading to such alterations. PMID:26518480

  15. Frequency of private electrophoretic variants and indirect estimates of mutation rate in Papua New Guinea.

    PubMed Central

    Bhatia, K K; Blake, N M; Serjeantson, S W; Kirk, R L

    1981-01-01

    Data on rare and private electrophoretic variants have been used to estimate mutation rates for populations belonging to 55 language groups in Papua New Guinea. Three different methods yield values of 1.42 x 10(-6), 1.40 x 10(-6), and 5.58 x 10(-6)/locus per generation. The estimates for three islands populations off the north coast of New Guinea--Manus, Karkar, and Siassi--are much lower. The variability in mutation rates estimated from rare electrophoretic variants as a function of population size is discussed. The mean mutation rate in Papua New Guinea is less than half the estimates obtained for Australian Aborigines and Amerindians. PMID:7468589

  16. No evidence of increased mutation rates at microsatellite loci in offspring of A-bomb survivors.

    PubMed

    Kodaira, M; Ryo, H; Kamada, N; Furukawa, K; Takahashi, N; Nakajima, H; Nomura, T; Nakamura, N

    2010-02-01

    To evaluate the genetic effects of A-bomb radiation, we examined mutations at 40 microsatellite loci in exposed families (father-mother-offspring, mostly uni-parental exposures), which consisted of 66 offspring having a mean paternal dose of 1.87 Gy and a mean maternal dose of 1.27 Gy. The control families consisted of 63 offspring whose parents either were exposed to low doses of radiation (< 0.01 Gy) or were not in the cities of Hiroshima or Nagasaki at the time of the bombs. We found seven mutations in the exposed alleles (7/2,789; mutation rate 0.25 x 10(-2)/locus/generation) and 26 in the unexposed alleles (26/7,465; 0.35 x 10(-2)/locus/generation), which does not indicate an effect from parental exposure to radiation. Although we could not assign the parental origins of four mutations, the conclusion may hold since even if we assume that these four mutations had occurred in the exposed alleles, the estimated mean mutation rate would be 0.39 x 10(-2) in the exposed group [(7 + 4)/2,789)], which is slightly higher than 0.35 x 10(-2) in the control group, but the difference is not statistically significant. PMID:20095853

  17. Mutations in Haemophilus influenzae mismatch repair genes increase mutation rates of dinucleotide repeat tracts but not dinucleotide repeat-driven pilin phase variation rates.

    PubMed

    Bayliss, Christopher D; Sweetman, Wendy A; Moxon, E Richard

    2004-05-01

    High-frequency, reversible switches in expression of surface antigens, referred to as phase variation (PV), are characteristic of Haemophilus influenzae. PV enables this bacterial species, an obligate commensal and pathogen of the human upper respiratory tract, to adapt to changes in the host environment. Phase-variable hemagglutinating pili are expressed by many H. influenzae isolates. PV involves alterations in the number of 5' TA repeats located between the -10 and -35 promoter elements of the overlapping, divergently orientated promoters of hifA and hifBCDE, whose products mediate biosynthesis and assembly of pili. Dinucleotide repeat tracts are destabilized by mismatch repair (MMR) mutations in Escherichia coli. The influence of mutations in MMR genes of H. influenzae strain Rd on dinucleotide repeat-mediated PV rates was investigated by using reporter constructs containing 20 5' AT repeats. Mutations in mutS, mutL, and mutH elevated rates approximately 30-fold, while rates in dam and uvrD mutants were increased 14- and 3-fold, respectively. PV rates of constructs containing 10 to 12 5' AT repeats were significantly elevated in mutS mutants of H. influenzae strains Rd and Eagan. An intact hif locus was found in 14 and 12% of representative nontypeable H. influenzae isolates associated with either otitis media or carriage, respectively. Nine or more tandem 5' TA repeats were present in the promoter region. Surprisingly, inactivation of mutS in two serotype b H. influenzae strains did not alter pilin PV rates. Thus, although functionally analogous to the E. coli MMR pathway and active on dinucleotide repeat tracts, defects in H. influenzae MMR do not affect 5' TA-mediated pilin PV. PMID:15126452

  18. DNA fingerprinting reveals elevated mutation rates in herring gulls inhabiting a genotoxically contaminated site

    SciTech Connect

    Yauk, C.L.; Quinn, J.S.

    1995-12-31

    The authors used multi-locus DNA fingerprinting to examine families of herring gulls (Larus argentatus) from a genotoxically contaminated site (Hamilton Harbour) and from a pristine location (Kent Island, Bay of Fundy) to show significant differences in mutation rates between the locations. Overall the authors identified 17 mutant bands from 15 individuals of the 35 examined from Hamilton Harbour, and 7 mutant fragments from 7 individuals, of the 43 examined from Kent Island; a mutation frequency of 0.429 per nestling for Hamilton Harbour and 0.163 for Kent Island. The total number of individuals with mutant bands was significantly higher at Hamilton Harbour than at Kent Island (X{sup 2}=6.734; df = 1; P < 0.01). Ongoing analysis of other less contaminated sites also reveals lower mutation rates than those seen in Hamilton Harbour. With multi-locus DNA fingerprinting many regions of the genome can be surveyed simultaneously. The tandemly repeated arrays of nucleotides examined with DNA fingerprinting are known to have elevated rates of mutation. Furthermore, the mutations seen with DNA fingerprinting are predominantly heritable. Other biomarkers currently used in situ are not able to monitor direct and heritable DNA mutation, or measure biological endpoints that frequently result in spontaneous abortion creating difficulty in observing significantly elevated levels in viable offspring. The authors suggest that multilocus DNA fingerprinting can be used as a biomarker to identify potentially heritable risks before the onset of other types of ecological damage. This approach provides a direct measure of mutation in situ and in vivo in a vertebrate species under ambient conditions.

  19. Estimation of Mutation Rates Based on the Analysis of Polypeptide Constituents of Cultured Human Lymphoblastoid Cells

    PubMed Central

    Chu, EHY.; Boehnke, M.; Hanash, S. M.; Kuick, R. D.; Lamb, B. J.; Neel, J. V.; Niezgoda, W.; Pivirotto, S.; Sundling, G.

    1988-01-01

    A subclone of a human diploid lymphoblastoid cell line, TK-6, with consistently high cloning efficiency has been used to estimate the rates of somatic mutations on the basis of protein variation detected by two-dimensional polyacrylamide gel electrophoresis. A panel of 267 polypeptide spots per gel was screened, representing the products of approximately 263 unselected loci. The rate of human somatic mutation in vitro was estimated by measuring the proportion of protein variants among cell clones isolated at various times during continuous exponential growth of a TK-6 cell population. Three mutants of spontaneous origin were observed, giving an estimated spontaneous rate of 6 X 10(-8) electrophoretic mutations per allele per cell generation (i.e., 1.2 X 10(-7) per locus per cell generation). Following treatment of cells with N-ethyl-N-nitrosourea, a total of 74 confirmed variants at 54 loci were identified among 1143 clones analyzed (approximately 601,000 allele tests). The induced variants include 65 electromorphs which exhibit altered isoelectric charge and/or apparent molecular weight and nine nullimorphs for each of which a gene product was not detected at its usual location on the gel. The induced frequency for these 65 structural gene mutants is 1.1 X 10(-4) per allele. An excess of structural gene mutations at ten known polymorphic loci and repeat mutations at these and other loci suggest nonrandomness of mutation in human somatic cells. Nullimorphs occurring at three heterozygous loci in TK-6 cells may be caused by genetic processes other than structural gene mutation. PMID:3402732

  20. Strategy abundance in 2 × 2 games for arbitrary mutation rates

    PubMed Central

    Antal, Tibor; Nowak, Martin A.; Traulsen, Arne

    2009-01-01

    We study evolutionary game dynamics in a well-mixed populations of finite size, N. A well-mixed population means that any two individuals are equally likely to interact. In particular we consider the average abundances of two strategies, A and B, under mutation and selection. The game dynamical interaction between the two strategies is given by the 2 × 2 payoff matrix (abcd). It has previously been shown that A is more abundant than B, if a(N − 2) + bN > cN + d(N − 2). This result has been derived for particular stochastic processes that operate either in the limit of asymptotically small mutation rates or in the limit of weak selection. Here we show that this result holds in fact for a wide class of stochastic birth-death processes for arbitrary mutation rate and for any intensity of selection. PMID:19111558

  1. Bottleneck Effect on Evolutionary Rate in the Nearly Neutral Mutation Model

    PubMed Central

    Araki, H.; Tachida, H.

    1997-01-01

    Variances of evolutionary rates among lineages in some proteins are larger than those expected from simple Poisson processes. This phenomenon is called overdispersion of the molecular clock. If population size N is constant, the overdispersion is observed only in a limited range of 2Nσ under the nearly neutral mutation model, where σ represents the standard deviation of selection coefficients of new mutants. In this paper, we investigated effects of changing population size on the evolutionary rate by computer simulations assuming the nearly neutral mutation model. The size was changed cyclically between two numbers, N(1) and N(2) (N(1) > N(2)), in the simulations. The overdispersion is observed if 2N(2)σ is less than two and the state of reduced size (bottleneck state) continues for more than ~0.1/u generations, where u is the mutation rate. The overdispersion results mainly because the average fitnesses of only a portion of populations go down when the population size is reduced and only in these populations subsequent advantageous substitutions occur after the population size becomes large. Since the fitness reduction after the bottleneck is stochastic, acceleration of the evolutionary rate does not necessarily occur uniformly among loci. From these results, we argue that the nearly neutral mutation model is a candidate mechanism to explain the overdispersed molecular clock. PMID:9335622

  2. Cellular Defense Enzyme Drives Exceptionally High Rate of Mutation in HIV.

    PubMed

    Robinson, Richard

    2015-09-01

    HIV-1 is already known to have an extremely fast mutation rate, but a new study shows it to be more than two orders of magnitude higher than previously believed, and that this is largely due to host cytidine deaminases. Read the Research Article. PMID:26375682

  3. Factors Influencing Ascertainment Bias of Microsatellite Allele Sizes: Impact on Estimates of Mutation Rates

    PubMed Central

    Li, Biao; Kimmel, Marek

    2013-01-01

    Microsatellite loci play an important role as markers for identification, disease gene mapping, and evolutionary studies. Mutation rate, which is of fundamental importance, can be obtained from interspecies comparisons, which, however, are subject to ascertainment bias. This bias arises, for example, when a locus is selected on the basis of its large allele size in one species (cognate species 1), in which it is first discovered. This bias is reflected in average allele length in any noncognate species 2 being smaller than that in species 1. This phenomenon was observed in various pairs of species, including comparisons of allele sizes in human and chimpanzee. Various mechanisms were proposed to explain observed differences in mean allele lengths between two species. Here, we examine the framework of a single-step asymmetric and unrestricted stepwise mutation model with genetic drift. Analysis is based on coalescent theory. Analytical results are confirmed by simulations using the simuPOP software. The mechanism of ascertainment bias in this model is a tighter correlation of allele sizes within a cognate species 1 than of allele sizes in two different species 1 and 2. We present computations of the expected average allele size difference, given the mutation rate, population sizes of species 1 and 2, time of separation of species 1 and 2, and the age of the allele. We show that when the past demographic histories of the cognate and noncognate taxa are different, the rate and directionality of mutations affect the allele sizes in the two taxa differently from the simple effect of ascertainment bias. This effect may exaggerate or reverse the effect of difference in mutation rates. We reanalyze literature data, which indicate that despite the bias, the microsatellite mutation rate estimate in the ancestral population is consistently greater than that in either human or chimpanzee and the mutation rate estimate in human exceeds or equals that in chimpanzee with the rate

  4. Characterization of spectrum, de novo rate and genotype-phenotype correlation of dominant GJB2 mutations in Chinese hans.

    PubMed

    Pang, Xiuhong; Chai, Yongchuan; Sun, Lianhua; Chen, Dongye; Chen, Ying; Zhang, Zhihua; Wu, Hao; Yang, Tao

    2014-01-01

    Dominant mutations in GJB2 may lead to various degrees of sensorineural hearing impairment and/or hyperproliferative epidermal disorders. So far studies of dominant GJB2 mutations were mostly limited to case reports of individual patients and families. In this study, we identified 7 families, 11 subjects with dominant GJB2 mutations by sequencing of GJB2 in 2168 Chinese Han probands with sensorineural hearing impairment and characterized the associated spectrum, de novo rate and genotype-phenotype correlation. We identified p.R75Q, p.R75W and p.R184Q as the most frequent dominant GJB2 mutations among Chinese Hans, which had a very high de novo rate (71% of probands). A majority (10/11) of subjects carrying dominant GJB2 mutations exhibited palmoplantar keratoderma in addition to hearing impairment. In two families segregated with additional c.235delC or p.V37I mutations of GJB2, family members with the compound heterozygous mutations exhibited more severe phenotype than those with single dominant GJB2 mutation. Our study suggested that the high de novo mutation rate gives rise to a significant portion of dominant GJB2 mutations. The severity of the hearing and epidermal phenotypes associated with dominant GJB2 mutations may be modified by additional recessive mutations of GJB2. PMID:24945352

  5. Mutation rates and evolution of multiple coding in RNA-based protocells.

    PubMed

    de Boer, Folkert K; Hogeweg, Paulien

    2014-12-01

    RNA has a myriad of biological roles in contemporary life. We use the RNA paradigm for genotype-phenotype mappings to study the evolution of multiple coding in dependence to mutation rates. We study three different one-to-many genotype-phenotype mappings which have the potential to encode the information for multiple functions on a single sequence. These three different maps are (i) cofolding, where two sequences can bind and "cofold," (ii) suboptimal folding, where the alternative foldings within a certain range of the native state of sequences are considered, and (iii) adapter-based folding, in which protocells can evolve adapter-mediated alternative foldings. We study how protocells with a set of sequences can code for a set of predefined functional structures, while avoiding all other structures, which are considered to be misfoldings. Note that such misfolded structures are far more prevalent than functional ones. Our results highlight the flexibility of the RNA sequence to secondary structure mapping and the power of evolution to shape the genotype-phenotype mapping. We show that high fitness can be achieved even at high mutation rates. Mutation rates affect genome size, but differently depending on which folding method is used. We observe that cofolding limits the possibility to avoid misfolded structures and that adapters are always beneficial for fitness, but even more beneficial at low mutation rates. In all cases, the evolution procedure selects for molecules that can form additional structures. Our results indicate that inherent properties of RNA molecules and their interactions allow the evolution of complexity even at high mutation rates. PMID:25280530

  6. Prediction of change in protein unfolding rates upon point mutations in two state proteins.

    PubMed

    Chaudhary, Priyashree; Naganathan, Athi N; Gromiha, M Michael

    2016-09-01

    Studies on protein unfolding rates are limited and challenging due to the complexity of unfolding mechanism and the larger dynamic range of the experimental data. Though attempts have been made to predict unfolding rates using protein sequence-structure information there is no available method for predicting the unfolding rates of proteins upon specific point mutations. In this work, we have systematically analyzed a set of 790 single mutants and developed a robust method for predicting protein unfolding rates upon mutations (Δlnku) in two-state proteins by combining amino acid properties and knowledge-based classification of mutants with multiple linear regression technique. We obtain a mean absolute error (MAE) of 0.79/s and a Pearson correlation coefficient (PCC) of 0.71 between predicted unfolding rates and experimental observations using jack-knife test. We have developed a web server for predicting protein unfolding rates upon mutation and it is freely available at https://www.iitm.ac.in/bioinfo/proteinunfolding/unfoldingrace.html. Prominent features that determine unfolding kinetics as well as plausible reasons for the observed outliers are also discussed. PMID:27264959

  7. A Bayesian Approach to Inferring Rates of Selfing and Locus-Specific Mutation.

    PubMed

    Redelings, Benjamin D; Kumagai, Seiji; Tatarenkov, Andrey; Wang, Liuyang; Sakai, Ann K; Weller, Stephen G; Culley, Theresa M; Avise, John C; Uyenoyama, Marcy K

    2015-11-01

    We present a Bayesian method for characterizing the mating system of populations reproducing through a mixture of self-fertilization and random outcrossing. Our method uses patterns of genetic variation across the genome as a basis for inference about reproduction under pure hermaphroditism, gynodioecy, and a model developed to describe the self-fertilizing killifish Kryptolebias marmoratus. We extend the standard coalescence model to accommodate these mating systems, accounting explicitly for multilocus identity disequilibrium, inbreeding depression, and variation in fertility among mating types. We incorporate the Ewens sampling formula (ESF) under the infinite-alleles model of mutation to obtain a novel expression for the likelihood of mating system parameters. Our Markov chain Monte Carlo (MCMC) algorithm assigns locus-specific mutation rates, drawn from a common mutation rate distribution that is itself estimated from the data using a Dirichlet process prior model. Our sampler is designed to accommodate additional information, including observations pertaining to the sex ratio, the intensity of inbreeding depression, and other aspects of reproduction. It can provide joint posterior distributions for the population-wide proportion of uniparental individuals, locus-specific mutation rates, and the number of generations since the most recent outcrossing event for each sampled individual. Further, estimation of all basic parameters of a given model permits estimation of functions of those parameters, including the proportion of the gene pool contributed by each sex and relative effective numbers. PMID:26374460

  8. DNA transposon activity is associated with increased mutation rates in genes of rice and other grasses.

    PubMed

    Wicker, Thomas; Yu, Yeisoo; Haberer, Georg; Mayer, Klaus F X; Marri, Pradeep Reddy; Rounsley, Steve; Chen, Mingsheng; Zuccolo, Andrea; Panaud, Olivier; Wing, Rod A; Roffler, Stefan

    2016-01-01

    DNA (class 2) transposons are mobile genetic elements which move within their 'host' genome through excising and re-inserting elsewhere. Although the rice genome contains tens of thousands of such elements, their actual role in evolution is still unclear. Analysing over 650 transposon polymorphisms in the rice species Oryza sativa and Oryza glaberrima, we find that DNA repair following transposon excisions is associated with an increased number of mutations in the sequences neighbouring the transposon. Indeed, the 3,000 bp flanking the excised transposons can contain over 10 times more mutations than the genome-wide average. Since DNA transposons preferably insert near genes, this is correlated with increases in mutation rates in coding sequences and regulatory regions. Most importantly, we find this phenomenon also in maize, wheat and barley. Thus, these findings suggest that DNA transposon activity is a major evolutionary force in grasses which provide the basis of most food consumed by humankind. PMID:27599761

  9. Experimental Estimation of Mutation Rates in a Wheat Population With a Gene Genealogy Approach

    PubMed Central

    Raquin, Anne-Laure; Depaulis, Frantz; Lambert, Amaury; Galic, Nathalie; Brabant, Philippe; Goldringer, Isabelle

    2008-01-01

    Microsatellite markers are extensively used to evaluate genetic diversity in natural or experimental evolving populations. Their high degree of polymorphism reflects their high mutation rates. Estimates of the mutation rates are therefore necessary when characterizing diversity in populations. As a complement to the classical experimental designs, we propose to use experimental populations, where the initial state is entirely known and some intermediate states have been thoroughly surveyed, thus providing a short timescale estimation together with a large number of cumulated meioses. In this article, we derived four original gene genealogy-based methods to assess mutation rates with limited bias due to relevant model assumptions incorporating the initial state, the number of new alleles, and the genetic effective population size. We studied the evolution of genetic diversity at 21 microsatellite markers, after 15 generations in an experimental wheat population. Compared to the parents, 23 new alleles were found in generation 15 at 9 of the 21 loci studied. We provide evidence that they arose by mutation. Corresponding estimates of the mutation rates ranged from 0 to 4.97 × 10−3 per generation (i.e., year). Sequences of several alleles revealed that length polymorphism was only due to variation in the core of the microsatellite. Among different microsatellite characteristics, both the motif repeat number and an independent estimation of the Nei diversity were correlated with the novel diversity. Despite a reduced genetic effective size, global diversity at microsatellite markers increased in this population, suggesting that microsatellite diversity should be used with caution as an indicator in biodiversity conservation issues. PMID:18689900

  10. Calculation of Heavy Ion Inactivation and Mutation Rates in Radial Dose Model of Track Structure

    NASA Technical Reports Server (NTRS)

    Cucinotta, Francis A.; Wilson, John W.; Shavers, Mark R.; Katz, Robert

    1997-01-01

    In the track structure model, the inactivation cross section is found by summing an inactivation probability over all impact parameters from the ion to the sensitive sites within the cell nucleus. The inactivation probability is evaluated by using the dose response of the system to gamma rays and the radial dose of the ions and may be equal to unity at small impact parameters. We apply the track structure model to recent data with heavy ion beams irradiating biological samples of E. Coli, B. Subtilis spores, and Chinese hamster (V79) cells. Heavy ions have observed cross sections for inactivation that approach and sometimes exceed the geometric size of the cell nucleus. We show how the effects of inactivation may be taken into account in the evaluation of the mutation cross sections in the track structure model through correlation of sites for gene mutation and cell inactivation. The model is fit to available data for HPRT (hypoxanthine guanine phosphoribosyl transferase) mutations in V79 cells, and good agreement is found. Calculations show the high probability for mutation by relativistic ions due to the radial extension of ions track from delta rays. The effects of inactivation on mutation rates make it very unlikely that a single parameter such as LET (linear energy transfer) can be used to specify radiation quality for heavy ion bombardment.

  11. Comparing mutation rates under the Luria-Delbrück protocol.

    PubMed

    Zheng, Qi

    2016-06-01

    Comparison of microbial mutation rates under the Luria-Delbrück protocol is a routine laboratory task. However, execution of this important task has been hampered by the lack of proper statistical methods. Visual inspection or improper use of the t test and the Mann-Whitney test can impair the quality of genetic research. This paper proposes a unified framework for constructing likelihood ratio tests that overcome three important obstacles to the proper comparison of microbial mutation rates. Specifically, algorithms for likelihood ratio tests have been devised that allow for partial plating, differential growth rates and unequal terminal cell population sizes. The new algorithms were assessed by computer simulations. In addition, a strategy for multiple comparison was illustrated by reanalyzing the experimental data from a study of bacterial resistance against tuberculosis antibiotics. PMID:27188462

  12. Mutation Rate and Dominance of Genes Affecting Viability in DROSOPHILA MELANOGASTER

    PubMed Central

    Mukai, Terumi; Chigusa, Sadao I.; Mettler, L. E.; Crow, James F.

    1972-01-01

    Spontaneous mutations were allowed to accumulate in a second chromosome that was transmitted only through heterozygous males for 40 generations. At 10-generation intervals the chromosomes were assayed for homozygous effects of the accumulated mutants. From the regression of homozygous viability on the number of generations of mutant accumulation and from the increase in genetic variance between replicate chromosomes it is possible to estimate the mutation rate and average effect of the individual mutants. Lethal mutations arose at a rate of 0.0060 per chromosome per generation. The mutants having small effects on viability are estimated to arise with a frequency at least 10 times as high as lethals, more likely 20 times as high, and possibly many more times as high if there is a large class of very nearly neutral mutations.—The dominance of such mutants was measured for chromosomes extracted from a natural population. This was determined from the regression of heterozygous viability on that of the sum of the two constituent homozygotes. The average dominance for minor viability genes in an equilibrium population was estimated to be 0.21. This is lower than the value for new mutants, as expected since those with the greatest heterozygous effect are most quickly eliminated from the population. That these mutants have a disproportionately large heterozygous effect on total fitness (as well as on the viability component thereof) is shown by the low ratio of the genetic load in equilibrium homozygotes to that of new mutant homozygotes. PMID:4630587

  13. Resolving rates of mutation in the brain using single-neuron genomics

    PubMed Central

    Evrony, Gilad D; Lee, Eunjung; Park, Peter J; Walsh, Christopher A

    2016-01-01

    Whether somatic mutations contribute functional diversity to brain cells is a long-standing question. Single-neuron genomics enables direct measurement of somatic mutation rates in human brain and promises to answer this question. A recent study (Upton et al., 2015) reported high rates of somatic LINE-1 element (L1) retrotransposition in the hippocampus and cerebral cortex that would have major implications for normal brain function, and suggested that these events preferentially impact genes important for neuronal function. We identify aspects of the single-cell sequencing approach, bioinformatic analysis, and validation methods that led to thousands of artifacts being interpreted as somatic mutation events. Our reanalysis supports a mutation frequency of approximately 0.2 events per cell, which is about fifty-fold lower than reported, confirming that L1 elements mobilize in some human neurons but indicating that L1 mosaicism is not ubiquitous. Through consideration of the challenges identified, we provide a foundation and framework for designing single-cell genomics studies. DOI: http://dx.doi.org/10.7554/eLife.12966.001 PMID:26901440

  14. Patterns and rates of exonic de novo mutations in autism spectrum disorders

    PubMed Central

    Neale, Benjamin M.; Kou, Yan; Liu, Li; Ma'ayan, Avi; Samocha, Kaitlin E.; Sabo, Aniko; Lin, Chiao-Feng; Stevens, Christine; Wang, Li-San; Makarov, Vladimir; Polak, Paz; Yoon, Seungtai; Maguire, Jared; Crawford, Emily L.; Campbell, Nicholas G.; Geller, Evan T.; Valladares, Otto; Shafer, Chad; Liu, Han; Zhao, Tuo; Cai, Guiqing; Lihm, Jayon; Dannenfelser, Ruth; Jabado, Omar; Peralta, Zuleyma; Nagaswamy, Uma; Muzny, Donna; Reid, Jeffrey G.; Newsham, Irene; Wu, Yuanqing; Lewis, Lora; Han, Yi; Voight, Benjamin F.; Lim, Elaine; Rossin, Elizabeth; Kirby, Andrew; Flannick, Jason; Fromer, Menachem; Shakir, Khalid; Fennell, Tim; Garimella, Kiran; Banks, Eric; Poplin, Ryan; Gabriel, Stacey; DePristo, Mark; Wimbish, Jack R.; Boone, Braden E.; Levy, Shawn E.; Betancur, Catalina; Sunyaev, Shamil; Boerwinkle, Eric; Buxbaum, Joseph D.; Cook, Edwin H.; Devlin, Bernie; Gibbs, Richard A.; Roeder, Kathryn; Schellenberg, Gerard D.; Sutcliffe, James S.; Daly, Mark J.

    2013-01-01

    Autism spectrum disorders (ASD) are believed to have genetic and environmental origins, yet in only a modest fraction of individuals can specific causes be identified1,2. To identify further genetic risk factors, we assess the role of de novo mutations in ASD by sequencing the exomes of ASD cases and their parents (n= 175 trios). Fewer than half of the cases (46.3%) carry a missense or nonsense de novo variant and the overall rate of mutation is only modestly higher than the expected rate. In contrast, there is significantly enriched connectivity among the proteins encoded by genes harboring de novo missense or nonsense mutations, and excess connectivity to prior ASD genes of major effect, suggesting a subset of observed events are relevant to ASD risk. The small increase in rate of de novo events, when taken together with the connections among the proteins themselves and to ASD, are consistent with an important but limited role for de novo point mutations, similar to that documented for de novo copy number variants. Genetic models incorporating these data suggest that the majority of observed de novo events are unconnected to ASD, those that do confer risk are distributed across many genes and are incompletely penetrant (i.e., not necessarily causal). Our results support polygenic models in which spontaneous coding mutations in any of a large number of genes increases risk by 5 to 20-fold. Despite the challenge posed by such models, results from de novo events and a large parallel case-control study provide strong evidence in favor of CHD8 and KATNAL2 as genuine autism risk factors. PMID:22495311

  15. The Rate and Molecular Spectrum of Spontaneous Mutations in the GC-Rich Multichromosome Genome of Burkholderia cenocepacia

    PubMed Central

    Dillon, Marcus M.; Sung, Way; Lynch, Michael; Cooper, Vaughn S.

    2015-01-01

    Spontaneous mutations are ultimately essential for evolutionary change and are also the root cause of many diseases. However, until recently, both biological and technical barriers have prevented detailed analyses of mutation profiles, constraining our understanding of the mutation process to a few model organisms and leaving major gaps in our understanding of the role of genome content and structure on mutation. Here, we present a genome-wide view of the molecular mutation spectrum in Burkholderia cenocepacia, a clinically relevant pathogen with high %GC content and multiple chromosomes. We find that B. cenocepacia has low genome-wide mutation rates with insertion–deletion mutations biased toward deletions, consistent with the idea that deletion pressure reduces prokaryotic genome sizes. Unlike prior studies of other organisms, mutations in B. cenocepacia are not AT biased, which suggests that at least some genomes with high %GC content experience unusual base-substitution mutation pressure. Importantly, we also observe variation in both the rates and spectra of mutations among chromosomes and elevated G:C > T:A transversions in late-replicating regions. Thus, although some patterns of mutation appear to be highly conserved across cellular life, others vary between species and even between chromosomes of the same species, potentially influencing the evolution of nucleotide composition and genome architecture. PMID:25971664

  16. Mutations in ARS1 increase the rate of simple loss of plasmids in Saccharomyces cerevisiae.

    PubMed

    Strich, R; Woontner, M; Scott, J F

    1986-09-01

    Autonomously replicating sequence (ARS) elements are DNA sequences that promote extrachromosomal maintenance of plasmids in yeast. Mutations generated in vitro in the ARS1 region were examined for their effect on plasmid maintenance in a yeast centromeric plasmid. Our data show that mutations in the regions surrounding the ARS1 consensus sequence cause increases in the frequency of simple loss (1:0) events without affecting the rate of nondisjunction (2:0). Removal of the consensus sequence itself causes a drastic increase in the rate of simple loss. Sequences sensitive to mutagenesis were identified in each flanking region and differ with respect to their location and importance to ARS function. These results suggest that the role ARS1 plays in plasmid maintenance deals with the replication and/or localization of the plasmid in yeast. PMID:3333306

  17. Mutation rate estimates for 13 STR loci in a large population from Rio Grande do Sul, Southern Brazil.

    PubMed

    Mardini, Ana Carolina; Rodenbusch, Rodrigo; Schumacher, Simone; Chula, Fernanda Goulart Lanes; Michelon, Candice Tosi; Gastaldo, André Zoratto; Maciel, Lila Partichelli; de Matos Almeida, Sabrina Esteves; da Silva, Cláudia Maria Dornelles

    2013-01-01

    Short tandem repeat (STR) polymorphisms have been extensively used in forensic genetics analysis. Knowledge about the locus-specific mutation rates of STRs improves forensic probability calculations and interpretations of diversity data. To incorporate single-locus diversity information into autosomal STR mutation rate estimations, 13 STR loci were studied during 2007-2009 in 10,959 paternity investigation cases from Rio Grande do Sul, the southernmost state of Brazil, covering an overall number of 284,934 allelic transfers. A total of 355 mutations were identified; 348 repeats were gains or losses of one step, three were gains or losses of two steps, and four were gains or losses of not stepwise mutation. The mutation rates ranged from 4.6 × 10(-5) to 2.3 × 10(-3), and the overall mutation rate estimate was 1.2 × 10(-3). The average of the paternal mutation rate (1.8 × 10(-3)) was five times higher than the maternal rate (0.36 × 10(-3)). The observed mutational features for STRs have important consequences for forensic applications, including the definition of criteria for exclusion in paternity testing and the interpretation of DNA profiles in identification analysis. PMID:22072310

  18. Evidence for recent, population-specific evolution of the human mutation rate.

    PubMed

    Harris, Kelley

    2015-03-17

    As humans dispersed out of Africa they adapted to new environmental challenges, including changes in exposure to mutagenic solar radiation. Humans in temperate latitudes have acquired light skin that is relatively transparent to UV light, and some evidence suggests that their DNA damage response pathways have also experienced local adaptation. This raises the possibility that different populations have experienced different selective pressures affecting genome integrity. Here, I present evidence that the rate of a particular mutation type has recently increased in the European population, rising in frequency by 50% during the 40,000-80,000 y since Europeans began diverging from Asians. A comparison of SNPs private to Africa, Asia, and Europe in the 1000 Genomes data reveals that private European variation is enriched for the transition 5'-TCC-3' → 5'-TTC-3'. Although it is not clear whether UV played a causal role in changing the European mutational spectrum, 5'-TCC-3' → 5'-TTC-3' is known to be the most common somatic mutation present in melanoma skin cancers, as well as the mutation most frequently induced in vitro by UV. Regardless of its causality, this change indicates that DNA replication fidelity has not remained stable even since the origin of modern humans and might have changed numerous times during our recent evolutionary history. PMID:25733855

  19. Efficiency of carcinogenesis: is the mutator phenotype inevitable?

    PubMed

    Beckman, Robert A

    2010-10-01

    Cancer development requires multiple oncogenic mutations. Pathogenic mechanisms which accelerate this process may be favored carcinogenic pathways. Mutator mutations are mutations in genetic stability genes, and increase the mutation rate, speeding up the accumulation of oncogenic mutations. The mutator hypothesis states that mutator mutations play a critical role in carcinogenesis. Alternatively, tumors might arise by mutations occurring at the normal rate followed by selection and expansion of various premalignant lineages on the path to cancer. This alternative pathway is a significant argument against the mutator hypothesis. Mutator mutations may also lead to accumulation of deleterious mutations, which could lead to extinction of premalignant lineages before they become cancerous, another argument against the mutator hypothesis. Finally, the need for acquisition of a mutator mutation imposes an additional step on the carcinogenic process. Accordingly, the mutator hypothesis has been a seminal but controversial idea for several decades despite considerable experimental and theoretical work. To resolve this debate, the concept of efficiency has been introduced as a metric for comparing carcinogenic mechanisms, and a new theoretical approach of focused quantitative modeling has been applied. The results demonstrate that, given what is already known, the predominance of mutator mechanisms is likely inevitable, as they overwhelm less efficient non-mutator pathways to cancer. PMID:20934514

  20. Quantitative evaluation of DNA damage and mutation rate by atmospheric and room-temperature plasma (ARTP) and conventional mutagenesis.

    PubMed

    Zhang, Xue; Zhang, Chong; Zhou, Qian-Qian; Zhang, Xiao-Fei; Wang, Li-Yan; Chang, Hai-Bo; Li, He-Ping; Oda, Yoshimitsu; Xing, Xin-Hui

    2015-07-01

    DNA damage is the dominant source of mutation, which is the driving force of evolution. Therefore, it is important to quantitatively analyze the DNA damage caused by different mutagenesis methods, the subsequent mutation rates, and their relationship. Atmospheric and room temperature plasma (ARTP) mutagenesis has been used for the mutation breeding of more than 40 microorganisms. However, ARTP mutagenesis has not been quantitatively compared with conventional mutation methods. In this study, the umu test using a flow-cytometric analysis was developed to quantify the DNA damage in individual viable cells using Salmonella typhimurium NM2009 as the model strain and to determine the mutation rate. The newly developed method was used to evaluate four different mutagenesis systems: a new ARTP tool, ultraviolet radiation, 4-nitroquinoline-1-oxide (4-NQO), and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) mutagenesis. The mutation rate was proportional to the corresponding SOS response induced by DNA damage. ARTP caused greater DNA damage to individual living cells than the other conventional mutagenesis methods, and the mutation rate was also higher. By quantitatively comparing the DNA damage and consequent mutation rate after different types of mutagenesis, we have shown that ARTP is a potentially powerful mutagenesis tool with which to improve the characteristics of microbial cell factories. PMID:26025015

  1. Rates of Mutation and Host Transmission for an Escherichia coli Clone over 3 Years

    PubMed Central

    Reeves, Peter R.; Liu, Bin; Zhou, Zhemin; Li, Dan; Guo, Dan; Ren, Yan; Clabots, Connie; Lan, Ruiting; Johnson, James R.; Wang, Lei

    2011-01-01

    Although over 50 complete Escherichia coli/Shigella genome sequences are available, it is only for closely related strains, for example the O55:H7 and O157:H7 clones of E. coli, that we can assign differences to individual evolutionary events along specific lineages. Here we sequence the genomes of 14 isolates of a uropathogenic E. coli clone that persisted for 3 years within a household, including a dog, causing a urinary tract infection (UTI) in the dog after 2 years. The 20 mutations observed fit a single tree that allows us to estimate the mutation rate to be about 1.1 per genome per year, with minimal evidence for adaptive change, including in relation to the UTI episode. The host data also imply at least 6 host transfer events over the 3 years, with 2 lineages present over much of that period. To our knowledge, these are the first direct measurements for a clone in a well-defined host community that includes rates of mutation and host transmission. There is a concentration of non-synonymous mutations associated with 2 transfers to the dog, suggesting some selection pressure from the change of host. However, there are no changes to which we can attribute the UTI event in the dog, which suggests that this occurrence after 2 years of the clone being in the household may have been due to chance, or some unknown change in the host or environment. The ability of a UTI strain to persist for 2 years and also to transfer readily within a household has implications for epidemiology, diagnosis, and clinical intervention. PMID:22046404

  2. Phase variable genes of Campylobacter jejuni exhibit high mutation rates and specific mutational patterns but mutability is not the major determinant of population structure during host colonization

    PubMed Central

    Bayliss, Christopher D.; Bidmos, Fadil A.; Anjum, Awais; Manchev, Vladimir T.; Richards, Rebecca L .; Grossier, Jean-Philippe; Wooldridge, Karl G.; Ketley, Julian M.; Barrow, Paul A.; Jones, Michael A.; Tretyakov, Michael V.

    2012-01-01

    Phase variation of surface structures occurs in diverse bacterial species due to stochastic, high frequency, reversible mutations. Multiple genes of Campylobacter jejuni are subject to phase variable gene expression due to mutations in polyC/G tracts. A modal length of nine repeats was detected for polyC/G tracts within C. jejuni genomes. Switching rates for these tracts were measured using chromosomally-located reporter constructs and high rates were observed for cj1139 (G8) and cj0031 (G9). Alteration of the cj1139 tract from G8 to G11 increased mutability 10-fold and changed the mutational pattern from predominantly insertions to mainly deletions. Using a multiplex PCR, major changes were detected in ‘on/off’ status for some phase variable genes during passage of C. jejuni in chickens. Utilization of observed switching rates in a stochastic, theoretical model of phase variation demonstrated links between mutability and genetic diversity but could not replicate observed population diversity. We propose that modal repeat numbers have evolved in C. jejuni genomes due to molecular drivers associated with the mutational patterns of these polyC/G repeats, rather than by selection for particular switching rates, and that factors other than mutational drift are responsible for generating genetic diversity during host colonization by this bacterial pathogen. PMID:22434884

  3. Microsatellite frequencies vary with body mass and body temperature in mammals, suggesting correlated variation in mutation rate

    PubMed Central

    Filipe, Laura N.S.

    2014-01-01

    Substitution rate is often found to correlate with life history traits such as body mass, a predictor of population size and longevity, and body temperature. The underlying mechanism is unclear but most models invoke either natural selection or factors such as generation length that change the number of mutation opportunities per unit time. Here we use published genome sequences from 69 mammals to ask whether life history traits impact another form of genetic mutation, the high rates of predominantly neutral slippage in microsatellites. We find that the length-frequency distributions of three common dinucleotide motifs differ greatly between even closely related species. These frequency differences correlate with body mass and body temperature and can be used to predict the phenotype of an unknown species. Importantly, different length microsatellites show complicated patterns of excess and deficit that cannot be explained by a simple model where species with short generation lengths have experienced more mutations. Instead, the patterns probably require changes in mutation rate that impact alleles of different length to different extents. Body temperature plausibly influences mutation rate by modulating the propensity for slippage. Existing hypotheses struggle to account for a link between body mass and mutation rate. However, body mass correlates inversely with population size, which in turn predicts heterozygosity. We suggest that heterozygote instability, HI, the idea that heterozygous sites show increased mutability, could provide a plausible link between body mass and mutation rate. PMID:25392761

  4. Microsatellite frequencies vary with body mass and body temperature in mammals, suggesting correlated variation in mutation rate.

    PubMed

    Amos, William; Filipe, Laura N S

    2014-01-01

    Substitution rate is often found to correlate with life history traits such as body mass, a predictor of population size and longevity, and body temperature. The underlying mechanism is unclear but most models invoke either natural selection or factors such as generation length that change the number of mutation opportunities per unit time. Here we use published genome sequences from 69 mammals to ask whether life history traits impact another form of genetic mutation, the high rates of predominantly neutral slippage in microsatellites. We find that the length-frequency distributions of three common dinucleotide motifs differ greatly between even closely related species. These frequency differences correlate with body mass and body temperature and can be used to predict the phenotype of an unknown species. Importantly, different length microsatellites show complicated patterns of excess and deficit that cannot be explained by a simple model where species with short generation lengths have experienced more mutations. Instead, the patterns probably require changes in mutation rate that impact alleles of different length to different extents. Body temperature plausibly influences mutation rate by modulating the propensity for slippage. Existing hypotheses struggle to account for a link between body mass and mutation rate. However, body mass correlates inversely with population size, which in turn predicts heterozygosity. We suggest that heterozygote instability, HI, the idea that heterozygous sites show increased mutability, could provide a plausible link between body mass and mutation rate. PMID:25392761

  5. Estimation of the spontaneous mutation rate per nucleotide site in a Drosophila melanogaster full-sib family.

    PubMed

    Keightley, Peter D; Ness, Rob W; Halligan, Daniel L; Haddrill, Penelope R

    2014-01-01

    We employed deep genome sequencing of two parents and 12 of their offspring to estimate the mutation rate per site per generation in a full-sib family of Drosophila melanogaster recently sampled from a natural population. Sites that were homozygous for the same allele in the parents and heterozygous in one or more offspring were categorized as candidate mutations and subjected to detailed analysis. In 1.23 × 10(9) callable sites from 12 individuals, we confirmed six single nucleotide mutations. We estimated the false negative rate in the experiment by generating synthetic mutations using the empirical distributions of numbers of nonreference bases at heterozygous sites in the offspring. The proportion of synthetic mutations at callable sites that we failed to detect was <1%, implying that the false negative rate was extremely low. Our estimate of the point mutation rate is 2.8 × 10(-9) (95% confidence interval = 1.0 × 10(-9) - 6.1 × 10(-9)) per site per generation, which is at the low end of the range of previous estimates, and suggests an effective population size for the species of ∼1.4 × 10(6). At one site, point mutations were present in two individuals, indicating that there had been a premeiotic mutation cluster, although surprisingly one individual had a G→A transition and the other a G→T transversion, possibly associated with error-prone mismatch repair. We also detected three short deletion mutations and no insertions, giving a deletion mutation rate of 1.2 × 10(-9) (95% confidence interval = 0.7 × 10(-9) - 11 × 10(-9)). PMID:24214343

  6. Estimation of the Spontaneous Mutation Rate per Nucleotide Site in a Drosophila melanogaster Full-Sib Family

    PubMed Central

    Keightley, Peter D.; Ness, Rob W.; Halligan, Daniel L.; Haddrill, Penelope R.

    2014-01-01

    We employed deep genome sequencing of two parents and 12 of their offspring to estimate the mutation rate per site per generation in a full-sib family of Drosophila melanogaster recently sampled from a natural population. Sites that were homozygous for the same allele in the parents and heterozygous in one or more offspring were categorized as candidate mutations and subjected to detailed analysis. In 1.23 × 109 callable sites from 12 individuals, we confirmed six single nucleotide mutations. We estimated the false negative rate in the experiment by generating synthetic mutations using the empirical distributions of numbers of nonreference bases at heterozygous sites in the offspring. The proportion of synthetic mutations at callable sites that we failed to detect was <1%, implying that the false negative rate was extremely low. Our estimate of the point mutation rate is 2.8 × 10−9 (95% confidence interval = 1.0 × 10−9 − 6.1 × 10−9) per site per generation, which is at the low end of the range of previous estimates, and suggests an effective population size for the species of ∼1.4 × 106. At one site, point mutations were present in two individuals, indicating that there had been a premeiotic mutation cluster, although surprisingly one individual had a G→A transition and the other a G→T transversion, possibly associated with error-prone mismatch repair. We also detected three short deletion mutations and no insertions, giving a deletion mutation rate of 1.2 × 10−9 (95% confidence interval = 0.7 × 10−9 − 11 × 10−9). PMID:24214343

  7. Is the rate of insertion and deletion mutation male biased?: Molecular evolutionary analysis of avian and primate sex chromosome sequences.

    PubMed Central

    Sundström, Hannah; Webster, Matthew T; Ellegren, Hans

    2003-01-01

    The rate of mutation for nucleotide substitution is generally higher among males than among females, likely owing to the larger number of DNA replications in spermatogenesis than in oogenesis. For insertion and deletion (indel) mutations, data from a few human genetic disease loci indicate that the two sexes may mutate at similar rates, possibly because such mutations arise in connection with meiotic crossing over. To address origin- and sex-specific rates of indel mutation we have conducted the first large-scale molecular evolutionary analysis of indels in noncoding DNA sequences from sex chromosomes. The rates are similar on the X and Y chromosomes of primates but about twice as high on the avian Z chromosome as on the W chromosome. The fact that indels are not uncommon on the nonrecombining Y and W chromosomes excludes meiotic crossing over as the main cause of indel mutation. On the other hand, the similar rates on X and Y indicate that the number of DNA replications (higher for Y than for X) is also not the main factor. Our observations are therefore consistent with a role of both DNA replication and recombination in the generation of short insertion and deletion mutations. A significant excess of deletion compared to insertion events is observed on the avian W chromosome, consistent with gradual DNA loss on a nonrecombining chromosome. PMID:12750337

  8. Direct Estimate of the Spontaneous Mutation Rate Uncovers the Effects of Drift and Recombination in the Chlamydomonas reinhardtii Plastid Genome.

    PubMed

    Ness, Rob W; Kraemer, Susanne A; Colegrave, Nick; Keightley, Peter D

    2016-03-01

    Plastids perform crucial cellular functions, including photosynthesis, across a wide variety of eukaryotes. Since endosymbiosis, plastids have maintained independent genomes that now display a wide diversity of gene content, genome structure, gene regulation mechanisms, and transmission modes. The evolution of plastid genomes depends on an input of de novo mutation, but our knowledge of mutation in the plastid is limited to indirect inference from patterns of DNA divergence between species. Here, we use a mutation accumulation experiment, where selection acting on mutations is rendered ineffective, combined with whole-plastid genome sequencing to directly characterize de novo mutation in Chlamydomonas reinhardtii. We show that the mutation rates of the plastid and nuclear genomes are similar, but that the base spectra of mutations differ significantly. We integrate our measure of the mutation rate with a population genomic data set of 20 individuals, and show that the plastid genome is subject to substantially stronger genetic drift than the nuclear genome. We also show that high levels of linkage disequilibrium in the plastid genome are not due to restricted recombination, but are instead a consequence of increased genetic drift. One likely explanation for increased drift in the plastid genome is that there are stronger effects of genetic hitchhiking. The presence of recombination in the plastid is consistent with laboratory studies in C. reinhardtii and demonstrates that although the plastid genome is thought to be uniparentally inherited, it recombines in nature at a rate similar to the nuclear genome. PMID:26615203

  9. Balancing drug resistance and growth rates via compensatory mutations in the Plasmodium falciparum chloroquine resistance transporter.

    PubMed

    Petersen, Ines; Gabryszewski, Stanislaw J; Johnston, Geoffrey L; Dhingra, Satish K; Ecker, Andrea; Lewis, Rebecca E; de Almeida, Mariana Justino; Straimer, Judith; Henrich, Philipp P; Palatulan, Eugene; Johnson, David J; Coburn-Flynn, Olivia; Sanchez, Cecilia; Lehane, Adele M; Lanzer, Michael; Fidock, David A

    2015-07-01

    The widespread use of chloroquine to treat Plasmodium falciparum infections has resulted in the selection and dissemination of variant haplotypes of the primary resistance determinant PfCRT. These haplotypes have encountered drug pressure and within-host competition with wild-type drug-sensitive parasites. To examine these selective forces in vitro, we genetically engineered P. falciparum to express geographically diverse PfCRT haplotypes. Variant alleles from the Philippines (PH1 and PH2, which differ solely by the C72S mutation) both conferred a moderate gain of chloroquine resistance and a reduction in growth rates in vitro. Of the two, PH2 showed higher IC50 values, contrasting with reduced growth. Furthermore, a highly mutated pfcrt allele from Cambodia (Cam734) conferred moderate chloroquine resistance and enhanced growth rates, when tested against wild-type pfcrt in co-culture competition assays. These three alleles mediated cross-resistance to amodiaquine, an antimalarial drug widely used in Africa. Each allele, along with the globally prevalent Dd2 and 7G8 alleles, rendered parasites more susceptible to lumefantrine, the partner drug used in the leading first-line artemisinin-based combination therapy. These data reveal ongoing region-specific evolution of PfCRT that impacts drug susceptibility and relative fitness in settings of mixed infections, and raise important considerations about optimal agents to treat chloroquine-resistant malaria. PMID:25898991

  10. Reaction Rate Theory of Radiation Exposure and Scaling Hypothesis in Mutation Frequency

    NASA Astrophysics Data System (ADS)

    Manabe, Yuichiro; Nakamura, Issei; Bando, Masako

    2014-11-01

    We have developed a kinetic reaction model for cells with irradiated DNA molecules due to ionizing radiation exposure. Our theory simultaneously accounts for the time-dependent reactions of DNA damage, DNA mutation and DNA repair, and the proliferation and apoptosis of cells in a tissue with a minimal set of model parameters. In contrast to existing theories of radiation exposition, we do not assume the relationships between the total dose and the induced mutation frequency. Our theory provides a universal scaling function that reasonably explains the mega-mouse experiments by Russell and Kelly [Proc. Natl. Acad. Sci. U.S.A. 79, 542 (1982)] with different dose rates. Furthermore, we have estimated the effective dose rate, which is biologically equivalent to the ionizing effects other than those caused by artificial irradiation. This value is 1.11 × 10-3 Gy/h, which is significantly larger than the effect caused by natural background radiation.

  11. Balancing drug resistance and growth rates via compensatory mutations in the Plasmodium falciparum chloroquine resistance transporter

    PubMed Central

    Petersen, Ines; Gabryszewski, Stanislaw J.; Johnston, Geoffrey L.; Dhingra, Satish K.; Ecker, Andrea; Lewis, Rebecca E.; de Almeida, Mariana Justino; Straimer, Judith; Henrich, Philipp H.; Palatulan, Eugene; Johnson, David J.; Coburn-Flynn, Olivia; Sanchez, Cecilia; Lehane, Adele M.; Lanzer, Michael; Fidock, David A.

    2015-01-01

    Summary The widespread use of chloroquine to treat Plasmodium falciparum infections has resulted in the selection and dissemination of variant haplotypes of the primary resistance determinant PfCRT. These haplotypes have encountered drug pressure and within-host competition with wild-type drug-sensitive parasites. To examine these selective forces in vitro, we genetically engineered P. falciparum to express geographically diverse PfCRT haplotypes. Variant alleles from the Philippines (PH1 and PH2, which differ solely by the C72S mutation) both conferred a moderate gain of chloroquine resistance and a reduction in growth rates in vitro. Of the two, PH2 showed higher IC50 values, contrasting with reduced growth. Furthermore, a highly mutated pfcrt allele from Cambodia (Cam734) conferred moderate chloroquine resistance and enhanced growth rates, when tested against wild-type pfcrt in co-culture competition assays. These three alleles mediated cross-resistance to amodiaquine, an antimalarial drug widely used in Africa. Each allele, along with the globally prevalent Dd2 and 7G8 alleles, rendered parasites more susceptible to lumefantrine, the partner drug used in the leading first-line artemisinin-based combination therapy. These data reveal ongoing region-specific evolution of PfCRT that impacts drug susceptibility and relative fitness in settings of mixed infections, and raise important considerations about optimal agents to treat chloroquine-resistant malaria. PMID:25898991

  12. Virology. Mutation rate and genotype variation of Ebola virus from Mali case sequences.

    PubMed

    Hoenen, T; Safronetz, D; Groseth, A; Wollenberg, K R; Koita, O A; Diarra, B; Fall, I S; Haidara, F C; Diallo, F; Sanogo, M; Sarro, Y S; Kone, A; Togo, A C G; Traore, A; Kodio, M; Dosseh, A; Rosenke, K; de Wit, E; Feldmann, F; Ebihara, H; Munster, V J; Zoon, K C; Feldmann, H; Sow, S

    2015-04-01

    The occurrence of Ebola virus (EBOV) in West Africa during 2013-2015 is unprecedented. Early reports suggested that in this outbreak EBOV is mutating twice as fast as previously observed, which indicates the potential for changes in transmissibility and virulence and could render current molecular diagnostics and countermeasures ineffective. We have determined additional full-length sequences from two clusters of imported EBOV infections into Mali, and we show that the nucleotide substitution rate (9.6 × 10(-4) substitutions per site per year) is consistent with rates observed in Central African outbreaks. In addition, overall variation among all genotypes observed remains low. Thus, our data indicate that EBOV is not undergoing rapid evolution in humans during the current outbreak. This finding has important implications for outbreak response and public health decisions and should alleviate several previously raised concerns. PMID:25814067

  13. Divergence times in Caenorhabditis and Drosophila inferred from direct estimates of the neutral mutation rate.

    PubMed

    Cutter, Asher D

    2008-04-01

    Accurate inference of the dates of common ancestry among species forms a central problem in understanding the evolutionary history of organisms. Molecular estimates of divergence time rely on the molecular evolutionary prediction that neutral mutations and substitutions occur at the same constant rate in genomes of related species. This underlies the notion of a molecular clock. Most implementations of this idea depend on paleontological calibration to infer dates of common ancestry, but taxa with poor fossil records must rely on external, potentially inappropriate, calibration with distantly related species. The classic biological models Caenorhabditis and Drosophila are examples of such problem taxa. Here, I illustrate internal calibration in these groups with direct estimates of the mutation rate from contemporary populations that are corrected for interfering effects of selection on the assumption of neutrality of substitutions. Divergence times are inferred among 6 species each of Caenorhabditis and Drosophila, based on thousands of orthologous groups of genes. I propose that the 2 closest known species of Caenorhabditis shared a common ancestor <24 MYA (Caenorhabditis briggsae and Caenorhabditis sp. 5) and that Caenorhabditis elegans diverged from its closest known relatives <30 MYA, assuming that these species pass through at least 6 generations per year; these estimates are much more recent than reported previously with molecular clock calibrations from non-nematode phyla. Dates inferred for the common ancestor of Drosophila melanogaster and Drosophila simulans are roughly concordant with previous studies. These revised dates have important implications for rates of genome evolution and the origin of self-fertilization in Caenorhabditis. PMID:18234705

  14. Genetic polymorphisms and mutation rates of 27 Y-chromosomal STRs in a Han population from Guangdong Province, Southern China.

    PubMed

    Wang, Ying; Zhang, Yong-Ji; Zhang, Chu-chu; Li, Ran; Yang, Yang; Ou, Xue-Ling; Tong, Da-yue; Sun, Hong-Yu

    2016-03-01

    In this study, we collected blood samples from 1033 father-son pairs of a Han population from Guangdong Province, Southern China, of which 1007 fathers were unrelated male individuals. All together, 2040 male individuals were analyzed at 27 Y-chromosomal short tandem repeats (Y-STRs) with Yfiler(®) Plus system. A total of 1003 different haplotypes were observed among 1007 unrelated fathers, with the overall haplotype diversity (HD) 0.999992 and discrimination capacity (DC) 0.996. The gene diversity (GD) values for the 27 Y-STR loci ranged from 0.4400 at DYS438 to 0.9597 at DYS385a/b. 11 off-ladder alleles and 25 copy number variants were detected in 1007 males. Population relationships were analyzed by comparison with 19 other worldwide populations. With 27,920 allele transfers in 1033 father-son pairs, 124 mutation events occurred, of which 118 were one-step mutations and 6 were two-step mutations. Eleven father-son pairs were found to have mutations at two loci, while one pair at three loci. The estimated locus-specific mutation rates varied from 0 to 1.74×10(-2), with an average estimated mutation rate 4.4×10(-3) (95%CI: 3.7×10(-3) to 5.3×10(-3)). Mutations were most frequently observed at three rapidly mutating Y-STRs (RM Y-STRs), DYS576, DYS518 and DYS627. However, at DYS570, DYS449 and DYF387S1 loci, which were also described as RM Y-STRs, the mutation rates in Guangdong Han population were not as high as estimated in other populations. PMID:26619377

  15. TEX11 is mutated in infertile men with azoospermia and regulates genome-wide recombination rates in mouse.

    PubMed

    Yang, Fang; Silber, Sherman; Leu, N Adrian; Oates, Robert D; Marszalek, Janet D; Skaletsky, Helen; Brown, Laura G; Rozen, Steve; Page, David C; Wang, P Jeremy

    2015-09-01

    Genome-wide recombination is essential for genome stability, evolution, and speciation. Mouse Tex11, an X-linked meiosis-specific gene, promotes meiotic recombination and chromosomal synapsis. Here, we report that TEX11 is mutated in infertile men with non-obstructive azoospermia and that an analogous mutation in the mouse impairs meiosis. Genetic screening of a large cohort of idiopathic infertile men reveals that TEX11 mutations, including frameshift and splicing acceptor site mutations, cause infertility in 1% of azoospermic men. Functional evaluation of three analogous human TEX11 missense mutations in transgenic mouse models identified one mutation (V748A) as a potential infertility allele and found two mutations non-causative. In the mouse model, an intronless autosomal Tex11 transgene functionally substitutes for the X-linked Tex11 gene, providing genetic evidence for the X-to-autosomal retrotransposition evolution phenomenon. Furthermore, we find that TEX11 protein levels modulate genome-wide recombination rates in both sexes. These studies indicate that TEX11 alleles affecting expression level or substituting single amino acids may contribute to variations in recombination rates between sexes and among individuals in humans. PMID:26136358

  16. Mutation induction by different dose rates of gamma rays in radiation-sensitive mutants of mouse leukemia cells

    SciTech Connect

    Furuno-Fukushi, I.; Matsudaira, H. )

    1989-11-01

    Induction of cell killing and mutation to 6-thioguanine resistance was examined in a radiation-sensitive mutant strain LX830 of mouse leukemia cells following gamma irradiation at dose rates of 30 Gy/h (acute), 20 cGy/h (low dose rate), and 6.2 mGy/h (very low dose rate). LX830 cells were hypersensitive to killing by acute gamma rays. A slight but significant increase was observed in cell survival with decreasing dose rate down to 6.2 mGy/h, where the survival leveled off above certain total doses. The cells were also hypersensitive to mutation induction compared to the wild type. The mutation frequency increased linearly with increasing dose for all dose rates. No significant difference was observed in the frequency of induced mutations versus total dose at the three different dose rates so that the mutation frequency in LX830 cells at 6.2 mGy/h was not significantly different from that for moderate or acute irradiation.

  17. Bayesian Procedures for the Estimation of Mutation Rates from Fluctuation Experiments

    PubMed Central

    Asteris, G.; Sarkar, S.

    1996-01-01

    Bayesian procedures are developed for estimating mutation rates from fluctuation experiments. Three Bayesian point estimators are compared with four traditional ones using the results of 10,000 simulated experiments. The Bayesian estimators were found to be at least as efficient as the best of the previously known estimators. The best Bayesian estimator is one that uses (1/m(2)) as the prior probability density function and a quadratic loss function. The advantage of using these estimators is most pronounced when the number of fluctuation test tubes is small. Bayesian estimation allows the incorporation of prior knowledge about the estimated parameter, in which case the resulting estimators are the most efficient. It enables the straightforward construction of confidence intervals for the estimated parameter. The increase of efficiency with prior information and the narrowing of the confidence intervals with additional experimental results are investigated. The results of the simulations show that any potential inaccuracy of estimation arising from lumping together all cultures with more than n mutants (the jackpots) almost disappears at n = 70 (provided that the number of mutations in a culture is low). These methods are applied to a set of experimental data to illustrate their use. PMID:8770608

  18. Novel variation and de novo mutation rates in population-wide de novo assembled Danish trios

    PubMed Central

    Besenbacher, Søren; Liu, Siyang; Izarzugaza, José M. G.; Grove, Jakob; Belling, Kirstine; Bork-Jensen, Jette; Huang, Shujia; Als, Thomas D.; Li, Shengting; Yadav, Rachita; Rubio-García, Arcadio; Lescai, Francesco; Demontis, Ditte; Rao, Junhua; Ye, Weijian; Mailund, Thomas; Friborg, Rune M.; Pedersen, Christian N. S.; Xu, Ruiqi; Sun, Jihua; Liu, Hao; Wang, Ou; Cheng, Xiaofang; Flores, David; Rydza, Emil; Rapacki, Kristoffer; Damm Sørensen, John; Chmura, Piotr; Westergaard, David; Dworzynski, Piotr; Sørensen, Thorkild I. A.; Lund, Ole; Hansen, Torben; Xu, Xun; Li, Ning; Bolund, Lars; Pedersen, Oluf; Eiberg, Hans; Krogh, Anders; Børglum, Anders D.; Brunak, Søren; Kristiansen, Karsten; Schierup, Mikkel H.; Wang, Jun; Gupta, Ramneek; Villesen, Palle; Rasmussen, Simon

    2015-01-01

    Building a population-specific catalogue of single nucleotide variants (SNVs), indels and structural variants (SVs) with frequencies, termed a national pan-genome, is critical for further advancing clinical and public health genetics in large cohorts. Here we report a Danish pan-genome obtained from sequencing 10 trios to high depth (50 × ). We report 536k novel SNVs and 283k novel short indels from mapping approaches and develop a population-wide de novo assembly approach to identify 132k novel indels larger than 10 nucleotides with low false discovery rates. We identify a higher proportion of indels and SVs than previous efforts showing the merits of high coverage and de novo assembly approaches. In addition, we use trio information to identify de novo mutations and use a probabilistic method to provide direct estimates of 1.27e−8 and 1.5e−9 per nucleotide per generation for SNVs and indels, respectively. PMID:25597990

  19. Enhanced somatic mutation rates induced in stem cells of mice by low chronic exposure to ethylnitrosourea.

    PubMed Central

    Shaver-Walker, P M; Urlando, C; Tao, K S; Zhang, X B; Heddle, J A

    1995-01-01

    We have found that the somatic mutation rate at the Dlb-1 locus increases exponentially during low daily exposure to ethylnitrosourea over 4 months. This effect, enhanced mutagenesis, was not observed at a lacI transgene in the same tissue, although the two loci respond very similarly to acute doses. Since both mutations are neutral, the mutant frequency was expected to increase linearly with time in response to a constant mutagenic exposure, as it did for lacI. Enhanced mutagenesis does not result from an overall sensitization of the animals, since mice that had first been treated with a low daily dose for 90 days and then challenged with a large acute dose were not sensitized to the acute dose. Nor was the increased mutant frequency due to selection, since animals that were treated for 90 days and then left untreated for up to 60 days showed little change from the 90-day frequency. The effect is substantial: about 8 times as many Dlb-1 mutants were induced between 90 and 120 days as in the first 30 days. This resulted in a reverse dose rate effect such that 90 mg/kg induced more mutants when delivered at 1 mg/kg per day than at 3 mg/kg per day. We postulate that enhanced mutagenesis arises from increased stem cell proliferation and the preferential repair of transcribed genes. Enhanced mutagenesis may be important for risk evaluation, as the results show that chronic exposures can be more mutagenic than acute ones and raise the possibility of synergism between chemicals at low doses. PMID:8524785

  20. Effects of track structure and cell inactivation on the calculation of heavy ion mutation rates in mammalian cells

    NASA Technical Reports Server (NTRS)

    Cucinotta, F. A.; Wilson, J. W.; Shavers, M. R.; Katz, R.

    1996-01-01

    It has long been suggested that inactivation severely effects the probability of mutation by heavy ions in mammalian cells. Heavy ions have observed cross sections of inactivation that approach and sometimes exceed the geometric size of the cell nucleus in mammalian cells. In the track structure model of Katz the inactivation cross section is found by summing an inactivation probability over all impact parameters from the ion to the sensitive sites within the cell nucleus. The inactivation probability is evaluated using the dose-response of the system to gamma-rays and the radial dose of the ions and may be equal to unity at small impact parameters for some ions. We show how the effects of inactivation may be taken into account in the evaluation of the mutation cross sections from heavy ions in the track structure model through correlation of sites for gene mutation and cell inactivation. The model is fit to available data for HPRT mutations in Chinese hamster cells and good agreement is found. The resulting calculations qualitatively show that mutation cross sections for heavy ions display minima at velocities where inactivation cross sections display maxima. Also, calculations show the high probability of mutation by relativistic heavy ions due to the radial extension of ions track from delta-rays in agreement with the microlesion concept. The effects of inactivation on mutations rates make it very unlikely that a single parameter such as LET or Z*2/beta(2) can be used to specify radiation quality for heavy ion bombardment.

  1. Investigations of the Y Chromosome, Male Founder Structure and YSTR Mutation Rates in the Old Order Amish

    PubMed Central

    Pollin, Toni I.; McBride, Daniel J.; Agarwala, Richa; Schäffer, Alejandro A.; Shuldiner, Alan R.; Mitchell, Braxton D.; O'Connell, Jeffrey R.

    2007-01-01

    Objectives Using Y chromosome short tandem repeat (YSTR) genotypes, (1) evaluate the accuracy and completeness of the Lancaster County Old Order Amish (OOA) genealogical records and (2) estimate YSTR mutation rates. Methods Nine YSTR markers were genotyped in 739 Old Order Amish males who participated in several ongoing genetic studies of complex traits and could be connected into one of 28 all-male lineage pedigrees constructed using the Anabaptist Genealogy Database and the query software PedHunter. A putative founder YSTR haplotype was constructed for each pedigree, and observed and inferred father-son transmissions were used to estimate YSTR mutation rates. Results We inferred 27 distinct founder Y chromosome haplotypes in the 28 male lineages, which encompassed 27 surnames accounting for 98% of Lancaster OOA households. Nearly all deviations from founder haplotypes were consistent with mutation events rather than errors. The estimated marker-specific mutation rates ranged from 0 to 1.09% (average 0.33% using up to 283 observed meioses only and 0.28% using up to 1,232 observed and inferred meioses combined). Conclusions These data confirm the accuracy and completeness of the male lineage portion of the Anabaptist Genealogy Database and contribute mutation rate estimates for several commonly used Y chromosome STR markers. PMID:17898540

  2. Mutation rate is reduced by increased dosage of mutL gene in Escherichia coli K-12.

    PubMed

    Galán, Juan-Carlos; Turrientes, María-Carmen; Baquero, María-Rosario; Rodríguez-Alcayna, Manuel; Martínez-Amado, Jorge; Martínez, José-Luis; Baquero, Fernando

    2007-10-01

    A variable but substantial proportion of wild Escherichia coli isolates present consistently lower mutation frequencies than that found in the ensemble of strains. The genetic mechanisms responsible for the hypo-mutation phenotype are much less known than those involved in hyper-mutation. Changes in E. coli mutation frequencies derived from the gene-copy effect of mutS, mutL, mutH, uvrD, mutT, mutY, mutM, mutA, dnaE, dnaQ, and rpoS are explored. When present in a very high copy number ( approximately 300 copies cell(-1)), mutL, mutH, and mutA gene copies yielded >/=twofold decrease in mutation rates determined by Luria-Delbrück fluctuation tests. Nevertheless, when the copy number was not such high ( approximately 15 copies cell(-1)), only mutL results in a consistent twofold decrease in the mutation rate. This reduction seems to be independent from the RecA background, phase of growth, or from the presence of proficient MutS. An increase in mutL gene copies was also able to partially compensate the hypermutator phenotype of a mutS-defective E. coli derivative. PMID:17825069

  3. The Rate and Spectrum of Spontaneous Mutations in Mycobacterium smegmatis, a Bacterium Naturally Devoid of the Postreplicative Mismatch Repair Pathway.

    PubMed

    Kucukyildirim, Sibel; Long, Hongan; Sung, Way; Miller, Samuel F; Doak, Thomas G; Lynch, Michael

    2016-01-01

    Mycobacterium smegmatis is a bacterium that is naturally devoid of known postreplicative DNA mismatch repair (MMR) homologs, mutS and mutL, providing an opportunity to investigate how the mutation rate and spectrum has evolved in the absence of a highly conserved primary repair pathway. Mutation accumulation experiments of M. smegmatis yielded a base-substitution mutation rate of 5.27 × 10(-10) per site per generation, or 0.0036 per genome per generation, which is surprisingly similar to the mutation rate in MMR-functional unicellular organisms. Transitions were found more frequently than transversions, with the A:T→G:C transition rate significantly higher than the G:C→A:T transition rate, opposite to what is observed in most studied bacteria. We also found that the transition-mutation rate of M. smegmatis is significantly lower than that of other naturally MMR-devoid or MMR-knockout organisms. Two possible candidates that could be responsible for maintaining high DNA fidelity in this MMR-deficient organism are the ancestral-like DNA polymerase DnaE1, which contains a highly efficient DNA proofreading histidinol phosphatase (PHP) domain, and/or the existence of a uracil-DNA glycosylase B (UdgB) homolog that might protect the GC-rich M. smegmatis genome against DNA damage arising from oxidation or deamination. Our results suggest that M. smegmatis has a noncanonical Dam (DNA adenine methylase) methylation system, with target motifs differing from those previously reported. The mutation features of M. smegmatis provide further evidence that genomes harbor alternative routes for improving replication fidelity, even in the absence of major repair pathways. PMID:27194804

  4. The Rate and Spectrum of Spontaneous Mutations in Mycobacterium smegmatis, a Bacterium Naturally Devoid of the Postreplicative Mismatch Repair Pathway

    PubMed Central

    Kucukyildirim, Sibel; Long, Hongan; Sung, Way; Miller, Samuel F.; Doak, Thomas G.; Lynch, Michael

    2016-01-01

    Mycobacterium smegmatis is a bacterium that is naturally devoid of known postreplicative DNA mismatch repair (MMR) homologs, mutS and mutL, providing an opportunity to investigate how the mutation rate and spectrum has evolved in the absence of a highly conserved primary repair pathway. Mutation accumulation experiments of M. smegmatis yielded a base-substitution mutation rate of 5.27 × 10−10 per site per generation, or 0.0036 per genome per generation, which is surprisingly similar to the mutation rate in MMR-functional unicellular organisms. Transitions were found more frequently than transversions, with the A:T→G:C transition rate significantly higher than the G:C→A:T transition rate, opposite to what is observed in most studied bacteria. We also found that the transition-mutation rate of M. smegmatis is significantly lower than that of other naturally MMR-devoid or MMR-knockout organisms. Two possible candidates that could be responsible for maintaining high DNA fidelity in this MMR-deficient organism are the ancestral-like DNA polymerase DnaE1, which contains a highly efficient DNA proofreading histidinol phosphatase (PHP) domain, and/or the existence of a uracil-DNA glycosylase B (UdgB) homolog that might protect the GC-rich M. smegmatis genome against DNA damage arising from oxidation or deamination. Our results suggest that M. smegmatis has a noncanonical Dam (DNA adenine methylase) methylation system, with target motifs differing from those previously reported. The mutation features of M. smegmatis provide further evidence that genomes harbor alternative routes for improving replication fidelity, even in the absence of major repair pathways. PMID:27194804

  5. Ultra deep sequencing detects a low rate of mosaic mutations in Tuberous Sclerosis Complex

    PubMed Central

    Qin, Wei; Kozlowski, Piotr; Taillon, Bruce E.; Bouffard, Pascal; Holmes, Alison J.; Janne, Pasi; Camposano, Susana; Thiele, Elizabeth; Franz, David; Kwiatkowski, David J.

    2010-01-01

    Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous syndrome caused by mutations in TSC1 and TSC2. However, 10 to 15% TSC patients have no mutation identified with conventional molecular diagnostic studies. We used the ultra-deep pyrosequencing technique of 454 Sequencing to search for mosaicism in 38 TSC patients who had no TSC1 or TSC2 mutation identified by conventional methods. Two TSC2 mutations were identified, each at 5.3% read frequency in different patients, consistent with mosaicism. Both mosaic mutations were confirmed by several methods. Five of 38 samples were found to have heterozygous non-mosaic mutations, which had been missed in earlier analyses. Several other possible low frequency mosaic mutations were identified by deep sequencing, but were discarded as artifacts by secondary studies. The low frequency of detection of mosaic mutations, 2 (6%) of 33, suggests that the majority of TSC patients who have no mutation identified are not due to mosaicism, but rather other causes, which remain to be determined. These findings indicate the ability of deep sequencing, coupled with secondary confirmatory analyses, to detect low frequency mosaic mutations. PMID:20165957

  6. JAK2V617F somatic mutation in the general population: myeloproliferative neoplasm development and progression rate

    PubMed Central

    Nielsen, Camilla; Bojesen, Stig E.; Nordestgaard, Børge G.; Kofoed, Klaus F.; Birgens, Henrik S.

    2014-01-01

    Clinical significance of the JAK2V617F mutation in patients with a myeloproliferative neoplasm has been the target of intensive research in recent years. However, there is considerably uncertainty about prognosis in JAK2V617F positive individuals without overt signs of myeloproliferative disease. In this study, we tested the hypothesis that increased JAK2V617F somatic mutation burden is associated with myeloproliferative neoplasm progression rate in the general population. Among 49,488 individuals from the Copenhagen General Population Study, 63 (0.1%) tested positive for the JAK2V617F mutation in the time period 2003–2008. Of these, 48 were available for re-examination in 2012. Level of JAK2V617F mutation burden was associated with myeloproliferative neoplasm progression rate, consistent with a biological continuum of increasing JAK2V617F mutation burden across increasing severity of myeloproliferative neoplasm from no disease (n=8 at re-examination) through essential thrombocythemia (n=20) and polycythemia vera (n=13) to primary myelofibrosis (n=7). Among those diagnosed with a myeloproliferative neoplasm only at re-examination in 2012, in the preceding years JAK2V617F mutation burden increased by 0.55% per year, erythrocyte volume fraction increased by 1.19% per year, and erythrocyte mean corpuscular volume increased by 1.25% per year, while there was no change in platelet count or erythropoietin levels. Furthermore, we established a JAK2V617F mutation burden cut-off point of 2% indicative of disease versus no disease; however, individuals with a mutation burden below 2% may suffer from a latent form of myeloproliferative disease revealed by a slightly larger spleen and/or slightly higher lactic acid dehydrogenase concentration compared to controls. Of all 63 JAK2V617F positive individuals, 48 were eventually diagnosed with a myeloproliferative neoplasm. PMID:24907356

  7. Historical variations in mutation rate in an epidemic pathogen, Yersinia pestis

    PubMed Central

    Cui, Yujun; Yu, Chang; Yan, Yanfeng; Li, Dongfang; Li, Yanjun; Jombart, Thibaut; Weinert, Lucy A.; Wang, Zuyun; Guo, Zhaobiao; Xu, Lizhi; Zhang, Yujiang; Zheng, Hancheng; Qin, Nan; Xiao, Xiao; Wu, Mingshou; Wang, Xiaoyi; Zhou, Dongsheng; Qi, Zhizhen; Du, Zongmin; Wu, Honglong; Yang, Xianwei; Cao, Hongzhi; Wang, Hu; Wang, Jing; Yao, Shusen; Rakin, Alexander; Li, Yingrui; Falush, Daniel; Balloux, Francois; Achtman, Mark; Song, Yajun; Wang, Jun; Yang, Ruifu

    2013-01-01

    The genetic diversity of Yersinia pestis, the etiologic agent of plague, is extremely limited because of its recent origin coupled with a slow clock rate. Here we identified 2,326 SNPs from 133 genomes of Y. pestis strains that were isolated in China and elsewhere. These SNPs define the genealogy of Y. pestis since its most recent common ancestor. All but 28 of these SNPs represented mutations that happened only once within the genealogy, and they were distributed essentially at random among individual genes. Only seven genes contained a significant excess of nonsynonymous SNP, suggesting that the fixation of SNPs mainly arises via neutral processes, such as genetic drift, rather than Darwinian selection. However, the rate of fixation varies dramatically over the genealogy: the number of SNPs accumulated by different lineages was highly variable and the genealogy contains multiple polytomies, one of which resulted in four branches near the time of the Black Death. We suggest that demographic changes can affect the speed of evolution in epidemic pathogens even in the absence of natural selection, and hypothesize that neutral SNPs are fixed rapidly during intermittent epidemics and outbreaks. PMID:23271803

  8. Elevated mutation rates in the germ line of first- and second-generation offspring of irradiated male mice

    PubMed Central

    Barber, Ruth; Plumb, Mark A.; Boulton, Emma; Roux, Isabelle; Dubrova, Yuri E.

    2002-01-01

    Mutation rates at two expanded simple tandem repeat loci were studied in the germ line of first- and second-generation offspring of inbred male CBA/H, C57BL/6, and BALB/c mice exposed to either high linear energy transfer fission neutrons or low linear energy transfer x-rays. Paternal CBA/H exposure to either x-rays or fission neutrons resulted in increased mutation rates in the germ line of two subsequent generations. Comparable transgenerational effects were observed also in neutron-irradiated C57BL/6 and x-irradiated BALB/c mice. The levels of spontaneous mutation rates and radiation-induced transgenerational instability varied between strains (BALB/c>CBA/H>C57BL/6). Pre- and postmeiotic paternal exposure resulted in similar increases in mutation rate in the germ line of both generations of CBA/H mice, which together with our previous results suggests that radiation-induced expanded simple tandem repeat instability is manifested in diploid cells after fertilization. The remarkable finding that radiation-induced germ-line instability persists for at least two generations raises important issues of risk evaluation in humans. PMID:11997464

  9. Protein Homeostasis Imposes a Barrier on Functional Integration of Horizontally Transferred Genes in Bacteria

    PubMed Central

    Bhattacharyya, Sanchari; Manhart, Michael; Choi, Jeong-Mo; Mu, Wanmeng; Zhou, Jingwen; Shakhnovich, Eugene I.

    2015-01-01

    Horizontal gene transfer (HGT) plays a central role in bacterial evolution, yet the molecular and cellular constraints on functional integration of the foreign genes are poorly understood. Here we performed inter-species replacement of the chromosomal folA gene, encoding an essential metabolic enzyme dihydrofolate reductase (DHFR), with orthologs from 35 other mesophilic bacteria. The orthologous inter-species replacements caused a marked drop (in the range 10–90%) in bacterial growth rate despite the fact that most orthologous DHFRs are as stable as E.coli DHFR at 37°C and are more catalytically active than E. coli DHFR. Although phylogenetic distance between E. coli and orthologous DHFRs as well as their individual molecular properties correlate poorly with growth rates, the product of the intracellular DHFR abundance and catalytic activity (k cat/KM), correlates strongly with growth rates, indicating that the drop in DHFR abundance constitutes the major fitness barrier to HGT. Serial propagation of the orthologous strains for ~600 generations dramatically improved growth rates by largely alleviating the fitness barriers. Whole genome sequencing and global proteome quantification revealed that the evolved strains with the largest fitness improvements have accumulated mutations that inactivated the ATP-dependent Lon protease, causing an increase in the intracellular DHFR abundance. In one case DHFR abundance increased further due to mutations accumulated in folA promoter, but only after the lon inactivating mutations were fixed in the population. Thus, by apparently distinguishing between self and non-self proteins, protein homeostasis imposes an immediate and global barrier to the functional integration of foreign genes by decreasing the intracellular abundance of their products. Once this barrier is alleviated, more fine-tuned evolution occurs to adjust the function/expression of the transferred proteins to the constraints imposed by the intracellular

  10. Genome-Wide Estimates of Mutation Rates and Spectrum in Schizosaccharomyces pombe Indicate CpG Sites are Highly Mutagenic Despite the Absence of DNA Methylation

    PubMed Central

    Behringer, Megan G.; Hall, David W.

    2015-01-01

    We accumulated mutations for 1952 generations in 79 initially identical, haploid lines of the fission yeast Schizosaccharomyces pombe, and then performed whole-genome sequencing to determine the mutation rates and spectrum. We captured 696 spontaneous mutations across the 79 mutation accumulation (MA) lines. We compared the mutation spectrum and rate to a recently published equivalent experiment on the same species, and to another model ascomycetous yeast, the budding yeast Saccharomyces cerevisiae. While the two species are approximately 600 million years diverged from each other, they share similar life histories, genome size and genomic G/C content. We found that Sc. pombe and S. cerevisiae have similar mutation rates, but Sc. pombe exhibits a stronger insertion bias. Intriguingly, we observed an increased mutation rate at cytosine nucleotides, specifically CpG nucleotides, which is also seen in S. cerevisiae. However, the absence of methylation in Sc. pombe and the pattern of mutation at these sites, primarily C → A as opposed to C → T, strongly suggest that the increased mutation rate is not caused by deamination of methylated cytosines. This result implies that the high mutability of CpG dinucleotides in other species may be caused in part by a methylation-independent mechanism. Many of our findings mirror those seen in the recent study, despite the use of different passaging conditions, indicating that MA is a reliable method for estimating mutation rates and spectra. PMID:26564949

  11. Dose-Dependent Mutation Rates Determine Optimum Erlotinib Dosing Strategies for EGFR Mutant Non-Small Cell Lung Cancer Patients

    PubMed Central

    Liu, Lin L.; Li, Fei; Pao, William; Michor, Franziska

    2015-01-01

    Background The advent of targeted therapy for cancer treatment has brought about a paradigm shift in the clinical management of human malignancies. Agents such as erlotinib used for EGFR-mutant non-small cell lung cancer or imatinib for chronic myeloid leukemia, for instance, lead to rapid tumor responses. Unfortunately, however, resistance often emerges and renders these agents ineffective after a variable amount of time. The FDA-approved dosing schedules for these drugs were not designed to optimally prevent the emergence of resistance. To this end, we have previously utilized evolutionary mathematical modeling of treatment responses to elucidate the dosing schedules best able to prevent or delay the onset of resistance. Here we expand on our approaches by taking into account dose-dependent mutation rates at which resistant cells emerge. The relationship between the serum drug concentration and the rate at which resistance mutations arise can lead to non-intuitive results about the best dose administration strategies to prevent or delay the emergence of resistance. Methods We used mathematical modeling, available clinical trial data, and different considerations of the relationship between mutation rate and drug concentration to predict the effectiveness of different dosing strategies. Results We designed several distinct measures to interrogate the effects of different treatment dosing strategies and found that a low-dose continuous strategy coupled with high-dose pulses leads to the maximal delay until clinically observable resistance. Furthermore, the response to treatment is robust against different assumptions of the mutation rate as a function of drug concentration. Conclusions For new and existing targeted drugs, our methodology can be employed to compare the effectiveness of different dose administration schedules and investigate the influence of changing mutation rates on outcomes. PMID:26536620

  12. De novo rearrangements found in 2% of index patients with spinal muscular atrophy: mutational mechanisms, parental origin, mutation rate, and implications for genetic counseling.

    PubMed Central

    Wirth, B; Schmidt, T; Hahnen, E; Rudnik-Schöneborn, S; Krawczak, M; Müller-Myhsok, B; Schönling, J; Zerres, K

    1997-01-01

    Spinal muscular atrophy (SMA) is a relatively common autosomal recessive neuromuscular disorder. We have identified de novo rearrangements in 7 (approximately 2%) index patients from 340 informative SMA families. In each, the rearrangements resulted in the absence of the telomeric copy of the survival motor neuron (SMN) gene (telSMN), in two cases accompanied by the loss of the neuronal apoptosis-inhibitory protein gene . Haplotype analysis revealed unequal recombination in four cases, with loss of markers Ag1-CA and C212, which are near the 5' ends of the SMN genes. In one case, an interchromosomal rearrangement involving both the SMN genes and a regrouping of Ag1-CA and C212 alleles must have occurred, suggesting either interchromosomal gene conversion or double recombination. In two cases, no such rearrangement was observed, but loss of telSMN plus Ag1-CA and C212 alleles in one case suggested intrachromosomal deletion or gene conversion. In six of the seven cases, the de novo rearrangement had occurred during paternal meiosis. Direct detection of de novo SMA mutations by molecular genetic means has allowed us to estimate for the first time the mutation rate for a recessive disorder in humans. The sex-averaged rate of 1.1 x 10(-4), arrived at in a proband-based approach, compares well with the rate of 0.9 x 10(-4) expected under a mutation-selection equilibrium for SMA. These findings have important implications for genetic counseling and prenatal diagnosis in that they emphasize the relevance of indirect genotype analysis in combination with direct SMN-gene deletion testing in SMA families. PMID:9345102

  13. De novo rearrangements found in 2% of index patients with spinal muscular atrophy: mutational mechanisms, parental origin, mutation rate, and implications for genetic counseling.

    PubMed

    Wirth, B; Schmidt, T; Hahnen, E; Rudnik-Schöneborn, S; Krawczak, M; Müller-Myhsok, B; Schönling, J; Zerres, K

    1997-11-01

    Spinal muscular atrophy (SMA) is a relatively common autosomal recessive neuromuscular disorder. We have identified de novo rearrangements in 7 (approximately 2%) index patients from 340 informative SMA families. In each, the rearrangements resulted in the absence of the telomeric copy of the survival motor neuron (SMN) gene (telSMN), in two cases accompanied by the loss of the neuronal apoptosis-inhibitory protein gene . Haplotype analysis revealed unequal recombination in four cases, with loss of markers Ag1-CA and C212, which are near the 5' ends of the SMN genes. In one case, an interchromosomal rearrangement involving both the SMN genes and a regrouping of Ag1-CA and C212 alleles must have occurred, suggesting either interchromosomal gene conversion or double recombination. In two cases, no such rearrangement was observed, but loss of telSMN plus Ag1-CA and C212 alleles in one case suggested intrachromosomal deletion or gene conversion. In six of the seven cases, the de novo rearrangement had occurred during paternal meiosis. Direct detection of de novo SMA mutations by molecular genetic means has allowed us to estimate for the first time the mutation rate for a recessive disorder in humans. The sex-averaged rate of 1.1 x 10(-4), arrived at in a proband-based approach, compares well with the rate of 0.9 x 10(-4) expected under a mutation-selection equilibrium for SMA. These findings have important implications for genetic counseling and prenatal diagnosis in that they emphasize the relevance of indirect genotype analysis in combination with direct SMN-gene deletion testing in SMA families. PMID:9345102

  14. Women with BRCA1 and BRCA2 mutations survive ovarian cancer at higher rates

    Cancer.gov

    Results from a National Cancer Institute (NCI) sponsored multicenter study published in the Journal of the American Medical Association on January 25, 2012, provides strong evidence that BRCA1 and BRCA2 gene mutation carriers with ovarian cancer were more

  15. High rate of A2142G point mutation associated with clarithromycin resistance among Iranian Helicobacter pylori clinical isolates.

    PubMed

    Khashei, Reza; Dara, Mahintaj; Bazargani, Abdollah; Bagheri Lankarani, Kamran; Taghavi, Alireza; Moeini, Maryam; Dehghani, Behzad; Sohrabi, Maryam

    2016-09-01

    This study aimed to investigate the clarithromycin resistance and its associated molecular mechanisms among Helicobacter pylori isolates from dyspeptic patients in Shiraz, Iran. From January to May 2014, 100 H. pylori strains were isolated from patients with gastroduodenal disorders. The resistance to clarithromycin was quantitatively evaluated, using Epsilometer (E-test) method. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was performed on all the isolates to detect A2143G and A2142G mutations in 23S rRNA gene. The H. pylori isolation rate was found to be 31.4%. E-test showed that 20% of isolates were resistant to clarithromycin (MIC ≥ 1 mg/L). MIC of clarithromycin ranged between 0.016 and 24 mg/L. Findings of PCR-RFLP showed that the A2142G was the most (90%) frequently point mutation, followed by the A2143G (10%). No statistically significant difference was found between H. pylori clarithromycin resistance point mutations and patients' gender or age. To the best of our knowledge, this is the first report of high frequency of A2142G point mutation in Iran and probably in other regions of the world. Considering the increasing trend of H. pylori resistance to clarithromycin due to these mutations, it is crucial to investigate the new therapeutic approaches against H. pylori infection. PMID:27357065

  16. What limits affinity maturation of antibodies in Xenopus--the rate of somatic mutation or the ability to select mutants?

    PubMed Central

    Wilson, M; Hsu, E; Marcuz, A; Courtet, M; Du Pasquier, L; Steinberg, C

    1992-01-01

    Although the Xenopus immunoglobulin heavy chain locus is structurally and functionally similar to mammalian IgH loci, Xenopus antibodies are limited in heterogeneity, and they mature only slightly in affinity during immune responses. During the antibody response of isogenic frogs to DNP-KLH, mu and upsilon cDNA sequences using elements of the VH1 family were cloned, sequenced and compared with germline counterparts. There were zero to four mutations per sequence, mostly single base substitutions, in the framework and CDRs 1 and 2 of VH. No mutations were found in JH. Since the point mutation rate was only 4- to 7-fold lower than that calculated for mice, affinity maturation does not seem to be limited by mutant availability. Because of a relatively low ratio of replacement to silent mutations in the CDRs and a very high ratio of GC to AT base pairs altered by mutation, it is suggested that the problem results from the absence of an effective mechanism for selecting mutants, which in turn might be related to the absence of germinal centers in Xenopus. Images PMID:1425571

  17. Genotyping analysis of 3 RET polymorphisms demonstrates low somatic mutation rate in Chinese Hirschsprung disease patients

    PubMed Central

    Zhang, Zhen; Jiang, Qian; Li, Qi; Cheng, Wei; Qiao, Guoliang; Xiao, Ping; Gan, Liang; Su, Lin; Miao, Chunyue; Li, Long

    2015-01-01

    Background: Genetic mosaicism has been reported for both coding and non-coding sequences in the RET gene in Hirschsprung disease (HSCR) patients. This study aimed to investigate somatic mutation rate in Chinese population by comparing both homozygous genotype percentage and risk allele frequency of 3 RET single nucleotide polymorphisms (SNPs) among blood and colon samples. Methods: DNA was extracted from 59 HSCR blood samples, 59 control blood samples and 76 fresh frozen colon tissue samples (grouped into ganglionic, transitional and aganglionic level). Genotype status of rs2435357 and rs2506030 was examined by competitive allele specific hydrolysis probes (Taqman) PCR technology, and rs2506004 was examined by Sanger sequencing. Homozygous genotype percentage and risk allele frequency were calculated for each type of sample and compared by chi-square test. P<0.05 was regarded as being statistically significant. Results: Colon tissue DNA samples showed similar frequency of SNPs as that of the blood DNA samples in HSCR patients, both of which are significantly higher than the control blood group (rs2435357 TT genotype: 71.2%, 74.7% versus 22.0% in HSCR blood, HSCR colon and control blood DNA respectively, P=0.000; rs2506004 AA genotype: 72.4%, 83.1% versus 25.5%, P=0.000; rs2506030 GG genotype: 79.7%, 77.2% versus 54.2%, P=0.000 and 0.004). With respect to DNA extracted from ganglionic, transitional and aganglionic levels, no statistically significant difference was demonstrated in those 3 regions (rs2435357: P=0.897; rs2506004: P=0.740; rs2506030: P=0.901). Conclusion: Our data does not support the notion that high frequency of somatic changes as an underlying etiology of Chinese HSCR population. PMID:26191260

  18. Dihydropteroate synthase gene mutation rates in Pneumocystis jirovecii strains obtained from Iranian HIV-positive and non-HIV-positive patients.

    PubMed

    Sheikholeslami, Maryam-Fatemeh; Sadraei, Javid; Farnia, Parisa; Forozandeh Moghadam, Mehdi; Emadikochak, Hamid

    2015-05-01

    The dihydropteroate sulfate (DHPS) gene is associated with resistance to sulfa/sulfone drugs in Pneumocystis jirovecii. We investigated the DHPS mutation rate in three groups of Iranian HIV-positive and HIV-negative patients by polymerase chain reaction-restricted fragment length polymorphism analysis. Furthermore, an association between P. jirovecii DHPS mutations and strain typing was investigated based on direct sequencing of internal transcribed spacer region 1 (ITS1) and ITS2. The overall P. jirovecii DHPS mutation rate was (5/34; 14.7%), the lowest rate identified was in HIV-positive patients (1/16; 6.25%) and the highest rate was in malignancies patients (3/11; 27.3%). A moderate rate of mutation was detected in chronic obstructive pulmonary disease (COPD) patients (1/7; 14.3%). Most of the isolates were wild type (29/34; 85.3%). Double mutations in DHPS were detected in patients with malignancies, whereas single mutations at codons 55 and 57 were identified in the HIV-positive and COPD patients, respectively. In this study, two new and rare haplotypes were identified with DHPS mutations. Additionally, a positive relationship between P. jirovecii strain genotypes and DHPS mutations was identified. In contrast, no DHPS mutations were detected in the predominant (Eg) haplotype. This should be regarded as a warning of an increasing incidence of drug-resistant P. jirovecii strains. PMID:25631478

  19. The study of human mutation rates. Progress report, 1989--1992

    SciTech Connect

    Neel, J.V.

    1992-12-01

    We will describe recent developments regarding the question of induced mutations in the survivors of the atomic bombings of Hiroshima and Nagasaki. As part of that work we, describe some developments with respect to the Amerindian blood samples collected under DoE sponsorship between 1964 and 1982. Then developments regarding the application of two-dimensional polyacrylamide gel electrophoresis (2-D PAGE) to the study of genetic variation and mutation affecting protein characteristics. In particular, we will report on the identification and isolation of genes of especial interest as reflected in the behavior of the proteins which they encode.

  20. The G1138A mutation rate in the fibroblast growth factor receptor 3 (FGFR3) gene is increased in cells carrying the t (4; 14) translocation.

    PubMed

    Reddy, P L; Grewal, R P

    2009-01-01

    Spontaneous mutations are a common phenomenon, occurring in both germ-line and somatic genomes. They may have deleterious consequences including the development of genetic disorders or, when occurring in somatic tissues, may participate in the process of carcinogenesis. Similar to many mutational hotspots, the G1138A mutation in the fibroblast growth factor receptor 3 (FGFR3) gene occurs at a CpG site. In germ-line tissues, the G1138A mutation results in achondroplasia and has one of the highest spontaneous mutation rates in the human genome. Although not at the G1138A site, there are increased rates of other somatic mutations in the FGFR3 gene that have been reported in multiple myeloma cases associated with a translocation, t (4; 14). The chromosome-4 break points in this translocation are clustered in a 70-kb region centromeric to the FGFR3 gene. We hypothesized that this translocation may impact the mutation rate at the G1138A site. We employed a semi-quantitative polymerase chain reaction-based assay to measure the frequency of this mutation in multiple myeloma cell lines carrying t (4; 14) translocation. Analysis of these cell lines varied from no change to a 10-fold increase in the mutation frequency compared with normal controls. In general, there was an increase in the G1138A mutational frequency suggesting that chromosomal rearrangement can affect the stability of the CpG hotspots. PMID:19551630

  1. Proteomic Analysis of the Low Mutation Rate of Diploid Male Gametes Induced by Colchicine in Ginkgo biloba L.

    PubMed Central

    Yang, Nina; Sun, Yuhan; Wang, Yaru; Long, Cui; Li, Yingyue; Li, Yun

    2013-01-01

    Colchicine treatment of G. biloba microsporocytes results in a low mutation rate in the diploid (2n) male gamete. The mutation rate is significantly lower as compared to other tree species and impedes the breeding of new economic varieties. Proteomic analysis was done to identify the proteins that influence the process of 2n gamete formation in G. biloba. The microsporangia of G. biloba were treated with colchicine solution for 48 h and the proteins were analyzed using 2-D gel electrophoresis and compared to protein profiles of untreated microsporangia. A total of 66 proteins showed difference in expression levels. Twenty-seven of these proteins were identified by mass spectrometry. Among the 27 proteins, 14 were found to be up-regulated and the rest 13 were down-regulated. The identified proteins belonged to five different functional classes: ATP generation, transport and carbohydrate metabolism; protein metabolism; ROS scavenging and detoxifying enzymes; cell wall remodeling and metabolism; transcription, cell cycle and signal transduction. The identification of these differentially expressed proteins and their function could help in analysing the mechanism of lower mutation rate of diploid male gamete when the microsporangium of G. biloba was induced by colchicine. PMID:24167543

  2. Proteomic analysis of the low mutation rate of diploid male gametes induced by colchicine in Ginkgo biloba L.

    PubMed

    Yang, Nina; Sun, Yuhan; Wang, Yaru; Long, Cui; Li, Yingyue; Li, Yun

    2013-01-01

    Colchicine treatment of G. biloba microsporocytes results in a low mutation rate in the diploid (2n) male gamete. The mutation rate is significantly lower as compared to other tree species and impedes the breeding of new economic varieties. Proteomic analysis was done to identify the proteins that influence the process of 2n gamete formation in G. biloba. The microsporangia of G. biloba were treated with colchicine solution for 48 h and the proteins were analyzed using 2-D gel electrophoresis and compared to protein profiles of untreated microsporangia. A total of 66 proteins showed difference in expression levels. Twenty-seven of these proteins were identified by mass spectrometry. Among the 27 proteins, 14 were found to be up-regulated and the rest 13 were down-regulated. The identified proteins belonged to five different functional classes: ATP generation, transport and carbohydrate metabolism; protein metabolism; ROS scavenging and detoxifying enzymes; cell wall remodeling and metabolism; transcription, cell cycle and signal transduction. The identification of these differentially expressed proteins and their function could help in analysing the mechanism of lower mutation rate of diploid male gamete when the microsporangium of G. biloba was induced by colchicine. PMID:24167543

  3. Evolutionary constraints and the neutral theory. [mutation-caused nucleotide substitutions in DNA

    NASA Technical Reports Server (NTRS)

    Jukes, T. H.; Kimura, M.

    1984-01-01

    The neutral theory of molecular evolution postulates that nucleotide substitutions inherently take place in DNA as a result of point mutations followed by random genetic drift. In the absence of selective constraints, the substitution rate reaches the maximum value set by the mutation rate. The rate in globin pseudogenes is about 5 x 10 to the -9th substitutions per site per year in mammals. Rates slower than this indicate the presence of constraints imposed by negative (natural) selection, which rejects and discards deleterious mutations.

  4. Disentangling the effects of mating systems and mutation rates on cytoplamic diversity in gynodioecious Silene nutans and dioecious Silene otites

    PubMed Central

    Lahiani, E; Dufaÿ, M; Castric, V; Le Cadre, S; Charlesworth, D; Van Rossum, F; Touzet, P

    2013-01-01

    Many flowering plant species exhibit a variety of distinct sexual morphs, the two most common cases being the co-occurrence of females and males (dioecy) or the co-occurrence of hermaphrodites and females (gynodioecy). In this study, we compared DNA sequence variability of the three genomes (nuclear, mitochondrial and chloroplastic) of a gynodioecious species, Silene nutans, with that of a closely related dioecious species, Silene otites. In the light of theoretical models, we expect cytoplasmic diversity to differ between the two species due to the selective dynamics that acts on cytoplasmic genomes in gynodioecious species: under an epidemic scenario, the gynodioecious species is expected to exhibit lower cytoplasmic diversity than the dioecious species, while the opposite is expected in the case of balancing selection maintaining sterility cytoplasms in the gynodioecious species. We found no difference between the species for nuclear gene diversity, but, for the cytoplasmic loci, the gynodioecious S. nutans had more haplotypes, and higher nucleotide diversity, than the dioecious relative, S. otites, even though the latter has a relatively high rate of mitochondrial synonymous substitutions, and therefore presumably a higher mutation rate. Therefore, as the mitochondrial mutation rate cannot account for the higher cytoplasmic diversity found in S. nutans, our findings support the hypothesis that gynodioecy in S. nutans has been maintained by balancing selection rather than by epidemic-like dynamics. PMID:23591518

  5. Similarity of spontaneous germinal and in vitro somatic cell mutation rates in humans: implications for carcinogenesis and for the role of exogenous factors in "spontaneous" germinal mutagenesis.

    PubMed Central

    Kuick, R D; Neel, J V; Strahler, J R; Chu, E H; Bargal, R; Fox, D A; Hanash, S M

    1992-01-01

    The rate of spontaneous mutation resulting in electrophoretic variants per cell generation in a human lymphoblastoid cell line, on the basis of experiments described in this paper, is found to be 7.2 x 10(-8) per locus. A review of similar data on electrophoretic variants resulting from spontaneous mutation in the human germ line leads to an estimate of 3.3 x 10(-8) per locus per cell generation. It is argued that the similarity of these two estimates, despite an average cell generation time of 18.5 hr for the cultured somatic cells but about 26 days in the germ line, suggests that spontaneous mutation involving nucleotide substitutions is much more dependent on cell generation than on time. This finding permits the inference that environmental (exogenous) variables make a relatively small contribution to the rate of this type of human germinal spontaneous mutation. While in vitro somatic-cell mutation rates, such as derived in this study, provide a basis for modeling the contribution of nucleotide substitutions in multihit/clonal theories of carcinogenesis, it is also argued that the complex of events involved in carcinogenesis, including chromosomal rearrangements and mitotic recombination, could have very different individual probabilities. Estimates for the rates of these other types of mutation are needed to provide a better understanding of the manner in which multiple mutations accumulate in malignant cells. Images PMID:1495998

  6. Modification of a Hydrophobic Layer by a Point Mutation in Syntaxin 1A Regulates the Rate of Synaptic Vesicle Fusion

    PubMed Central

    Lagow, Robert D; Bao, Hong; Cohen, Evan N; Daniels, Richard W; Zuzek, Aleksej; Williams, Wade H; Macleod, Gregory T; Sutton, R. Bryan; Zhang, Bing

    2007-01-01

    Both constitutive secretion and Ca2+-regulated exocytosis require the assembly of the soluble N-ethylmaleimide–sensitive factor attachment protein receptor (SNARE) complexes. At present, little is known about how the SNARE complexes mediating these two distinct pathways differ in structure. Using the Drosophila neuromuscular synapse as a model, we show that a mutation modifying a hydrophobic layer in syntaxin 1A regulates the rate of vesicle fusion. Syntaxin 1A molecules share a highly conserved threonine in the C-terminal +7 layer near the transmembrane domain. Mutation of this threonine to isoleucine results in a structural change that more closely resembles those found in syntaxins ascribed to the constitutive secretory pathway. Flies carrying the I254 mutant protein have increased levels of SNARE complexes and dramatically enhanced rate of both constitutive and evoked vesicle fusion. In contrast, overexpression of the T254 wild-type protein in neurons reduces vesicle fusion only in the I254 mutant background. These results are consistent with molecular dynamics simulations of the SNARE core complex, suggesting that T254 serves as an internal brake to dampen SNARE zippering and impede vesicle fusion, whereas I254 favors fusion by enhancing intermolecular interaction within the SNARE core complex. PMID:17341138

  7. Understanding differences between phylogenetic and pedigree-derived mtDNA mutation rate: a model using families from the Azores Islands (Portugal).

    PubMed

    Santos, Cristina; Montiel, Rafael; Sierra, Blanca; Bettencourt, Conceição; Fernandez, Elisabet; Alvarez, Luis; Lima, Manuela; Abade, Augusto; Aluja, M Pilar

    2005-06-01

    We analyzed the control region of the mitochondrial DNA (mtDNA) from maternally related individuals originating from the Azores Islands (Portugal) in order to estimate the mutation rate of mtDNA and to gain insights into the process by which a new mutation arises and segregates into heteroplasmy. Length and/or point heteroplasmies were found at least in one individual of 72% of the studied families. Eleven new point substitutions were found, all of them in heteroplasmy, from which five appear to be somatic mutations and six can be considered germinal, evidencing the high frequency of somatic mutations in mtDNA in healthy young individuals. Different values of the mutation rate according to different assumptions were estimated. When considering all the germinal mutations, the value of the mutation rate obtained is one of the highest reported so far in family studies. However, when corrected for gender (assuming that the mutations present in men have the same evolutionary weight of somatic mutations because they will inevitably be lost) and for the probability of intraindividual fixation, the value for the mutation rate obtained for HVRI and HVRII (0.2415 mutations/site/Myr) was in the upper end of the values provided by phylogenetic estimations. These results indicate that the discrepancy, that has been reported previously, between the human mtDNA mutation rates observed along evolutionary timescales and the estimations obtained using family pedigrees can be minimized when corrections for gender proportions in newborn individuals and for the probability of intraindividual fixation are introduced. The analyses performed support the hypothesis that (1) in a constant, tight bottleneck genetic drift alone can explain different patterns of heteroplasmy segregation and (2) in neutral conditions, the destiny of a new mutation is strictly related to the initial proportion of the new variant. Another important point arising from the data obtained is that, even in the absence

  8. Influence of low-dose and low-dose-rate ionizing radiation on mutation induction in human cells

    NASA Astrophysics Data System (ADS)

    Yatagai, F.; Umebayashi, Y.; Suzuki, M.; Abe, T.; Suzuki, H.; Shimazu, T.; Ishioka, N.; Iwaki, M.; Honma, M.

    This is a review paper to introduce our recent studies on the genetic effects of low-dose and low-dose-rate ionizing radiation (IR). Human lymphoblastoid TK6 cells were exposed to γ-rays at a dose-rate of 1.2 mGy/h (total 30 mGy). The frequency of early mutations (EMs) in the thymidine kinase ( TK) gene locus was determined to be 1.7 × 10 -6, or 1.9-fold higher than the level seen in unirradated controls [Umebayashi, Y., Honma, M., Suzuki, M., Suzuki, H., Shimazu, T., Ishioka, N., Iwaki, M., Yatagai, F., Mutation induction in cultured human cells after low-dose and low-dose-rate γ-ray irradiation: detection by LOH analysis. J. Radiat. Res., 48, 7-11, 2007]. These mutants were then analyzed for loss of heterozygosity (LOH) events. Small interstitial-deletion events were restricted to the TK gene locus and were not observed in EMs in unirradated controls, but they comprised about half of the EMs (8/15) after IR exposure. Because of the low level of exposure to IR, this specific type of event cannot be considered to be the direct result of an IR-induced DNA double strand break (DSB). To better understand the effects of low-level IR exposure, the repair efficiency of site-specific chromosomal DSBs was also examined. The pre γ-irradiation under the same condition did not largely influence the efficiency of DSB repair via end-joining, but enhanced such efficiency via homologous recombination to an about 40% higher level (unpublished data). All these results suggest that DNA repair and mutagenesis can be indirectly influenced by low-dose/dose-rate IR.

  9. Response to Comment on "Mutation rate and genotype variation of Ebola virus from Mali case sequences".

    PubMed

    Hoenen, Thomas; Groseth, Allison; Safronetz, David; Wollenberg, Kurt; Feldmann, Heinz

    2016-08-12

    Rambaut et al show that the erratum to our report on Ebola virus Makona evolution not only corrected sample dates modified by others in GenBank but also corrected an additional transcriptional error in our original analysis. We agree with their observation that both factors contributed to our revised evolutionary rate estimate but continue to stand by our revised estimate and conclusions. PMID:27516593

  10. Comment on "Mutation rate and genotype variation of Ebola virus from Mali case sequences".

    PubMed

    Rambaut, Andrew; Dudas, Gytis; de Carvalho, Luiz Max; Park, Daniel J; Yozwiak, Nathan L; Holmes, Edward C; Andersen, Kristian G

    2016-08-12

    Hoenen et al (Reports, 3 April 2015, p. 117; published online 26 March) suggested that the Ebola virus Makona responsible for the West African epidemic evolved more slowly than previously reported. We show that this was based on corrupted data. An erratum provided a rate compatible with the initial and later, more precise, estimates but did not correctly state the nature of the error. PMID:27516592

  11. Mutations in FMN Binding Pocket Diminish Chromate Reduction Rates for Gh-ChrR Isolated from Gluconacetobacter hansenii

    SciTech Connect

    Khaleel, Janin A.; Gong, Chunhong; Zhang, Yanfeng; Tan, Ruimin; Squier, Thomas C.; Jin, Hongjun

    2013-06-01

    A putative chromate ion binding site was identified proximal to a rigidly bound FMN from electron densities in the crystal structure of the quinone reductase from Gluconacetobacter hansenii (Gh-ChrR) (3s2y.pdb). To clarify the location of the chromate binding site, and to understand the role of FMN in the NADPH-dependent reduction of chromate, we have expressed and purified four mutant enzymes involving the site-specific substitution of individual side chains within the FMN binding pocket that form non-covalent bonds with the ribityl phosphate (i.e., S15A and R17A in loop 1 between β1 sheet and α1 helix) or the isoalloxanzine ring (E83A or Y84A in loop 4 between the β3 sheet and α4 helix). Mutations that selectively disrupt hydrogen bonds between either the N3 nitrogen on the isoalloxanzine ring (i.e., E83) or the ribitylphos- phoate (i.e., S15) respectively result in 50% or 70% reductions in catalytic rates of chromate reduction. In comparison, mutations that disrupt π-π ring stacking interactions with the isoal-loxanzine ring (i.e., Y84) or a salt bridge with the ribityl phosphate result in 87% and 97% inhibittion. In all cases there are minimal alterations in chromate binding affinities. Collectively, these results support the hypothesis that chromate binds proximal to FMN, and implicate a structural role for FMN positioning for optimal chromate reduction rates. As side chains proximal to the β3/α4 FMN binding loop 4 contribute to both NADH and metal ion binding, we propose a model in which structural changes around the FMN binding pocket couples to both chromate and NADH binding sites.

  12. The Jackprot Simulation Couples Mutation Rate with Natural Selection to Illustrate How Protein Evolution Is Not Random

    PubMed Central

    Espinosa, Avelina; Bai, Chunyan Y.

    2016-01-01

    Protein evolution is not a random process. Views which attribute randomness to molecular change, deleterious nature to single-gene mutations, insufficient geological time, or population size for molecular improvements to occur, or invoke “design creationism” to account for complexity in molecular structures and biological processes, are unfounded. Scientific evidence suggests that natural selection tinkers with molecular improvements by retaining adaptive peptide sequence. We used slot-machine probabilities and ion channels to show biological directionality on molecular change. Because ion channels reside in the lipid bilayer of cell membranes, their residue location must be in balance with the membrane's hydrophobic/philic nature; a selective “pore” for ion passage is located within the hydrophobic region. We contrasted the random generation of DNA sequence for KcsA, a bacterial two-transmembrane-domain (2TM) potassium channel, from Streptomyces lividans, with an under-selection scenario, the “jackprot,” which predicted much faster evolution than by chance. We wrote a computer program in JAVA APPLET version 1.0 and designed an online interface, The Jackprot Simulation http://faculty.rwu.edu/cbai/JackprotSimulation.htm, to model a numerical interaction between mutation rate and natural selection during a scenario of polypeptide evolution. Winning the “jackprot,” or highest-fitness complete-peptide sequence, required cumulative smaller “wins” (rewarded by selection) at the first, second, and third positions in each of the 161 KcsA codons (“jackdons” that led to “jackacids” that led to the “jackprot”). The “jackprot” is a didactic tool to demonstrate how mutation rate coupled with natural selection suffices to explain the evolution of specialized proteins, such as the complex six-transmembrane (6TM) domain potassium, sodium, or calcium channels. Ancestral DNA sequences coding for 2TM-like proteins underwent nucleotide

  13. The Effect of Dose Rate on the Frequency of Specific-Locus Mutations Induced in Mouse Spermatogonia is Restricted to Larger Lesions; a Retrospective Analysis of Historical Data

    SciTech Connect

    Russell, Liane B; Hunsicker, Patricia R

    2012-01-01

    A series of 19 large-scale germ-cell mutagenesis experiments conducted several decades ago led to the conclusion that low-LET radiation delivered to mouse spermatogonia at dose rates of 0.8 R/min and below induced only about one-third as many specific-locus mutations as did single, acute exposures at 24 R/min and above. A two-hit origin of the mutations was deemed unlikely in view of the then prevailing evidence for the small size of genetic lesions in spermatogonia. Instead, the dose-rate effect was hypothesized to be the result of a repair system that exists in spermatogonia, but not in more mature male reproductive cells. More recent genetic and molecular studies on the marker genes have identified the phenotypes associated with specific states of the mutant chromosomes, and it is now possible retrospectively to classify individual past mutations as "large lesions" or "other lesions". The mutation-frequency difference between high and low dose rates is restricted to the large lesion mutations, for which the dose-curve slopes differ by a factor exceeding 3.4. For other lesion mutations, there is essentially no difference between the slopes for protracted and acute irradiations; induced other lesions frequencies per unit dose remain similar for dose rates ranging over more than 7 orders of magnitude. For large lesions, these values rise sharply at dose rates >0.8 R/min, though they remain similar within the whole range of protracted doses, failing to provide evidence for a threshold dose rate. The downward bend at high doses that had been noted for X-ray-induced specific-locus mutations as a whole and ascribed to a positive correlation between spermatogonial death and mutation load is now found to be restricted to large lesion mutations. There is a marked difference between the mutation spectra (distributions among the seven loci) for large lesions and other lesions. Within each class, however, the spectra are similar for acute and protracted irradiation.

  14. mlRho – a program for estimating the population mutation and recombination rates from shotgun-sequenced diploid genomes

    PubMed Central

    HAUBOLD, BERNHARD; PFAFFELHUBER, PETER; LYNCH, MICHAEL

    2016-01-01

    Improvements in sequencing technology over the past 5 years are leading to routine application of shotgun sequencing in the fields of ecology and evolution. However, the theory to estimate evolutionary parameters from these data is still being worked out. Here we present an extension and implementation of part of this theory, mlRho. This program can efficiently compute the following three maximum likelihood estimators based on shotgun sequence data obtained from single diploid individuals: the population mutation rate (4Neμ), the sequencing error rate, and the population recombination rate (4Nec). We demonstrate the accuracy of mlRho by applying it to simulated data sets. In addition, we analyse the genomes of the sea squirt Ciona intestinalis and the water flea Daphnia pulex. Ciona intestinalis is an obligate outcrosser, while D. pulex is a cyclic parthenogen, and we discuss how these contrasting life histories are reflected in our parameter estimates. The program mlRho is freely available from http://guanine.evolbio.mpg.de/mlRho. PMID:20331786

  15. mlRho - a program for estimating the population mutation and recombination rates from shotgun-sequenced diploid genomes.

    PubMed

    Haubold, Bernhard; Pfaffelhuber, Peter; Lynch, Michael

    2010-03-01

    Improvements in sequencing technology over the past 5 years are leading to routine application of shotgun sequencing in the fields of ecology and evolution. However, the theory to estimate evolutionary parameters from these data is still being worked out. Here we present an extension and implementation of part of this theory, mlRho. This program can efficiently compute the following three maximum likelihood estimators based on shotgun sequence data obtained from single diploid individuals: the population mutation rate (4N(e)mu), the sequencing error rate, and the population recombination rate (4N(e)c). We demonstrate the accuracy of mlRho by applying it to simulated data sets. In addition, we analyse the genomes of the sea squirt Ciona intestinalis and the water flea Daphnia pulex. Ciona intestinalis is an obligate outcrosser, while D. pulex is a cyclic parthenogen, and we discuss how these contrasting life histories are reflected in our parameter estimates. The program mlRho is freely available from http://guanine.evolbio.mpg.de/mlRho. PMID:20331786

  16. Towards Improvements in the Estimation of the Coalescent: Implications for the Most Effective Use of Y Chromosome Short Tandem Repeat Mutation Rates

    PubMed Central

    Bird, Steven C.

    2012-01-01

    Over the past two decades, many short tandem repeat (STR) microsatellite loci on the human Y chromosome have been identified together with mutation rate estimates for the individual loci. These have been used to estimate the coalescent age, or the time to the most recent common ancestor (TMRCA) expressed in generations, in conjunction with the average square difference measure (ASD), an unbiased point estimator of TMRCA based upon the average within-locus allele variance between haplotypes. The ASD estimator, in turn, depends on accurate mutation rate estimates to be able to produce good approximations of the coalescent age of a sample. Here, a comparison is made between three published sets of per locus mutation rate estimates as they are applied to the calculation of the coalescent age for real and simulated population samples. A novel evaluation method is developed for estimating the degree of conformity of any Y chromosome STR locus of interest to the strict stepwise mutation model and specific recommendations are made regarding the suitability of thirty-two commonly used Y-STR loci for the purpose of estimating the coalescent. The use of the geometric mean for averaging ASD and across loci is shown to improve the consistency of the resulting estimates, with decreased sensitivity to outliers and to the number of STR loci compared or the particular set of mutation rates selected. PMID:23119076

  17. Estimation of hominoid ancestral population sizes under bayesian coalescent models incorporating mutation rate variation and sequencing errors.

    PubMed

    Burgess, Ralph; Yang, Ziheng

    2008-09-01

    Estimation of population parameters for the common ancestors of humans and the great apes is important in understanding our evolutionary history. In particular, inference of population size for the human-chimpanzee common ancestor may shed light on the process by which the 2 species separated and on whether the human population experienced a severe size reduction in its early evolutionary history. In this study, the Bayesian method of ancestral inference of Rannala and Yang (2003. Bayes estimation of species divergence times and ancestral population sizes using DNA sequences from multiple loci. Genetics. 164:1645-1656) was extended to accommodate variable mutation rates among loci and random species-specific sequencing errors. The model was applied to analyze a genome-wide data set of approximately 15,000 neutral loci (7.4 Mb) aligned for human, chimpanzee, gorilla, orangutan, and macaque. We obtained robust and precise estimates for effective population sizes along the hominoid lineage extending back approximately 30 Myr to the cercopithecoid divergence. The results showed that ancestral populations were 5-10 times larger than modern humans along the entire hominoid lineage. The estimates were robust to the priors used and to model assumptions about recombination. The unusually low X chromosome divergence between human and chimpanzee could not be explained by variation in the male mutation bias or by current models of hybridization and introgression. Instead, our parameter estimates were consistent with a simple instantaneous process for human-chimpanzee speciation but showed a major reduction in X chromosome effective population size peculiar to the human-chimpanzee common ancestor, possibly due to selective sweeps on the X prior to separation of the 2 species. PMID:18603620

  18. Albino mutation rates in red mangroves (Rhizophora mangle L.) as a bioassay of contamination history in Tampa Bay, Florida, USA

    USGS Publications Warehouse

    Proffitt, C.E.; Travis, S.E.

    2005-01-01

    We assessed the sensitivity of a viviparous estuarine tree species, Rhizophora mangle, to historic sublethal mutagenic stress across a fine spatial scale by comparing the frequency of trees producing albino propagules in historically contaminated (n=4) and uncontaminated (n=11) forests in Tampa Bay, Florida, USA. Data from uncontaminated forests were used to provide estimates of background mutation rates. We also determined whether other fitness parameters were negatively correlated with mutagenic stress (e.g., degree of outcrossing and numbers of reproducing trees km-1). Contaminated sites in Tampa Bay had significantly higher frequencies of trees that were heterozygous for albinism per 1000 total reproducing trees (FHT) than uncontaminated forests (mean ?? SE: 11.4 ?? 4.3 vs 4.3 ?? 0.73, P 25 yrs of subsequent recruitment and tree replacement may have allowed an initial elevation in the FHT to decay. Patterns of FHT were not explained by distance from the bay mouth or the degree of urbanization. However, there was a significant positive relationship between tree size and FHT (r=0.83, P<0.018), which suggests that forests with older or larger trees provide a more lasting record of cumulative mutagenic stress. No other fitness parameters correlated with FHT. There was a difference in FHT between two latitudes, as determined by comparing Tampa Bay with literature values for Puerto Rico. The sensitivity of this bioassay for the effects of mutagens will facilitate future monitoring of contamination events and comparisons of bay-wide recovery in future decades. Development of a database of FHT values for a range of subtropical and tropical estuaries is underway that will provide a baseline against which to compare mutational consequences of global change. ?? 2005, The Society of Wetland Scientists.

  19. Fate of Mutation Rate Depends on agr Locus Expression during Oxacillin-Mediated Heterogeneous-Homogeneous Selection in Methicillin-Resistant Staphylococcus aureus Clinical Strains ▿ †

    PubMed Central

    Plata, Konrad B.; Rosato, Roberto R.; Rosato, Adriana E.

    2011-01-01

    Methicillin-resistant Staphylococcus aureus (MRSA) strains are characterized by a heterogeneous expression of resistance. We have previously shown in clinical oxacillin-susceptible, mecA-positive MRSA strains that selection from a very heterogeneous (HeR) to highly homogeneous (HoR) resistant phenotype was mediated by acquisition of mutations through an oxacillin-induced SOS response. In the present study, we used a spotted DNA microarray to evaluate differential gene expression during HeR-HoR selection and found increased expression of the agr two-component regulatory system. We hypothesized that increased expression of agr represents a mechanistically relevant component of this process. We demonstrated that inactivation of agr during the HeR-HoR selection process results in a significant increase in mutation rate; these effects were reversed by complementing the agr mutant. Furthermore, we found that extemporal ectopic expression of agr and, more specifically, RNAII in agr-null mutant HeR cells suppressed mutation frequency and the capacity of these cells to undergo the HeR-HoR selection. These findings sustain the concept that increased expression of agr during HeR-HoR selection plays a critical role in regulating the β-lactam-induced increased mutation rate in very heterogeneous MRSA strains. Moreover, they indicate that a temporally controlled increase in agr expression is required to tightly modulate SOS-mediated mutation rates, which then allows for full expression of oxacillin homogeneous resistance in very heterogeneous clinical MRSA strains. PMID:21537016

  20. Stress-induced mutation rates show a sigmoidal and saturable increase due to the RpoS sigma factor in Escherichia coli.

    PubMed

    Maharjan, Ram; Ferenci, Thomas

    2014-11-01

    Stress-induced mutagenesis was investigated in the absence of selection for growth fitness by using synthetic biology to control perceived environmental stress in Escherichia coli. We find that controlled intracellular RpoS dosage is central to a sigmoidal, saturable three- to fourfold increase in mutation rates and associated changes in DNA repair proteins. PMID:25213168

  1. Superoxide Dismutase (Sod-1) Null Mutants of Neurospora Crassa: Oxidative Stress Sensitivity, Spontaneous Mutation Rate and Response to Mutagens

    PubMed Central

    Chary, P.; Dillon, D.; Schroeder, A. L.; Natvig, D. O.

    1994-01-01

    Enzymatic superoxide-dismutase activity is believed to be important in defense against the toxic effects of superoxide. Although superoxide dismutases are among the best studied proteins, numerous questions remain concerning the specific biological roles of the various superoxide-dismutase types. In part, this is because the proposed damaging effects of superoxide are manifold, ranging from inactivation of certain metabolic enzymes to DNA damage. Studies with superoxide-deficient mutants have proven valuable, but surprisingly few such studies have been reported. We have constructed and characterized Neurospora crassa mutants that are null for sod-1, the gene that encodes copper-zinc superoxide dismutase. Mutant strains are sensitive to paraquat and elevated oxygen concentrations, and they exhibit an increased spontaneous mutation rate. They appear to have near wild-type sensitivities to near- and far-UV, heat shock and γ-irradiation. Unlike the equivalent Saccharomyces cerevisiae mutant and the sodA sodB double mutant of Escherichia coli, they do not exhibit aerobic auxotrophy. These results are discussed in the context of an attempt to identify consensus phenotypes among superoxide dismutase-deficient mutants. N. crassa sod-1 null mutant strains were also employed in genetic and subcellular fractionation studies. Results support the hypothesis that a single gene (sod-1), located between Fsr-12 and leu-3 on linkage group I, is responsible for most or all CuZn superoxide dismutase activity in this organism. PMID:8088518

  2. Efficient inference of population size histories and locus-specific mutation rates from large-sample genomic variation data

    PubMed Central

    Bhaskar, Anand; Wang, Y.X. Rachel; Song, Yun S.

    2015-01-01

    With the recent increase in study sample sizes in human genetics, there has been growing interest in inferring historical population demography from genomic variation data. Here, we present an efficient inference method that can scale up to very large samples, with tens or hundreds of thousands of individuals. Specifically, by utilizing analytic results on the expected frequency spectrum under the coalescent and by leveraging the technique of automatic differentiation, which allows us to compute gradients exactly, we develop a very efficient algorithm to infer piecewise-exponential models of the historical effective population size from the distribution of sample allele frequencies. Our method is orders of magnitude faster than previous demographic inference methods based on the frequency spectrum. In addition to inferring demography, our method can also accurately estimate locus-specific mutation rates. We perform extensive validation of our method on simulated data and show that it can accurately infer multiple recent epochs of rapid exponential growth, a signal that is difficult to pick up with small sample sizes. Lastly, we use our method to analyze data from recent sequencing studies, including a large-sample exome-sequencing data set of tens of thousands of individuals assayed at a few hundred genic regions. PMID:25564017

  3. Fourteen cases of imposed upper airway obstruction.

    PubMed Central

    Samuels, M P; McClaughlin, W; Jacobson, R R; Poets, C F; Southall, D P

    1992-01-01

    Imposed upper airway obstruction was diagnosed as the cause of recurrent and severe cyanotic episodes in 14 patients. Episodes started between 0.8 and 33 months of age (median 1.4) and occurred over a period of 0.8 to 20 months (median 3.5). Diagnosis was made by covert video surveillance, instituted after either (a) the observation that episodes began only in the presence of one person, or (b) characteristic findings on physiological recordings, lasting between 12 hours and three weeks, performed in hospital or at home. Surveillance was undertaken for between 15 minutes and 12 days (median 24 hours) and resulted in safety for the patient and psychiatric assessment of the parent: mother (n = 12), father (n = 1), and grandmother (n = 1). These revealed histories of sexual, physical, or emotional abuse (n = 11), self harm (n = 9), factitious illness (n = 7), eating disorder (n = 10), and previous involvement with a psychiatrist (n = 7). Management of the abusing parents is complex, but recognition of their psychosocial characteristics may allow earlier diagnosis. Imposed upper airway obstruction should be considered and excluded by physiological recordings in any infant or young child with recurrent cyanotic episodes. If physiological recordings fail to substantiate a natural cause for episodes, covert video surveillance may be essential to protect the child from further injury or death. PMID:1543373

  4. Disparity mutagenesis model possesses the ability to realize both stable and rapid evolution in response to changing environments without altering mutation rates.

    PubMed

    Fujihara, Ichiro; Furusawa, Mitsuru

    2016-08-01

    It has been shown that the disparity model, in which mutations are introduced exclusively in the lagging strand, has a great advantage in the promotion of evolution, compared with the conventional parity mutagenesis model. To understand much more about the characteristic of the disparity model, a novel 2-D genetic algorithm (GA) which reflected gene interactions was developed. The GA consisting of the lattice model showed powerful abilities to evolve. Even under conditions of high mutation rates with an extra genetic load, the GA could quickly evolve and finally attain a long stable state with high fitness scores. Arbitrary interruption of the stable state of evolution by various lengths of environmental stress could produce new individuals with different genotypes within relatively short periods and the mutants finally occupy the population; that brought back the picture of "punctuated equilibrium". Interestingly, this phenomenon could be reproduced with certainty without changing mutation rates at all. As long as the fidelity difference between the lagging and leading strand was kept high enough, the robustness of the disparity model was very high. The acceleration or slowdown of evolution can be unambiguously introduced only by environmental changes, and the seesawing mutation rate is not the necessary condition for changing the speed of evolution. PMID:27579448

  5. Improving clustering by imposing network information

    PubMed Central

    Gerber, Susanne; Horenko, Illia

    2015-01-01

    Cluster analysis is one of the most popular data analysis tools in a wide range of applied disciplines. We propose and justify a computationally efficient and straightforward-to-implement way of imposing the available information from networks/graphs (a priori available in many application areas) on a broad family of clustering methods. The introduced approach is illustrated on the problem of a noninvasive unsupervised brain signal classification. This task is faced with several challenging difficulties such as nonstationary noisy signals and a small sample size, combined with a high-dimensional feature space and huge noise-to-signal ratios. Applying this approach results in an exact unsupervised classification of very short signals, opening new possibilities for clustering methods in the area of a noninvasive brain-computer interface. PMID:26601225

  6. Sequential imposed layer epitaxy of cuprate films

    SciTech Connect

    Laguees, M.; Tebbji, H.; Mairet, V.; Hatterer, C.; Beuran, C.F.; Hass, N.; Xu, X.Z. ); Cavellin, C.D. )

    1994-02-01

    Layer-by-layer epitaxy has been used to grow cuprate films since the discovery of high-Tc compounds. This deposition technique is in principle suitable for the growth of layered crystalline structures. However, the sequential deposition of atomic layer by atomic layer of cuprate compounds has presently not been optimized. Nevertheless, this deposition process is the only one which allows one to build artificial cell structures such as Bi[sub 2]Sr[sub 2]Ca[sub (n[minus]1)]Cu[sub n]O[sub y] with n as large as 10. This process will also be the best one to grow films of the so-called infinite layer phase compounds belonging to the Sr[sub 1[minus]x]Ca[sub x]CuO[sub 2] family, in order to improve the transport properties and the morphological properties of the cuprate films. When performed at high substrate temperature (typically more than 600[degree]C), the layer-by-layer epitaxy of cuprates exhibits usually 3D aggregate nucleation. Then the growth of the film no longer obeys the layer-by-layer sequence imposed during the deposition. We present here two experimental situations of true 2D sequential imposed layer epitaxy; the growth at 500[degree]C under atomic oxygen pressure of Bi[sub 2]Sr[sub 2]CuO[sub 6] and of Sr[sub 1[minus]x]Ca[sub y]CuO[sub 2] phases. 20 refs., 2 figs.

  7. Is imposing risk awareness cultural imperialism?

    PubMed

    Førde, O H

    1998-11-01

    Epidemiology is the main supplier of "bases of action" for preventive medicine and health promotion. Epidemiology and epidemiologists therefore have a responsibility not only for the quality and soundness of the risk estimates they deliver and for the way they are interpreted and used, but also for their consequences. In the industrialised world, the value of, and fascination with health is greater than ever, and the revelation from epidemiological research of new hazards and risks, conveyed to the public by the media, has become almost an every-day phenomenon. This "risk epidemic" in the modern media is paralleled in professional medical journals. It is in general endorsed by health promoters as a necessary foundation for increased health awareness and a desirable impetus for people to take responsibility for their own health through behavioural changes. Epidemiologists and health promoters, however, have in general not taken the possible side effects of increased risk awareness seriously enough. By increasing anxiety regarding disease, accidents and other adverse events, the risk epidemic enhances both health care dependence and health care consumption. More profoundly, and perhaps even more seriously, it changes the way people think about health, disease and death--and ultimately and at least potentially, their perspective on life more generally. The message from the odds ratios from epidemiological research advocates a rationalistic, individualistic, prospective life perspective where maximising control and minimising uncertainty is seen as a superior goal. The inconsistency between applying an expanded health concept, comprising elements of coping, self-realisation and psycho-physical functioning, and imposing intolerance to risk and uncertainty, is regularly overlooked. Acceptance and tolerance of risk and uncertainty, which are inherent elements of human life, is a prerequisite for coping and self-realisation. A further shift away from traditional working

  8. Gestational mutations in radiation carcinogenesis

    NASA Astrophysics Data System (ADS)

    Meza, R.; Luebeck, G.; Moolgavkar, S.

    Mutations in critical genes during gestation could increase substantially the risk of cancer. We examine the consequences of such mutations using the Luebeck-Moolgavkar model for colorectal cancer and the Lea-Coulson modification of the Luria-Delbruck model for the accumulation of mutations during gestation. When gestational mutation rates are high, such mutations make a significant contribution to cancer risk even for adult tumors. Furthermore, gestational mutations ocurring at distinct times during emryonic developmemt lead to substantially different numbers of mutated cells at birth, with early mutations leading to a large number (jackpots) of mutated cells at birth and mutation occurring late leading to only a few mutated cells. Thus gestational mutations could confer considerable heterogeneity of the risk of cancer. If the fetus is exposed to an environmental mutagen, such as ionizing radiation, the gestational mutation rate would be expected to increase. We examine the consequences of such exposures during gestation on the subsequent development of cancer.

  9. Terrestrial locomotion imposes high metabolic requirements on bats.

    PubMed

    Voigt, Christian C; Borrisov, Ivailo M; Voigt-Heucke, Silke L

    2012-12-15

    The evolution of powered flight involved major morphological changes in Chiroptera. Nevertheless, all bats are also capable of crawling on the ground and some are even skilled sprinters. We asked if a highly derived morphology adapted for flapping flight imposes high metabolic requirements on bats when moving on the ground. We measured the metabolic rate during terrestrial locomotion in mastiff bats, Molossus currentium, a species that is both a fast-flying aerial-hawking bat and an agile crawler on the ground. Metabolic rates of bats averaged 8.0±4.0 ml CO(2) min(-1) during a 1-min period of sprinting at 1.3±0.6 km h(-1). With rising average speed, mean metabolic rates increased, reaching peak values that were similar to those of flying conspecifics. Metabolic rates of M. currentium were higher than those of similar-sized rodents that sprinted at similar velocities under steady-state conditions. When M. currentium sprinted at peak velocities, its aerobic metabolic rate was 3-5 times higher than those of rodent species running continuously in steady-state conditions. Costs of transport (J kg(-1) m(-1)) were more than 10 times higher for running than for flying bats. We conclude that at the same speed bats experience higher metabolic rates during short sprints than quadruped mammals during steady-state terrestrial locomotion, yet running bats achieve higher maximal mass-specific aerobic metabolic rates than non-volant mammals such as rodents. PMID:22972883

  10. Weakly Deleterious Mutations and Low Rates of Recombination Limit the Impact of Natural Selection on Bacterial Genomes

    SciTech Connect

    Price, Morgan N.; Arkin, Adam P.

    2015-12-15

    Free-living bacteria are usually thought to have large effective population sizes, and so tiny selective differences can drive their evolution. However, because recombination is infrequent, “background selection” against slightly deleterious alleles should reduce the effective population size (Ne) by orders of magnitude. For example, for a well-mixed population with 1012 individuals and a typical level of homologous recombination (r/m= 3, i.e., nucleotide changes due to recombination [r] occur at 3 times the mutation rate [m]), we predict that Ne is<107. An argument for high Ne values for bacteria has been the high genetic diversity within many bacterial “species,” but this diversity may be due to population structure: diversity across subpopulations can be far higher than diversity within a subpopulation, which makes it difficult to estimate Ne correctly. Given an estimate ofNe, standard population genetics models imply that selection should be sufficient to drive evolution if Ne ×s is >1, where s is the selection coefficient. We found that this remains approximately correct if background selection is occurring or when population structure is present. Overall, we predict that even for free-living bacteria with enormous populations, natural selection is only a significant force ifs is above 10-7 or so. Because bacteria form huge populations with trillions of individuals, the simplest theoretical prediction is that the better allele at a site would predominate even if its advantage was just 10-9 per generation. In other words, virtually every nucleotide would be at the local optimum in most individuals. A more

  11. Weakly Deleterious Mutations and Low Rates of Recombination Limit the Impact of Natural Selection on Bacterial Genomes

    DOE PAGESBeta

    Price, Morgan N.; Arkin, Adam P.

    2015-12-15

    Free-living bacteria are usually thought to have large effective population sizes, and so tiny selective differences can drive their evolution. However, because recombination is infrequent, “background selection” against slightly deleterious alleles should reduce the effective population size (Ne) by orders of magnitude. For example, for a well-mixed population with 1012 individuals and a typical level of homologous recombination (r/m= 3, i.e., nucleotide changes due to recombination [r] occur at 3 times the mutation rate [m]), we predict that Ne is<107. An argument for high Ne values for bacteria has been the high genetic diversity within many bacterial “species,” but thismore » diversity may be due to population structure: diversity across subpopulations can be far higher than diversity within a subpopulation, which makes it difficult to estimate Ne correctly. Given an estimate ofNe, standard population genetics models imply that selection should be sufficient to drive evolution if Ne ×s is >1, where s is the selection coefficient. We found that this remains approximately correct if background selection is occurring or when population structure is present. Overall, we predict that even for free-living bacteria with enormous populations, natural selection is only a significant force ifs is above 10-7 or so. Because bacteria form huge populations with trillions of individuals, the simplest theoretical prediction is that the better allele at a site would predominate even if its advantage was just 10-9 per generation. In other words, virtually every nucleotide would be at the local optimum in most individuals. A more sophisticated theory considers that bacterial genomes have millions of sites each and selection events on these many sites could interfere with each other, so that only larger effects would be important. However, bacteria can exchange genetic material, and in principle, this exchange could eliminate the interference between the evolution of

  12. A novel papillation assay for the identification of genes affecting mutation rate in Pseudomonas putida and other pseudomonads.

    PubMed

    Tagel, Mari; Tavita, Kairi; Hõrak, Rita; Kivisaar, Maia; Ilves, Heili

    2016-08-01

    Formation of microcolonies (papillae) permits easy visual screening of mutational events occurring in single colonies of bacteria. In this study, we have established a novel papillation assay employable in a wide range of pseudomonads including Pseudomonas aeruginosa and Pseudomonas putida for monitoring mutation frequency in distinct colonies. With the aid of this assay, we conducted a genome-wide search for the factors affecting mutation frequency in P. putida. Screening ∼27,000 transposon mutants for increased mutation frequency allowed us to identify 34 repeatedly targeted genes. In addition to genes involved in DNA replication and repair, we identified genes participating in metabolism and transport of secondary metabolites, cell motility, and cell wall synthesis. The highest effect on mutant frequency was observed when truA (tRNA pseudouridine synthase), mpl (UDP-N-acetylmuramate-alanine ligase) or gacS (multi-sensor hybrid histidine kinase) were inactivated. Inactivation of truA elevated the mutant frequency only in growing cells, while the deficiency of gacS affected mainly stationary-phase mutagenesis. Thus, our results demonstrate the feasibility of the assay for isolating mutants with elevated mutagenesis in growing as well as stationary-phase bacteria. PMID:27447898

  13. High response rates to neoadjuvant platinum-based therapy in ovarian cancer patients carrying germ-line BRCA mutation.

    PubMed

    Gorodnova, Tatiana V; Sokolenko, Anna P; Ivantsov, Alexandr O; Iyevleva, Aglaya G; Suspitsin, Evgeny N; Aleksakhina, Svetlana N; Yanus, Grigory A; Togo, Alexandr V; Maximov, Sergey Ya; Imyanitov, Evgeny N

    2015-12-28

    Preoperative therapy provides an advantage for clinical drug assessment, as it involves yet untreated patients and facilitates access to the post-treatment biological material. Testing for Slavic founder BRCA mutations was performed for 225 ovarian cancer (OC) patients, who were treated by platinum-based neoadjuvant therapy. 34 BRCA1 and 1 BRCA2 mutation carriers were identified. Complete clinical response was documented in 12/35 (34%) mutation carriers and 8/190 (4%) non-carriers (P = 0.000002). Histopathologic response was observed in 16/35 (46%) women with the germ-line mutation versus 42/169 (25%) patients with the wild-type genotype (P = 0.02). Somatic loss of heterozygosity (LOH) for the remaining wild-type BRCA1 allele was detected only in 7/24 (29%) post-neoadjuvant therapy residual tumor tissues as compared to 9/11 (82%) BRCA1-associated OC, which were not exposed to systemic treatment before the surgery (P = 0.009). Furthermore, comparison of pre- and post-treatment tumor material obtained from the same patients revealed restoration of BRCA1 heterozygosity in 2 out of 3 sample pairs presenting with LOH at diagnosis. The obtained data confirm high sensitivity of BRCA-driven OC to platinating agents and provide evidence for a rapid selection of tumor cell clones without LOH during the course of therapy. PMID:26342406

  14. 14 CFR 158.5 - Authority to impose PFC's.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 14 Aeronautics and Space 3 2014-01-01 2014-01-01 false Authority to impose PFC's. 158.5 Section...) AIRPORTS PASSENGER FACILITY CHARGES (PFC'S) General § 158.5 Authority to impose PFC's. Subject to the... service airport to impose a PFC of $1, $2, $3, $4, or $4.50 on passengers enplaned at such an airport....

  15. 14 CFR 158.5 - Authority to impose PFC's.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 14 Aeronautics and Space 3 2013-01-01 2013-01-01 false Authority to impose PFC's. 158.5 Section...) AIRPORTS PASSENGER FACILITY CHARGES (PFC'S) General § 158.5 Authority to impose PFC's. Subject to the... service airport to impose a PFC of $1, $2, $3, $4, or $4.50 on passengers enplaned at such an airport....

  16. 14 CFR 158.5 - Authority to impose PFC's.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 3 2010-01-01 2010-01-01 false Authority to impose PFC's. 158.5 Section...) AIRPORTS PASSENGER FACILITY CHARGES (PFC'S) General § 158.5 Authority to impose PFC's. Subject to the... service airport to impose a PFC of $1, $2, $3, $4, or $4.50 on passengers enplaned at such an airport....

  17. 14 CFR 158.5 - Authority to impose PFC's.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 14 Aeronautics and Space 3 2011-01-01 2011-01-01 false Authority to impose PFC's. 158.5 Section...) AIRPORTS PASSENGER FACILITY CHARGES (PFC'S) General § 158.5 Authority to impose PFC's. Subject to the... service airport to impose a PFC of $1, $2, $3, $4, or $4.50 on passengers enplaned at such an airport....

  18. 14 CFR 158.5 - Authority to impose PFC's.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 14 Aeronautics and Space 3 2012-01-01 2012-01-01 false Authority to impose PFC's. 158.5 Section...) AIRPORTS PASSENGER FACILITY CHARGES (PFC'S) General § 158.5 Authority to impose PFC's. Subject to the... service airport to impose a PFC of $1, $2, $3, $4, or $4.50 on passengers enplaned at such an airport....

  19. Deep Phylogenetic Analysis of Haplogroup G1 Provides Estimates of SNP and STR Mutation Rates on the Human Y-Chromosome and Reveals Migrations of Iranic Speakers

    PubMed Central

    Balanovsky, Oleg; Zhabagin, Maxat; Agdzhoyan, Anastasiya; Chukhryaeva, Marina; Zaporozhchenko, Valery; Utevska, Olga; Highnam, Gareth; Sabitov, Zhaxylyk; Greenspan, Elliott; Dibirova, Khadizhat; Skhalyakho, Roza; Kuznetsova, Marina; Koshel, Sergey; Yusupov, Yuldash; Nymadawa, Pagbajabyn; Zhumadilov, Zhaxybay; Pocheshkhova, Elvira; Haber, Marc; A. Zalloua, Pierre; Yepiskoposyan, Levon; Dybo, Anna; Tyler-Smith, Chris; Balanovska, Elena

    2015-01-01

    Y-chromosomal haplogroup G1 is a minor component of the overall gene pool of South-West and Central Asia but reaches up to 80% frequency in some populations scattered within this area. We have genotyped the G1-defining marker M285 in 27 Eurasian populations (n= 5,346), analyzed 367 M285-positive samples using 17 Y-STRs, and sequenced ~11 Mb of the Y-chromosome in 20 of these samples to an average coverage of 67X. This allowed detailed phylogenetic reconstruction. We identified five branches, all with high geographical specificity: G1-L1323 in Kazakhs, the closely related G1-GG1 in Mongols, G1-GG265 in Armenians and its distant brother clade G1-GG162 in Bashkirs, and G1-GG362 in West Indians. The haplotype diversity, which decreased from West Iran to Central Asia, allows us to hypothesize that this rare haplogroup could have been carried by the expansion of Iranic speakers northwards to the Eurasian steppe and via founder effects became a predominant genetic component of some populations, including the Argyn tribe of the Kazakhs. The remarkable agreement between genetic and genealogical trees of Argyns allowed us to calibrate the molecular clock using a historical date (1405 AD) of the most recent common genealogical ancestor. The mutation rate for Y-chromosomal sequence data obtained was 0.78×10-9 per bp per year, falling within the range of published rates. The mutation rate for Y-chromosomal STRs was 0.0022 per locus per generation, very close to the so-called genealogical rate. The “clan-based” approach to estimating the mutation rate provides a third, middle way between direct farther-to-son comparisons and using archeologically known migrations, whose dates are subject to revision and of uncertain relationship to genetic events. PMID:25849548

  20. Mutations to R. sphaeroides Reaction Center Perturb Energy Levels and Vibronic Coupling but Not Observed Energy Transfer Rates.

    PubMed

    Flanagan, Moira L; Long, Phillip D; Dahlberg, Peter D; Rolczynski, Brian S; Massey, Sara C; Engel, Gregory S

    2016-03-10

    The bacterial reaction center is capable of both efficiently collecting and quickly transferring energy within the complex; therefore, the reaction center serves as a convenient model for both energy transfer and charge separation. To spectroscopically probe the interactions between the electronic excited states on the chromophores and their intricate relationship with vibrational motions in their environment, we examine coherences between the excited states. Here, we investigate this question by introducing a series of point mutations within 12 Å of the special pair of bacteriochlorophylls in the Rhodobacter sphaeroides reaction center. Using two-dimensional spectroscopy, we find that the time scales of energy transfer dynamics remain unperturbed by these mutations. However, within these spectra, we detect changes in the mixed vibrational-electronic coherences in these reaction centers. Our results indicate that resonance between bacteriochlorophyll vibrational modes and excitonic energy gaps promote electronic coherences and support current vibronic models of photosynthetic energy transfer. PMID:26630123

  1. Mutation Rate Switch inside Eurasian Mitochondrial Haplogroups: Impact of Selection and Consequences for Dating Settlement in Europe

    PubMed Central

    Pierron, Denis; Chang, Ivan; Arachiche, Amal; Heiske, Margit; Thomas, Olivier; Borlin, Marine; Pennarun, Erwan; Murail, Pacal; Thoraval, Didier; Rocher, Christophe; Letellier, Thierry

    2011-01-01

    R-lineage mitochondrial DNA represents over 90% of the European population and is significantly present all around the planet (North Africa, Asia, Oceania, and America). This lineage played a major role in migration “out of Africa” and colonization in Europe. In order to determine an accurate dating of the R lineage and its sublineages, we analyzed 1173 individuals and complete mtDNA sequences from Mitomap. This analysis revealed a new coalescence age for R at 54.500 years, as well as several limitations of standard dating methods, likely to lead to false interpretations. These findings highlight the association of a striking under-accumulation of synonymous mutations, an over-accumulation of non-synonymous mutations, and the phenotypic effect on haplogroup J. Consequently, haplogroup J is apparently not a Neolithic group but an older haplogroup (Paleolithic) that was subjected to an underestimated selective force. These findings also indicated an under-accumulation of synonymous and non-synonymous mutations localized on coding and non-coding (HVS1) sequences for haplogroup R0, which contains the major haplogroups H and V. These new dates are likely to impact the present colonization model for Europe and confirm the late glacial resettlement scenario. PMID:21738700

  2. Haplotype data and mutation rates for the 23 Y-STR loci of PowerPlex® Y 23 System in a Northeast Italian population sample.

    PubMed

    Turrina, Stefania; Caratti, Stefano; Ferrian, Melissa; De Leo, Domenico

    2015-07-01

    The PowerPlex® Y 23 System (Promega) is a short tandem repeat (STR) multiplex that allows co-amplification of 23 gonosomal Y-STRs, combining 17 loci commonly included in commercially available kits (DYS389I, DYS448, DYS389II, DYS19, DYS391, DYS438, DYS437, DYS635, DYS390, DYS439, DYS392, DYS393, DYS458, DYS385a/b, DYS456, and Y-GATA-H4) and six new loci (DYS481, DYS549, DYS533, DYS643, DYS576, and DYS570) with the last two being rapidly mutating Y-STRs (RM Y-STRs). In order to assess the possible gain in forensic efficiency provided by the six additional markers, a population sample of 410 unrelated healthy males originating from Northeast Italy (Veneto, Trentino Alto Adige, Lombardia, and Friuli Venezia Giulia regions) was typed. The data (335 of the 410 samples) are available in the Y chromosome haplotype reference database under accession number YA003327. Overall, 410 unique haplotypes were found corresponding to a global haplotype diversity (HD) of 0.999994 with a discriminatory capacity (DC) of 100%. Allelic microvariants, null alleles, and duplications were detected. Pairwise genetic distances (R(ST)) calculated among neighboring European reference populations revealed no significant differences. Furthermore, for studying Y-STR mutation rates, 90 father-son pairs, in which the fathers were already included in the full dataset, were tested. On a total of 2,070 meioses considered, eight single-step mutational events were observed, two of which within the same father-son pair and the average mutation rate was 3.38 × 10(-3) per locus per generation (95% confidence interval, 1.36 × 10(-3)-6.95 × 10(-3)). PMID:25099381

  3. Decreasing population selection rates of resistance mutation K65R over time in HIV-1 patients receiving combination therapy including tenofovir

    PubMed Central

    Theys, K.; Snoeck, J.; Vercauteren, J.; Abecasis, A. B.; Vandamme, A.-M.; Camacho, R. J.

    2013-01-01

    Objectives The use of tenofovir is highly associated with the emergence of mutation K65R, which confers broad resistance to nucleoside/nucleotide analogue reverse transcriptase inhibitors (NRTIs), especially when tenofovir is combined with other NRTIs also selecting for K65R. Although recent HIV-1 treatment guidelines discouraging these combinations resulted in reduced K65R selection with tenofovir, updated information on the impact of currently recommended regimens on the population selection rate of K65R is presently lacking. Methods In this study, we evaluated changes over time in the selection rate of resistance mutation K65R in a large population of 2736 HIV-1-infected patients failing combination antiretroviral treatment between 2002 and 2010. Results The K65R resistance mutation was detected in 144 patients, a prevalence of 5.3%. A large majority of observed K65R cases were explained by the use of tenofovir, reflecting its wide use in clinical practice. However, changing patterns over time in NRTIs accompanying tenofovir resulted in a persistent decreasing probability of K65R selection by tenofovir-based therapy. The currently recommended NRTI combination tenofovir/emtricitabine was associated with a low probability of K65R emergence. For any given dual NRTI combination including tenofovir, higher selection rates of K65R were consistently observed with a non-nucleoside reverse transcriptase inhibitor than with a protease inhibitor as the third agent. Discussion Our finding of a stable time trend of K65R despite elevated use of tenofovir illustrates increased potency of current HIV-1 therapy including tenofovir. PMID:23027713

  4. Genetic data and de novo mutation rates in father-son pairs of 23 Y-STR loci in Southern Brazil population.

    PubMed

    Da Fré, Nicole Nascimento; Rodenbusch, Rodrigo; Gastaldo, André Zoratto; Hanson, Erin; Ballantyne, Jack; Alho, Clarice Sampaio

    2015-11-01

    We evaluated haplotype and allele frequencies, as well as statistical forensic parameters, for 23 Y-chromosome short tandem repeats (STRs) loci of the PowerPlex®Y23 system (DYS19, DYS385a/b, DYS389I/II, DYS390, DYS391, DYS392, DYS393, DYS437, DYS438, DYS439, DYS448, DYS456, DYS458, DYS635, Y-GATA-H4, DYS481, DYS533, DYS549, DYS570, DYS576, DYS643) in a sample of 150 apparently healthy males, resident in South Brazil. A total of 150 different haplotypes were identified. The highest gene diversity (GD) was observed for the single locus marker DYS570 (GD = 0.7888) and for a two-locus system DYS385 (GD = 0.9009). We also examined 150 father-son pairs by the same system, and a total of 13 mutations were identified in the 3450 father-son allelic transfers, with an overall mutation rate across the 23 loci of 3.768 × 10(-3) (95% CI: 3.542 × 10(-3) to 3.944 × 10(-3)). In all cases there was only one locus mutated with gain/loss of repeats in the son (5 one-repeat gains, and 7 one-repeat and 1 two-repeat losses); we observed no instances of mutations involving a non-integral number of repeats. PMID:25391811

  5. Cellstat--A continuous culture system of a bacteriophage for the study of the mutation rate and the selection process at the DNA level

    NASA Astrophysics Data System (ADS)

    Husimi, Yuzuru; Nishigaki, Koichi; Kinoshita, Yasunori; Tanaka, Toyosuke

    1982-04-01

    A bacteriophage is continuously cultured in the flow of the host bacterial cell under the control of a minicomputer. In the culture, the population of the noninfected cell is kept constant by the endogeneous regulation mechanism, so it is called the ''cellstat'' culture. Due to the high dilution rate of the host cell, the mutant cell cannot be selected in the cellstat. Therefore, the cellstat is suitable for the study of the mutation rate and the selection process of a bacteriophage under well-defined environmental conditions (including physiological condition of the host cell) without being interfered by host-cell mutations. Applications to coliphage fd, a secretion type phage, are shown as a measurement example. A chimera between fd and a plasmid pBR322 is cultured more than 100 h. The process of population changeovers by deletion mutants indicates that the deletion hot spots exist in this cloning vector and that this apparatus can be used also for testing instability of a recombinant DNA.

  6. The Imposed Query: Implications for Library Service Evaluation.

    ERIC Educational Resources Information Center

    Gross, Melissa

    1998-01-01

    Explores the potential impact of imposed query, a new model of information-seeking behavior, on current approaches to library service and system evaluation. Discusses reference service evaluation, user studies, output measures, and relevance as an evaluation tool. Argues that imposed query broadens understanding of the user and of the role that…

  7. 49 CFR 382.111 - Other requirements imposed by employers.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 5 2013-10-01 2013-10-01 false Other requirements imposed by employers. 382.111 Section 382.111 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL MOTOR... CONTROLLED SUBSTANCES AND ALCOHOL USE AND TESTING General § 382.111 Other requirements imposed by...

  8. Disease dynamics and costly punishment can foster socially imposed monogamy

    PubMed Central

    Bauch, Chris T.; McElreath, Richard

    2016-01-01

    Socially imposed monogamy in humans is an evolutionary puzzle because it requires costly punishment by those who impose the norm. Moreover, most societies were—and are—polygynous; yet many larger human societies transitioned from polygyny to socially imposed monogamy beginning with the advent of agriculture and larger residential groups. We use a simulation model to explore how interactions between group size, sexually transmitted infection (STI) dynamics and social norms can explain the timing and emergence of socially imposed monogamy. Polygyny dominates when groups are too small to sustain STIs. However, in larger groups, STIs become endemic (especially in concurrent polygynist networks) and have an impact on fertility, thereby mediating multilevel selection. Punishment of polygynists improves monogamist fitness within groups by reducing their STI exposure, and between groups by enabling punishing monogamist groups to outcompete polygynists. This suggests pathways for the emergence of socially imposed monogamy, and enriches our understanding of costly punishment evolution. PMID:27044573

  9. Disease dynamics and costly punishment can foster socially imposed monogamy.

    PubMed

    Bauch, Chris T; McElreath, Richard

    2016-01-01

    Socially imposed monogamy in humans is an evolutionary puzzle because it requires costly punishment by those who impose the norm. Moreover, most societies were--and are--polygynous; yet many larger human societies transitioned from polygyny to socially imposed monogamy beginning with the advent of agriculture and larger residential groups. We use a simulation model to explore how interactions between group size, sexually transmitted infection (STI) dynamics and social norms can explain the timing and emergence of socially imposed monogamy. Polygyny dominates when groups are too small to sustain STIs. However, in larger groups, STIs become endemic (especially in concurrent polygynist networks) and have an impact on fertility, thereby mediating multilevel selection. Punishment of polygynists improves monogamist fitness within groups by reducing their STI exposure, and between groups by enabling punishing monogamist groups to outcompete polygynists. This suggests pathways for the emergence of socially imposed monogamy, and enriches our understanding of costly punishment evolution. PMID:27044573

  10. Rational design of mutations that change the aggregation rate of a protein while maintaining its native structure and stability

    PubMed Central

    Camilloni, Carlo; Sala, Benedetta Maria; Sormanni, Pietro; Porcari, Riccardo; Corazza, Alessandra; De Rosa, Matteo; Zanini, Stefano; Barbiroli, Alberto; Esposito, Gennaro; Bolognesi, Martino; Bellotti, Vittorio; Vendruscolo, Michele; Ricagno, Stefano

    2016-01-01

    A wide range of human diseases is associated with mutations that, destabilizing proteins native state, promote their aggregation. However, the mechanisms leading from folded to aggregated states are still incompletely understood. To investigate these mechanisms, we used a combination of NMR spectroscopy and molecular dynamics simulations to compare the native state dynamics of Beta-2 microglobulin (β2m), whose aggregation is associated with dialysis-related amyloidosis, and its aggregation-resistant mutant W60G. Our results indicate that W60G low aggregation propensity can be explained, beyond its higher stability, by an increased average protection of the aggregation-prone residues at its surface. To validate these findings, we designed β2m variants that alter the aggregation-prone exposed surface of wild-type and W60G β2m modifying their aggregation propensity. These results allowed us to pinpoint the role of dynamics in β2m aggregation and to provide a new strategy to tune protein aggregation by modulating the exposure of aggregation-prone residues. PMID:27150430

  11. Rational design of mutations that change the aggregation rate of a protein while maintaining its native structure and stability.

    PubMed

    Camilloni, Carlo; Sala, Benedetta Maria; Sormanni, Pietro; Porcari, Riccardo; Corazza, Alessandra; De Rosa, Matteo; Zanini, Stefano; Barbiroli, Alberto; Esposito, Gennaro; Bolognesi, Martino; Bellotti, Vittorio; Vendruscolo, Michele; Ricagno, Stefano

    2016-01-01

    A wide range of human diseases is associated with mutations that, destabilizing proteins native state, promote their aggregation. However, the mechanisms leading from folded to aggregated states are still incompletely understood. To investigate these mechanisms, we used a combination of NMR spectroscopy and molecular dynamics simulations to compare the native state dynamics of Beta-2 microglobulin (β2m), whose aggregation is associated with dialysis-related amyloidosis, and its aggregation-resistant mutant W60G. Our results indicate that W60G low aggregation propensity can be explained, beyond its higher stability, by an increased average protection of the aggregation-prone residues at its surface. To validate these findings, we designed β2m variants that alter the aggregation-prone exposed surface of wild-type and W60G β2m modifying their aggregation propensity. These results allowed us to pinpoint the role of dynamics in β2m aggregation and to provide a new strategy to tune protein aggregation by modulating the exposure of aggregation-prone residues. PMID:27150430

  12. Rational design of mutations that change the aggregation rate of a protein while maintaining its native structure and stability

    NASA Astrophysics Data System (ADS)

    Camilloni, Carlo; Sala, Benedetta Maria; Sormanni, Pietro; Porcari, Riccardo; Corazza, Alessandra; De Rosa, Matteo; Zanini, Stefano; Barbiroli, Alberto; Esposito, Gennaro; Bolognesi, Martino; Bellotti, Vittorio; Vendruscolo, Michele; Ricagno, Stefano

    2016-05-01

    A wide range of human diseases is associated with mutations that, destabilizing proteins native state, promote their aggregation. However, the mechanisms leading from folded to aggregated states are still incompletely understood. To investigate these mechanisms, we used a combination of NMR spectroscopy and molecular dynamics simulations to compare the native state dynamics of Beta-2 microglobulin (β2m), whose aggregation is associated with dialysis-related amyloidosis, and its aggregation-resistant mutant W60G. Our results indicate that W60G low aggregation propensity can be explained, beyond its higher stability, by an increased average protection of the aggregation-prone residues at its surface. To validate these findings, we designed β2m variants that alter the aggregation-prone exposed surface of wild-type and W60G β2m modifying their aggregation propensity. These results allowed us to pinpoint the role of dynamics in β2m aggregation and to provide a new strategy to tune protein aggregation by modulating the exposure of aggregation-prone residues.

  13. Role of metabolic rate and DNA-repair in Drosophila aging Implications for the mitochondrial mutation theory of aging

    NASA Technical Reports Server (NTRS)

    Miquel, J.; Binnard, R.; Fleming, J. E.

    1983-01-01

    The notion that injury to mitochondrial DNA is a cause of intrinsic aging was tested by correlating the different respiration rates of several wild strains of Drosophila melanogaster with the life-spans. Respiration rate and aging in a mutant of D. melanogaster deficient in postreplication repair were also investigated. In agreement with the rate of living theory, there was an inverse relation between oxygen consumption and median life-span in flies having normal DNA repair. The mutant showed an abnormally low life-span as compared to the controls and also exhibited significant deficiency in mating fitness and a depressed metabolic rate. Therefore, the short life-span of the mutant may be due to the congenital condition rather than to accelerated aging.

  14. Divergence between the high rate of p53 mutations in skin carcinomas and the low prevalence of anti-p53 antibodies

    PubMed Central

    Moch, C; Moysan, A; Lubin, R; Salmonière, P de La; Soufir, N; Galisson, F; Vilmer, C; Venutolo, E; Pelletier, F Le; Janin, A; Basset-Séguin, N

    2001-01-01

    Circulating anti-p53 antibodies have been described and used as tumoural markers in patients with various cancers and strongly correlate with the p53 mutated status of the tumours. No study has yet looked at the prevalence of such antibodies in skin carcinoma patients although these tumours have been shown to be frequently p53 mutated. Most skin carcinoma can be diagnosed by examination or biopsy, but aggressive, recurrent and/or non-surgical cases' follow up would be helped by a biological marker of residual disease. We performed a prospective study looking at the prevalence of anti-p53 antibodies using an ELISA technique in a series of 105 skin carcinoma patients in comparison with a sex- and age-matched control skin carcinoma-free group (n = 130). Additionally, p53 accumulation was studied by immunohistochemistry to confirm p53 protein altered expression in a sample of tumours. Anti-p53 antibodies were detected in 2.9% of the cases, with a higher prevalence in patients suffering from the more aggressive squamous cell type (SCC) of skin carcinoma (8%) than for the more common and slowly growing basal cell carcinoma type or BCC (1.5%). p53 protein stabilization could be confirmed in 80% of tumours studied by IHC. This low level of anti-p53 antibody detection contrasts with the high rate of p53 mutations reported in these tumours. This observation shows that the anti-p53 humoral response is a complex and tissue-specific mechanism. © 2001 Cancer Research Campaign http://www.bjcancer.com PMID:11747330

  15. 26 CFR 1.6664-3 - Ordering rules for determining the total amount of penalties imposed.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Additions to the Tax... for negligence or disregard of rules or regulations, substantial understatement of income tax, or... been imposed at a 75 percent rate (i.e., a penalty for fraud under section 6663). (c) Manner in...

  16. 26 CFR 1.6664-3 - Ordering rules for determining the total amount of penalties imposed.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Additions to the Tax... for negligence or disregard of rules or regulations, substantial understatement of income tax, or... been imposed at a 75 percent rate (i.e., a penalty for fraud under section 6663). (c) Manner in...

  17. 26 CFR 1.6664-3 - Ordering rules for determining the total amount of penalties imposed.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Additions to the Tax... for negligence or disregard of rules or regulations, substantial understatement of income tax, or... been imposed at a 75 percent rate (i.e., a penalty for fraud under section 6663). (c) Manner in...

  18. The experience of mutation rate quantitative evaluation in connection with environmental pollution (based on studies of congenital anomalies in human populations).

    PubMed

    Antipenko YeN; Kogut, N N

    1993-10-01

    relation between average annual general emission of atmospheric pollutants (M./Z.) was 2.21, the frequency of dominant and X-linked CA 2.20 and of new skeleton mutations 2.24. The difference of mutation rate in the towns studied was due to the dynamics of demographic processes. PMID:7690882

  19. The L76V Drug Resistance Mutation Decreases the Dimer Stability and Rate of Autoprocessing of HIV-1 Protease by Reducing Internal Hydrophobic Contacts

    SciTech Connect

    Louis, John M.; Zhang, Ying; Sayer, Jane M.; Wang, Yuan-Fang; Harrison, Robert W.; Weber, Irene T.

    2011-09-06

    The mature HIV-1 protease (PR) bearing the L76V drug resistance mutation (PR{sub L76V}) is significantly less stable, with a >7-fold higher dimer dissociation constant (K{sub d}) of 71 {+-} 24 nM and twice the sensitivity to urea denaturation (UC{sub 50} = 0.85 M) relative to those of PR. Differential scanning calorimetry showed decreases in T{sub m} of 12 C for PR{sub L76V} in the absence of inhibitors and 5-7 C in the presence of inhibitors darunavir (DRV), saquinavir (SQV), and lopinavir (LPV), relative to that of PR. Isothermal titration calorimetry gave a ligand dissociation constant of 0.8 nM for DRV, {approx}160-fold higher than that of PR, consistent with DRV resistance. Crystal structures of PR{sub L76V} in complexes with DRV and SQV were determined at resolutions of 1.45-1.46 {angstrom}. Compared to the corresponding PR complexes, the mutated Val76 lacks hydrophobic interactions with Asp30, Lys45, Ile47, and Thr74 and exhibits closer interactions with Val32 and Val56. The bound DRV lacks one hydrogen bond with the main chain of Asp30 in PR{sub L76V} relative to PR, possibly accounting for the resistance to DRV. SQV shows slightly improved polar interactions with PR{sub L76V} compared to those with PR. Although the L76V mutation significantly slows the N-terminal autoprocessing of the precursor TFR-PR{sub L76V} to give rise to the mature PR{sub L76V}, the coselected M46I mutation counteracts the effect by enhancing this rate but renders the TFR-PRM46I/L76V precursor less responsive to inhibition by 6 {micro}M LPV while preserving inhibition by SQV and DRV. The correlation of lowered stability, higher K{sub d}, and impaired autoprocessing with reduced internal hydrophobic contacts suggests a novel molecular mechanism for drug resistance.

  20. Non-axisymmetric instabilities in discs with imposed zonal flows

    NASA Astrophysics Data System (ADS)

    Vanon, R.; Ogilvie, G. I.

    2016-09-01

    We conduct a linear stability calculation of an ideal Keplerian flow on which a sinusoidal zonal flow is imposed. The analysis uses the shearing sheet model and is carried out both in isothermal and adiabatic conditions, with and without self-gravity (SG). In the non-SG regime a structure in the potential vorticity (PV) leads to a non-axisymmetric Kelvin-Helmholtz (KH) instability; in the short-wavelength limit its growth rate agrees with the incompressible calculation by Lithwick (2007), which only considers perturbations elongated in the streamwise direction. The instability's strength is analysed as a function of the structure's properties, and zonal flows are found to be stable if their wavelength is ≳ 8H, where H is the disc's scale height, regardless of the value of the adiabatic index γ. The non-axisymmetric KH instability can operate in Rayleigh-stable conditions, and it therefore represents the limiting factor to the structure's properties. Introducing SG triggers a second non-axisymmetric instability, which is found to be located around a PV maximum, while the KH instability is linked to a PV minimum, as expected. In the adiabatic regime, the same gravitational instability is detected even when the structure is present only in the entropy (not in the PV) and the instability spreads to weaker SG conditions as the entropy structure's amplitude is increased. This eventually yields a non-axisymmetric instability in the non-SG regime, albeit of weak strength, localised around an entropy maximum.

  1. Imposed Radiation Effects on Flame Spread over Black PMMA in Low Gravity

    NASA Technical Reports Server (NTRS)

    Olson, S. L.; Hegde, U.

    1994-01-01

    The objective of this work is to determine the effect of varying imposed radiation levels on the flame spread and burning characteristics of PMMA in low gravity. The NASA Learjet is used for these experiments; it provides an environment of 10(exp -2) g's for approximately 20 seconds. Flame spread rates are found to increase non-linearly with increased external radiant flux over the range studied. This range of imposed flux values is believed to be sufficient to compensate for the radiative loss from the flame and the surface.

  2. Mutations in Type I and Type IV Pilus Biosynthetic Genes Affect Twitching Motility Rates in Xylella fastidiosa▿ †

    PubMed Central

    De La Fuente, Leonardo; Burr, Thomas J.; Hoch, Harvey C.

    2007-01-01

    Xylella fastidiosa possesses both type I and type IV pili at the same cell pole. By use of a microfluidic device, the speed of twitching movement by wild-type cells on a glass surface against the flow direction of media was measured as 0.86 (standard error [SE], 0.04) μm min−1. A type I pilus mutant (fimA) moved six times faster (4.85 [SE, 0.27] μm min−1) and a pilY1 mutant moved three times slower (0.28 [SE, 0.03] μm min−1) than wild-type cells. Type I pili slow the rate of movement, while the putative type IV pilus protein PilY1 is likely important for attachment to surfaces. PMID:17693510

  3. A mutation that eliminates bundle sheath extensions reduces leaf hydraulic conductance, stomatal conductance and assimilation rates in tomato (Solanum lycopersicum).

    PubMed

    Zsögön, Agustin; Negrini, Ana Clarissa Alves; Peres, Lázaro Eustáquio Pereira; Nguyen, Hoa Thi; Ball, Marilyn C

    2015-01-01

    Bundle sheath extensions (BSEs) are key features of leaf structure whose distribution differs among species and ecosystems. The genetic control of BSE development is unknown, so BSE physiological function has not yet been studied through mutant analysis. We screened a population of ethyl methanesulfonate (EMS)-induced mutants in the genetic background of the tomato (Solanum lycopersicum) model Micro-Tom and found a mutant lacking BSEs. The leaf phenotype of the mutant strongly resembled the tomato mutant obscuravenosa (obv). We confirmed that obv lacks BSEs and that it is not allelic to our induced mutant, which we named obv-2. Leaves lacking BSEs had lower leaf hydraulic conductance and operated with lower stomatal conductance and correspondingly lower assimilation rates than wild-type leaves. This lower level of function occurred despite similarities in vein density, midvein vessel diameter and number, stomatal density, and leaf area between wild-type and mutant leaves, the implication being that the lack of BSEs hindered water dispersal within mutant leaves. Our results comparing near-isogenic lines within a single species confirm the hypothesised role of BSEs in leaf hydraulic function. They further pave the way for a genetic model-based analysis of a common leaf structure with deep ecological consequences. PMID:25267094

  4. Control of rare events in reaction and population systems by deterministically imposed transitions

    NASA Astrophysics Data System (ADS)

    Khasin, M.; Dykman, M. I.

    2011-03-01

    We consider control of reaction and population systems by imposing transitions between states with different numbers of particles or individuals. The transitions take place at predetermined instants of time. Even where they are significantly less frequent than spontaneous transitions, they can exponentially strongly modify the rates of rare events, including switching between metastable states or population extinction. We also study optimal control of rare events. Specifically, we are interested in the optimal control of disease extinction for a limited vaccine supply. A comparison is made with control of rare events by modulating the rates of elementary transitions rather than imposing transitions deterministically. It is found that, unexpectedly, for the same mean control parameters, controlling the transitions rates can be more efficient.

  5. Unexpectedly Low Mutation Rates in Beta-Myosin Heavy Chain and Cardiac Myosin Binding Protein Genes in Italian Patients With Hypertrophic Cardiomyopathy

    PubMed Central

    Roncarati, Roberta; Latronico, Michael VG; Musumeci, Beatrice; Aurino, Stefania; Torella, Annalaura; Bang, Marie-Louise; Jotti, Gloria Saccani; Puca, Annibale A; Volpe, Massimo; Nigro, Vincenzo; Autore, Camillo; Condorelli, Gianluigi

    2011-01-01

    Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiac disease. Fourteen sarcomeric and sarcomere-related genes have been implicated in HCM etiology, those encoding β-myosin heavy chain (MYH7) and cardiac myosin binding protein C (MYBPC3) reported as the most frequently mutated: in fact, these account for around 50% of all cases related to sarcomeric gene mutations, which are collectively responsible for approximately 70% of all HCM cases. Here, we used denaturing high-performance liquid chromatography followed by bidirectional sequencing to screen the coding regions of MYH7 and MYBPC3 in a cohort (n = 125) of Italian patients presenting with HCM. We found 6 MHY7 mutations in 9/125 patients and 18 MYBPC3 mutations in 19/125 patients. Of the three novel MYH7 mutations found, two were missense, and one was a silent mutation; of the eight novel MYBPC3 mutations, one was a substitution, three were stop codons, and four were missense mutations. Thus, our cohort of Italian HCM patients did not harbor the high frequency of mutations usually found in MYH7 and MYBPC3. This finding, coupled to the clinical diversity of our cohort, emphasizes the complexity of HCM and the need for more inclusive investigative approaches in order to fully understand the pathogenesis of this disease. J. Cell. Physiol. 226: 2894–2900, 2011. © 2011 Wiley-Liss, Inc. PMID:21302287

  6. Periodically varying externally imposed environmental effects on population dynamics

    NASA Astrophysics Data System (ADS)

    Ballard, M.; Kenkre, V. M.; Kuperman, M. N.

    2004-09-01

    Effects of externally imposed periodic changes in the environment on population dynamics are studied with the help of a simple model. The environmental changes are represented by the temporal and spatial dependence of the competition terms in a standard equation of evolution. Possible applications of the analysis are on the one hand to bacteria in Petri dishes and on the other to rodents in the context of the spread of the Hantavirus epidemic. The analysis shows that spatiotemporal structures emerge, with interesting features which depend on the interplay of separately controllable aspects of the externally imposed environmental changes.

  7. Method to amplify variable sequences without imposing primer sequences

    DOEpatents

    Bradbury, Andrew M.; Zeytun, Ahmet

    2006-11-14

    The present invention provides methods of amplifying target sequences without including regions flanking the target sequence in the amplified product or imposing amplification primer sequences on the amplified product. Also provided are methods of preparing a library from such amplified target sequences.

  8. 42 CFR 23.34 - What other conditions are imposed?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... enter into private full-time clinical practice in a HMSA for the time period specified in the loan... HEALTH SERVICE CORPS Private Practice Special Loans for Former Corps Members § 23.34 What other conditions are imposed? (a) The borrower must sign a loan agreement describing the loan and...

  9. 42 CFR 23.34 - What other conditions are imposed?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... enter into private full-time clinical practice in a HMSA for the time period specified in the loan... HEALTH SERVICE CORPS Private Practice Special Loans for Former Corps Members § 23.34 What other conditions are imposed? (a) The borrower must sign a loan agreement describing the loan and...

  10. Molecular mechanisms of cardiomyopathy phenotypes associated with myosin light chain mutations.

    PubMed

    Huang, Wenrui; Szczesna-Cordary, Danuta

    2015-12-01

    We discuss here the potential mechanisms of action associated with hypertrophic (HCM) or dilated (DCM) cardiomyopathy causing mutations in the myosin regulatory (RLC) and essential (ELC) light chains. Specifically, we focus on four HCM mutations: RLC-A13T, RLC-K104E, ELC-A57G and ELC-M173V, and one DCM RLC-D94A mutation shown by population studies to cause different cardiomyopathy phenotypes in humans. Our studies indicate that RLC and ELC mutations lead to heart disease through different mechanisms with RLC mutations triggering alterations of the secondary structure of the RLC which further affect the structure and function of the lever arm domain and impose changes in the cross bridge cycling rates and myosin force generation ability. The ELC mutations exert their detrimental effects through changes in the interaction of the N-terminus of ELC with actin altering the cross talk between the thick and thin filaments and ultimately resulting in an altered force-pCa relationship. We also discuss the effect of mutations on myosin light chain phosphorylation. Exogenous myosin light chain phosphorylation and/or pseudo-phosphorylation were explored as potential rescue tools to treat hypertrophy-related cardiac phenotypes. PMID:26385864

  11. Genome Destabilizing Mutator Alleles Drive Specific Mutational Trajectories in Saccharomyces cerevisiae

    PubMed Central

    Stirling, Peter C.; Shen, Yaoqing; Corbett, Richard; Jones, Steven J. M.; Hieter, Philip

    2014-01-01

    In addition to environmental factors and intrinsic variations in base substitution rates, specific genome-destabilizing mutations can shape the mutational trajectory of genomes. How specific alleles influence the nature and position of accumulated mutations in a genomic context is largely unknown. Understanding the impact of genome-destabilizing alleles is particularly relevant to cancer genomes where biased mutational signatures are identifiable. We first created a more complete picture of cellular pathways that impact mutation rate using a primary screen to identify essential Saccharomyces cerevisiae gene mutations that cause mutator phenotypes. Drawing primarily on new alleles identified in this resource, we measure the impact of diverse mutator alleles on mutation patterns directly by whole-genome sequencing of 68 mutation-accumulation strains derived from wild-type and 11 parental mutator genotypes. The accumulated mutations differ across mutator strains, displaying base-substitution biases, allele-specific mutation hotspots, and break-associated mutation clustering. For example, in mutants of POLα and the Cdc13–Stn1–Ten1 complex, we find a distinct subtelomeric bias for mutations that we show is independent of the target sequence. Together our data suggest that specific genome-instability mutations are sufficient to drive discrete mutational signatures, some of which share properties with mutation patterns seen in tumors. Thus, in a population of cells, genome-instability mutations could influence clonal evolution by establishing discrete mutational trajectories for genomes. PMID:24336748

  12. NPM1 but not FLT3-ITD mutations predict early blast cell clearance and CR rate in patients with normal karyotype AML (NK-AML) or high-risk myelodysplastic syndrome (MDS).

    PubMed

    Schneider, Friederike; Hoster, Eva; Unterhalt, Michael; Schneider, Stephanie; Dufour, Annika; Benthaus, Tobias; Mellert, Gudrun; Zellmeier, Evelin; Bohlander, Stefan K; Feuring-Buske, Michaela; Buske, Christian; Braess, Jan; Fritsch, Susanne; Heinecke, Achim; Sauerland, Maria C; Berdel, Wolfgang E; Buechner, Thomas; Woermann, Bernhard J; Hiddemann, Wolfgang; Spiekermann, Karsten

    2009-05-21

    Mutations in the NPM1 gene represent the most frequent genetic alterations in patients with acute myeloid leukemia (AML) and are associated with a favorable outcome. In 690 normal karyotype (NK) AML patients the complete remission rates (CRs) and the percentage of patients with adequate in vivo blast cell reduction 1 week after the end of the first induction cycle were significantly higher in NPM1(+) (75% and 80%, respectively) than in NPM1(-) (57% and 57%, respectively) patients, but were unaffected by the FLT3-ITD status. Multivariate analyses revealed the presence of a NPM1 mutation as an independent positive prognostic factor for the achievement of an adequate day-16 blast clearance and a CR. In conclusion, NPM1(+) blast cells show a high in vivo sensitivity toward induction chemotherapy irrespective of the FLT3-ITD mutation status. These findings provide insight into the pathophysiology and help to understand the favorable clinical outcome of patients with NPM1(+) AML. PMID:19279329

  13. Clock-like mutational processes in human somatic cells

    SciTech Connect

    Alexandrov, Ludmil B.; Jones, Philip H.; Wedge, David C.; Sale, Julian E.; Campbell, Peter J.; Nik-Zainal, Serena; Stratton, Michael R.

    2015-11-09

    During the course of a lifetime, somatic cells acquire mutations. Different mutational processes may contribute to the mutations accumulated in a cell, with each imprinting a mutational signature on the cell's genome. Some processes generate mutations throughout life at a constant rate in all individuals, and the number of mutations in a cell attributable to these processes will be proportional to the chronological age of the person. Using mutations from 10,250 cancer genomes across 36 cancer types, we investigated clock-like mutational processes that have been operating in normal human cells. Two mutational signatures show clock-like properties. Both exhibit different mutation rates in different tissues. However, their mutation rates are not correlated, indicating that the underlying processes are subject to different biological influences. For one signature, the rate of cell division may influence its mutation rate. This paper provides the first survey of clock-like mutational processes operating in human somatic cells.

  14. Clock-like mutational processes in human somatic cells

    PubMed Central

    Alexandrov, Ludmil B.; Jones, Philip H.; Wedge, David C.; Sale, Julian E.; Campbell, Peter J.; Nik-Zainal, Serena; Stratton, Michael R.

    2016-01-01

    During the course of a lifetime somatic cells acquire mutations. Different mutational processes may contribute to the mutations accumulated in a cell, with each imprinting a mutational signature on the cell’s genome. Some processes generate mutations throughout life at a constant rate in all individuals and the number of mutations in a cell attributable to these processes will be proportional to the chronological age of the person. Using mutations from 10,250 cancer genomes across 36 cancer types, we investigated clock-like mutational processes that have been operating in normal human cells. Two mutational signatures show clock-like properties. Both exhibit different mutation rates in different tissues. However, their mutation rates are not correlated indicating that the underlying processes are subject to different biological influences. For one signature, the rate of cell division may influence its mutation rate. This study provides the first survey of clock-like mutational processes operative in human somatic cells. PMID:26551669

  15. 26 CFR 1.337(d)-6 - New transitional rules imposing tax on property owned by a C corporation that becomes property of...

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 4 2010-04-01 2010-04-01 false New transitional rules imposing tax on property... TAXES Effects on Corporation § 1.337(d)-6 New transitional rules imposing tax on property owned by a C... corporate tax rate is 35%. (ii) Under this paragraph (b), Y is treated as if it sold the converted...

  16. Two Galpha(i1) rate-modifying mutations act in concert to allow receptor-independent, steady-state measurements of RGS protein activity.

    PubMed

    Zielinski, Thomas; Kimple, Adam J; Hutsell, Stephanie Q; Koeff, Mark D; Siderovski, David P; Lowery, Robert G

    2009-12-01

    RGS proteins are critical modulators of G-protein-coupled receptor (GPCR) signaling given their ability to deactivate Galpha subunits via GTPase-accelerating protein (GAP) activity. Their selectivity for specific GPCRs makes them attractive therapeutic targets. However, measuring GAP activity is complicated by slow guanosine diphosphate (GDP) release from Galpha and lack of solution phase assays for detecting free GDP in the presence of excess guanosine triphosphate (GTP). To overcome these hurdles, the authors developed a Galpha(i1) mutant with increased GDP dissociation and decreased GTP hydrolysis rates, enabling detection of GAP activity using steady-state GTP hydrolysis. Galpha(i1)(R178M/A326S) GTPase activity was stimulated 6- to 12-fold by RGS proteins known to act on Galpha(i) subunits and not affected by those unable to act on Galpha(i), demonstrating that the Galpha/RGS domain interaction selectivity was not altered by mutation. The selectivity and affinity of Galpha( i1)(R178M/A326S) interaction with RGS proteins was confirmed by molecular binding studies. To enable nonradioactive, homogeneous detection of RGS protein effects on Galpha(i1)(R178M/A326S), the authors developed a Transcreener fluorescence polarization immunoassay based on a monoclonal antibody that recognizes GDP with greater than 100-fold selectivity over GTP. Combining Galpha(i1)(R178M/A326S) with a homogeneous, fluorescence-based GDP detection assay provides a facile means to explore the targeting of RGS proteins as a new approach for selective modulation of GPCR signaling. PMID:19820068

  17. Variation in Mutation Rates Caused by RB69pol Fidelity Mutants Can Be Rationalized on the Basis of Their Kinetic Behavior and Crystal Structures

    SciTech Connect

    S Xia; M Wang; H Lee; A Sinha; G Blaha; T Christian; J Wang; W Konigsberg

    2011-12-31

    We have previously observed that stepwise replacement of amino acid residues in the nascent base-pair binding pocket of RB69 DNA polymerase (RB69pol) with Ala or Gly expanded the space in this pocket, resulting in a progressive increase in misincorporation. However, in vivo results with similar RB69pol nascent base-pair binding pocket mutants showed that mutation rates, as determined by the T4 phage rI forward assay and rII reversion assay, were significantly lower for the RB69pol S565G/Y567A double mutant than for the Y567A single mutant, the opposite of what we would have predicted. To investigate the reasons for this unexpected result, we have determined the pre-steady-state kinetic parameters and crystal structures of relevant ternary complexes. We found that the S565G/Y567A mutant generally had greater base selectivity than the Y567A mutant and that the kinetic parameters for dNMP insertion, excision of the 3'-terminal nucleotide residue, and primer extension beyond a mispair differed not only between these two mutants but also between the two highly mutable sequences in the T4 rI complementary strand. Comparison of the crystal structures of these two mutants with correct and incorrect incoming dNTPs provides insight into the unexpected increase in the fidelity of the S565G/Y567A double mutant. Taken together, the kinetic and structural results provide a basis for integrating and interpreting in vivo and in vitro observations.

  18. Doubling the referral rate of monogenic diabetes through a nationwide information campaign--update on glucokinase gene mutations in a Polish cohort.

    PubMed

    Borowiec, M; Fendler, W; Antosik, K; Baranowska, A; Gnys, P; Zmyslowska, A; Malecki, M; Mlynarski, W

    2012-12-01

    In order to improve recruitment efficiency of patients with monogenic diabetes in Poland, in September 2010 a nationwide advertising campaign was launched to inform multiple target groups interested or participating in pediatric diabetologic care. Promotional actions aimed at informing physicians, patients, parents and educators were carried out through nationwide newspapers, medical and patient-developed websites and educational conference presentations. Recruitment efficiency was compared between September 2010 (publication of the first report on project's results) and the following 12 months. The number of families and patients referred to genetic screening was increased by 92% and 96% respectively nearly reaching the numbers recruited throughout the initial 4 years of the project. Participation of non-academic centers was also significantly increased from 2.3% to 7.5% (p = 0.0005). DNA sequencing and Multiplex Ligation-dependant Probe Amplification of the glucokinase gene resulted in finding 50 different mutations. Among those mutations, 19 were novel variants, which included: 17 missense mutations (predicted to be pathogenic according to bioinformatic analysis), 1 nonsense mutation and 1 mutation affecting a consensus intronic splice site. Advertising actions directed at increasing recruitment efficiency are a powerful and possibly neglected tool in screening for rare genetic disorders with a clinically defined phenotype. PMID:22035297

  19. AID-initiated purposeful mutations in immunoglobulin genes.

    PubMed

    Goodman, Myron F; Scharff, Matthew D; Romesberg, Floyd E

    2007-01-01

    Exposure brings risk to all living organisms. Using a remarkably effective strategy, higher vertebrates mitigate risk by mounting a complex and sophisticated immune response to counter the potentially toxic invasion by a virtually limitless army of chemical and biological antagonists. Mutations are almost always deleterious, but in the case of antibody diversification there are mutations occurring at hugely elevated rates within the variable (V) and switch regions (SR) of the immunoglobulin (Ig) genes that are responsible for binding to and neutralizing foreign antigens throughout the body. These mutations are truly purposeful. This chapter is centered on activation-induced cytidine deaminase (AID). AID is required for initiating somatic hypermutation (SHM) in the V regions and class switch recombination (CSR) in the SR portions of Ig genes. By converting C --> U, while transcription takes place, AID instigates a cascade of mutational events involving error-prone DNA polymerases, base excision and mismatch repair enzymes, and recombination pathways. Together, these processes culminate in highly mutated antibody genes and the B cells expressing antibodies that have achieved optimal antigenic binding undergo positive selection in germinal centers. We will discuss the biological role of AID in this complex process, primarily in terms of its biochemical properties in relation to SHM in vivo. The chapter also discusses recent advances in experimental methods to characterize antibody dynamics as a function of SHM to help elucidate the role that the AID-induced mutations play in tailoring molecular recognition. The emerging experimental techniques help to address long-standing conundrums concerning evolution-imposed constraints on antibody structure and function. PMID:17560274

  20. Constraints imposed by cosmic evolution towards the development of life

    NASA Technical Reports Server (NTRS)

    Oro, J.

    1988-01-01

    The probability of terrestrial-type life emerging in any other place of the universe will depend on the constraints imposed by cosmic evolution on that particular place. A systematic examination of cosmic constraints, which must have provided the necessary and sufficient conditions for the origin and evolution of life on earth, shows that they are concerned with the nature of the central star, the planetary system, and the specific life-bearing planet, as well as with the chemical and biological evolution processes involved. These constraints or universal requirements for life are briefly described.

  1. Loads imposed on intermediate frames of stiffened shells

    NASA Technical Reports Server (NTRS)

    Kuhn, Paul

    1939-01-01

    The loads imposed on intermediate frames by the curvature of the longitudinal and by the diagonal-tension effects are treated. A new empirical method is proposed for analyzing diagonal-tension effects. The basic formulas of the pure diagonal-tension theory are used, and the part of the total shear S carried by diagonal tension is assumed to be given the expression S (sub DT) = S (1-tau sub o/tau)(sup n) where tau (sub o) is the critical shear stress, tau the total (nominal shear stress), and n = 3 - sigma/tau where sigma is the stress in the intermediate frame. Numerical examples illustrate all cases treated.

  2. Self-imposed timeouts under increasing response requirements.

    NASA Technical Reports Server (NTRS)

    Dardano, J. F.

    1973-01-01

    Three male White Carneaux pigeons were used in the investigation. None of the results obtained contradicts the interpretation of self-imposed timeouts as an escape response reinforced by the removal of unfavorable reinforcement conditions, although some details of the performances reflect either a weak control and/or operation of other controlling variables. Timeout key responding can be considered as one of several classes of behavior having a low probability of occurrence, all of which compete with the behavior maintained by positive reinforcement schedule.

  3. 26 CFR 52.4681-1 - Taxes imposed with respect to ozone-depleting chemicals.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 17 2012-04-01 2012-04-01 false Taxes imposed with respect to ozone-depleting... to ozone-depleting chemicals. (a) Taxes imposed. Sections 4681 and 4682 impose the following taxes with respect to ozone-depleting chemicals (ODCs): (1) Tax on ODCs. Section 4681(a)(1) imposes a tax...

  4. 26 CFR 52.4681-1 - Taxes imposed with respect to ozone-depleting chemicals.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 17 2014-04-01 2014-04-01 false Taxes imposed with respect to ozone-depleting... to ozone-depleting chemicals. (a) Taxes imposed. Sections 4681 and 4682 impose the following taxes with respect to ozone-depleting chemicals (ODCs): (1) Tax on ODCs. Section 4681(a)(1) imposes a tax...

  5. The fitness burden imposed by synthesising quorum sensing signals.

    PubMed

    Ruparell, A; Dubern, J F; Ortori, C A; Harrison, F; Halliday, N M; Emtage, A; Ashawesh, M M; Laughton, C A; Diggle, S P; Williams, P; Barrett, D A; Hardie, K R

    2016-01-01

    It is now well established that bacterial populations utilize cell-to-cell signaling (quorum-sensing, QS) to control the production of public goods and other co-operative behaviours. Evolutionary theory predicts that both the cost of signal production and the response to signals should incur fitness costs for producing cells. Although costs imposed by the downstream consequences of QS have been shown, the cost of QS signal molecule (QSSM) production and its impact on fitness has not been examined. We measured the fitness cost to cells of synthesising QSSMs by quantifying metabolite levels in the presence of QSSM synthases. We found that: (i) bacteria making certain QSSMs have a growth defect that exerts an evolutionary cost, (ii) production of QSSMs negatively correlates with intracellular concentrations of QSSM precursors, (iii) the production of heterologous QSSMs negatively impacts the production of a native QSSM that shares common substrates, and (iv) supplementation with exogenously added metabolites partially rescued growth defects imposed by QSSM synthesis. These data identify the sources of the fitness costs incurred by QSSM producer cells, and indicate that there may be metabolic trade-offs associated with QS signaling that could exert selection on how signaling evolves. PMID:27616328

  6. Voluntary drinking versus imposed drinking in the methodology of investigations about the drinking-induced thermoregulatory sweating

    PubMed Central

    Hosseinlou, Abdollah; Khamnei, Saeed; Zamanlu, Masumeh

    2014-01-01

    Studies have shown that dehydrated humans or animals in a warm environment begin to sweat within seconds to minutes after drinking. This phenomenon is one of the drinking-induced thermoregulatory responses; being investigated from different aspects. Our objective is to show the difference of voluntary drinking and imposed drinking in the methodology of these experiments. Six healthy subjects 23.7 ± 0.6 yr old and 80.7 ± 5.7 kg wt were dehydrated by performing mild exercise (ergometer cycling) in a hot and humid chamber (38-40°C, 20-28% relative humidity). We incorporated two protocols: after dehydration, subjects were allowed to drink water with 1) imposed volumes of 1, 3, 5 ml/kg and 2) voluntary volumes; on four separate days. The sweating rate was measured on the forehead area before and after drinking. Sweating increased markedly just a few minutes after the onset of drinking. The mean sweat rates of the imposed volumes of 1, 3, 5 ml/Kg were 0.33 ± 0.15, 0.31 ± 0.17, 0.47 ± 0.21 respectively and for the voluntary volume it was 0.54 ± 0.19. The mean intake in the voluntary trial was 6.58 ± 1.14 ml/Kg, more than the imposed volume of 5 ml/Kg. The trend of the rate of the sweating response in the imposed trials was distinct from the response in the voluntary trial. Conclusion: There exists a difference between voluntary drinking and imposed drinking in the sweating response that follows rehydration. So it is suggested to use the methods of voluntary drinking in the investigations of this phenomenon, to reveal the natural events that happen in the actual circumstances. PMID:25419429

  7. A Low Frequency of Losses in 11q Chromosome Is Associated with Better Outcome and Lower Rate of Genomic Mutations in Patients with Chronic Lymphocytic Leukemia.

    PubMed

    Hernández, José Ángel; Hernández-Sánchez, María; Rodríguez-Vicente, Ana Eugenia; Grossmann, Vera; Collado, Rosa; Heras, Cecilia; Puiggros, Anna; Martín, Ana África; Puig, Noemí; Benito, Rocío; Robledo, Cristina; Delgado, Julio; González, Teresa; Queizán, José Antonio; Galende, Josefina; de la Fuente, Ignacio; Martín-Núñez, Guillermo; Alonso, José María; Abrisqueta, Pau; Luño, Elisa; Marugán, Isabel; González-Gascón, Isabel; Bosch, Francesc; Kohlmann, Alexander; González, Marcos; Espinet, Blanca; Hernández-Rivas, Jesús María

    2015-01-01

    To analyze the impact of the 11q deleted (11q-) cells in CLL patients on the time to first therapy (TFT) and overall survival (OS), 2,493 patients with CLL were studied. 242 patients (9.7%) had 11q-. Fluorescence in situ hybridization (FISH) studies showed a threshold of 40% of deleted cells to be optimal for showing that clinical differences in terms of TFT and OS within 11q- CLLs. In patients with ≥40% of losses in 11q (11q-H) (74%), the median TFT was 19 months compared with 44 months in CLL patients with <40% del(11q) (11q-L) (P<0.0001). In the multivariate analysis, only the presence of 11q-L, mutated IGHV status, early Binet stage and absence of extended lymphadenopathy were associated with longer TFT. Patients with 11q-H had an OS of 90 months, while in the 11q-L group the OS was not reached (P = 0.008). The absence of splenomegaly (P = 0.02), low LDH (P = 0.018) or β2M (P = 0.006), and the presence of 11q-L (P = 0.003) were associated with a longer OS. In addition, to detect the presence of mutations in the ATM, TP53, NOTCH1, SF3B1, MYD88, FBXW7, XPO1 and BIRC3 genes, a select cohort of CLL patients with losses in 11q was sequenced by next-generation sequencing of amplicons. Eighty % of CLLs with 11q- showed mutations and fewer patients with low frequencies of 11q- had mutations among genes examined (50% vs 94.1%, P = 0.023). In summary, CLL patients with <40% of 11q- had a long TFT and OS that could be associated with the presence of fewer mutated genes. PMID:26630574

  8. A Low Frequency of Losses in 11q Chromosome Is Associated with Better Outcome and Lower Rate of Genomic Mutations in Patients with Chronic Lymphocytic Leukemia

    PubMed Central

    Rodríguez-Vicente, Ana Eugenia; Grossmann, Vera; Collado, Rosa; Heras, Cecilia; Puiggros, Anna; Martín, Ana África; Puig, Noemí; Benito, Rocío; Robledo, Cristina; Delgado, Julio; González, Teresa; Queizán, José Antonio; Galende, Josefina; de la Fuente, Ignacio; Martín-Núñez, Guillermo; Alonso, José María; Abrisqueta, Pau; Luño, Elisa; Marugán, Isabel; González-Gascón, Isabel; Bosch, Francesc; Kohlmann, Alexander; González, Marcos; Espinet, Blanca; Hernández-Rivas, Jesús María

    2015-01-01

    To analyze the impact of the 11q deleted (11q-) cells in CLL patients on the time to first therapy (TFT) and overall survival (OS), 2,493 patients with CLL were studied. 242 patients (9.7%) had 11q-. Fluorescence in situ hybridization (FISH) studies showed a threshold of 40% of deleted cells to be optimal for showing that clinical differences in terms of TFT and OS within 11q- CLLs. In patients with ≥40% of losses in 11q (11q-H) (74%), the median TFT was 19 months compared with 44 months in CLL patients with <40% del(11q) (11q-L) (P<0.0001). In the multivariate analysis, only the presence of 11q-L, mutated IGHV status, early Binet stage and absence of extended lymphadenopathy were associated with longer TFT. Patients with 11q-H had an OS of 90 months, while in the 11q-L group the OS was not reached (P = 0.008). The absence of splenomegaly (P = 0.02), low LDH (P = 0.018) or β2M (P = 0.006), and the presence of 11q-L (P = 0.003) were associated with a longer OS. In addition, to detect the presence of mutations in the ATM, TP53, NOTCH1, SF3B1, MYD88, FBXW7, XPO1 and BIRC3 genes, a select cohort of CLL patients with losses in 11q was sequenced by next-generation sequencing of amplicons. Eighty % of CLLs with 11q- showed mutations and fewer patients with low frequencies of 11q- had mutations among genes examined (50% vs 94.1%, P = 0.023). In summary, CLL patients with <40% of 11q- had a long TFT and OS that could be associated with the presence of fewer mutated genes. PMID:26630574

  9. KRAS Mutation

    PubMed Central

    Franklin, Wilbur A.; Haney, Jerry; Sugita, Michio; Bemis, Lynne; Jimeno, Antonio; Messersmith, Wells A.

    2010-01-01

    Treatment of colon carcinoma with the anti-epidermal growth factor receptor antibody Cetuximab is reported to be ineffective in KRAS-mutant tumors. Mutation testing techniques have therefore become an urgent concern. We have compared three methods for detecting KRAS mutations in 59 cases of colon carcinoma: 1) high resolution melting, 2) the amplification refractory mutation system using a bifunctional self-probing primer (ARMS/Scorpion, ARMS/S), and 3) direct sequencing. We also evaluated the effects of the methods of sectioning and coring of paraffin blocks to obtain tumor DNA on assay sensitivity and specificity. The most sensitive and specific combination of block sampling and mutational analysis was ARMS/S performed on DNA derived from 1-mm paraffin cores. This combination of tissue sampling and testing method detected KRAS mutations in 46% of colon tumors. Four samples were positive by ARMS/S, but initially negative by direct sequencing. Cloned DNA samples were retested by direct sequencing, and in all four cases KRAS mutations were identified in the DNA. In six cases, high resolution melting abnormalities could not be confirmed as specific mutations either by ARMS/S or direct sequencing. We conclude that coring of the paraffin blocks and testing by ARMS/S is a sensitive, specific, and efficient method for KRAS testing. PMID:20007845

  10. Analysis of 454 sequencing error rate, error sources, and artifact recombination for detection of Low-frequency drug resistance mutations in HIV-1 DNA

    PubMed Central

    2013-01-01

    Background 454 sequencing technology is a promising approach for characterizing HIV-1 populations and for identifying low frequency mutations. The utility of 454 technology for determining allele frequencies and linkage associations in HIV infected individuals has not been extensively investigated. We evaluated the performance of 454 sequencing for characterizing HIV populations with defined allele frequencies. Results We constructed two HIV-1 RT clones. Clone A was a wild type sequence. Clone B was identical to clone A except it contained 13 introduced drug resistant mutations. The clones were mixed at ratios ranging from 1% to 50% and were amplified by standard PCR conditions and by PCR conditions aimed at reducing PCR-based recombination. The products were sequenced using 454 pyrosequencing. Sequence analysis from standard PCR amplification revealed that 14% of all sequencing reads from a sample with a 50:50 mixture of wild type and mutant DNA were recombinants. The majority of the recombinants were the result of a single crossover event which can happen during PCR when the DNA polymerase terminates synthesis prematurely. The incompletely extended template then competes for primer sites in subsequent rounds of PCR. Although less often, a spectrum of other distinct crossover patterns was also detected. In addition, we observed point mutation errors ranging from 0.01% to 1.0% per base as well as indel (insertion and deletion) errors ranging from 0.02% to nearly 50%. The point errors (single nucleotide substitution errors) were mainly introduced during PCR while indels were the result of pyrosequencing. We then used new PCR conditions designed to reduce PCR-based recombination. Using these new conditions, the frequency of recombination was reduced 27-fold. The new conditions had no effect on point mutation errors. We found that 454 pyrosequencing was capable of identifying minority HIV-1 mutations at frequencies down to 0.1% at some nucleotide positions. Conclusion

  11. Incompatibilities Involving Yeast Mismatch Repair Genes: A Role for Genetic Modifiers and Implications for Disease Penetrance and Variation in Genomic Mutation Rates

    PubMed Central

    Demogines, Ann; Wong, Alex; Aquadro, Charles; Alani, Eric

    2008-01-01

    Genetic background effects underlie the penetrance of most genetically determined phenotypes, including human diseases. To explore how such effects can modify a mutant phenotype in a genetically tractable system, we examined an incompatibility involving the MLH1 and PMS1 mismatch repair genes using a large population sample of geographically and ecologically diverse Saccharomyces cerevisiae strains. The mismatch repair incompatibility segregates into naturally occurring yeast strains, with no strain bearing the deleterious combination. In assays measuring the mutator phenotype conferred by different combinations of MLH1 and PMS1 from these strains, we observed a mutator phenotype only in combinations predicted to be incompatible. Surprisingly, intragenic modifiers could be mapped that specifically altered the strength of the incompatibility over a 20-fold range. Together, these observations provide a powerful model in which to understand the basis of disease penetrance and how such genetic variation, created through mating, could result in new mutations that could be the raw material of adaptive evolution in yeast populations. PMID:18566663

  12. Mutation breeding by ion implantation

    NASA Astrophysics Data System (ADS)

    Yu, Zengliang; Deng, Jianguo; He, Jianjun; Huo, Yuping; Wu, Yuejin; Wang, Xuedong; Lui, Guifu

    1991-07-01

    Ion implantation as a new mutagenic method has been used in the rice breeding program since 1986, and for mutation breeding of other crops later. It has been shown, in principle and in practice, that this method has many outstanding advantages: lower damage rate; higher mutation rate and wider mutational spectrum. Many new lines of rice with higher yield rate; broader disease resistance; shorter growing period but higher quality have been bred from ion beam induced mutants. Some of these lines have been utilized for the intersubspecies hybridization. Several new lines of cotton, wheat and other crops are now in breeding. Some biophysical effects of ion implantation for crop seeds have been studied.

  13. Reversible cell cycle inhibition and premature aging features imposed by conditional expression of p16Ink4a

    PubMed Central

    Boquoi, Amelie; Arora, Sanjeevani; Chen, Tina; Litwin, Sam; Koh, James; Enders, Greg H

    2015-01-01

    The cyclin-dependent kinase (Cdk) inhibitor p16Ink4a (p16) is a canonical mediator of cellular senescence and accumulates in aging tissues, where it constrains proliferation of some progenitor cells. However, whether p16 induction in tissues is sufficient to inhibit cell proliferation, mediate senescence, and/or impose aging features has remained unclear. To address these issues, we generated transgenic mice that permit conditional p16 expression. Broad induction at weaning inhibited proliferation of intestinal transit-amplifying and Lgr5+ stem cells and rapidly imposed features of aging, including hair loss, skin wrinkling, reduced body weight and subcutaneous fat, an increased myeloid fraction in peripheral blood, poor dentition, and cataracts. Aging features were observed with multiple combinations of p16 transgenes and transactivators and were largely abrogated by a germline Cdk4 R24C mutation, confirming that they reflect Cdk inhibition. Senescence markers were not found, and de-induction of p16, even after weeks of sustained expression, allowed rapid recovery of intestinal cell proliferation and reversal of aging features in most mice. These results suggest that p16-mediated inhibition of Cdk activity is sufficient to inhibit cell proliferation and impose aging features in somatic tissues of mammals and that at least some of these aging features are reversible. PMID:25481981

  14. Reversible cell cycle inhibition and premature aging features imposed by conditional expression of p16Ink4a.

    PubMed

    Boquoi, Amelie; Arora, Sanjeevani; Chen, Tina; Litwin, Sam; Koh, James; Enders, Greg H

    2015-02-01

    The cyclin-dependent kinase (Cdk) inhibitor p16(Ink4a) (p16) is a canonical mediator of cellular senescence and accumulates in aging tissues, where it constrains proliferation of some progenitor cells. However, whether p16 induction in tissues is sufficient to inhibit cell proliferation, mediate senescence, and/or impose aging features has remained unclear. To address these issues, we generated transgenic mice that permit conditional p16 expression. Broad induction at weaning inhibited proliferation of intestinal transit-amplifying and Lgr5+ stem cells and rapidly imposed features of aging, including hair loss, skin wrinkling, reduced body weight and subcutaneous fat, an increased myeloid fraction in peripheral blood, poor dentition, and cataracts. Aging features were observed with multiple combinations of p16 transgenes and transactivators and were largely abrogated by a germline Cdk4 R24C mutation, confirming that they reflect Cdk inhibition. Senescence markers were not found, and de-induction of p16, even after weeks of sustained expression, allowed rapid recovery of intestinal cell proliferation and reversal of aging features in most mice. These results suggest that p16-mediated inhibition of Cdk activity is sufficient to inhibit cell proliferation and impose aging features in somatic tissues of mammals and that at least some of these aging features are reversible. PMID:25481981

  15. Fast Growth Increases the Selective Advantage of a Mutation Arising Recurrently during Evolution under Metal Limitation

    PubMed Central

    Chou, Hsin-Hung; Berthet, Julia; Marx, Christopher J.

    2009-01-01

    Understanding the evolution of biological systems requires untangling the molecular mechanisms that connect genetic and environmental variations to their physiological consequences. Metal limitation across many environments, ranging from pathogens in the human body to phytoplankton in the oceans, imposes strong selection for improved metal acquisition systems. In this study, we uncovered the genetic and physiological basis of adaptation to metal limitation using experimental populations of Methylobacterium extorquens AM1 evolved in metal-deficient growth media. We identified a transposition mutation arising recurrently in 30 of 32 independent populations that utilized methanol as a carbon source, but not in any of the 8 that utilized only succinate. These parallel insertion events increased expression of a novel transporter system that enhanced cobalt uptake. Such ability ensured the production of vitamin B12, a cobalt-containing cofactor, to sustain two vitamin B12–dependent enzymatic reactions essential to methanol, but not succinate, metabolism. Interestingly, this mutation provided higher selective advantages under genetic backgrounds or incubation temperatures that permit faster growth, indicating growth-rate–dependent epistatic and genotype-by-environment interactions. Our results link beneficial mutations emerging in a metal-limiting environment to their physiological basis in carbon metabolism, suggest that certain molecular features may promote the emergence of parallel mutations, and indicate that the selective advantages of some mutations depend generically upon changes in growth rate that can stem from either genetic or environmental influences. PMID:19763169

  16. Distinctive mutation spectrum of the HBB gene in an urban eastern Indian population.

    PubMed

    Sahoo, Subhransu Sekhar; Biswal, Sebaranjan; Dixit, Manjusha

    2014-01-01

    ABSTRACT Hemoglobinopathies such as β-thalassemia (β-thal) and sickle cell anemia (or Hb S [β6(A3)Glu→Val]) impose a major health burden in the Indian population. To determine the frequencies of the HBB gene mutations in eastern Indian populations and to compare with the available data, a comprehensive molecular analysis of the HBB gene was done in the normal Odisha State population. Using polymerase chain reaction (PCR), restriction fragment length polymorphism (RFLP), amplification refractory mutation system (ARMS) and DNA sequencing techniques, β-thal and sickle cell anemia mutations were characterized in 267 healthy individuals. Entire HBB gene sequencing showed 63 different mutations including 11 new ones. The predominant mutation HBB: c.9T > C was observed at a high frequency (19.57%) in the normal population. In the urban population of Odisha State, India, carrier frequency of hemoglobinopathies was found to be 18.48%, and for β-thal, the carrier rate was 14.13%, which is very high indeed. In the absence of a complete cure by any expensive treatment and drug administration, this information would be helpful for planning a population screening program and establishing prenatal diagnosis of β-thal in order to reduce the burden of such a genetic disease. PMID:24099628

  17. An Imposed Dynamo Current Drive Experiment: Demonstration of Confinement

    NASA Astrophysics Data System (ADS)

    Jarboe, Thomas; Hansen, Chris; Hossack, Aaron; Marklin, George; Morgan, Kyle; Nelson, Brian; Sutherland, Derek; Victor, Brian

    2014-10-01

    An experiment for studying and developing the efficient sustainment of a spheromak with sufficient confinement (current-drive power heats the plasma to its stability β-limit) and in the keV temperature range is discussed. A high- β spheromak sustained by imposed dynamo current drive (IDCD) is justified because: previous transient experiments showed sufficient confinement in the keV range with no external toroidal field coil; recent results on HIT-SI show sustainment with sufficient confinement at low temperature; the potential of IDCD of solving other fusion issues; a very attractive reactor concept; and the general need for efficient current drive in magnetic fusion. The design of a 0.55 m minor radius machine with the required density control, wall loading, and neutral shielding for a 2 s pulse is presented. Peak temperatures of 1 keV and toroidal currents of 1.35 MA and 16% wall-normalized plasma beta are envisioned. The experiment is large enough to address the key issues yet small enough for rapid modification and for extended MHD modeling of startup and code validation.

  18. Externally imposed electric field enhances plant root tip regeneration.

    PubMed

    Kral, Nicolas; Hanna Ougolnikova, Alexandra; Sena, Giovanni

    2016-06-01

    In plants, shoot and root regeneration can be induced in the distinctive conditions of tissue culture (in vitro) but is also observed in intact individuals (in planta) recovering from tissue damage. Roots, for example, can regenerate their fully excised meristems in planta, even in mutants with impaired apical stem cell niches. Unfortunately, to date a comprehensive understanding of regeneration in plants is still missing. Here, we provide evidence that an imposed electric field can perturb apical root regeneration in Arabidopsis. Crucially, we explored both spatial and temporal competences of the stump to respond to electrical stimulation, by varying respectively the position of the cut and the time interval between excision and stimulation. Our data indicate that a brief pulse of an electric field parallel to the root is sufficient to increase by up to two-fold the probability of its regeneration, and to perturb the local distribution of the hormone auxin, as well as cell division regulation. Remarkably, the orientation of the root towards the anode or the cathode is shown to play a role. PMID:27606066

  19. Externally imposed electric field enhances plant root tip regeneration

    PubMed Central

    Kral, Nicolas; Hanna Ougolnikova, Alexandra

    2016-01-01

    Abstract In plants, shoot and root regeneration can be induced in the distinctive conditions of tissue culture (in vitro) but is also observed in intact individuals (in planta) recovering from tissue damage. Roots, for example, can regenerate their fully excised meristems in planta, even in mutants with impaired apical stem cell niches. Unfortunately, to date a comprehensive understanding of regeneration in plants is still missing. Here, we provide evidence that an imposed electric field can perturb apical root regeneration in Arabidopsis. Crucially, we explored both spatial and temporal competences of the stump to respond to electrical stimulation, by varying respectively the position of the cut and the time interval between excision and stimulation. Our data indicate that a brief pulse of an electric field parallel to the root is sufficient to increase by up to two‐fold the probability of its regeneration, and to perturb the local distribution of the hormone auxin, as well as cell division regulation. Remarkably, the orientation of the root towards the anode or the cathode is shown to play a role. PMID:27606066

  20. The corporation and the community: Credibility, legitimacy, and imposed risk

    SciTech Connect

    Wade, C. ); Rosenthal, I. . Center for Risk and Decision Processes)

    1991-10-01

    In this age of rapid changes, large segments of society no longer trust any institution or authority in regard to pronouncements on what is safe. Because of this distrust, the public has demanded and obtained increased rights for individuals to intervene directly in decisions affecting them. Rosenthal warns that an organization that just fulfills its legal requirements for safety is no longer doing enough. Industry leaders must work toward re-establishing credibility by identifying persons who are potentially at risk as a result of industry activities, involving them in the communication process, and justifying the firm's social benefits. Seeking social legitimacy, chemical manufacturers have formed self-assessment groups and community councils, which have reaped unexpected benefits but have forced them to deal with issues they would have preferred to avoid. To industry leaders who contend that these types of activities are not worth the effort, Rosenthal presents a timely warning. Government and business must reduce public concerns significantly and make stakeholders more willing to tolerate imposed risk because of perceived benefits. It the public's concern is not reduced, we will all be required to make greater and greater investments in an inefficient and largely fruitless pursuit of absolute safety. 16 refs.

  1. 75 FR 1683 - Application and Renewal Fees Imposed on Surety Companies and Reinsuring Companies; Increase in...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-01-12

    ... notice should be directed to the Surety Bond Branch, Financial Accounting and Services Division...; Increase in Fees Imposed AGENCY: Financial Management Service, Fiscal Service, Department of the Treasury... fees imposed. SUMMARY: Effective December 31, 2009, The Department of the Treasury,...

  2. 76 FR 416 - Application and Renewal Fees Imposed on Surety Companies and Reinsuring Companies Increase in...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-04

    ... notice should be directed to the Surety Bond Branch, Financial Accounting and Services Division... in Fees Imposed AGENCY: Financial Management Service, Fiscal Service, Department of the Treasury... Fees Imposed. SUMMARY: Effective December 31, 2010, The Department of the Treasury,...

  3. 42 CFR 488.430 - Civil money penalties: Basis for imposing penalty.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 5 2010-10-01 2010-10-01 false Civil money penalties: Basis for imposing penalty... PROCEDURES Enforcement of Compliance for Long-Term Care Facilities with Deficiencies § 488.430 Civil money penalties: Basis for imposing penalty. (a) CMS or the State may impose a civil money penalty for either...

  4. 26 CFR 52.4681-1 - Taxes imposed with respect to ozone-depleting chemicals.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ...)) for the calendar year in which the sale or use occurs; and (iii) The ozone-depletion factor... 26 Internal Revenue 17 2011-04-01 2011-04-01 false Taxes imposed with respect to ozone-depleting... to ozone-depleting chemicals. (a) Taxes imposed. Sections 4681 and 4682 impose the following...

  5. 26 CFR 52.4681-1 - Taxes imposed with respect to ozone-depleting chemicals.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ...)) for the calendar year in which the sale or use occurs; and (iii) The ozone-depletion factor... 26 Internal Revenue 17 2010-04-01 2010-04-01 false Taxes imposed with respect to ozone-depleting... to ozone-depleting chemicals. (a) Taxes imposed. Sections 4681 and 4682 impose the following...

  6. 26 CFR 1.802-3 - Tax imposed on life insurance companies.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 8 2011-04-01 2011-04-01 false Tax imposed on life insurance companies. 1.802-3... TAX (CONTINUED) INCOME TAXES (CONTINUED) Life Insurance Companies § 1.802-3 Tax imposed on life...) imposes a tax on the life insurance company taxable income (as defined in section 802(b) and paragraph...

  7. 42 CFR 488.430 - Civil money penalties: Basis for imposing penalty.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 5 2013-10-01 2013-10-01 false Civil money penalties: Basis for imposing penalty... PROCEDURES Enforcement of Compliance for Long-Term Care Facilities with Deficiencies § 488.430 Civil money penalties: Basis for imposing penalty. (a) CMS or the State may impose a civil money penalty for either...

  8. 42 CFR 488.430 - Civil money penalties: Basis for imposing penalty.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 5 2012-10-01 2012-10-01 false Civil money penalties: Basis for imposing penalty... PROCEDURES Enforcement of Compliance for Long-Term Care Facilities with Deficiencies § 488.430 Civil money penalties: Basis for imposing penalty. (a) CMS or the State may impose a civil money penalty for either...

  9. 42 CFR 488.430 - Civil money penalties: Basis for imposing penalty.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 5 2014-10-01 2014-10-01 false Civil money penalties: Basis for imposing penalty... PROCEDURES Enforcement of Compliance for Long-Term Care Facilities with Deficiencies § 488.430 Civil money penalties: Basis for imposing penalty. (a) CMS or the State may impose a civil money penalty for either...

  10. 42 CFR 488.430 - Civil money penalties: Basis for imposing penalty.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 5 2011-10-01 2011-10-01 false Civil money penalties: Basis for imposing penalty... PROCEDURES Enforcement of Compliance for Long-Term Care Facilities with Deficiencies § 488.430 Civil money penalties: Basis for imposing penalty. (a) CMS or the State may impose a civil money penalty for either...

  11. Radiation-induced mutation at minisatellite loci

    SciTech Connect

    Dubrova, Y.E. |; Nesterov, V.N.; Krouchinsky, N.G.

    1997-10-01

    We are studying the radiation-induced increase of mutation rate in minisatellite loci in mice and humans. Minisatellite mutations were scored by multilocus DNA fingerprint analysis in the progeny of {gamma}-irradiated and non-irradiated mice. The frequency of mutation in offspring of irradiated males was 1.7 higher that in the control group. Germline mutation at human minisatellite loci was studied among children born in heavily polluted areas of the Mogilev district of Belarus after the Chernobyl accident and in a control population. The frequency of mutation assayed both by DNA fingerprinting and by eight single locus probes was found to be two times higher in the exposed families than in the control group. Furthermore, mutation rate was correlated with the parental radiation dose for chronic exposure {sup 137}Cs, consistent with radiation-induction of germline mutation. The potential use of minisatellites in monitoring germline mutation in humans will be discussed.

  12. 14 CFR 382.33 - May carriers impose other restrictions on passengers with a disability that they do not impose on...

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 14 Aeronautics and Space 4 2013-01-01 2013-01-01 false May carriers impose other restrictions on passengers with a disability that they do not impose on other passengers? 382.33 Section 382.33 Aeronautics and Space OFFICE OF THE SECRETARY, DEPARTMENT OF TRANSPORTATION (AVIATION PROCEEDINGS) SPECIAL REGULATIONS NONDISCRIMINATION ON THE BASIS...

  13. 49 CFR 39.45 - May PVOs impose other restrictions on passengers with a disability that they do not impose on...

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... with a disability that they do not impose on other passengers? 39.45 Section 39.45 Transportation... with a disability that they do not impose on other passengers? (a) As a PVO, you must not subject passengers with a disability to restrictions that do not apply to other passengers, except as...

  14. 49 CFR 39.45 - May PVOs impose other restrictions on passengers with a disability that they do not impose on...

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... with a disability that they do not impose on other passengers? 39.45 Section 39.45 Transportation... with a disability that they do not impose on other passengers? (a) As a PVO, you must not subject passengers with a disability to restrictions that do not apply to other passengers, except as...

  15. 49 CFR 39.45 - May PVOs impose other restrictions on passengers with a disability that they do not impose on...

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... with a disability that they do not impose on other passengers? 39.45 Section 39.45 Transportation... with a disability that they do not impose on other passengers? (a) As a PVO, you must not subject passengers with a disability to restrictions that do not apply to other passengers, except as...

  16. 49 CFR 39.45 - May PVOs impose other restrictions on passengers with a disability that they do not impose on...

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... with a disability that they do not impose on other passengers? 39.45 Section 39.45 Transportation... with a disability that they do not impose on other passengers? (a) As a PVO, you must not subject passengers with a disability to restrictions that do not apply to other passengers, except as...

  17. 49 CFR 39.45 - May PVOs impose other restrictions on passengers with a disability that they do not impose on...

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... with a disability that they do not impose on other passengers? 39.45 Section 39.45 Transportation... with a disability that they do not impose on other passengers? (a) As a PVO, you must not subject passengers with a disability to restrictions that do not apply to other passengers, except as...

  18. Phenotypic responses of wild barley to experimentally imposed water stress.

    PubMed

    Ivandic, V; Hackett, C A; Zhang, Z J; Staub, J E; Nevo, E; Thomas, W T; Forster, B P

    2000-12-01

    Responses to water stress within a population of wild barley from Tabigha, Israel, were examined. The population's distribution spans two soil types: Terra Rossa (TR) and Basalt (B). Seeds were collected from plants along a 100 m transect; 24 genotypes were sampled from TR and 28 from B. Due to different soil water-holding capacities, plants growing on TR naturally experience more intense drought than plants growing on B. In a glasshouse experiment, water was withheld from plants for two periods (10 d and 14 d) after flag leaf emergence. A total of 15 agronomic, morphological, developmental, and fertility related traits were examined by analysis of variance (ANOVA). Ten of these traits were significantly affected by the treatment. A high degree of phenotypic variation was found in the population with significant genotypextreatment and soil typextreatment interactions. Principal component analysis (PCA) was performed using combined control and stress treatment data sets. The first three principal components (pc) explained 88.8% of the variation existing in the population with pc1 (47.9%) comprising yield-related and morphological traits, pc2 (22.9%) developmental characteristics and pc3 (18.0%) fertility-related traits. The relative performance of individual genotypes was determined and water stress tolerant genotypes identified. TR genotypes were significantly less affected by the imposed water stress than B genotypes. Moreover, TR genotypes showed accelerated development under water deficit conditions. Data indicate that specific genotypes demonstrating differential responses may be useful for comparative physiological studies, and that TR genotypes exhibiting yield stability may have value for breeding barley better adapted to drought. PMID:11141176

  19. Climate response to imposed solar radiation reductions in high latitudes

    NASA Astrophysics Data System (ADS)

    MacCracken, M. C.; Shin, H.-J.; Caldeira, K.; Ban-Weiss, G. A.

    2012-07-01

    Increasing concentrations of greenhouse gases are the primary contributor to the 0.8 °C increase in the global average temperature since the late 19th century, shortening cold seasons and lengthening warm seasons. The warming is amplified in polar regions, causing retreat of sea ice, snow cover, permafrost, mountain glaciers, and ice sheets, while also modifying mid-latitude weather, amplifying global sea level rise, and initiating high-latitude carbon feedbacks. Model simulations in which we reduced solar insolation over high latitudes not only cooled those regions, but also drew energy from lower latitudes, exerting a cooling influence over much of the hemisphere in which the reduction was imposed. Our simulations, which used the National Center for Atmospheric Research's CAM3.1 atmospheric model coupled to a slab ocean, indicated that, on a normalized basis, high-latitude reductions in absorbed solar radiation have a significantly larger cooling influence than equivalent solar reductions spread evenly over the Earth. This amplified influence occurred because high-latitude surface cooling preferentially increased sea ice fraction and, therefore, surface albedo, leading to a larger deficit in the radiation budget at the top of the atmosphere than from an equivalent global reduction in solar radiation. Reductions in incoming solar radiation in one polar region (either north or south) resulted in increased poleward energy transport during that hemisphere's cold season and shifted the Inter-Tropical Convergence Zone (ITCZ) away from that pole, whereas equivalent reductions in both polar regions tended to leave the ITCZ approximately in place. Together, these results suggest that, until emissions reductions are sufficient to limit the warming influence of greenhouse gas concentrations, polar reductions in solar radiation, if they can be efficiently and effectively implemented, might, because of fewer undesirable side effects than for global solar radiation reductions

  20. Efforts underway to impose harsh regulations on abortion providers.

    PubMed

    Sollom, T

    1996-09-01

    Legislators or regulators in Mississippi, South Carolina, and Missouri have imposed burdensome and unnecessary clinic requirements on abortion providers. In each case, the legislators or regulators designed the requirements to make abortions more difficult to obtain. Mississippi, a state with only two licensed abortion clinics, already had restrictive abortion laws. In August 1996, it implemented stringent regulations on private physicians who provide abortion services in their offices. Some requirements include purchasing specific equipment, widening hallways, and hiring more staff. Several physicians have filed a lawsuit to stop enforcement of the regulations because they make the provision of abortion services so cumbersome and expensive as to discourage physicians from offering abortions. Antiabortion groups testified before the legislature that the Department of Health had been negligent in monitoring private practices for compliance with Mississippi's many abortion laws, particularly counseling requirements. The Republican governor signed the legislation in March 1996. In July 1996, a federal judge prohibited the South Carolina Department of Health from enforcing a new regulation making physicians who perform as few as five abortions a month to meet strict specifications for their office (e.g., disclosure of patient records and medical agreements). The regulation was a response to a 1995 law targeting private physicians who perform abortions in their offices. The judge held that the substantial changes in terms of privacy and expense could bring an undue burden on women seeking abortions. The state denied that the regulation would close clinics or would increase costs so much as to make abortions inaccessible. In September 1996, the House did not override the Democratic governor's veto of a bill that would have required all facilities where abortions are done to be licensed and undergo annual inspections and that would have required all physicians to have

  1. Quantifying Community Assembly Processes and Identifying Features that Impose Them

    SciTech Connect

    Stegen, James C.; Lin, Xueju; Fredrickson, Jim K.; Chen, Xingyuan; Kennedy, David W.; Murray, Christopher J.; Rockhold, Mark L.; Konopka, Allan

    2013-06-06

    Across a set of ecological communities connected to each other through organismal dispersal (a ‘meta-community’), turnover in composition is governed by (ecological) Drift, Selection, and Dispersal Limitation. Quantitative estimates of these processes remain elusive, but would represent a common currency needed to unify community ecology. Using a novel analytical framework we quantitatively estimate the relative influences of Drift, Selection, and Dispersal Limitation on subsurface, sediment-associated microbial meta-communities. The communities we study are distributed across two geologic formations encompassing ~12,500m3 of uranium-contaminated sediments within the Hanford Site in eastern Washington State. We find that Drift consistently governs ~25% of spatial turnover in community composition; Selection dominates (governing ~60% of turnover) across spatially-structured habitats associated with fine-grained, low permeability sediments; and Dispersal Limitation is most influential (governing ~40% of turnover) across spatially-unstructured habitats associated with coarse-grained, highly-permeable sediments. Quantitative influences of Selection and Dispersal Limitation may therefore be predictable from knowledge of environmental structure. To develop a system-level conceptual model we extend our analytical framework to compare process estimates across formations, characterize measured and unmeasured environmental variables that impose Selection, and identify abiotic features that limit dispersal. Insights gained here suggest that community ecology can benefit from a shift in perspective; the quantitative approach developed here goes beyond the ‘niche vs. neutral’ dichotomy by moving towards a style of natural history in which estimates of Selection, Dispersal Limitation and Drift can be described, mapped and compared across ecological systems.

  2. Studies on hemophilia A in Sardinia bearing on the problems of multiple allelism, carrier detection, and differential mutation rate in the two sexes.

    PubMed Central

    Filippi, G; Mannucci, P M; Coppola, R; Farris, A; Rinaldi, A; Siniscalco, M

    1984-01-01

    A large survey of hemophilia A carried out with almost complete ascertainment on the island of Sardinia suggests that the variation of plasma levels of Factor VIII coagulant activity in normal individuals is largely controlled by a series of normal isoalleles or by closely linked modifiers. This variation is expected to affect the laboratory detection of the hemophilia A (HA) heterozygotes in addition to the X-inactivation-dependent mosaicism and the type of deficient mutant present in a given pedigree. The Sardinian pedigrees yielded 13 new cases of nonrecombinants between the loci for HA and glucose-6-phosphate dehydrogenase (G6PD), as well as four nonrecombinants between HA and Deutan color blindness. These findings bring to a total of 58 the number of scorable sibs and nonrecombinants thus far known for the linkage HA-G6PD. From such a figure it has been possible to infer that the 90% upper limit of meiotic recombination between the two loci is below 4%, thus justifying the application of the "linkage diagnostic test" for the detection of HA heterozygotes and the prenatal diagnosis of the hemophilic fetuses in families that segregate at both loci. In three out of the five HA pedigrees of our series that segregate also for G6PD or Deutan color blindness, the observed segregation of the combined phenotypes can be best explained by assuming the occurrence of a fresh mutation in the maternal grandfathers. Such a finding points out the opportunity to reevaluate Haldane's hypothesis of a possible higher incidence of X-linked mutations in the human male. It is anticipated that each of the issues addressed by the present study will be amenable to experimental verification as soon as suitable molecular probes become available to screen for common multiallelic DNA polymorphisms in the subtelomeric region of the X-chromosome long arm. PMID:6421151

  3. Role of the conserved distal heme asparagine of coral allene oxide synthase (Asn137) and human catalase (Asn148): mutations affect the rate but not the essential chemistry of the enzymatic transformations.

    PubMed

    Gao, Benlian; Boeglin, William E; Brash, Alan R

    2008-09-15

    A catalase-related allene oxide synthase (cAOS) and true catalases that metabolize hydrogen peroxide have similar structure around the heme. One of the distal heme residues considered to help control catalysis is a highly conserved asparagine. Here we addressed the role of this residue in metabolism of the natural substrate 8R-hydroperoxyeicosatetraenoic acid by cAOS and in H(2)O(2) breakdown by catalase. In cAOS, the mutations N137A, N137Q, N137S, N137D, and N137H drastically reduced the rate of reaction (to 0.8-4% of wild-type), yet the mutants all formed the allene oxide as product. This is remarkable because there are many potential heme-catalyzed transformations of fatty acid hydroperoxides and special enzymatic control must be required. In human catalase, the N148A, N148S, or N148D mutations only reduced rates to approximately 20% of wild-type. The distal heme Asn is not essential in either catalase or cAOS. Its conservation throughout evolution may relate to a role in optimizing catalysis. PMID:18652800

  4. Imposing Neumann boundary condition on cosmological perturbation equations and trajectories of particles

    NASA Astrophysics Data System (ADS)

    Shenavar, Hossein

    2016-03-01

    We impose Neumann boundary condition to solve cosmological perturbation equations and we derive a modified Friedmann equation and a new lensing equation. To check the new lensing equation and the value of Neumann constant, a sample that contains ten strong lensing systems is surveyed. Except for one lens, masses of the other lenses are found to be within the constrains of the observational data. Furthermore, we argue that by using the concept of geometrodynamic clocks it is possible to modify the equation of motion of massive particles too. Also, a sample that includes 101 HSB and LSB galaxies is used to re-estimate the value of the Neumann constant and we found that this value is consistent with the prior evaluation from Friedmann and lensing equations. Finally, the growth of structure is studied by a Newtonian approach which resulted in a more rapid rate of the structure formation in matter dominated era.

  5. Fundamental limitations imposed by high doping on the performance of pn junction silicon solar cells

    NASA Technical Reports Server (NTRS)

    Lindholm, F. A.; Li, S. S.; Sah, C. T.

    1975-01-01

    Fundamental limitations imposed on the performance of silicon junction solar cells by physical mechanisms accompanying high doping are described. The one-dimensional mechanisms divide into two broad categories: those associated with band-gap shrinkage and those associated with interband transition rates. By extending the traditional method of analysis and comparing with measurement, it is shown that the latter kind of mechanism dominates in determining the open-circuit voltage in a one-dimensional model of a 0.1 ohm-cm cell at 300 K. As an alternative dominant mechanism, a three-dimensional model involving thermodynamically stable clusters of impurities in the highly-doped diffused layer is suggested.

  6. Amount of bone marrow blasts is strongly correlated to NPM1 and FLT3-ITD mutation rate in AML with normal karyotype.

    PubMed

    Haferlach, Torsten; Bacher, Ulrike; Alpermann, Tamara; Haferlach, Claudia; Kern, Wolfgang; Schnittger, Susanne

    2012-01-01

    FLT3-ITDs are linked to higher leukocytes/blasts in acute myeloid leukemia. To evaluate the effect of NPM1 mutations, we correlated NPM1mut status with morphology in 805 adult normal karyotype AML. NPM1mut were found in 391/805 (48.6%), FLT3-ITD in 219/805 (27.2%). Frequencies of FLT3-ITD and NPM1mut cases were continuously increasing by blast decades: NPM1mut from 38/123 (30.9%) in 20-29% blast decade to 70/103 (68.0%) in 90-100% decade (p<0.001), FLT3-ITDs from 15/123 (12.2%) to 58/103 (56.3%) (p<0.001). Mean WBC count was highest in NPM1-mut/FLT3-ITD-positive and lowest in NPM1-wildtype/FLT3-ITD-negative patients (p<0.0001); similar for BM blasts. Therefore, FLT3-ITD and NPM1mut might synergistically stimulate blast proliferation. PMID:21621842

  7. Tobacco exposure results in increased E6 and E7 oncogene expression, DNA damage and mutation rates in cells maintaining episomal human papillomavirus 16 genomes

    PubMed Central

    Wei, Lanlan; Griego, Anastacia M.; Chu, Ming; Ozbun, Michelle A.

    2014-01-01

    High-risk human papillomavirus (HR-HPV) infections are necessary but insufficient agents of cervical and other epithelial cancers. Epidemiological studies support a causal, but ill-defined, relationship between tobacco smoking and cervical malignancies. In this study, we used mainstream tobacco smoke condensate (MSTS-C) treatments of cervical cell lines that maintain either episomal or integrated HPV16 or HPV31 genomes to model tobacco smoke exposure to the cervical epithelium of the smoker. MSTS-C exposure caused a dose-dependent increase in viral genome replication and correspondingly higher early gene transcription in cells with episomal HPV genomes. However, MSTS-C exposure in cells with integrated HR-HPV genomes had no effect on genome copy number or early gene transcription. In cells with episomal HPV genomes, the MSTS-C-induced increases in E6 oncogene transcription led to decreased p53 protein levels and activity. As expected from loss of p53 activity in tobacco-exposed cells, DNA strand breaks were significantly higher but apoptosis was minimal compared with cells containing integrated viral genomes. Furthermore, DNA mutation frequencies were higher in surviving cells with HPV episomes. These findings provide increased understanding of tobacco smoke exposure risk in HPV infection and indicate tobacco smoking acts more directly to alter HR-HPV oncogene expression in cells that maintain episomal viral genomes. This suggests a more prominent role for tobacco smoke in earlier stages of HPV-related cancer progression. PMID:25064354

  8. Environmental Patterns Are Imposed on the Population Structure of Escherichia coli after Fecal Deposition ▿ †

    PubMed Central

    Bergholz, Peter W.; Noar, Jesse D.; Buckley, Daniel H.

    2011-01-01

    The intestinal microbe Escherichia coli is subject to fecal deposition in secondary habitats, where it persists transiently, allowing for the opportunity to colonize new hosts. Selection in the secondary habitat can be postulated, but its impact on the genomic diversity of E. coli is unknown. Environmental selective pressure on extrahost E. coli can be revealed by landscape genetic analysis, which examines the influences of dispersal processes, landscape features, and the environment on the spatiotemporal distribution of genes in natural populations. We conducted multilocus sequence analysis of 353 E. coli isolates from soil and fecal samples obtained in a recreational meadow to examine the ecological processes controlling their distributions. Soil isolates, as a group, were not genetically distinct from fecal isolates, with only 0.8% of genetic variation and no fixed mutations attributed to the isolate source. Analysis of the landscape genetic structure of E. coli populations showed a patchy spatial structure consistent with patterns of fecal deposition. Controlling for the spatial pattern made it possible to detect environmental gradients of pH, moisture, and organic matter corresponding to the genetic structure of E. coli in soil. Ecological distinctions among E. coli subpopulations (i.e., E. coli reference collection [ECOR] groups) contributed to variation in subpopulation distributions. Therefore, while fecal deposition is the major predictor of E. coli distributions on the field scale, selection imposed by the soil environment has a significant impact on E. coli population structure and potentially amplifies the occasional introduction of stress-tolerant strains to new host individuals by transmission through water or food. PMID:21075897

  9. Characterization of Staphylococcus aureus Strains Isolated from Czech Cystic Fibrosis Patients: High Rate of Ribosomal Mutation Conferring Resistance to MLS(B) Antibiotics as a Result of Long-Term and Low-Dose Azithromycin Treatment.

    PubMed

    Tkadlec, Jan; Vařeková, Eva; Pantůček, Roman; Doškař, Jiří; Růžičková, Vladislava; Botka, Tibor; Fila, Libor; Melter, Oto

    2015-08-01

    Staphylococcus aureus is one of the most frequent pathogens infecting the respiratory tract of patients with cystic fibrosis (CF). This study was the first to examine S. aureus isolates from CF patients in the Czech Republic. Among 100 S. aureus isolates from 92 of 107 observed patients, we found a high prevalence of resistance to macrolide-lincosamide-streptogramin B (MLS(B)) antibiotics (56%). More than half of the resistant strains (29 of 56) carried a mutation in the MLS(B) target site. The emergence of MLS(B) resistance and mutations conferring resistance to MLS(B) antibiotics was associated with azithromycin treatment (p=0.000000184 and p=0.000681, respectively). Methicillin resistance was only detected in 3% of isolates and the rate of resistance to other antibiotics did not exceed 12%. The prevalence of small-colony variant (SCV) strains was relatively low (9%) and eight of nine isolates with the SCV phenotype were thymidine dependent. The study population of S. aureus was heterogeneous in structure and both the most prevalent community-associated and hospital-acquired clonal lineages were represented. Of the virulence genes, enterotoxin genes seg (n=52), sei (n=49), and sec (n=16) were the most frequently detected among the isolates. The PVL genes (lukS-PV and lukF-PV) have not been revealed in any of the isolates. PMID:25826283

  10. The Effect of Linkage on Establishment and Survival of Locally Beneficial Mutations

    PubMed Central

    Aeschbacher, Simon; Bürger, Reinhard

    2014-01-01

    We study invasion and survival of weakly beneficial mutations arising in linkage to an established migration–selection polymorphism. Our focus is on a continent–island model of migration, with selection at two biallelic loci for adaptation to the island environment. Combining branching and diffusion processes, we provide the theoretical basis for understanding the evolution of islands of divergence, the genetic architecture of locally adaptive traits, and the importance of so-called “divergence hitchhiking” relative to other mechanisms, such as “genomic hitchhiking”, chromosomal inversions, or translocations. We derive approximations to the invasion probability and the extinction time of a de novo mutation. Interestingly, the invasion probability is maximized at a nonzero recombination rate if the focal mutation is sufficiently beneficial. If a proportion of migrants carries a beneficial background allele, the mutation is less likely to become established. Linked selection may increase the survival time by several orders of magnitude. By altering the timescale of stochastic loss, it can therefore affect the dynamics at the focal site to an extent that is of evolutionary importance, especially in small populations. We derive an effective migration rate experienced by the weakly beneficial mutation, which accounts for the reduction in gene flow imposed by linked selection. Using the concept of the effective migration rate, we also quantify the long-term effects on neutral variation embedded in a genome with arbitrarily many sites under selection. Patterns of neutral diversity change qualitatively and quantitatively as the position of the neutral locus is moved along the chromosome. This will be useful for population-genomic inference. Our results strengthen the emerging view that physically linked selection is biologically relevant if linkage is tight or if selection at the background locus is strong. PMID:24610861

  11. Individually Ventilated Cages Impose Cold Stress on Laboratory Mice: A Source of Systemic Experimental Variability

    PubMed Central

    David, John M; Knowles, Scott; Lamkin, Donald M; Stout, David B

    2013-01-01

    Individual ventilated cages (IVC) are increasing in popularity. Although mice avoid IVC in preference testing, they show no aversion when provided additional nesting material or the cage is not ventilated. Given the high ventilation rate in IVC, we developed 3 hypotheses: that mice housed in IVC experience more cold stress than do mice housed in static cages; that IVC-induced cold stress affects the results of experiments using mice; and that, when provided shelters, mice behaviorally thermoregulate and thereby rescue the cold-stress effects of IVC. To test these hypotheses, we housed mice in IVC, IVC with shelters, and static cages maintained at 20 to 21 °C. We quantified the cold stress of each housing system on mice by assessing nonshivering thermogenesis and brown adipose vacuolation. To test housing effects in a common, murine model of human disease, we implanted mice with subcutaneous epidermoid carcinoma cells and quantified tumor growth, tumor metabolism, and adrenal weight. Mice housed in IVC had histologic signs of cold stress and significantly higher nonshivering thermogenesis, smaller subcutaneous tumors, lower tumor metabolism, and larger adrenal weights than did mice in static cages. Shelters rescued IVC-induced nonshivering thermogenesis, adrenal enlargement, and phenotype-dependent cold-mediated histologic changes in brown adipose tissue and tumor size. IVC impose chronic cold stress on mice, alter experimental results, and are a source of systemic confounders throughout rodent-dependent research. Allowing mice to exhibit behavioral thermoregulation through seeking shelter markedly rescues the experiment-altering effects of housing-imposed cold stress, improves physiologic uniformity, and increases experimental reproducibility across housing systems. PMID:24351762

  12. Evapotranspiration Controls Imposed by Soil Moisture: A Spatial Analysis across the United States

    NASA Astrophysics Data System (ADS)

    Rigden, A. J.; Tuttle, S. E.; Salvucci, G.

    2014-12-01

    We spatially analyze the control over evapotranspiration (ET) imposed by soil moisture across the United States using daily estimates of satellite-derived soil moisture and data-driven ET over a nine-year period (June 2002-June 2011) at 305 locations. The soil moisture data are developed using 0.25-degree resolution satellite observations from the Advanced Microwave Scanning Radiometer for the Earth Observing System (AMSR-E), where the 9-year time series for each 0.25-degree pixel was selected from three potential algorithms (VUA-NASA, U. Montana, & NASA) based on the maximum mutual information between soil moisture and precipitation (Tuttle & Salvucci (2014), Remote Sens Environ, 114: 207-222). The ET data are developed independent of soil moisture using an emergent relationship between the diurnal cycle of the relative humidity profile and ET. The emergent relation is that the vertical variance of the relative humidity profile is less than what would occur for increased or decreased ET rates, suggesting that land-atmosphere feedback processes minimize this variance (Salvucci and Gentine (2013), PNAS, 110(16): 6287-6291). The key advantage of using this approach to estimate ET is that no measurements of surface limiting factors (soil moisture, leaf area, canopy conductance) are required; instead, ET is estimated from meteorological data measured at 305 common weather stations that are approximately uniformly distributed across the United States. The combination of these two independent datasets allows for a unique spatial analysis of the control on ET imposed by the availability of soil moisture. We fit evaporation efficiency curves across the United States at each of the 305 sites during the summertime (May-June-July-August-September). Spatial patterns are visualized by mapping optimal curve fitting coefficients across the Unites States. An analysis of efficiency curves and their spatial patterns will be presented.

  13. Nucleotide sequence of a region of the herpes simplex virus type 1 gB glycoprotein gene: mutations affecting rate of virus entry and cell fusion.

    PubMed

    Bzik, D J; Fox, B A; DeLuca, N A; Person, S

    1984-08-01

    The tsB5 isolate of herpes simplex virus type I (HSV-1) enters host cells more rapidly than does KOS, an independent isolate of HSV-1, and this rate-of-entry determinant is located between prototypic map coordinates 0.350 and 0.360 (1). The nucleotide sequence of strain tsB5 has now been determined between prototypic map coordinates 0.347 and 0.360. Comparison of the tsB5 sequence to the homologous KOS sequence revealed that the rate-of-entry difference between these two HSV-1 strains may be due to the single amino acid difference observed within these sequences (0.350 to 0.360). A cell fusion determinant in tsB5 is located between coordinates 0.345 and 0.355 and to the left of the rate-of-entry determinant (1). Nucleotide sequence analysis revealed a second amino acid difference between tsB5 and KOS at coordinate 0.349. The cell fusion determinant was tentatively assigned to this location. PMID:6089415

  14. Experiments on the Richtmyer-Meshkov instability with an imposed, random initial perturbation

    NASA Astrophysics Data System (ADS)

    Tsiklashvili, Vladimer

    The Richtmyer-Meshkov instability is studied in vertical shock tube experiment. The instability is initiated by the passage of an incident shock wave over an interface between two dissimilar gases. The interface is formed by opposed gas flows in which air and SF6 enter the shock tube from the top and from the bottom of the shock tube driven section. The gases exit the test section through a series of small holes in the test section side walls, leaving behind a flat, diffuse membrane-free interface at that location. Random three-dimensional perturbations are imposed on the interface by oscillating the column of gases in the vertical direction, using two loud speakers mounted in the shock tube wall. The development of the turbulent mixing is observed as a result of the shock-interface interaction. The flow is visualized using planar Mie scattering in which the light from a laser sheet is scattered by smoke particles seeded in one of the experimental gases and image sequences are captured using high-speed CMOS cameras. The primary interest of the study is the determination of the growth rate of the turbulent mixing layer that develops after an impulsive acceleration of the perturbed interface between the two gases (air/SF6) by a weak M=1.2 incident shock wave. Measurements of the mixing layer width following the initial shock interaction show a power law growth h˜ tthetasimilar to the those observed in previous experiments and simulations with theta ≈ 0.40. The experiments reveal that the growth rate of the mixing width significantly varies from one experiment to another. This is attributed to the influence of initial perturbations imposed on the interface. However, better consistency for the mixing layer growth rate is obtained from the mixing generated by the reflected shock wave. A novel approach that is based on mass and linear momentum conservation laws in the moving reference frame leads to a new definition of the spike and bubble mixing layer widths, which

  15. Growth Rate of and Gene Expression in Bradyrhizobium diazoefficiens USDA110 due to a Mutation in blr7984, a TetR Family Transcriptional Regulator Gene

    PubMed Central

    Ohkama-Ohtsu, Naoko; Honma, Haruna; Nakagome, Mariko; Nagata, Maki; Yamaya-Ito, Hiroko; Sano, Yoshiaki; Hiraoka, Norina; Ikemi, Takaaki; Suzuki, Akihiro; Okazaki, Shin; Minamisawa, Kiwamu; Yokoyama, Tadashi

    2016-01-01

    Previous transcriptome analyses have suggested that a gene cluster including a transcriptional regulator (blr7984) of the tetracycline repressor family was markedly down-regulated in symbiosis. Since blr7984 is annotated to be the transcriptional repressor, we hypothesized that it is involved in the repression of genes in the genomic cluster including blr7984 in symbiotic bacteroids. In order to examine the function and involvement of the blr7984 gene in differentiation into bacteroids, we compared the free-living growth/symbiotic phenotype and gene expression between a blr7984-knockout mutant and the wild-type strain of Bradyrhizobium diazoefficiens USDA110. The mutant transiently increased the cell growth rate under free-living conditions and nodule numbers over those with the wild-type strain USDA110. The expression of three genes adjacent to the disrupted blr7984 gene was strongly up-regulated in the mutant in free-living and symbiotic cells. The mutant also induced the expression of genes for glutathione S-transferase, cytochrome c oxidases, ABC transporters, PTS sugar transport systems, and flagella synthesis under free-living conditions. bll7983 encoding glutathione S-transferase was up-regulated the most by the blr7984 disruption. Since redox regulation by glutathione is known to be involved in cell division in prokaryotes and eukaryotes, the strong expression of glutathione S-transferase encoded by the bll7983 gene may have caused redox changes in mutant cells, which resulted in higher rates of cell division. PMID:27383683

  16. Cyst number but not the rate of cystic growth is associated with the mutated gene in autosomal dominant polycystic kidney disease.

    PubMed

    Harris, Peter C; Bae, Kyongtae T; Rossetti, Sandro; Torres, Vicente E; Grantham, Jared J; Chapman, Arlene B; Guay-Woodford, Lisa M; King, Bernard F; Wetzel, Louis H; Baumgarten, Deborah A; Kenney, Philip J; Consugar, Mark; Klahr, Saulo; Bennett, William M; Meyers, Catherine M; Zhang, Qin Jean; Thompson, Paul A; Zhu, Fang; Miller, J Philip

    2006-11-01

    Data from serial renal magnetic resonance imaging of the Consortium of Radiologic Imaging Study of PKD (CRISP) autosomal dominant polycystic kidney disease (PKD) population showed that cystic expansion occurs at a consistent rate per individual, although it is heterogeneous in the population, and that larger kidneys are associated with more rapid disease progression. The significance of gene type to disease progression is analyzed in this study of the CRISP cohort. Gene type was determined in 183 families (219 cases); 156 (85.2%) had PKD1, and 27 (14.8%) had PKD2. PKD1 kidneys were significantly larger, but the rate of cystic growth (PKD1 5.68%/yr; PKD2 4.82%/yr) was not different (P = 0.24). Cyst number increased with age, and more cysts were detected in PKD1 kidneys (P < 0.0001). PKD1 is more severe because more cysts develop earlier, not because they grow faster, implicating the disease gene in cyst initiation but not expansion. These insights will inform the development of targeted therapies in autosomal dominant PKD. PMID:17035604

  17. 13 CFR 126.900 - What penalties may be imposed under this part?

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 13 Business Credit and Assistance 1 2010-01-01 2010-01-01 false What penalties may be imposed under this part? 126.900 Section 126.900 Business Credit and Assistance SMALL BUSINESS ADMINISTRATION HUBZONE PROGRAM Penalties § 126.900 What penalties may be imposed under this part? (a) Suspension or debarment. The Agency debarring official...

  18. 13 CFR 125.29 - What penalties may be imposed under this part?

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 13 Business Credit and Assistance 1 2010-01-01 2010-01-01 false What penalties may be imposed under this part? 125.29 Section 125.29 Business Credit and Assistance SMALL BUSINESS ADMINISTRATION GOVERNMENT CONTRACTING PROGRAMS Penalties and Retention of Records § 125.29 What penalties may be imposed under this part? (a) Suspension or...

  19. 14 CFR 158.31 - Duration of authority to impose a PFC after project implementation.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 14 Aeronautics and Space 3 2013-01-01 2013-01-01 false Duration of authority to impose a PFC after..., DEPARTMENT OF TRANSPORTATION (CONTINUED) AIRPORTS PASSENGER FACILITY CHARGES (PFC'S) Application and Approval § 158.31 Duration of authority to impose a PFC after project implementation. A public agency that...

  20. 14 CFR 158.33 - Duration of authority to impose a PFC before project implementation.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 14 Aeronautics and Space 3 2013-01-01 2013-01-01 false Duration of authority to impose a PFC... ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIRPORTS PASSENGER FACILITY CHARGES (PFC'S) Application and Approval § 158.33 Duration of authority to impose a PFC before project implementation. (a)...

  1. 14 CFR 158.85 - Termination of authority to impose PFC's.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 14 Aeronautics and Space 3 2012-01-01 2012-01-01 false Termination of authority to impose PFC's... TRANSPORTATION (CONTINUED) AIRPORTS PASSENGER FACILITY CHARGES (PFC'S) Termination § 158.85 Termination of authority to impose PFC's. (a) The FAA begins proceedings to terminate the public agency's authority...

  2. 14 CFR 158.85 - Termination of authority to impose PFC's.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 14 Aeronautics and Space 3 2011-01-01 2011-01-01 false Termination of authority to impose PFC's... TRANSPORTATION (CONTINUED) AIRPORTS PASSENGER FACILITY CHARGES (PFC'S) Termination § 158.85 Termination of authority to impose PFC's. (a) The FAA begins proceedings to terminate the public agency's authority...

  3. 14 CFR 158.31 - Duration of authority to impose a PFC after project implementation.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 14 Aeronautics and Space 3 2011-01-01 2011-01-01 false Duration of authority to impose a PFC after..., DEPARTMENT OF TRANSPORTATION (CONTINUED) AIRPORTS PASSENGER FACILITY CHARGES (PFC'S) Application and Approval § 158.31 Duration of authority to impose a PFC after project implementation. A public agency that...

  4. 14 CFR 158.31 - Duration of authority to impose a PFC after project implementation.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 14 Aeronautics and Space 3 2014-01-01 2014-01-01 false Duration of authority to impose a PFC after..., DEPARTMENT OF TRANSPORTATION (CONTINUED) AIRPORTS PASSENGER FACILITY CHARGES (PFC'S) Application and Approval § 158.31 Duration of authority to impose a PFC after project implementation. A public agency that...

  5. 14 CFR 158.31 - Duration of authority to impose a PFC after project implementation.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 3 2010-01-01 2010-01-01 false Duration of authority to impose a PFC after..., DEPARTMENT OF TRANSPORTATION (CONTINUED) AIRPORTS PASSENGER FACILITY CHARGES (PFC'S) Application and Approval § 158.31 Duration of authority to impose a PFC after project implementation. A public agency that...

  6. 14 CFR 158.33 - Duration of authority to impose a PFC before project implementation.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 14 Aeronautics and Space 3 2011-01-01 2011-01-01 false Duration of authority to impose a PFC... ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIRPORTS PASSENGER FACILITY CHARGES (PFC'S) Application and Approval § 158.33 Duration of authority to impose a PFC before project implementation. (a)...

  7. 14 CFR 158.85 - Termination of authority to impose PFC's.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 14 Aeronautics and Space 3 2013-01-01 2013-01-01 false Termination of authority to impose PFC's... TRANSPORTATION (CONTINUED) AIRPORTS PASSENGER FACILITY CHARGES (PFC'S) Termination § 158.85 Termination of authority to impose PFC's. (a) The FAA begins proceedings to terminate the public agency's authority...

  8. 14 CFR 158.85 - Termination of authority to impose PFC's.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 3 2010-01-01 2010-01-01 false Termination of authority to impose PFC's... TRANSPORTATION (CONTINUED) AIRPORTS PASSENGER FACILITY CHARGES (PFC'S) Termination § 158.85 Termination of authority to impose PFC's. (a) The FAA begins proceedings to terminate the public agency's authority...

  9. 14 CFR 158.85 - Termination of authority to impose PFC's.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 14 Aeronautics and Space 3 2014-01-01 2014-01-01 false Termination of authority to impose PFC's... TRANSPORTATION (CONTINUED) AIRPORTS PASSENGER FACILITY CHARGES (PFC'S) Termination § 158.85 Termination of authority to impose PFC's. (a) The FAA begins proceedings to terminate the public agency's authority...

  10. 14 CFR 158.31 - Duration of authority to impose a PFC after project implementation.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 14 Aeronautics and Space 3 2012-01-01 2012-01-01 false Duration of authority to impose a PFC after..., DEPARTMENT OF TRANSPORTATION (CONTINUED) AIRPORTS PASSENGER FACILITY CHARGES (PFC'S) Application and Approval § 158.31 Duration of authority to impose a PFC after project implementation. A public agency that...

  11. 14 CFR 158.33 - Duration of authority to impose a PFC before project implementation.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 14 Aeronautics and Space 3 2014-01-01 2014-01-01 false Duration of authority to impose a PFC... ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIRPORTS PASSENGER FACILITY CHARGES (PFC'S) Application and Approval § 158.33 Duration of authority to impose a PFC before project implementation. (a)...

  12. 14 CFR 158.33 - Duration of authority to impose a PFC before project implementation.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 14 Aeronautics and Space 3 2012-01-01 2012-01-01 false Duration of authority to impose a PFC... ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIRPORTS PASSENGER FACILITY CHARGES (PFC'S) Application and Approval § 158.33 Duration of authority to impose a PFC before project implementation. (a)...

  13. 26 CFR 1.665(d)-1 - Taxes imposed on the trust.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 8 2014-04-01 2014-04-01 false Taxes imposed on the trust. 1.665(d)-1 Section 1.665(d)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX... Beginning Before January 1, 1969 § 1.665(d)-1 Taxes imposed on the trust. (a) For the purpose of subpart...

  14. 26 CFR 1.665(d)-1 - Taxes imposed on the trust.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Taxes imposed on the trust. 1.665(d)-1 Section 1.665(d)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX... Before January 1, 1969 § 1.665(d)-1 Taxes imposed on the trust. (a) For the purpose of subpart D...

  15. 26 CFR 1.665(d)-1 - Taxes imposed on the trust.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 8 2011-04-01 2011-04-01 false Taxes imposed on the trust. 1.665(d)-1 Section 1.665(d)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX... Beginning Before January 1, 1969 § 1.665(d)-1 Taxes imposed on the trust. (a) For the purpose of subpart...

  16. 26 CFR 1.665(d)-1 - Taxes imposed on the trust.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 8 2013-04-01 2013-04-01 false Taxes imposed on the trust. 1.665(d)-1 Section 1.665(d)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX... Beginning Before January 1, 1969 § 1.665(d)-1 Taxes imposed on the trust. (a) For the purpose of subpart...

  17. 26 CFR 1.665(d)-1 - Taxes imposed on the trust.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 8 2012-04-01 2012-04-01 false Taxes imposed on the trust. 1.665(d)-1 Section 1.665(d)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX... Beginning Before January 1, 1969 § 1.665(d)-1 Taxes imposed on the trust. (a) For the purpose of subpart...

  18. 26 CFR 52.4681-1 - Taxes imposed with respect to ozone-depleting chemicals.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 17 2013-04-01 2013-04-01 false Taxes imposed with respect to ozone-depleting chemicals. 52.4681-1 Section 52.4681-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) MISCELLANEOUS EXCISE TAXES (CONTINUED) ENVIRONMENTAL TAXES § 52.4681-1 Taxes imposed with respect to ozone-depleting chemicals....

  19. The Effect of Imposed Silence on Food Consumption at a Nursery School.

    ERIC Educational Resources Information Center

    Knight, Kathy B.; Bomba, Anne K.

    1993-01-01

    Observed 19 preschool children at lunch for 20 days to determine the effects of imposed silence at lunch on the amount of food consumed during meals in a nursery school setting. Found that imposing silence during mealtime did not increase food consumption but did foster a stressful atmosphere. (MM)

  20. 42 CFR 422.758 - Collection of civil money penalties imposed by CMS.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 3 2010-10-01 2010-10-01 false Collection of civil money penalties imposed by CMS... § 422.758 Collection of civil money penalties imposed by CMS. (a) When an MA organization does not request a hearing, CMS initiates collection of the civil money penalty following the expiration of...

  1. 42 CFR 423.758 - Collection of civil money penalties imposed by CMS.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 3 2014-10-01 2014-10-01 false Collection of civil money penalties imposed by CMS... BENEFIT Intermediate Sanctions § 423.758 Collection of civil money penalties imposed by CMS. (a) When a Part D plan sponsor does not request a hearing CMS initiates collection of the civil money...

  2. 42 CFR 422.756 - Procedures for imposing intermediate sanctions and civil money penalties.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... civil money penalties. 422.756 Section 422.756 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES... Intermediate Sanctions § 422.756 Procedures for imposing intermediate sanctions and civil money penalties. (a... contract in accordance with § 422.510. (e) Notice to impose civil money penalties—(1) CMS notice to OIG....

  3. 42 CFR 422.758 - Collection of civil money penalties imposed by CMS.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 3 2014-10-01 2014-10-01 false Collection of civil money penalties imposed by CMS... Sanctions § 422.758 Collection of civil money penalties imposed by CMS. (a) When an MA organization does not request a hearing, CMS initiates collection of the civil money penalty following the expiration of...

  4. Descriptions of two new, cryptic species of Metasiro (Arachnida: Opiliones: Cyphophthalmi: Neogoveidae) from South Carolina, USA, including a discussion of mitochondrial mutation rates.

    PubMed

    Clouse, Ronald M; Wheeler, Ward C

    2014-01-01

    Specimens of Metasiro from its three known disjunct population centers in the southeastern US were examined and had a 769 bp fragement of the mitochondrial gene cytochrome c oxidase subunit I (COI) sequenced. These populations are located in the western panhandle of Florida and nearby areas of Georgia, in the Savannah River delta of South Carolina, and on Sassafras Mt. in South Carolina. This range extends over as much as 500 km, which is very large for a species of cyphophthalmid harvestmen and presents a degree of physical separation among populations such that we would expect them to actually be distinguishable species. We examined the morphology, including the spermatopositors of males, and sequences from 221 specimens. We found no discernible differences in the morphologies of specimens from the different populations, but corrected pairwise distances of COI were about 15% among the three population centers. We also analyzed COI data using a General Mixed Yule Coalescent (GMYC) model implemented in the R package SPLITS; with a single threshold, the most likely model had four species within Metasiro. Given this level of molecular divergence, the monophyly of the population haplotypes, and the number of exclusive COI nucleotide and amino acid differences distinguishing the populations, we here raise the Savannah River and Sassafras Mt. populations to species status: M. savannahensis sp. nov., and M. sassafrasensis sp. nov., respectively. This restricts M. americanus (Davis, 1933) to just the Lower Chattahoochee Watershed, which in this study includes populations along the Apalachicola River and around Florida Caverns State Park. GMYC models reconstructed the two main haplotype clades within M. americanus as different species, but they are not exclusive to different areas. We estimate COI percent divergence rates in certain cyphophthalmid groups and discuss problems with historical measures of this rate. We hypothesize that Metasiro began diversifying over 20

  5. Affective Responses to Acute Resistance Exercise Performed at Self-Selected and Imposed Loads in Trained Women.

    PubMed

    Focht, Brian C; Garver, Matthew J; Cotter, Joshua A; Devor, Steven T; Lucas, Alexander R; Fairman, Ciaran M

    2015-11-01

    The purpose of this study was to examine the affective responses to acute resistance exercise (RE) performed at self-selected (SS) and imposed loads in recreationally trained women. Secondary purposes were to (a) examine differences in correlates of motivation for future participation in RE and (b) determine whether affective responses to RE were related to these select motivational correlates of RE participation. Twenty recreationally trained young women (mean age = 23 years) completed 3 RE sessions involving 3 sets of 10 repetitions using loads of 40% of 1 repetition maximum (1RM), 70% 1RM, and an SS load. Affective responses were assessed before, during, and after each RE session using the Feeling Scale. Self-efficacy and intention for using the imposed and SS loads for their regular RE participation during the next month were also assessed postexercise. Results revealed that although the SS and imposed load RE sessions yielded different trajectories of change in affect during exercise (p < 0.01), comparable improvements in affect emerged after RE. Additionally, the SS condition was associated with the highest ratings of self-efficacy and intention for future RE participation (p < 0.01), but affective responses to acute RE were unrelated to self-efficacy or intention. It is concluded that acute bouts of SS and imposed load RE resulted in comparable improvements in affect; recreationally trained women reported the highest self-efficacy and intention to use the load chosen in SS condition in their own resistance training; and affective responses were unrelated to motivational correlates of resistance training. PMID:26506060

  6. Mutation in the Drosophila melanogaster adenosine receptor gene selectively decreases the mosaic hyperplastic epithelial outgrowth rates in wts or dco heterozygous flies.

    PubMed

    Sidorov, Roman; Kucerova, Lucie; Kiss, Istvan; Zurovec, Michal

    2015-03-01

    Adenosine (Ado) is a ubiquitous metabolite that plays a prominent role as a paracrine homeostatic signal of metabolic imbalance within tissues. It quickly responds to various stress stimuli by adjusting energy metabolism and influencing cell growth and survival. Ado is also released by dead or dying cells and is present at significant concentrations in solid tumors. Ado signaling is mediated by Ado receptors (AdoR) and proteins modulating its concentration, including nucleoside transporters and Ado deaminases. We examined the impact of genetic manipulations of three Drosophila genes involved in Ado signaling on the incidence of somatic mosaic clones formed by the loss of heterozygosity (LOH) of tumor suppressor and marker genes. We show here that genetic manipulations with the AdoR, equilibrative nucleoside transporter 2 (Ent2), and Ado deaminase growth factor-A (Adgf-A) cause dramatic changes in the frequency of hyperplastic outgrowth clones formed by LOH of the warts (wts) tumor suppressor, while they have almost no effect on control yellow (y) clones. In addition, the effect of AdoR is dose-sensitive and its overexpression leads to the increase in wts hyperplastic epithelial outgrowth rates. Consistently, the frequency of mosaic hyperplastic outgrowth clones generated by the LOH of another tumor suppressor, discs overgrown (dco), belonging to the wts signaling pathway is also dependent on AdoR. Our results provide interesting insight into the maintenance of tissue homeostasis at a cellular level. PMID:25528157

  7. 26 CFR 31.3308-1 - Instrumentalities of the United States specifically exempted from tax imposed by section 3301.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... specifically exempted from tax imposed by section 3301. 31.3308-1 Section 31.3308-1 Internal Revenue INTERNAL... from tax imposed by section 3301. Section 3308 makes ineffectual as to the tax imposed by section 3301... provisions grant a specific exemption from the tax imposed by section 3301 by an express reference to...

  8. 26 CFR 31.3308-1 - Instrumentalities of the United States specifically exempted from tax imposed by section 3301.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... specifically exempted from tax imposed by section 3301. 31.3308-1 Section 31.3308-1 Internal Revenue INTERNAL... from tax imposed by section 3301. Section 3308 makes ineffectual as to the tax imposed by section 3301... provisions grant a specific exemption from the tax imposed by section 3301 by an express reference to...

  9. 26 CFR 31.3308-1 - Instrumentalities of the United States specifically exempted from tax imposed by section 3301.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... specifically exempted from tax imposed by section 3301. 31.3308-1 Section 31.3308-1 Internal Revenue INTERNAL... from tax imposed by section 3301. Section 3308 makes ineffectual as to the tax imposed by section 3301... provisions grant a specific exemption from the tax imposed by section 3301 by an express reference to...

  10. 26 CFR 31.3308-1 - Instrumentalities of the United States specifically exempted from tax imposed by section 3301.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... specifically exempted from tax imposed by section 3301. 31.3308-1 Section 31.3308-1 Internal Revenue INTERNAL... from tax imposed by section 3301. Section 3308 makes ineffectual as to the tax imposed by section 3301... provisions grant a specific exemption from the tax imposed by section 3301 by an express reference to...

  11. A spontaneously arising mutation in connexin32 with repeated passage of FRTL-5 cells coincides with increased growth rate and reduced thyroxine release

    NASA Technical Reports Server (NTRS)

    Green, L. M.; Murray, D. K.; Tran, D. T.; Nelson, G. A.; Shah, M. M.; Luben, R. A.

    2001-01-01

    In this study we examine changes in the cellular properties of FRTL-5 cells as a function of passage number, with particular emphasis on gap junction expression, karyotype, morphology, growth rate and thyroxine (T(4)) release. Early passage FRTL-5 follicular cells transfer dye through gap junctions from injected cell(s) to third-order neighboring cells and beyond within their respective follicles and have immuno-detectable connexin32 (Cx32) type gap junctional plaques in their lateral contacting plasma membranes. By contrast, FRTL-5 cells established as monolayers, or as follicles from cultures passed more than 15 times, did not transfer microinjected Lucifer Yellow dye to contiguous neighboring cells and did not express any immuno-detectable rat thyroid specific connexins (Cx43, Cx32 or Cx26). Western blots confirmed that total, membrane and cytosolic Cx32 protein was present only in early pass follicular cultures. To better understand the passage-dependent loss of Cx32 expression, RT-PCR primers were made to the most unique sequences of the rat Cx32 molecule, the cytoplasmic and carboxyl-terminal regions. These primers were used to screen FRTL-5 RNA from cultures of various passage numbers. The results revealed that later passage cultures had a single base deletion in the middle of the Cx32 cytoplasmic loop region at nucleotide position 378. This base deletion was in the middle position of the codon for amino acid 116, which is normally a CAC (histidine) but read with the frame shift was a CCC (proline). The four amino acids that followed this deletion were also altered with the fourth one becoming UAA, the ochre translation stop codon. This premature stopping of translation resulted in a truncation of 60% of the protein, which included the remaining cytoplasmic loop, third and fourth transmembrane regions and the carboxyl-terminus. The later passage cultures did not produce a carboxyl-terminal RT-PCR product, indicating that the mRNA was also truncated. These

  12. A spontaneously arising mutation in connexin32 with repeated passage of FRTL-5 cells coincides with increased growth rate and reduced thyroxine release

    NASA Technical Reports Server (NTRS)

    Green, L. M.; Murray, D. K.; Tran, D. T.; Nelson, G. A.; Shah, M. M.; Luben, R. A.

    2001-01-01

    In this study we examine changes in the cellular properties of FRTL-5 cells as a function of passage number, with particular emphasis on gap junction expression, karyotype, morphology, growth rate and thyroxine (T(4)) release. Early passage FRTL-5 follicular cells transfer dye through gap junctions from injected cell(s) to third-order neighboring cells and beyond within their respective follicles and have immuno-detectable connexin32 (Cx32) type gap junctional plaques in their lateral contacting plasma membranes. By contrast, FRTL-5 cells established as monolayers, or as follicles from cultures passed more than 15 times, did not transfer microinjected Lucifer Yellow dye to contiguous neighboring cells and did not express any immuno-detectable rat thyroid specific connexins (Cx43, Cx32 or Cx26). Western blots confirmed that total, membrane and cytosolic Cx32 protein was present only in early pass follicular cultures. To better understand the passage-dependent loss of Cx32 expression, RT-PCR primers were made to the most unique sequences of the rat Cx32 molecule, the cytoplasmic and carboxyl-terminal regions. These primers were used to screen FRTL-5 RNA from cultures of various passage numbers. The results revealed that later passage cultures had a single base deletion in the middle of the Cx32 cytoplasmic loop region at nucleotide position 378. This base deletion was in the middle position of the codon for amino acid 116, which is normally a CAC (histidine) but read with the frame shift was a CCC (proline). The four amino acids that followed this deletion were also altered with the fourth one becoming UAA, the ochre translation stop codon. This premature stopping of translation resulted in a truncation of 60% of the protein, which included the remaining cytoplasmic loop, third and fourth transmembrane regions and the carboxyl-terminus. The later passage cultures did not produce a carboxyl-terminal RT-PCR product, indicating that the mRNA was also truncated. These

  13. Amikacin-Fosfomycin at a Five-to-Two Ratio: Characterization of Mutation Rates in Microbial Strains Causing Ventilator-Associated Pneumonia and Interactions with Commonly Used Antibiotics

    PubMed Central

    Rhomberg, Paul R.; Abuan, Tammy; Walters, Kathie-Anne; Flamm, Robert K.

    2014-01-01

    The amikacin-fosfomycin inhalation system (AFIS), a combination of antibiotics administered with an in-line nebulizer delivery system, is being developed for adjunctive treatment of ventilator-associated pneumonia (VAP). The in vitro characterization of amikacin-fosfomycin (at a 5:2 ratio) described here included determining resistance selection rates for pathogens that are representative of those commonly associated with VAP (including multidrug-resistant strains) and evaluating interactions with antibiotics commonly used intravenously to treat VAP. Spontaneous resistance to amikacin-fosfomycin (5:2) was not observed for most strains tested (n, 10/14). Four strains had spontaneously resistant colonies (frequencies, 4.25 × 10−8 to 3.47 × 10−10), for which amikacin-fosfomycin (5:2) MICs were 2- to 8-fold higher than those for the original strains. After 7 days of serial passage, resistance (>4-fold increase over the baseline MIC) occurred in fewer strains (n, 4/14) passaged in the presence of amikacin-fosfomycin (5:2) than with either amikacin (n, 7/14) or fosfomycin (n, 12/14) alone. Interactions between amikacin-fosfomycin (5:2) and 10 comparator antibiotics in checkerboard testing against 30 different Gram-positive or Gram-negative bacterial strains were synergistic (fractional inhibitory concentration [FIC] index, ≤0.5) for 6.7% (n, 10/150) of combinations tested. No antagonism was observed. Synergy was confirmed by time-kill methodology for amikacin-fosfomycin (5:2) plus cefepime (against Escherichia coli), aztreonam (against Pseudomonas aeruginosa), daptomycin (against Enterococcus faecalis), and azithromycin (against Staphylococcus aureus). Amikacin-fosfomycin (5:2) was bactericidal at 4-fold the MIC for 7 strains tested. The reduced incidence of development of resistance to amikacin-fosfomycin (5:2) compared with that for amikacin or fosfomycin alone, and the lack of negative interactions with commonly used intravenous antibiotics, further supports

  14. Amikacin-fosfomycin at a five-to-two ratio: characterization of mutation rates in microbial strains causing ventilator-associated pneumonia and interactions with commonly used antibiotics.

    PubMed

    Montgomery, A Bruce; Rhomberg, Paul R; Abuan, Tammy; Walters, Kathie-Anne; Flamm, Robert K

    2014-07-01

    The amikacin-fosfomycin inhalation system (AFIS), a combination of antibiotics administered with an in-line nebulizer delivery system, is being developed for adjunctive treatment of ventilator-associated pneumonia (VAP). The in vitro characterization of amikacin-fosfomycin (at a 5:2 ratio) described here included determining resistance selection rates for pathogens that are representative of those commonly associated with VAP (including multidrug-resistant strains) and evaluating interactions with antibiotics commonly used intravenously to treat VAP. Spontaneous resistance to amikacin-fosfomycin (5:2) was not observed for most strains tested (n, 10/14). Four strains had spontaneously resistant colonies (frequencies, 4.25 × 10(-8) to 3.47 × 10(-10)), for which amikacin-fosfomycin (5:2) MICs were 2- to 8-fold higher than those for the original strains. After 7 days of serial passage, resistance (>4-fold increase over the baseline MIC) occurred in fewer strains (n, 4/14) passaged in the presence of amikacin-fosfomycin (5:2) than with either amikacin (n, 7/14) or fosfomycin (n, 12/14) alone. Interactions between amikacin-fosfomycin (5:2) and 10 comparator antibiotics in checkerboard testing against 30 different Gram-positive or Gram-negative bacterial strains were synergistic (fractional inhibitory concentration [FIC] index, ≤ 0.5) for 6.7% (n, 10/150) of combinations tested. No antagonism was observed. Synergy was confirmed by time-kill methodology for amikacin-fosfomycin (5:2) plus cefepime (against Escherichia coli), aztreonam (against Pseudomonas aeruginosa), daptomycin (against Enterococcus faecalis), and azithromycin (against Staphylococcus aureus). Amikacin-fosfomycin (5:2) was bactericidal at 4-fold the MIC for 7 strains tested. The reduced incidence of development of resistance to amikacin-fosfomycin (5:2) compared with that for amikacin or fosfomycin alone, and the lack of negative interactions with commonly used intravenous antibiotics, further supports

  15. 14 CFR 382.33 - May carriers impose other restrictions on passengers with a disability that they do not impose on...

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 4 2010-01-01 2010-01-01 false May carriers impose other restrictions on... and Space OFFICE OF THE SECRETARY, DEPARTMENT OF TRANSPORTATION (AVIATION PROCEEDINGS) SPECIAL REGULATIONS NONDISCRIMINATION ON THE BASIS OF DISABILITY IN AIR TRAVEL Nondiscrimination and Access...

  16. 14 CFR 382.33 - May carriers impose other restrictions on passengers with a disability that they do not impose on...

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 14 Aeronautics and Space 4 2011-01-01 2011-01-01 false May carriers impose other restrictions on... and Space OFFICE OF THE SECRETARY, DEPARTMENT OF TRANSPORTATION (AVIATION PROCEEDINGS) SPECIAL REGULATIONS NONDISCRIMINATION ON THE BASIS OF DISABILITY IN AIR TRAVEL Nondiscrimination and Access...

  17. 14 CFR 382.33 - May carriers impose other restrictions on passengers with a disability that they do not impose on...

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 14 Aeronautics and Space 4 2012-01-01 2012-01-01 false May carriers impose other restrictions on... and Space OFFICE OF THE SECRETARY, DEPARTMENT OF TRANSPORTATION (AVIATION PROCEEDINGS) SPECIAL REGULATIONS NONDISCRIMINATION ON THE BASIS OF DISABILITY IN AIR TRAVEL Nondiscrimination and Access...

  18. 14 CFR 382.33 - May carriers impose other restrictions on passengers with a disability that they do not impose on...

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 14 Aeronautics and Space 4 2014-01-01 2014-01-01 false May carriers impose other restrictions on... and Space OFFICE OF THE SECRETARY, DEPARTMENT OF TRANSPORTATION (AVIATION PROCEEDINGS) SPECIAL REGULATIONS NONDISCRIMINATION ON THE BASIS OF DISABILITY IN AIR TRAVEL Nondiscrimination and Access...

  19. Plasma membrane NADH oxidase of maize roots responds to gravity and imposed centrifugal forces

    NASA Technical Reports Server (NTRS)

    Bacon, E.; Morre, D. J.

    2001-01-01

    NADH oxidase activities measured with excised roots of dark-grown maize (Zea mays) seedlings and with isolated plasma membrane vesicles from roots of dark-grown maize oscillated with a regular period length of 24 min and were inhibited by the synthetic auxin 2,4-dichlorophenoxyacetic [correction of dichorophenoxyacetic] acid. The activities also responded to orientation with respect to gravity and to imposed centrifugal forces. Turning the roots upside down resulted in stimulation of the activity with a lag of about 10 min. Returning the sections to the normal upright position resulted in a return to initial rates. The activity was stimulated reversibly to a maximum of about 2-fold with isolated plasma membrane vesicles, when subjected to centrifugal forces of 25 to 250 x g for 1 to 4 min duration. These findings are the first report of a gravity-responsive enzymatic activity of plant roots inhibited by auxin and potentially related to the gravity-induced growth response. c2001 Editions scientifiques et medicales Elsevier SAS.

  20. 24 CFR 266.120 - Actions for which sanctions may be imposed.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... which sanctions may be imposed against the HFA by HUD's Mortgagee Review Board under 24 CFR 25.9. (e... the requirements of this part. (c) Engagement in business practices that do not conform to...

  1. 42 CFR 422.756 - Procedures for imposing intermediate sanctions and civil money penalties.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... instances where marketing or enrollment or both intermediate sanctions have been imposed, CMS may require an... part to challenge CMS' determination to keep the intermediate sanctions in effect. (d) Termination...

  2. Mutation and the environment

    SciTech Connect

    Mendelsohn, M.L. ); Albertini, R.J. )

    1990-01-01

    This book is organized under the following headings: Plenary lectures; Brook mutational mechanisms; Adduction and DNA damage; Recombination and gene conversion; Repair: Prokoyote mechanisms and induction; Repair: Lower eukaryote and plant mechanisms; Repair: Higher eukaryote mechanisms and selectivity; Repair: Human genes and mechanisms; Mutation: Spectra and mechanisms; Mutation: Shuttle vectors; Mutation: Transgenic animals; New methods: Polymerase chain reaction.

  3. Imposed Cold-water Ingestion during Open Water Swimming in Internationally Ranked Swimmers.

    PubMed

    Hue, O; Monjo, R; Riera, F

    2015-11-01

    The authors explored the effects of open water swimming in a tropical environment on both core temperature (T c) and thermal perceptions of high-level swimmers during an official international 10-km race and two 5-km swimming tests. The swimmers drank neutral water (i. e., 28.0±3.0°C) ad libitum every 2,000 m during Competition, whereas the ingested volume was imposed in the 5-km tests: every 1,000 m, they drank 190 mL of cold water (CW, 1.1±0.7°C) or neutral water (NW, 28.0±3.0°C). They also self-rated their thermal comfort and sensation (TC and TS), and their T c was recorded. The study demonstrated that adequate fluid intake significantly decreased T c in swimmers swimming at race pace in hot water (i. e., 37.5±0.3°C vs. 38.3±0.4°C, in NW vs. Competition, respectively). This effect was more pronounced with cold water (i. e., 36.7±1.1°C, in CW). No significant changes were noted in mean heart rate (i. e., 145±5, 143±4 and 141±5 bpm for NW, CW and Competition, respectively). Further studies are needed to explore the effect of this cooling method on the performances of international swimmers during tropical swimming events. PMID:26258824

  4. Compensating the Fitness Costs of Synonymous Mutations.

    PubMed

    Knöppel, Anna; Näsvall, Joakim; Andersson, Dan I

    2016-06-01

    Synonymous mutations do not change the sequence of the polypeptide but they may still influence fitness. We investigated in Salmonella enterica how four synonymous mutations in the rpsT gene (encoding ribosomal protein S20) reduce fitness (i.e., growth rate) and the mechanisms by which this cost can be genetically compensated. The reduced growth rates of the synonymous mutants were correlated with reduced levels of the rpsT transcript and S20 protein. In an adaptive evolution experiment, these fitness impairments could be compensated by mutations that either caused up-regulation of S20 through increased gene dosage (due to duplications), increased transcription of the rpsT gene (due to an rpoD mutation or mutations in rpsT), or increased translation from the rpsT transcript (due to rpsT mutations). We suggest that the reduced levels of S20 in the synonymous mutants result in production of a defective subpopulation of 30S subunits lacking S20 that reduce protein synthesis and bacterial growth and that the compensatory mutations restore S20 levels and the number of functional ribosomes. Our results demonstrate how specific synonymous mutations can cause substantial fitness reductions and that many different types of intra- and extragenic compensatory mutations can efficiently restore fitness. Furthermore, this study highlights that also synonymous sites can be under strong selection, which may have implications for the use of dN/dS ratios as signature for selection. PMID:26882986

  5. Compensating the Fitness Costs of Synonymous Mutations

    PubMed Central

    Knöppel, Anna; Näsvall, Joakim; Andersson, Dan I.

    2016-01-01

    Synonymous mutations do not change the sequence of the polypeptide but they may still influence fitness. We investigated in Salmonella enterica how four synonymous mutations in the rpsT gene (encoding ribosomal protein S20) reduce fitness (i.e., growth rate) and the mechanisms by which this cost can be genetically compensated. The reduced growth rates of the synonymous mutants were correlated with reduced levels of the rpsT transcript and S20 protein. In an adaptive evolution experiment, these fitness impairments could be compensated by mutations that either caused up-regulation of S20 through increased gene dosage (due to duplications), increased transcription of the rpsT gene (due to an rpoD mutation or mutations in rpsT), or increased translation from the rpsT transcript (due to rpsT mutations). We suggest that the reduced levels of S20 in the synonymous mutants result in production of a defective subpopulation of 30S subunits lacking S20 that reduce protein synthesis and bacterial growth and that the compensatory mutations restore S20 levels and the number of functional ribosomes. Our results demonstrate how specific synonymous mutations can cause substantial fitness reductions and that many different types of intra- and extragenic compensatory mutations can efficiently restore fitness. Furthermore, this study highlights that also synonymous sites can be under strong selection, which may have implications for the use of dN/dS ratios as signature for selection. PMID:26882986

  6. Clock-like mutational processes in human somatic cells

    DOE PAGESBeta

    Alexandrov, Ludmil B.; Jones, Philip H.; Wedge, David C.; Sale, Julian E.; Campbell, Peter J.; Nik-Zainal, Serena; Stratton, Michael R.

    2015-11-09

    During the course of a lifetime, somatic cells acquire mutations. Different mutational processes may contribute to the mutations accumulated in a cell, with each imprinting a mutational signature on the cell's genome. Some processes generate mutations throughout life at a constant rate in all individuals, and the number of mutations in a cell attributable to these processes will be proportional to the chronological age of the person. Using mutations from 10,250 cancer genomes across 36 cancer types, we investigated clock-like mutational processes that have been operating in normal human cells. Two mutational signatures show clock-like properties. Both exhibit different mutationmore » rates in different tissues. However, their mutation rates are not correlated, indicating that the underlying processes are subject to different biological influences. For one signature, the rate of cell division may influence its mutation rate. This paper provides the first survey of clock-like mutational processes operating in human somatic cells.« less

  7. TERT Promoter Mutations in Thyroid Cancer.

    PubMed

    Alzahrani, Ali S; Alsaadi, Rawan; Murugan, Avaniyapuram Kannan; Sadiq, Bakr Bin

    2016-06-01

    Two mutations (C228T and C250T) in the promoter region of the telomerase reverse transcriptase (TERT) have recently been described in different types of cancer including follicular cell-derived thyroid cancer (TC). In this paper, we reviewed the rates of these mutations in different types and subtypes of TC, their association with a number of clinical and histopathological features and outcome of TC, and their potential diagnostic and prognostic roles in TC. The overall rate of these mutations in TC is about 14 % with least prevalence in the well-differentiated subtypes of papillary thyroid cancer (10-13 %). Their rates increase significantly with increasing aggressiveness of TC reaching about 40 % in the undifferentiated and anaplastic thyroid cancers. There is also clear association with increasing age of patients at the time of diagnosis of TC. The evidence is compelling but with some conflicting results for associations between TERT promoter mutations and tumor size, extrathyroidal invasion, distant metastases, high tumor TNM stage, BRAF (V600E) mutation, recurrence, and mortality. A couple of studies reported a potential diagnostic role for TERT promoter mutations in thyroid nodules with indeterminate cytology of fine needle aspiration biopsy. These studies showed 100 % specificity but very low sensitivity of 7-10 %. The sensitivity increases significantly when TERT promoter mutation testing is combined with other gene mutations, particularly BRAF (V600E) and RAS mutations. Although TERT promoter mutations seem to play significant roles in the pathogenesis of TC, the mechanisms by which they contribute to carcinogenesis remain elusive and future work is needed to fully assess the roles, interactions, and impact of these mutations on the pathogenesis, diagnosis, prognosis, and therapeutics of TC. PMID:26902827

  8. Confidence-based somatic mutation evaluation and prioritization.

    PubMed

    Löwer, Martin; Renard, Bernhard Y; de Graaf, Jos; Wagner, Meike; Paret, Claudia; Kneip, Christoph; Türeci, Ozlem; Diken, Mustafa; Britten, Cedrik; Kreiter, Sebastian; Koslowski, Michael; Castle, John C; Sahin, Ugur

    2012-01-01

    Next generation sequencing (NGS) has enabled high throughput discovery of somatic mutations. Detection depends on experimental design, lab platforms, parameters and analysis algorithms. However, NGS-based somatic mutation detection is prone to erroneous calls, with reported validation rates near 54% and congruence between algorithms less than 50%. Here, we developed an algorithm to assign a single statistic, a false discovery rate (FDR), to each somatic mutation identified by NGS. This FDR confidence value accurately discriminates true mutations from erroneous calls. Using sequencing data generated from triplicate exome profiling of C57BL/6 mice and B16-F10 melanoma cells, we used the existing algorithms GATK, SAMtools and SomaticSNiPer to identify somatic mutations. For each identified mutation, our algorithm assigned an FDR. We selected 139 mutations for validation, including 50 somatic mutations assigned a low FDR (high confidence) and 44 mutations assigned a high FDR (low confidence). All of the high confidence somatic mutations validated (50 of 50), none of the 44 low confidence somatic mutations validated, and 15 of 45 mutations with an intermediate FDR validated. Furthermore, the assignment of a single FDR to individual mutations enables statistical comparisons of lab and computation methodologies, including ROC curves and AUC metrics. Using the HiSeq 2000, single end 50 nt reads from replicates generate the highest confidence somatic mutation call set. PMID:23028300

  9. Confidence-based Somatic Mutation Evaluation and Prioritization

    PubMed Central

    de Graaf, Jos; Wagner, Meike; Paret, Claudia; Kneip, Christoph; Türeci, Özlem; Diken, Mustafa; Britten, Cedrik; Kreiter, Sebastian; Koslowski, Michael; Castle, John C.; Sahin, Ugur

    2012-01-01

    Next generation sequencing (NGS) has enabled high throughput discovery of somatic mutations. Detection depends on experimental design, lab platforms, parameters and analysis algorithms. However, NGS-based somatic mutation detection is prone to erroneous calls, with reported validation rates near 54% and congruence between algorithms less than 50%. Here, we developed an algorithm to assign a single statistic, a false discovery rate (FDR), to each somatic mutation identified by NGS. This FDR confidence value accurately discriminates true mutations from erroneous calls. Using sequencing data generated from triplicate exome profiling of C57BL/6 mice and B16-F10 melanoma cells, we used the existing algorithms GATK, SAMtools and SomaticSNiPer to identify somatic mutations. For each identified mutation, our algorithm assigned an FDR. We selected 139 mutations for validation, including 50 somatic mutations assigned a low FDR (high confidence) and 44 mutations assigned a high FDR (low confidence). All of the high confidence somatic mutations validated (50 of 50), none of the 44 low confidence somatic mutations validated, and 15 of 45 mutations with an intermediate FDR validated. Furthermore, the assignment of a single FDR to individual mutations enables statistical comparisons of lab and computation methodologies, including ROC curves and AUC metrics. Using the HiSeq 2000, single end 50 nt reads from replicates generate the highest confidence somatic mutation call set. PMID:23028300

  10. More Frequent than Desired: Midgut Stem Cell Somatic Mutations.

    PubMed

    Li, Qi; Ip, Y Tony

    2015-12-01

    The accumulation of somatic mutations in adult stem cells contributes to the decline of tissue functions and cancer initiation. In this issue of Cell Stem Cell, Siudeja et al. (2015) investigate the rate and mechanism of naturally occurring mutations in Drosophila midgut intestinal stem cells during aging and find high-frequency mutations arising from multiple mechanisms. PMID:26637937

  11. Contact transmission of influenza virus between ferrets imposes a looser bottleneck than respiratory droplet transmission allowing propagation of antiviral resistance

    PubMed Central

    Frise, Rebecca; Bradley, Konrad; van Doremalen, Neeltje; Galiano, Monica; Elderfield, Ruth A.; Stilwell, Peter; Ashcroft, Jonathan W.; Fernandez-Alonso, Mirian; Miah, Shahjahan; Lackenby, Angie; Roberts, Kim L.; Donnelly, Christl A.; Barclay, Wendy S.

    2016-01-01

    Influenza viruses cause annual seasonal epidemics and occasional pandemics. It is important to elucidate the stringency of bottlenecks during transmission to shed light on mechanisms that underlie the evolution and propagation of antigenic drift, host range switching or drug resistance. The virus spreads between people by different routes, including through the air in droplets and aerosols, and by direct contact. By housing ferrets under different conditions, it is possible to mimic various routes of transmission. Here, we inoculated donor animals with a mixture of two viruses whose genomes differed by one or two reverse engineered synonymous mutations, and measured the transmission of the mixture to exposed sentinel animals. Transmission through the air imposed a tight bottleneck since most recipient animals became infected by only one virus. In contrast, a direct contact transmission chain propagated a mixture of viruses suggesting the dose transferred by this route was higher. From animals with a mixed infection of viruses that were resistant and sensitive to the antiviral drug oseltamivir, resistance was propagated through contact transmission but not by air. These data imply that transmission events with a looser bottleneck can propagate minority variants and may be an important route for influenza evolution. PMID:27430528

  12. Contact transmission of influenza virus between ferrets imposes a looser bottleneck than respiratory droplet transmission allowing propagation of antiviral resistance.

    PubMed

    Frise, Rebecca; Bradley, Konrad; van Doremalen, Neeltje; Galiano, Monica; Elderfield, Ruth A; Stilwell, Peter; Ashcroft, Jonathan W; Fernandez-Alonso, Mirian; Miah, Shahjahan; Lackenby, Angie; Roberts, Kim L; Donnelly, Christl A; Barclay, Wendy S

    2016-01-01

    Influenza viruses cause annual seasonal epidemics and occasional pandemics. It is important to elucidate the stringency of bottlenecks during transmission to shed light on mechanisms that underlie the evolution and propagation of antigenic drift, host range switching or drug resistance. The virus spreads between people by different routes, including through the air in droplets and aerosols, and by direct contact. By housing ferrets under different conditions, it is possible to mimic various routes of transmission. Here, we inoculated donor animals with a mixture of two viruses whose genomes differed by one or two reverse engineered synonymous mutations, and measured the transmission of the mixture to exposed sentinel animals. Transmission through the air imposed a tight bottleneck since most recipient animals became infected by only one virus. In contrast, a direct contact transmission chain propagated a mixture of viruses suggesting the dose transferred by this route was higher. From animals with a mixed infection of viruses that were resistant and sensitive to the antiviral drug oseltamivir, resistance was propagated through contact transmission but not by air. These data imply that transmission events with a looser bottleneck can propagate minority variants and may be an important route for influenza evolution. PMID:27430528

  13. Molecular Analysis of Hereditary Nonpolyposis Colorectal Cancer in the United States: High Mutation Detection Rate among Clinically Selected Families and Characterization of an American Founder Genomic Deletion of the MSH2 Gene

    PubMed Central

    Wagner, Anja; Barrows, Alicia; Wijnen, Juul Th.; van der Klift, Heleen; Franken, Patrick F.; Verkuijlen, Paul; Nakagawa, Hidewaki; Geugien, Marjan; Jaghmohan-Changur, Shantie; Breukel, Cor; Meijers-Heijboer, Hanne; Morreau, Hans; van Puijenbroek, Marjo; Burn, John; Coronel, Stephany; Kinarski, Yulia; Okimoto, Ross; Watson, Patrice; Lynch, Jane F.; de la Chapelle, Albert; Lynch, Henry T.; Fodde, Riccardo

    2003-01-01

    The identification of germline mutations in families with HNPCC is hampered by genetic heterogeneity and clinical variability. In previous studies, MSH2 and MLH1 mutations were found in approximately two-thirds of the Amsterdam-criteria–positive families and in much lower percentages of the Amsterdam-criteria–negative families. Therefore, a considerable proportion of HNPCC seems not to be accounted for by the major mismatch repair (MMR) genes. Does the latter result from a lack of sensitivity of mutation detection techniques, or do additional genes underlie the remaining cases? In this study we address these questions by thoroughly investigating a cohort of clinically selected North American families with HNPCC. We analyzed 59 clinically well-defined U.S. families with HNPCC for MSH2, MLH1, and MSH6 mutations. To maximize mutation detection, different techniques were employed, including denaturing gradient gel electrophoresis, Southern analysis, microsatellite instability, immunohistochemistry, and monoallelic expression analysis. In 45 (92%) of the 49 Amsterdam-criteria–positive families and in 7 (70%) of the 10 Amsterdam-criteria–negative families, a mutation was detected in one of the three analyzed MMR genes. Forty-nine mutations were in MSH2 or MLH1, and only three were in MSH6. A considerable proportion (27%) of the mutations were genomic rearrangements (12 in MSH2 and 2 in MLH1). Notably, a deletion encompassing exons 1–6 of MSH2 was detected in seven apparently unrelated families (12% of the total cohort) and was subsequently proven to be a founder. Screening of a second U.S. cohort with HNPCC from Ohio allowed the identification of two additional kindreds with the identical founder deletion. In the present study, we show that optimal mutation detection in HNPCC is achieved by combining accurate and expert clinical selection with an extensive mutation detection strategy. Notably, we identified a common North American deletion in MSH2, accounting

  14. Null mutation of the nicotinamide adenine dinucleotide phosphate-oxidase subunit p67phox protects the Dahl-S rat from salt-induced reductions in medullary blood flow and glomerular filtration rate.

    PubMed

    Evans, Louise C; Ryan, Robert P; Broadway, Elizabeth; Skelton, Meredith M; Kurth, Theresa; Cowley, Allen W

    2015-03-01

    Null mutations in the p67(phox) subunit of nicotinamide adenine dinucleotide phosphate-oxidase confer protection from salt sensitivity on Dahl salt-sensitive rats. Here, we track the sequential changes in medullary blood flow (MBF), glomerular filtration rate (GFR), urinary protein, and mean arterial pressure in SSp67(phox) null rats and wild-type littermates during 21 days of 4.0% NaCl high-salt (HS) diet. Optical fibers were implanted in the renal medulla and MBF was measured in conscious rats by laser Doppler flowmetry. Separate groups of rats were prepared with femoral venous catheters and GFR was measured by the transcutaneous assessment of fluorescein isothiocyanate-sinistrin disappearance curves. Mean arterial blood pressure was measured by telemetry. In wild-type rats, HS caused a rapid reduction in MBF, which was significantly lower than control values by HS day-6. Reduced MBF was associated with a progressive increase in mean arterial pressure, averaging 170±5 mm Hg by HS salt day-21. A significant reduction in GFR was evident on day-14 HS, after the onset of hypertension and reduced MBF. In contrast, HS had no significant effect on MBF in SSp67(phox) null rats and the pressor response to sodium was blunted, averaging 150±3 mm Hg on day-21 HS. GFR was maintained throughout the study and proteinuria was reduced. In summary, when p67(phox) is not functional in the salt-sensitive rats, HS does not cause reduced MBF and salt-sensitive hypertension is attenuated, and consequently renal injury is reduced and GFR is maintained. PMID:25489057

  15. CF Mutation Panel

    MedlinePlus

    ... page: Was this page helpful? Also known as: Cystic Fibrosis Genotyping; CF DNA Analysis; CF Gene Mutation Panel; CF Molecular Genetic Testing Formal name: Cystic Fibrosis Gene Mutation Panel Related tests: Sweat Test ; Trypsinogen ; ...

  16. Colorectal cancer prognosis: is it all mutation, mutation, mutation?

    PubMed Central

    Hassan, A B; Paraskeva, C

    2005-01-01

    For the 500 000 new cases of colorectal cancer in the world each year, identification of patients with a worse prognosis and those who are more likely to respond to treatment is a challenge. There is an increasing body of evidence correlating genetic mutations with outcome in tumours derived from human colorectal cancer cohorts. K-ras, but not p53 or APC, mutations appear to be associated with poorer overall survival in colorectal cancer patients. PMID:16099785

  17. Novel EGFR mutation specific antibodies for NSCLC: Immunohistochemistry as a possible screening method for EGFR mutations

    PubMed Central

    Kato, Yasufumi; Peled, Nir; Wynes, Murry W.; Yoshida, Koichi; Pardo, Marta; Mascaux, Celine; Ohira, Tatsuo; Tsuboi, Masahiro; Matsubayashi, Jun; Nagao, Toshitaka; Ikeda, Norihiko; Hirsch, Fred R.

    2010-01-01

    Background Epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) predict better outcome to EGFR tyrosine kinase inhibitors (TKIs). The most common mutations are exon 19 deletions (most frequently E746-A750) and L858R point mutation in exon 21. Here, we evaluated the accuracy of novel EGFR mutation specific antibodies in a Japanese cohort with NSCLC and compared to direct DNA sequencing and clinical outcome. Materials and methods Immunohistochemistry (IHC) using antibodies specific for the E746-A750 and L858R mutations in EGFR was performed on tissue microarrays of tumors from 70 gefitinib treated NSCLC patients. Extracted DNA was sequenced for mutational analysis of EGFR exons 18 to 21. Results DNA sequencing showed EGFR mutations in 41 patients (58.6%), and exon 19 deletions in 18 patients (25.7%), 61% (11/18) had a deletion in the range of E746-A750) and 12 (17.1%) had exon 21 mutations (L858R). IHC showed, for the E746-A750 and L858R mutations, sensitivity (81.8% and 75%), specificity (100%, 96.6%), PPV (100%, 81.8%) and NPV (96.7%, 94.9%). Analysis for objective response rates (ORR) and survival were not correlated to IHC staining, although the combined staining showed non-significant trends towards better overall survival for patients with EGFR mutations. Conclusions The mutation specific IHC antibodies have high sensitivity and specificity for pre-defined EFGR mutations and may be suitable for screening for these pre-defined mutations. However, negative IHC results require further mutation analyses prior to excluding EGFR-targeted therapy. PMID:20697298

  18. Genome-wide patterns and properties of de novo mutations in humans.

    PubMed

    Francioli, Laurent C; Polak, Paz P; Koren, Amnon; Menelaou, Androniki; Chun, Sung; Renkens, Ivo; van Duijn, Cornelia M; Swertz, Morris; Wijmenga, Cisca; van Ommen, Gertjan; Slagboom, P Eline; Boomsma, Dorret I; Ye, Kai; Guryev, Victor; Arndt, Peter F; Kloosterman, Wigard P; de Bakker, Paul I W; Sunyaev, Shamil R

    2015-07-01

    Mutations create variation in the population, fuel evolution and cause genetic diseases. Current knowledge about de novo mutations is incomplete and mostly indirect. Here we analyze 11,020 de novo mutations from the whole genomes of 250 families. We show that de novo mutations in the offspring of older fathers are not only more numerous but also occur more frequently in early-replicating, genic regions. Functional regions exhibit higher mutation rates due to CpG dinucleotides and show signatures of transcription-coupled repair, whereas mutation clusters with a unique signature point to a new mutational mechanism. Mutation and recombination rates independently associate with nucleotide diversity, and regional variation in human-chimpanzee divergence is only partly explained by heterogeneity in mutation rate. Finally, we provide a genome-wide mutation rate map for medical and population genetics applications. Our results provide new insights and refine long-standing hypotheses about human mutagenesis. PMID:25985141

  19. Evolution on a Lattice under Strong Mutation

    NASA Astrophysics Data System (ADS)

    Otwinowski, Jakub; Boettcher, Stefan

    2011-03-01

    The most common approach to study biological evolution in a population considers mutations to arise one at a time, and spread to the whole population. However, recent experimental work has shown that under conditions of strong mutation and strong selection, multiple mutations may arise simultaneously. Such overlapping mutations compete with each other and make the results difficult to analyse. Theorists are working on understanding the relationships between different parameters such as population size, mutation rate, and selection coefficients, in the way they affect observables such as the speed of evolution, and the probability of fixation. We have shown with simulations that under additional spatial constraints the dynamics are very different compared to well-mixed populations. A surface in fitness space evolves, akin to surface growth phenomena, with non-trivial power-law exponents. The result is that the speed of evolution is restricted and the probability of fixation is reduced. With support from the NSF through grant DMR-0812204.

  20. The fitness costs of antibiotic resistance mutations

    PubMed Central

    Melnyk, Anita H; Wong, Alex; Kassen, Rees

    2015-01-01

    Antibiotic resistance is increasing in pathogenic microbial populations and is thus a major threat to public health. The fate of a resistance mutation in pathogen populations is determined in part by its fitness. Mutations that suffer little or no fitness cost are more likely to persist in the absence of antibiotic treatment. In this review, we performed a meta-analysis to investigate the fitness costs associated with single mutational events that confer resistance. Generally, these mutations were costly, although several drug classes and species of bacteria on average did not show a cost. Further investigations into the rate and fitness values of compensatory mutations that alleviate the costs of resistance will help us to better understand both the emergence and management of antibiotic resistance in clinical settings. PMID:25861385

  1. 12 CFR 1026.59 - Reevaluation of rate increases.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 12 Banks and Banking 8 2013-01-01 2013-01-01 false Reevaluation of rate increases. 1026.59 Section... credit plan. (2) Rate increases imposed between January 1, 2009 and February 21, 2010. For rate increases imposed between January 1, 2009 and February 21, 2010, an issuer must consider the factors described...

  2. 42 CFR 423.752 - Basis for imposing intermediate sanctions and civil money penalties.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 3 2010-10-01 2010-10-01 false Basis for imposing intermediate sanctions and civil money penalties. 423.752 Section 423.752 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICARE PROGRAM VOLUNTARY MEDICARE PRESCRIPTION DRUG BENEFIT Intermediate Sanctions § 423.752...

  3. 42 CFR 64a.104 - What requirements are imposed upon grantees?

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false What requirements are imposed upon grantees? 64a.104 Section 64a.104 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING OBLIGATED SERVICE FOR MENTAL HEALTH TRAINEESHIPS § 64a.104...

  4. 42 CFR 64a.104 - What requirements are imposed upon grantees?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false What requirements are imposed upon grantees? 64a.104 Section 64a.104 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING OBLIGATED SERVICE FOR MENTAL HEALTH TRAINEESHIPS § 64a.104...

  5. 42 CFR 64a.104 - What requirements are imposed upon grantees?

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false What requirements are imposed upon grantees? 64a.104 Section 64a.104 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING OBLIGATED SERVICE FOR MENTAL HEALTH TRAINEESHIPS § 64a.104...

  6. 42 CFR 64a.104 - What requirements are imposed upon grantees?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false What requirements are imposed upon grantees? 64a.104 Section 64a.104 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING OBLIGATED SERVICE FOR MENTAL HEALTH TRAINEESHIPS § 64a.104...

  7. 42 CFR 64a.104 - What requirements are imposed upon grantees?

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false What requirements are imposed upon grantees? 64a.104 Section 64a.104 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING OBLIGATED SERVICE FOR MENTAL HEALTH TRAINEESHIPS § 64a.104...

  8. Learning Mathematics from Procedural Instruction: Externally Imposed Goals Influence What Is Learned.

    ERIC Educational Resources Information Center

    McNeil, Nicole M.; Alibali, Martha W.

    2000-01-01

    Examines if externally imposed achievement goals influence what children learn from procedural instruction. Third- and 4th-grade children's goals were manipulated toward either learning or performance (N=77). Both initially and after a 2-week period, children who were given either goal were more likely to extend their knowledge beyond the taught…

  9. 12 CFR 1008.109 - Effective date of state requirements imposed on individuals.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 12 Banks and Banking 8 2014-01-01 2014-01-01 false Effective date of state requirements imposed on individuals. 1008.109 Section 1008.109 Banks and Banking BUREAU OF CONSUMER FINANCIAL PROTECTION S.A.F.E... obtaining state licenses within one year....

  10. 13 CFR 109.440 - Requirements imposed under other laws and orders.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 13 Business Credit and Assistance 1 2012-01-01 2012-01-01 false Requirements imposed under other laws and orders. 109.440 Section 109.440 Business Credit and Assistance SMALL BUSINESS ADMINISTRATION INTERMEDIARY LENDING PILOT PROGRAM Requirements for ILP Intermediary Loans to Small Businesses §...

  11. 13 CFR 109.440 - Requirements imposed under other laws and orders.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 13 Business Credit and Assistance 1 2014-01-01 2014-01-01 false Requirements imposed under other laws and orders. 109.440 Section 109.440 Business Credit and Assistance SMALL BUSINESS ADMINISTRATION INTERMEDIARY LENDING PILOT PROGRAM Requirements for ILP Intermediary Loans to Small Businesses §...

  12. 13 CFR 109.440 - Requirements imposed under other laws and orders.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 13 Business Credit and Assistance 1 2013-01-01 2013-01-01 false Requirements imposed under other laws and orders. 109.440 Section 109.440 Business Credit and Assistance SMALL BUSINESS ADMINISTRATION INTERMEDIARY LENDING PILOT PROGRAM Requirements for ILP Intermediary Loans to Small Businesses §...

  13. Carving up Space at Imaginary Joints: Can People Mentally Impose Arbitrary Spatial Category Boundaries?

    ERIC Educational Resources Information Center

    Simmering, Vanessa R.; Spencer, John P.

    2007-01-01

    Empirical attempts to understand connections between abstract cognition and sensori-motor processes have pointed toward an embodied view of cognition, where cognitive activity is strongly tied to sensori-motor activity. Here the authors test the ability of the cognitive system to impose structure on the world using a well-established phenomenon in…

  14. 45 CFR 261.65 - Under what circumstances will we impose a work verification penalty?

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 45 Public Welfare 2 2014-10-01 2012-10-01 true Under what circumstances will we impose a work verification penalty? 261.65 Section 261.65 Public Welfare Regulations Relating to Public Welfare OFFICE OF FAMILY ASSISTANCE (ASSISTANCE PROGRAMS), ADMINISTRATION FOR CHILDREN AND FAMILIES, DEPARTMENT OF HEALTH AND HUMAN SERVICES ENSURING...

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    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 5 2010-10-01 2010-10-01 false What penalties do we impose for violations of this part? 375.901 Section 375.901 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL MOTOR CARRIER SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION FEDERAL MOTOR CARRIER SAFETY REGULATIONS TRANSPORTATION OF...

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    Code of Federal Regulations, 2013 CFR

    2013-10-01

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  17. 45 CFR 261.65 - Under what circumstances will we impose a work verification penalty?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 45 Public Welfare 2 2010-10-01 2010-10-01 false Under what circumstances will we impose a work verification penalty? 261.65 Section 261.65 Public Welfare Regulations Relating to Public Welfare OFFICE OF FAMILY ASSISTANCE (ASSISTANCE PROGRAMS), ADMINISTRATION FOR CHILDREN AND FAMILIES, DEPARTMENT OF HEALTH AND HUMAN SERVICES ENSURING...

  18. 26 CFR 1.6664-3 - Ordering rules for determining the total amount of penalties imposed.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 13 2011-04-01 2011-04-01 false Ordering rules for determining the total amount of penalties imposed. 1.6664-3 Section 1.6664-3 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Additions to the Tax, Additional Amounts, and Assessable Penalties...

  19. 26 CFR 1.665(d)-1A - Taxes imposed on the trust.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 8 2011-04-01 2011-04-01 false Taxes imposed on the trust. 1.665(d)-1A Section 1.665(d)-1A Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Treatment of Excess Distributions of Trusts Applicable to Taxable Years Beginning on Or After January...

  20. 78 FR 14183 - Import Restrictions Imposed on Certain Archaeological Material From Belize

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-03-05

    ...This final rule amends the U.S. Customs and Border Protection (CBP) regulations to reflect the imposition of import restrictions on certain archaeological material from Belize. These restrictions are being imposed pursuant to an agreement between the United States and Belize that has been entered into under the authority of the Convention on Cultural Property Implementation Act in accordance......

  1. 78 FR 24599 - Order Imposing Recordkeeping and Reporting Obligations on Certain U.S. Financial Institutions...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-04-25

    ... Financial Institution of Primary Money Laundering Concern AGENCY: Financial Crimes Enforcement Network... States that is of primary money laundering concern. The Director of FinCEN is issuing an order imposing... 31 U.S.C. 5318A, found Rmeiti Exchange to be a Financial Institution of Primary Money...

  2. 78 FR 24601 - Order Imposing Recordkeeping and Reporting Obligations on Certain U.S. Financial Institutions...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-04-25

    ... of Primary Money Laundering Concern AGENCY: Financial Crimes Enforcement Network, Treasury (``FinCEN... money laundering concern. The Director of FinCEN is issuing an order imposing certain recordkeeping and... be a Financial Institution of Primary Money Laundering Concern (the ``Finding''). Notice of...

  3. 24 CFR 266.120 - Actions for which sanctions may be imposed.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... program; (7) Perform underwriting, insurance of advances, cost certification, management, servicing or... HOUSING AND URBAN DEVELOPMENT MORTGAGE AND LOAN INSURANCE PROGRAMS UNDER NATIONAL HOUSING ACT AND OTHER... which sanctions may be imposed against the HFA by HUD's Mortgagee Review Board under 24 CFR 25.9....

  4. Adolescent Drug Use and the Deterrent Effect of School-Imposed Penalties

    ERIC Educational Resources Information Center

    Waddell, G. R.

    2012-01-01

    Estimates of the effect of school-imposed penalties for drug use on a student's consumption of marijuana are biased if both are determined by unobservable school or individual attributes. Reverse causality is also a potential challenge to retrieving estimates of the causal relationship, as the severity of school sanctions may simply reflect the…

  5. Dress-Related Responses to the Columbine Shootings: Other-Imposed and Self-Designed.

    ERIC Educational Resources Information Center

    Ogle, Jennifer Paff; Eckman, Molly

    2002-01-01

    An inductive content analysis approach was used to examine 155 dress-related newspaper articles following the Columbine High School shootings in 1999. Analysis revealed two dress-related responses: (1) other-imposed regulation to protect students and deter them from expressing hatred and (2) self-designed acts of resistance for grieving. (Contains…

  6. 20 CFR 655.1110 - What requirements are imposed in the filing of an attestation?

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... ADMINISTRATION, DEPARTMENT OF LABOR TEMPORARY EMPLOYMENT OF FOREIGN WORKERS IN THE UNITED STATES What... requirements are imposed in the filing of an attestation? (a) Who may file Attestations? (1) Any hospital which meets the definition of facility in §§ 655.1102 and 655.1111 may file an Attestation. (2) ETA...

  7. 20 CFR 655.1110 - What requirements are imposed in the filing of an attestation?

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... ADMINISTRATION, DEPARTMENT OF LABOR TEMPORARY EMPLOYMENT OF FOREIGN WORKERS IN THE UNITED STATES What... requirements are imposed in the filing of an attestation? (a) Who may file Attestations? (1) Any hospital which meets the definition of facility in §§ 655.1102 and 655.1111 may file an Attestation. (2) ETA...

  8. 20 CFR 655.1110 - What requirements are imposed in the filing of an attestation?

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... ADMINISTRATION, DEPARTMENT OF LABOR TEMPORARY EMPLOYMENT OF FOREIGN WORKERS IN THE UNITED STATES What... requirements are imposed in the filing of an attestation? (a) Who may file Attestations? (1) Any hospital which meets the definition of facility in §§ 655.1102 and 655.1111 may file an Attestation. (2) ETA...

  9. Some loading conditions imposed by ground turning maneuvers with three jet transport airplanes

    NASA Technical Reports Server (NTRS)

    Hall, A. W.

    1972-01-01

    Some loading conditions imposed during ground turning maneuvers are presented for arrival and departure operations at several airports with C-141A, 727, and DC-9 airplanes. The data presented for a total of 809 turns include: ground speed, lateral acceleration, the number of turns required during arrival and departure, and the magnitude of the turns.

  10. 77 FR 58020 - Extension of Import Restrictions Imposed on Archaeological Material From Mali

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-09-19

    ... FR 49428) imposing emergency import restrictions on archaeological objects from the region of the... the Federal Register (62 FR 49594), which amended 19 CFR 12.104g(a) to reflect the imposition of these...-55 in the Federal Register (67 FR 59159), which amended 19 CFR 12.104g(a) to reflect the extension...

  11. 26 CFR 20.2101-1 - Estates of nonresidents not citizens; tax imposed.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    .... Section 2101 imposes a tax on the transfer of the taxable estate of a nonresident who is not a citizen of... estate of a citizen or resident of the United States in accordance with the provisions of sections 2101(b... decedents. In the case of an estate of a nonresident who was not a citizen of the United States and who...

  12. 26 CFR 20.2101-1 - Estates of nonresidents not citizens; tax imposed.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    .... Section 2101 imposes a tax on the transfer of the taxable estate of a nonresident who is not a citizen of... estate of a citizen or resident of the United States in accordance with the provisions of sections 2101(b... decedents. In the case of an estate of a nonresident who was not a citizen of the United States and who...

  13. 26 CFR 1.802-3 - Tax imposed on life insurance companies.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... life insurance business within the United States if with respect to its United States business it would... insurance companies. Foreign life insurance companies not carrying on an insurance business within the..., inclusive, are applicable to the assessment and collection of the tax imposed by section 802(a), and...

  14. 78 FR 40773 - Order Imposing Requirements for the Protection of Certain Safeguards Information (Effective...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-07-08

    ... entities participating under 10 CFR 2.315(c), must be filed in accordance with the NRC E-Filing rule (72 FR... COMMISSION Order Imposing Requirements for the Protection of Certain Safeguards Information (Effective... Information Described Herein I The Licensee, identified in Attachment 1 \\1\\ to this Order, holds a ]...

  15. 42 CFR 422.752 - Basis for imposing intermediate sanctions and civil money penalties.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... money penalties. 422.752 Section 422.752 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES... Intermediate Sanctions § 422.752 Basis for imposing intermediate sanctions and civil money penalties. (a) All... Money Penalties. (1) CMS. In addition to, or in place of, any intermediate sanctions, CMS may...

  16. 42 CFR 488.432 - Civil money penalties imposed by the State: NF-only.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 5 2012-10-01 2012-10-01 false Civil money penalties imposed by the State: NF-only... PROCEDURES Enforcement of Compliance for Long-Term Care Facilities with Deficiencies § 488.432 Civil money... a civil money penalty against a non-State operated NF that is not subject to imposition of...

  17. 42 CFR 423.756 - Procedures for imposing intermediate sanctions and civil money penalties.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... civil money penalties. 423.756 Section 423.756 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES... civil money penalties. (a) Notice of intermediate sanction and opportunity to respond—(1) Notice of....509. (e) Notice to impose civil money penalties—(1) CMS notice to OIG. If CMS determines that a Part...

  18. UV Signature Mutations

    PubMed Central

    2014-01-01

    Sequencing complete tumor genomes and exomes has sparked the cancer field's interest in mutation signatures for identifying the tumor's carcinogen. This review and meta-analysis discusses signatures and their proper use. We first distinguish between a mutagen's canonical mutations – deviations from a random distribution of base changes to create a pattern typical of that mutagen – and the subset of signature mutations, which are unique to that mutagen and permit inference backward from mutations to mutagen. To verify UV signature mutations, we assembled literature datasets on cells exposed to UVC, UVB, UVA, or solar simulator light (SSL) and tested canonical UV mutation features as criteria for clustering datasets. A confirmed UV signature was: ≥60% of mutations are C→T at a dipyrimidine site, with ≥5% CC→TT. Other canonical features such as a bias for mutations on the non-transcribed strand or at the 3' pyrimidine had limited application. The most robust classifier combined these features with criteria for the rarity of non-UV canonical mutations. In addition, several signatures proposed for specific UV wavelengths were limited to specific genes or species; non-signature mutations induced by UV may cause melanoma BRAF mutations; and the mutagen for sunlight-related skin neoplasms may vary between continents. PMID:25354245

  19. Kick-starting the ratchet: the fate of mutators in an asexual population.

    PubMed

    Söderberg, R Jonas; Berg, Otto G

    2011-04-01

    Muller's ratchet operates in asexual populations without intergenomic recombination. In this case, deleterious mutations will accumulate and population fitness will decline over time, possibly endangering the survival of the species. Mutator mutations, i.e., mutations that lead to an increased mutation rate, will play a special role for the behavior of the ratchet. First, they are part of the ratchet and can come to dominance through accumulation in the ratchet. Second, the fitness-loss rate of the ratchet is very sensitive to changes in the mutation rate and even a modest increase can easily set the ratchet in motion. In this article we simulate the interplay between fitness loss from Muller's ratchet and the evolution of the mutation rate from the fixation of mutator mutations. As long as the mutation rate is increased in sufficiently small steps, an accelerating ratchet and eventual extinction are inevitable. If this can be countered by antimutators, i.e., mutations that reduce the mutation rate, an equilibrium can be established for the mutation rate at some level that may allow survival. However, the presence of the ratchet amplifies fluctuations in the mutation rate and, even at equilibrium, these fluctuations can lead to dangerous bursts in the ratchet. We investigate the timescales of these processes and discuss the results with reference to the genome degradation of the aphid endosymbiont Buchnera aphidicola. PMID:21288878

  20. Evaluation of cognitive loads imposed by traditional paper-based and innovative computer-based instructional strategies.

    PubMed

    Khalil, Mohammed K; Mansour, Mahmoud M; Wilhite, Dewey R

    2010-01-01

    Strategies of presenting instructional information affect the type of cognitive load imposed on the learner's working memory. Effective instruction reduces extraneous (ineffective) cognitive load and promotes germane (effective) cognitive load. Eighty first-year students from two veterinary schools completed a two-section questionnaire that evaluated their perspectives on the educational value of a computer-based instructional program. They compared the difference between cognitive loads imposed by paper-based and computer-based instructional strategies used to teach the anatomy of the canine skeleton. Section I included 17 closed-ended items, rated on a five-point Likert scale, that assessed the use of graphics, content, and the learning process. Section II included a nine-point mental effort rating scale to measure the level of difficulty of instruction; students were asked to indicate the amount of mental effort invested in the learning task using both paper-based and computer-based presentation formats. The closed-ended data were expressed as means and standard deviations. A paired t test with an alpha level of 0.05 was used to determine the overall mean difference between the two presentation formats. Students positively evaluated their experience with the computer-based instructional program with a mean score of 4.69 (SD=0.53) for use of graphics, 4.70 (SD=0.56) for instructional content, and 4.45 (SD=0.67) for the learning process. The mean difference of mental effort (1.50) between the two presentation formats was significant, t=8.26, p≤.0001, df=76, for two-tailed distribution. Consistent with cognitive load theory, innovative computer-based instructional strategies decrease extraneous cognitive load compared with traditional paper-based instructional strategies. PMID:21135402

  1. Spectrum of mutations and genotype-phenotype analysis in Noonan syndrome patients with RIT1 mutations.

    PubMed

    Yaoita, Masako; Niihori, Tetsuya; Mizuno, Seiji; Okamoto, Nobuhiko; Hayashi, Shion; Watanabe, Atsushi; Yokozawa, Masato; Suzumura, Hiroshi; Nakahara, Akihiko; Nakano, Yusuke; Hokosaki, Tatsunori; Ohmori, Ayumi; Sawada, Hirofumi; Migita, Ohsuke; Mima, Aya; Lapunzina, Pablo; Santos-Simarro, Fernando; García-Miñaúr, Sixto; Ogata, Tsutomu; Kawame, Hiroshi; Kurosawa, Kenji; Ohashi, Hirofumi; Inoue, Shin-Ichi; Matsubara, Yoichi; Kure, Shigeo; Aoki, Yoko

    2016-02-01

    RASopathies are autosomal dominant disorders caused by mutations in more than 10 known genes that regulate the RAS/MAPK pathway. Noonan syndrome (NS) is a RASopathy characterized by a distinctive facial appearance, musculoskeletal abnormalities, and congenital heart defects. We have recently identified mutations in RIT1 in patients with NS. To delineate the clinical manifestations in RIT1 mutation-positive patients, we further performed a RIT1 analysis in RASopathy patients and identified 7 RIT1 mutations, including two novel mutations, p.A77S and p.A77T, in 14 of 186 patients. Perinatal abnormalities, including nuchal translucency, fetal hydrops, pleural effusion, or chylothorax and congenital heart defects, are observed in all RIT1 mutation-positive patients. Luciferase assays in NIH 3T3 cells demonstrated that the newly identified RIT1 mutants, including p.A77S and p.A77T, and the previously identified p.F82V, p.T83P, p.Y89H, and p.M90I, enhanced Elk1 transactivation. Genotype-phenotype correlation analyses of previously reported NS patients harboring RIT1, PTPN11, SOS1, RAF1, and KRAS revealed that hypertrophic cardiomyopathy (56 %) was more frequent in patients harboring a RIT1 mutation than in patients harboring PTPN11 (9 %) and SOS1 mutations (10 %). The rates of hypertrophic cardiomyopathy were similar between patients harboring RIT1 mutations and patients harboring RAF1 mutations (75 %). Short stature (52 %) was less prevalent in patients harboring RIT1 mutations than in patients harboring PTPN11 (71 %) and RAF1 (83 %) mutations. These results delineate the clinical manifestations of RIT1 mutation-positive NS patients: high frequencies of hypertrophic cardiomyopathy, atrial septal defects, and pulmonary stenosis; and lower frequencies of ptosis and short stature. PMID:26714497

  2. De novo mutations in epileptic encephalopathies.

    PubMed

    Allen, Andrew S; Berkovic, Samuel F; Cossette, Patrick; Delanty, Norman; Dlugos, Dennis; Eichler, Evan E; Epstein, Michael P; Glauser, Tracy; Goldstein, David B; Han, Yujun; Heinzen, Erin L; Hitomi, Yuki; Howell, Katherine B; Johnson, Michael R; Kuzniecky, Ruben; Lowenstein, Daniel H; Lu, Yi-Fan; Madou, Maura R Z; Marson, Anthony G; Mefford, Heather C; Esmaeeli Nieh, Sahar; O'Brien, Terence J; Ottman, Ruth; Petrovski, Slavé; Poduri, Annapurna; Ruzzo, Elizabeth K; Scheffer, Ingrid E; Sherr, Elliott H; Yuskaitis, Christopher J; Abou-Khalil, Bassel; Alldredge, Brian K; Bautista, Jocelyn F; Berkovic, Samuel F; Boro, Alex; Cascino, Gregory D; Consalvo, Damian; Crumrine, Patricia; Devinsky, Orrin; Dlugos, Dennis; Epstein, Michael P; Fiol, Miguel; Fountain, Nathan B; French, Jacqueline; Friedman, Daniel; Geller, Eric B; Glauser, Tracy; Glynn, Simon; Haut, Sheryl R; Hayward, Jean; Helmers, Sandra L; Joshi, Sucheta; Kanner, Andres; Kirsch, Heidi E; Knowlton, Robert C; Kossoff, Eric H; Kuperman, Rachel; Kuzniecky, Ruben; Lowenstein, Daniel H; McGuire, Shannon M; Motika, Paul V; Novotny, Edward J; Ottman, Ruth; Paolicchi, Juliann M; Parent, Jack M; Park, Kristen; Poduri, Annapurna; Scheffer, Ingrid E; Shellhaas, Renée A; Sherr, Elliott H; Shih, Jerry J; Singh, Rani; Sirven, Joseph; Smith, Michael C; Sullivan, Joseph; Lin Thio, Liu; Venkat, Anu; Vining, Eileen P G; Von Allmen, Gretchen K; Weisenberg, Judith L; Widdess-Walsh, Peter; Winawer, Melodie R

    2013-09-12

    Epileptic encephalopathies are a devastating group of severe childhood epilepsy disorders for which the cause is often unknown. Here we report a screen for de novo mutations in patients with two classical epileptic encephalopathies: infantile spasms (n = 149) and Lennox-Gastaut syndrome (n = 115). We sequenced the exomes of 264 probands, and their parents, and confirmed 329 de novo mutations. A likelihood analysis showed a significant excess of de novo mutations in the ∼4,000 genes that are the most intolerant to functional genetic variation in the human population (P = 2.9 × 10(-3)). Among these are GABRB3, with de novo mutations in four patients, and ALG13, with the same de novo mutation in two patients; both genes show clear statistical evidence of association with epileptic encephalopathy. Given the relevant site-specific mutation rates, the probabilities of these outcomes occurring by chance are P = 4.1 × 10(-10) and P = 7.8 × 10(-12), respectively. Other genes with de novo mutations in this cohort include CACNA1A, CHD2, FLNA, GABRA1, GRIN1, GRIN2B, HNRNPU, IQSEC2, MTOR and NEDD4L. Finally, we show that the de novo mutations observed are enriched in specific gene sets including genes regulated by the fragile X protein (P < 10(-8)), as has been reported previously for autism spectrum disorders. PMID:23934111

  3. Selection for mutational robustness in finite populations.

    PubMed

    Forster, Robert; Adami, Christoph; Wilke, Claus O

    2006-11-21

    We investigate the evolutionary dynamics of a finite population of RNA sequences replicating on a neutral network. Despite the lack of differential fitness between viable sequences, we observe typical properties of adaptive evolution, such as increase of mean fitness over time and punctuated-equilibrium transitions, after initial mutation-selection balance has been reached. We find that a product of population size and mutation rate of approximately 30 or larger is sufficient to generate selection pressure for mutational robustness, even if the population size is orders of magnitude smaller than the neutral network on which the population resides. Our results show that quasispecies effects and neutral drift can occur concurrently, and that the relative importance of each is determined by the product of population size and mutation rate. PMID:16901510

  4. Analysis of SDHD promoter mutations in various types of melanoma

    PubMed Central

    Scholz, Simone L.; Horn, Susanne; Murali, Rajmohan; Möller, Inga; Sucker, Antje; Sondermann, Wiebke; Stiller, Mathias; Schilling, Bastian; Livingstone, Elisabeth; Zimmer, Lisa; Reis, Henning; Metz, Claudia H.; Zeschnigk, Michael; Paschen, Annette; Steuhl, Klaus-Peter; Schadendorf, Dirk; Westekemper, Henrike; Griewank, Klaus G.

    2015-01-01

    Objectives Recently, recurrent mutations in regulatory DNA regions, such as promoter mutations in the TERT gene were identified in melanoma. Subsequently, Weinhold et al. reported SDHD promoter mutations occurring in 10% of melanomas and being associated with a lower overall survival rate. Our study analyzes the mutation rate and clinico-pathologic associations of SDHD promoter mutations in a large cohort of different melanoma subtypes. Methods 451 melanoma samples (incl. 223 non-acral cutaneous, 38 acral, 33 mucosal, 43 occult, 43 conjunctival and 51 uveal melanoma) were analyzed for the presence of SDHD promoter mutations by Sanger-sequencing. Statistical analysis was performed to screen for potential correlations of SDHD promoter mutation status with various clinico-pathologic criteria. Results The SDHD promoter was successfully sequenced in 451 tumor samples. ETS binding site changing SDHD promoter mutations were identified in 16 (4%) samples, of which 5 mutations had not been described previously. Additionally, 5 point mutations not located in ETS binding elements were identified. Mutations in UV-exposed tumors were frequently C>T. One germline C>A SDHD promoter mutation was identified. No statistically significant associations between SDHD promoter mutation status and various clinico-pathologic variables or overall patient survival were observed. Conclusions Melanomas harbor recurrent SDHD promoter mutations, which occur primarily as C>T alterations in UV-exposed melanomas. In contrast to the initial report and promoter mutations in the TERT gene, our analysis suggests that SDHD promoter mutations are a relatively rare event in melanoma (4% of tumors) of unclear clinical and prognostic relevance. PMID:26327518

  5. Fluoroquinolone Resistance Does Not Impose a Cost on the Fitness of Clostridium difficile In Vitro

    PubMed Central

    Wasels, François; Kuehne, Sarah A.; Cartman, Stephen T.; Barbanti, Fabrizio; Minton, Nigel P.; Mastrantonio, Paola

    2014-01-01

    Point mutations conferring resistance to fluoroquinolones were introduced in the gyr genes of the reference strain Clostridium difficile 630. Only mutants with the substitution Thr-82→Ile in GyrA, which characterizes the hypervirulent epidemic clone III/027/NAP1, were resistant to all fluoroquinolones tested. The absence of a fitness cost in vitro for the most frequent mutations detected in resistant clinical isolates suggests that resistance will be maintained even in the absence of antibiotic pressure. PMID:25534738

  6. UV signature mutations.

    PubMed

    Brash, Douglas E

    2015-01-01

    Sequencing complete tumor genomes and exomes has sparked the cancer field's interest in mutation signatures for identifying the tumor's carcinogen. This review and meta-analysis discusses signatures and their proper use. We first distinguish between a mutagen's canonical mutations—deviations from a random distribution of base changes to create a pattern typical of that mutagen—and the subset of signature mutations, which are unique to that mutagen and permit inference backward from mutations to mutagen. To verify UV signature mutations, we assembled literature datasets on cells exposed to UVC, UVB, UVA, or solar simulator light (SSL) and tested canonical UV mutation features as criteria for clustering datasets. A confirmed UV signature was: ≥60% of mutations are C→T at a dipyrimidine site, with ≥5% CC→TT. Other canonical features such as a bias for mutations on the nontranscribed strand or at the 3' pyrimidine had limited application. The most robust classifier combined these features with criteria for the rarity of non-UV canonical mutations. In addition, several signatures proposed for specific UV wavelengths were limited to specific genes or species; UV's nonsignature mutations may cause melanoma BRAF mutations; and the mutagen for sunlight-related skin neoplasms may vary between continents. PMID:25354245

  7. Axenic growth up-regulates mass-specific metabolic rate, stress resistance, and extends life span in Caenorhabditis elegans.

    PubMed

    Houthoofd, Koen; Braeckman, Bart P; Lenaerts, Isabelle; Brys, Kristel; De Vreese, Annemie; Van Eygen, Sylvie; Vanfleteren, Jacques R

    2002-12-01

    Culture in axenic medium causes two-fold increases in the length of development and adult life span in Caenorhabditis elegans. We asked whether axenic medium imposes dietary restriction (ADR), and causes changes in metabolic activity and stress resistance. Eat mutants, which have a reduced food intake, were studied in parallel with wild-type worms to assess potential synergistic actions of axenic culture and food restriction. We found that axenic culture enhances metabolic activity as assessed by mass-specific oxygen consumption rate and heat production. Axenic culture also caused higher activities of the antioxidant enzymes superoxide dismutase and catalase, and led to increased resistance to high temperature, which was further exacerbated by mutation in eat-2. These results show that axenic medium up-regulates a variety of somatic maintenance functions including oxidative and thermal stress resistance and that food restriction due to axenic growth and to mutation in eat-2 are very similar but not identical. PMID:12559406

  8. Stationary mutation models.

    PubMed

    Simonsson, Ivar; Mostad, Petter

    2016-07-01

    Probability calculations for relationship inference based on DNA tests are often performed with computer packages such as Familias. When mutations are assumed to be a possibility, one may notice a curious and problematic effect of including untested parents: results tend to change slightly. In this paper, we trace this effect back to fundamental model-formulating issues which can only be resolved by using stationary mutation models. We present several methods for obtaining such stationary mutation matrices from original mutation matrices, and evaluate essential properties of these methods. Our conclusion is that typically, stationary mutation models can be obtained, but for many types of markers, it may be impossible to combine specific biologically reasonable requirements for a mutation matrix with the requirement of stationarity. PMID:27231805

  9. Experimental studies of stationary reaction fronts in a chain of vortices with imposed wind

    NASA Astrophysics Data System (ADS)

    Solomon, Tom; Boyer, Carleen

    2013-03-01

    We present experiments that study the behavior of the excitable Belousov-Zhabotinsky (BZ) reaction in a chain of alternating vortices with an imposed uniform wind. Previous experiments[2] have shown that fronts in this system are pinned for a wide range of imposed wind speeds, propagating neither forward against the wind nor in the downwind direction. We explain this behavior with a recent theory[3] that proposes the existence of burning invariant manifolds (BIMs) that act as local barriers to front propagation. Fronts are pinned when a BIM or a combination of BIMs spans the width of the vortex chain, blocking the reaction front. We show experimental measurements of the shape of the pinned front for a range of different wind speeds, and compare these shapes to the BIMs calculated theoretically. We also consider the dependence of the front shape on the location of the initial trigger for the front. Supported by NSF Grants DMR-0703635, DMR-1004744, and and PHY-1156964.

  10. Imposing periodic suction to stabilise thin-film flow down an inclined plane

    NASA Astrophysics Data System (ADS)

    Thompson, Alice; Papageorgiou, Demetrios; Tseluiko, Dmitri; Imperial Collaboration; Loughborough Collaboration

    2014-11-01

    Flow of a thin film down an inclined plane becomes unstable when the slope angle or Reynolds number are sufficiently large; enhancement or suppression of these instabilities is relevant to a range of industrial applications. Here we study the effect of introducing spatially periodic blowing and sucking through the rigid planar boundary. We derive two long-wave, thin-film models to describe the system, including the imposed suction as well as inertia, surface tension, gravity and viscosity. We explore the bifurcation structure in each model, and perform linear stability and time-dependent simulations for both small and large forcing amplitude. Both models predict that forcing via imposed suction can be chosen to either destabilize or stabilize the flow, and we show that forcing at very long wavelengths always has a stabilizing effect on the flow. Support provided by the EPSRC Grant Number EP/K041134/1.

  11. The cost of self-imposed regulatory burden in animal research.

    PubMed

    Thulin, Joseph D; Bradfield, John F; Bergdall, Valerie K; Conour, Laura A; Grady, Andrew W; Hickman, Debra L; Norton, John N; Wallace, Jeanne M

    2014-08-01

    U.S. federal regulations and standards governing the care and use of research animals enacted in the mid- to late 1980s, while having positive effects on the welfare and quality of the animals, have resulted in dramatic increases in overall research costs. In addition to the expenses of housing and caring for animals according to the standards, establishing the requisite internal compliance bureaucracies has markedly driven up costs, in both institutional monetary expenditures and lost research effort. However, many institutions are increasing these costs even further through additional self-imposed regulatory burden, typically characterized by overly complex compliance organizations and unnecessary policies and procedures. We discuss the sources of this self-imposed burden and recommend strategies for avoiding it while preserving an appropriate focus on animal well-being and research success. PMID:24784580

  12. Effects of an externally imposed electric field on subcooled boiling critical heat flux

    SciTech Connect

    Masson, V.; Carrica, P.M.

    1995-07-01

    The effects of an externally imposed electric field on critical heat flux in subcooled pool boiling have been experimentally studied. The test section was a 0.3 mm diameter platinum wire electrically heated. A coaxial cage with high voltage provided the outer electrode forming a cylindrical symmetric electric field around the heater. It was observed that the effect of the electric field on critical heat flux decreases as subcooling increases.

  13. 26 CFR 1.665(d)-1A - Taxes imposed on the trust.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... term taxes imposed on the trust also includes the amount of taxes deemed distributed under §§ 1.666(b)-1A, 1.666(c)-1A, 1.669(d)-1A, and 1.669(e)-1A (whichever are applicable) as a result of such... deemed under § 1.666(b)-1A to be distributed to trust B. The partial tax on the accumulation...

  14. Effective Temperature of Mutations

    NASA Astrophysics Data System (ADS)

    Derényi, Imre; Szöllősi, Gergely J.

    2015-02-01

    Biological macromolecules experience two seemingly very different types of noise acting on different time scales: (i) point mutations corresponding to changes in molecular sequence and (ii) thermal fluctuations. Examining the secondary structures of a large number of microRNA precursor sequences and model lattice proteins, we show that the effects of single point mutations are statistically indistinguishable from those of an increase in temperature by a few tens of kelvins. The existence of such an effective mutational temperature establishes a quantitative connection between robustness to genetic (mutational) and environmental (thermal) perturbations.

  15. Spectrum of small mutations in the dystrophin coding region

    SciTech Connect

    Prior, T.W.; Bartolo, C.; Pearl, D.K.

    1995-07-01

    Duchenne and Becker muscular dystrophies (DMD and BMD) are caused by defects in the dystrophin gene. About two-thirds of the affected patients have large deletions or duplications, which occur in the 5` and central portion of the gene. The nondeletion/duplication cases are most likely the result of smaller mutations that cannot be identified by current diagnostic screening strategies. We screened {approximately} 80% of the dystrophin coding sequence for small mutations in 158 patients without deletions or duplications and identified 29 mutations. The study indicates that many of the DMD and the majority of the BMD small mutations lie in noncoding regions of the gene. All of the mutations identified were unique to single patients, and most of the mutations resulted in protein truncation. We did not find a clustering of small mutations similar to the deletion distribution but found > 40% of the small mutations 3` of exon 55. The extent of protein truncation caused by the 3` mutations did not determine the phenotype, since even the exon 76 nonsense mutation resulted in the severe DMD phenotype. Our study confirms that the dystrophin gene is subject to a high rate of mutation in CpG sequences. As a consequence of not finding any hotspots or prevalent small mutations, we conclude that it is presently not possible to perform direct carrier and prenatal diagnostics for many families without deletions or duplications. 71 refs., 2 figs., 2 tabs.

  16. Interaction between murine spf-ash mutation and genetic background yields different metabolic phenotypes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The spf-ash mutation in mice results in reduced hepatic and intestinal ornithine transcarbamylase. However, a reduction in enzyme activity only translates in reduced ureagenesis and hyperammonemia when an unbalanced nitrogen load is imposed. Six-week-old wild-type control and spf-ash mutant male mic...

  17. The mutation-drift balance in spatially structured populations.

    PubMed

    Schneider, David M; Martins, Ayana B; de Aguiar, Marcus A M

    2016-08-01

    In finite populations the action of neutral mutations is balanced by genetic drift, leading to a stationary distribution of alleles that displays a transition between two different behaviors. For small mutation rates most individuals will carry the same allele at equilibrium, whereas for high mutation rates of the alleles will be randomly distributed with frequencies close to one half for a biallelic gene. For well-mixed haploid populations the mutation threshold is μc=1/2N, where N is the population size. In this paper we study how spatial structure affects this mutation threshold. Specifically, we study the stationary allele distribution for populations placed on regular networks where connected nodes represent potential mating partners. We show that the mutation threshold is sensitive to spatial structure only if the number of potential mates is very small. In this limit, the mutation threshold decreases substantially, increasing the diversity of the population at considerably low mutation rates. Defining kc as the degree of the network for which the mutation threshold drops to half of its value in well-mixed populations we show that kc grows slowly as a function of the population size, following a power law. Our calculations and simulations are based on the Moran model and on a mapping between the Moran model with mutations and the voter model with opinion makers. PMID:27132184

  18. The mutational landscape of adenoid cystic carcinoma.

    PubMed

    Ho, Allen S; Kannan, Kasthuri; Roy, David M; Morris, Luc G T; Ganly, Ian; Katabi, Nora; Ramaswami, Deepa; Walsh, Logan A; Eng, Stephanie; Huse, Jason T; Zhang, Jianan; Dolgalev, Igor; Huberman, Kety; Heguy, Adriana; Viale, Agnes; Drobnjak, Marija; Leversha, Margaret A; Rice, Christine E; Singh, Bhuvanesh; Iyer, N Gopalakrishna; Leemans, C Rene; Bloemena, Elisabeth; Ferris, Robert L; Seethala, Raja R; Gross, Benjamin E; Liang, Yupu; Sinha, Rileen; Peng, Luke; Raphael, Benjamin J; Turcan, Sevin; Gong, Yongxing; Schultz, Nikolaus; Kim, Seungwon; Chiosea, Simion; Shah, Jatin P; Sander, Chris; Lee, William; Chan, Timothy A

    2013-07-01

    Adenoid cystic carcinomas (ACCs) are among the most enigmatic of human malignancies. These aggressive salivary gland cancers frequently recur and metastasize despite definitive treatment, with no known effective chemotherapy regimen. Here we determined the ACC mutational landscape and report the exome or whole-genome sequences of 60 ACC tumor-normal pairs. These analyses identified a low exonic somatic mutation rate (0.31 non-silent events per megabase) and wide mutational diversity. Notably, we found mutations in genes encoding chromatin-state regulators, such as SMARCA2, CREBBP and KDM6A, suggesting that there is aberrant epigenetic regulation in ACC oncogenesis. Mutations in genes central to the DNA damage response and protein kinase A signaling also implicate these processes. We observed MYB-NFIB translocations and somatic mutations in MYB-associated genes, solidifying the role of these aberrations as critical events in ACC. Lastly, we identified recurrent mutations in the FGF-IGF-PI3K pathway (30% of tumors) that might represent new avenues for therapy. Collectively, our observations establish a molecular foundation for understanding and exploring new treatments for ACC. PMID:23685749

  19. [Correlation of adult AML Npm1 mutations with prognosis and its relationship with gene mutation of FLT3 and CEBPA].

    PubMed

    Bao, Li-Yan; Wang, Ji-Shi

    2010-02-01

    This study was aimed to investigate the correlation of 12th exon mutations in the npm1 gene with prognosis of adult AML patients and to explore the relationship of 12th exon mutation with other gene mutations. The specimen of bone marrow and peripheral blood from AML patients, the informations of medical history, symptoms, related image examinations, blood routine examination, NAP, oxygen saturation level in artery blood and EPO level in serum were collected; the bcr/abl fusion gene was detected by routine examination of bone marrow + biopsy + chromosome mapping + FISH. The patients were typed according to WHO classification. The DNA in cells was extracted, the npm1 gene mutation was detected by allele specific PCR combined were the sequencing. The results indicated that the npm1 heterozygote gene mutation was found in 72 out of 150 AML patients with normal cytogenetics (48%, 72/150). 48% patients showed a frameshift mutation in the C-terminal region of the NPM1 protein. The AML patients with npm1 gene mutation had specific clinical, phenotypic and genetic characteristics. The statistical analysis demonstrated the relationship between npm1 and flt3 ITDs. The patients with npm1 mutation showed a better response to induction therapy, furthermore, the overall survival (OS) rate of patients without flt3 ITD mutation was enhanced. The multivariate analysis demonstrated that the npm1 gene mutation and cebpa mutation positively correlated to the OS rate, and the correlation of flt3 mutation to OS rate showed negative. It is concluded that npm1 mutation is a favorable independent prognostic factor for adult AML patients with normal cytogenetics under conditions without FIT3 gene mutation. PMID:20137111

  20. Prediction of stability changes upon mutation in an icosahedral capsid.

    PubMed

    Hickman, Samuel J; Ross, James F; Paci, Emanuele

    2015-09-01

    Identifying the contributions to thermodynamic stability of capsids is of fundamental and practical importance. Here we use simulation to assess how mutations affect the stability of lumazine synthase from the hyperthermophile Aquifex aeolicus, a T = 1 icosahedral capsid; in the simulations the icosahedral symmetry of the capsid is preserved by simulating a single pentamer and imposing crystal symmetry, in effect simulating an infinite cubic lattice of icosahedral capsids. The stability is assessed by estimating the free energy of association using an empirical method previously proposed to identify biological units in crystal structures. We investigate the effect on capsid formation of seven mutations, for which it has been experimentally assessed whether they disrupt capsid formation or not. With one exception, our approach predicts the effect of the mutations on the capsid stability. The method allows the identification of interaction networks, which drive capsid assembly, and highlights the plasticity of the interfaces between subunits in the capsid. PMID:26178267

  1. Mutations in Lettuce Improvement.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Mutations can make profound impact on the evolution and improvement of a self-pollinated crop such as lettuce. Since it is nontransgenic, mutation breeding is more acceptable to consumers. Combined with genomic advances in new technologies like TILLING, mutagenesis is becoming an even more powerfu...

  2. Ontogeny of the barley plant as related to mutation expression and detection of pollen mutations

    SciTech Connect

    Hodgdon, A.L.; Marcus, A.H.; Arenaz, P.; Rosichan, J.L.; Bogyo, T.P.; Nilan, R.A.

    1980-05-29

    Clustering of mutant pollen grains in a population of normal pollen due to premeiotic mutational events complicates translating mutation frequencies into rates. Embryo ontogeny in barley will be described and used to illustrate the formation of such mutant clusters. The nature of the statistics for mutation frequency will be described from a study of the reversion frequencies of various waxy mutants in barley. Computer analysis by a jackknife method of the reversion frequencies of a waxy mutant treated with the mutagen sodium azide showed a significantly higher reversion frequency than untreated material. Problems of the computer analysis suggest a better experimental design for pollen mutation experiments. Preliminary work on computer modeling for pollen development and mutation will be described.

  3. Ontogeny of the barley plant as related to mutation expression and detection of pollen mutations

    SciTech Connect

    Hodgdon, A.L.; Marcus, A.H.; Arenaz, P.; Rosichan, J.L.; Bogyo, T.P.; Nilan, R.A.

    1981-01-01

    Clustering of mutant pollen grains in a population of normal pollen due to premeiotic mutational events complicates translating mutation frequencies into rates. Embryo ontogeny in barley will be described and used to illustrate the formation of such mutant clusters. The nature of the statistics for mutation frequency will be described from a study of the reversion frequencies of various waxy mutants in barley. Computer analysis by a ''jackknife'' method of the reversion of a waxy mutant treated with the mutagen sodium azide showed a significantly higher reversion frequency than untreated material. Problems of the computer analysis suggest a better experimental design for pollen mutation experiments. Preliminary work on computer modeling for pollen development and mutation will be described.

  4. Multiple dispersed spontaneous mutations: A novel pathway of mutation in a malignant human cell line

    SciTech Connect

    Harwood, J.; Tachibana, Akira; Meuth, M. )

    1991-06-01

    The authors analyzed the nature of spontaneous mutations at the autosomal locus coding for adenine phosphoribosyltransferase in the human colorectal carcinoma cell line SW620 to establish whether distinctive mutational pathways exist that might underlie the more complex genome rearrangements arising in tumor cells. Point mutations occur at a low rate in part hemizygotes derived from SW620, largely as a result of base substitutions at G {center dot} C base pairs to yield transversions and transitions. However, a novel pathway is evident in the form of multiple dispersed mutations in which two errors, separated by as much as 1,800 bp, fall in the same mutant gene. Such mutations could be the result of error-prone DNA synthesis occurring during normal replication or during long-patch excision-repair of spontaneously arising DNA lesions. This process could also contribute to the chromosomal instability evident in these tumor cells.

  5. Mutations of short tandem repeat loci in cases of paternity testing in Chinese.

    PubMed

    Sun, Mao; Zhang, XiaoNan; Wu, Dan; Shen, Qi; Wu, YuanMing; Fu, ShanMin

    2016-09-01

    In order to find out the characteristics of genetic mutations in 15 short tandem repeat (STR) loci, 3734 parentage cases were analyzed using AmpFlSTR Sinofiler kit. The allele source, mutation rate, and mutation rule of the STR loci were determined. Seventy mutations were observed in all cases for paternity testing. Among 15 STR loci, the highest mutation rate was observed in D12S391 (0.21 %), but the D5S818 gene mutation rate was relatively low (0.02 %). One-step mutation cases accounted for 95.7 % of all of the cases monitored. And the mutations in this study mainly showed paternal mutation (64/70). The research results are of great significance for identification and paternity tests and for the improvement of genetic studies on Chinese population in the future. PMID:26223683

  6. The effect of spontaneous mutations on competitive ability.

    PubMed

    Schaack, S; Allen, D E; Latta, L C; Morgan, K K; Lynch, M

    2013-02-01

    Understanding the impact of spontaneous mutations on fitness has many theoretical and practical applications in biology. Although mutational effects on individual morphological or life-history characters have been measured in several classic genetic model systems, there are few estimates of the rate of decline due to mutation for complex fitness traits. Here, we estimate the effects of mutation on competitive ability, an important complex fitness trait, in a model system for ecological and evolutionary genomics, Daphnia. Competition assays were performed to compare fitness between mutation-accumulation (MA) lines and control lines from eight different genotypes from two populations of Daphnia pulicaria after 30 and 65 generations of mutation accumulation. Our results show a fitness decline among MA lines relative to controls as expected, but highlight the influence of genomic background on this effect. In addition, in some assays, MA lines outperform controls providing insight into the frequency of beneficial mutations. PMID:23252614

  7. Mutation and premating isolation

    NASA Technical Reports Server (NTRS)

    Woodruff, R. C.; Thompson, J. N. Jr

    2002-01-01

    While premating isolation might be traceable to different genetic mechanisms in different species, evidence supports the idea that as few as one or two genes may often be sufficient to initiate isolation. Thus, new mutation can theoretically play a key role in the process. But it has long been thought that a new isolation mutation would fail, because there would be no other individuals for the isolation-mutation-carrier to mate with. We now realize that premeiotic mutations are very common and will yield a cluster of progeny carrying the same new mutant allele. In this paper, we discuss the evidence for genetically simple premating isolation barriers and the role that clusters of an isolation mutation may play in initiating allopatric, and even sympatric, species divisions.

  8. 7 CFR 930.200 - Assessment rate.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 7 Agriculture 8 2013-01-01 2013-01-01 false Assessment rate. 930.200 Section 930.200 Agriculture... MICHIGAN, NEW YORK, PENNSYLVANIA, OREGON, UTAH, WASHINGTON, AND WISCONSIN Assessment Rates § 930.200 Assessment rate. On and after October 1, 2010, the assessment rate imposed on handlers shall be $0.0075...

  9. 36 CFR 1280.34 - What are the types of corrective action NARA imposes for prohibited behavior?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ..., notwithstanding the time periods set forth in 36 CFR 1254.48 . Research privileges remain revoked until the ban is... corrective action NARA imposes for prohibited behavior? 1280.34 Section 1280.34 Parks, Forests, and Public... corrective action NARA imposes for prohibited behavior? (a) Individuals who violate the provisions of...

  10. 36 CFR 1280.34 - What are the types of corrective action NARA imposes for prohibited behavior?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ..., notwithstanding the time periods set forth in 36 CFR 1254.48 . Research privileges remain revoked until the ban is... corrective action NARA imposes for prohibited behavior? 1280.34 Section 1280.34 Parks, Forests, and Public... corrective action NARA imposes for prohibited behavior? (a) Individuals who violate the provisions of...

  11. 45 CFR 156.805 - Bases and process for imposing civil money penalties in Federally-facilitated Exchanges.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ...-Facilitated Exchanges § 156.805 Bases and process for imposing civil money penalties in Federally-facilitated... 45 Public Welfare 1 2014-10-01 2014-10-01 false Bases and process for imposing civil money... accordance with this part, HHS will send a written notice of this decision to— (1) The QHP issuer...

  12. 45 CFR 156.805 - Bases and process for imposing civil money penalties in Federally-facilitated Exchanges.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ...-Facilitated Exchanges § 156.805 Bases and process for imposing civil money penalties in Federally-facilitated... 45 Public Welfare 1 2013-10-01 2013-10-01 false Bases and process for imposing civil money... accordance with this part, HHS will send a written notice of this decision to— (1) The QHP issuer...

  13. 45 CFR 155.285 - Bases and process for imposing civil penalties for provision of false or fraudulent information...

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... CFR part 150, subpart D, excluding §§ 150.461, 150.463, and 150.465. (g) Enforcement authority—(1) HHS... the rules and procedures of 42 CFR part 1003, and in place of imposition of penalties by CMS, the OIG... information. (a) Grounds for imposing civil money penalties. (1) HHS may impose civil money penalties on...

  14. 20 CFR 10.16 - What criminal penalties may be imposed in connection with a claim under the FECA?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... Labor's regulations implementing the PFRCA are found at 29 CFR part 22. ... 20 Employees' Benefits 1 2010-04-01 2010-04-01 false What criminal penalties may be imposed in... What criminal penalties may be imposed in connection with a claim under the FECA? (a) A number...

  15. 36 CFR 1280.34 - What are the types of corrective action NARA imposes for prohibited behavior?

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ..., notwithstanding the time periods set forth in 36 CFR 1254.48 . Research privileges remain revoked until the ban is... corrective action NARA imposes for prohibited behavior? 1280.34 Section 1280.34 Parks, Forests, and Public... corrective action NARA imposes for prohibited behavior? (a) Individuals who violate the provisions of...

  16. 36 CFR 1280.34 - What are the types of corrective action NARA imposes for prohibited behavior?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ..., notwithstanding the time periods set forth in 36 CFR 1254.48 . Research privileges remain revoked until the ban is... corrective action NARA imposes for prohibited behavior? 1280.34 Section 1280.34 Parks, Forests, and Public... corrective action NARA imposes for prohibited behavior? (a) Individuals who violate the provisions of...

  17. 34 CFR 270.6 - What limitation is imposed on providing race and national origin desegregation assistance under...

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 34 Education 1 2012-07-01 2012-07-01 false What limitation is imposed on providing race and... EDUCATION DESEGREGATION OF PUBLIC EDUCATION § 270.6 What limitation is imposed on providing race and... this section, a recipient of a grant for race or national origin desegregation assistance under...

  18. 34 CFR 270.6 - What limitation is imposed on providing race and national origin desegregation assistance under...

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 34 Education 1 2011-07-01 2011-07-01 false What limitation is imposed on providing race and... EDUCATION DESEGREGATION OF PUBLIC EDUCATION § 270.6 What limitation is imposed on providing race and... this section, a recipient of a grant for race or national origin desegregation assistance under...

  19. 34 CFR 270.6 - What limitation is imposed on providing race and national origin desegregation assistance under...

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 34 Education 1 2013-07-01 2013-07-01 false What limitation is imposed on providing race and... EDUCATION DESEGREGATION OF PUBLIC EDUCATION § 270.6 What limitation is imposed on providing race and... this section, a recipient of a grant for race or national origin desegregation assistance under...

  20. 34 CFR 270.6 - What limitation is imposed on providing race and national origin desegregation assistance under...

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 34 Education 1 2014-07-01 2014-07-01 false What limitation is imposed on providing race and... EDUCATION DESEGREGATION OF PUBLIC EDUCATION § 270.6 What limitation is imposed on providing race and... this section, a recipient of a grant for race or national origin desegregation assistance under...

  1. 34 CFR 270.6 - What limitation is imposed on providing race and national origin desegregation assistance under...

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 34 Education 1 2010-07-01 2010-07-01 false What limitation is imposed on providing race and... EDUCATION DESEGREGATION OF PUBLIC EDUCATION § 270.6 What limitation is imposed on providing race and... this section, a recipient of a grant for race or national origin desegregation assistance under...

  2. 42 CFR 488.431 - Civil money penalties imposed by CMS and independent informal dispute resolution: for SNFS...

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 5 2014-10-01 2014-10-01 false Civil money penalties imposed by CMS and independent informal dispute resolution: for SNFS, dually-participating SNF/NFs, and NF-only facilities. 488... imposed by CMS and independent informal dispute resolution: for SNFS, dually-participating SNF/NFs, and...

  3. 42 CFR 488.431 - Civil money penalties imposed by CMS and independent informal dispute resolution: for SNFS...

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 5 2012-10-01 2012-10-01 false Civil money penalties imposed by CMS and independent informal dispute resolution: for SNFS, dually-participating SNF/NFs, and NF-only facilities. 488... imposed by CMS and independent informal dispute resolution: for SNFS, dually-participating SNF/NFs, and...

  4. 42 CFR 488.431 - Civil money penalties imposed by CMS and independent informal dispute resolution: for SNFS...

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 5 2011-10-01 2011-10-01 false Civil money penalties imposed by CMS and independent informal dispute resolution: for SNFS, dually-participating SNF/NFs, and NF-only facilities. 488... imposed by CMS and independent informal dispute resolution: for SNFS, dually-participating SNF/NFs, and...

  5. 42 CFR 488.431 - Civil money penalties imposed by CMS and independent informal dispute resolution: for SNFS...

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 5 2013-10-01 2013-10-01 false Civil money penalties imposed by CMS and independent informal dispute resolution: for SNFS, dually-participating SNF/NFs, and NF-only facilities. 488... imposed by CMS and independent informal dispute resolution: for SNFS, dually-participating SNF/NFs, and...

  6. 45 CFR 264.72 - What requirements are imposed on a State if it receives contingency funds?

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 45 Public Welfare 2 2014-10-01 2012-10-01 true What requirements are imposed on a State if it... Contingency Fund? § 264.72 What requirements are imposed on a State if it receives contingency funds? (a)(1) A.... (2) A State must exceed the Contingency Fund MOE level to keep any of the contingency funds that...

  7. 45 CFR 264.72 - What requirements are imposed on a State if it receives contingency funds?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 45 Public Welfare 2 2010-10-01 2010-10-01 false What requirements are imposed on a State if it... Contingency Fund? § 264.72 What requirements are imposed on a State if it receives contingency funds? (a)(1) A.... (2) A State must exceed the Contingency Fund MOE level to keep any of the contingency funds that...

  8. 45 CFR 264.72 - What requirements are imposed on a State if it receives contingency funds?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 45 Public Welfare 2 2011-10-01 2011-10-01 false What requirements are imposed on a State if it... Contingency Fund? § 264.72 What requirements are imposed on a State if it receives contingency funds? (a)(1) A.... (2) A State must exceed the Contingency Fund MOE level to keep any of the contingency funds that...

  9. 42 CFR 488.433 - Civil money penalties: Uses and approval of civil money penalties imposed by CMS.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 5 2013-10-01 2013-10-01 false Civil money penalties: Uses and approval of civil money penalties imposed by CMS. 488.433 Section 488.433 Public Health CENTERS FOR MEDICARE & MEDICAID... Deficiencies § 488.433 Civil money penalties: Uses and approval of civil money penalties imposed by CMS....

  10. 42 CFR 488.433 - Civil money penalties: Uses and approval of civil money penalties imposed by CMS.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 5 2012-10-01 2012-10-01 false Civil money penalties: Uses and approval of civil money penalties imposed by CMS. 488.433 Section 488.433 Public Health CENTERS FOR MEDICARE & MEDICAID... Deficiencies § 488.433 Civil money penalties: Uses and approval of civil money penalties imposed by CMS....

  11. System for imposing directional stability on a rocket-propelled vehicle

    NASA Technical Reports Server (NTRS)

    Perkins, H. (Inventor)

    1976-01-01

    An improved system for use in imposing directional stability on a rocket-propelled vehicle is described. The system includes a pivotally supported engine-mounting platform, a gimbal ring mounted on the platform and adapted to pivotally support a rocket engine and an hydraulic actuator connected to the platform for imparting selected pivotal motion. An accelerometer and a signal comparator circuit for providing error intelligence indicative of aberration in vehicle acceleration is included along with an actuator control circuit connected with the actuator and responsive to error intelligence for imparting pivotal motion to the platform. Relocation of the engine's thrust vector is thus achieved for imparting directional stability to the vehicle.

  12. Market microstructure matters when imposing a Tobin tax—Evidence from the lab☆

    PubMed Central

    Kirchler, Michael; Huber, Jürgen; Kleinlercher, Daniel

    2011-01-01

    Trading in FX markets is dominated by two microstructures: exchanges with market makers and OTC-markets without market makers. Using laboratory experiments we test whether the impact of a Tobin tax is different in these two market microstructures. We find that (i) in markets without market makers an unilaterally imposed Tobin tax (i.e. a tax haven exists) increases volatility. (ii) In contrast, in markets with market makers we observe a decrease in volatility in unilaterally taxed markets. (iii) An encompassing Tobin tax has no impact on volatility in either setting. Efficiency does not vary significantly across tax regimes. PMID:22210970

  13. Market microstructure matters when imposing a Tobin tax-Evidence from the lab.

    PubMed

    Kirchler, Michael; Huber, Jürgen; Kleinlercher, Daniel

    2011-12-01

    TRADING IN FX MARKETS IS DOMINATED BY TWO MICROSTRUCTURES: exchanges with market makers and OTC-markets without market makers. Using laboratory experiments we test whether the impact of a Tobin tax is different in these two market microstructures. We find that (i) in markets without market makers an unilaterally imposed Tobin tax (i.e. a tax haven exists) increases volatility. (ii) In contrast, in markets with market makers we observe a decrease in volatility in unilaterally taxed markets. (iii) An encompassing Tobin tax has no impact on volatility in either setting. Efficiency does not vary significantly across tax regimes. PMID:22210970

  14. Mutation--The Engine of Evolution: Studying Mutation and Its Role in the Evolution of Bacteria.

    PubMed

    Hershberg, Ruth

    2015-09-01

    Mutation is the engine of evolution in that it generates the genetic variation on which the evolutionary process depends. To understand the evolutionary process we must therefore characterize the rates and patterns of mutation. Starting with the seminal Luria and Delbruck fluctuation experiments in 1943, studies utilizing a variety of approaches have revealed much about mutation rates and patterns and about how these may vary between different bacterial strains and species along the chromosome and between different growth conditions. This work provides a critical overview of the results and conclusions drawn from these studies, of the debate surrounding some of these conclusions, and of the challenges faced when studying mutation and its role in bacterial evolution. PMID:26330518

  15. Quantifying the Decanalizing Effects of Spontaneous Mutations in Rhabditid Nematodes

    PubMed Central

    Baer, Charles F.

    2013-01-01

    The evolution of canalization, the robustness of the phenotype to environmental or genetic perturbation, has attracted considerable recent interest. A key step toward understanding the evolution of any phenotype is characterizing the rate at which mutation introduces genetic variation for the trait (the mutational variance, VM) and the average directional effects of mutations on the trait mean (ΔM). In this study, the mutational parameters for canalization of productivity and body volume are quantified in two sets of mutation accumulation lines of nematodes in the genus Caenorhabditis and are compared with the mutational parameters for the traits themselves. Four results emerge: (1) spontaneous mutations consistently decanalize the phenotype; (2) the mutational parameters for decanalization, VM (quantified as mutational heritability) and ΔM, are of the same order of magnitude as the same parameters for the traits themselves; (3) the mutational parameters for canalization are roughly correlated with the parameters for the traits themselves across taxa; and (4) there is no evidence that residual segregating overdominant loci contribute to the decay of canalization. These results suggest that canalization is readily evolvable and that any evolutionary factor that causes mutations to accumulate will, on average, decanalize the phenotype. PMID:18582167

  16. Stochastic Demography and the Neutral Substitution Rate in Class-Structured Populations

    PubMed Central

    Lehmann, Laurent

    2014-01-01

    The neutral rate of allelic substitution is analyzed for a class-structured population subject to a stationary stochastic demographic process. The substitution rate is shown to be generally equal to the effective mutation rate, and under overlapping generations it can be expressed as the effective mutation rate in newborns when measured in units of average generation time. With uniform mutation rate across classes the substitution rate reduces to the mutation rate. PMID:24594520

  17. Germline mutations of STR-alleles include multi-step mutations as defined by sequencing of repeat and flanking regions.

    PubMed

    Dauber, Eva-Maria; Kratzer, Adelgunde; Neuhuber, Franz; Parson, Walther; Klintschar, Michael; Bär, Walter; Mayr, Wolfgang R

    2012-05-01

    Well defined estimates of mutation rates are a prerequisite for the use of short tandem repeat (STR-) loci in relationship testing. We investigated 65 isolated genetic inconsistencies, which were observed within 50,796 allelic transfers at 23 STR-loci (ACTBP2 (SE33), CD4, CSF1PO, F13A1, F13B, FES, FGA, vWA, TH01, TPOX, D2S1338, D3S1358, D5S818, D7S820, D8S1132, D8S1179, D12S391, D13S317, D16S539, D17S976, D18S51, D19S433, D21S11) in Caucasoid families residing in Austria and Switzerland. Sequencing data of repeat and flanking regions and the median of all theoretically possible mutational steps showed valuable information to characterise the mutational events with regard to parental origin, change of repeat number (mutational step size) and direction of mutation (losses and gains of repeats). Apart from predominant single-step mutations including one case with a double genetic inconsistency, two double-step and two apparent four-step mutations could be identified. More losses than gains of repeats and more mutations originating from the paternal than the maternal lineage were observed (31 losses, 22 gains, 12 losses or gains and 47 paternal, 11 maternal mutations and 7 unclear of parental origin). The mutation in the paternal germline was 3.3 times higher than in the maternal germline. The results of our study show, that apart from the vast majority of single-step mutations rare multi-step mutations can be observed. Therefore, the interpretation of mutational events should not rigidly be restricted to the shortest possible mutational step, because rare but true multi-step mutations can easily be overlooked, if haplotype analysis is not possible. PMID:21873136

  18. Imposed, ordered dust structures and other plasma features in a strongly magnetized plasma

    NASA Astrophysics Data System (ADS)

    Thomas, Edward; Leblanc, Spencer; Lynch, Brian; Konopka, Uwe; Merlino, Robert; Rosenberg, Marlene

    2015-11-01

    The Magnetized Dusty Plasma Experiment (MDPX) device has been in operation for just over one year. In that time, the MDPX device has been operating using a uniform magnetic field configuration up to 3.0 Tesla and has successfully produced plasmas and dusty plasmas at high magnetic fields. In these experimental studies, we have made observations of a new type of imposed, ordered structure in a dusty plasma at magnetic fields above 1 T. These dusty plasma structures are shown to scale inversely with neutral pressure and are shown to reflect the spatial structure of a wire mesh placed in the plasma. Additionally, recent measurements have been made that give insights into the effective potential that establishes the ordered structures in the plasma. In this presentation, we report on details of the imposed, ordered dusty plasma structure as well as filamentary features that also appear in the plasma and modify the confinement of the dusty plasma. This work is supported with funding from the NSF and Department of Energy.

  19. Transition to magnetorotational turbulence in Taylor-Couette flow with imposed azimuthal magnetic field

    NASA Astrophysics Data System (ADS)

    Guseva, A.; Willis, A. P.; Hollerbach, R.; Avila, M.

    2015-09-01

    The magnetorotational instability (MRI) is thought to be a powerful source of turbulence and momentum transport in astrophysical accretion discs, but obtaining observational evidence of its operation is challenging. Recently, laboratory experiments of Taylor-Couette flow with externally imposed axial and azimuthal magnetic fields have revealed the kinematic and dynamic properties of the MRI close to the instability onset. While good agreement was found with linear stability analyses, little is known about the transition to turbulence and transport properties of the MRI. We here report on a numerical investigation of the MRI with an imposed azimuthal magnetic field. We show that the laminar Taylor-Couette flow becomes unstable to a wave rotating in the azimuthal direction and standing in the axial direction via a supercritical Hopf bifurcation. Subsequently, the flow features a catastrophic transition to spatio-temporal defects which is mediated by a subcritical subharmonic Hopf bifurcation. Our results are in qualitative agreement with the PROMISE experiment and dramatically extend their realizable parameter range. We find that as the Reynolds number increases defects accumulate and grow into turbulence, yet the momentum transport scales weakly.

  20. The timing of vortex shedding in a cylinder wake imposed by periodic inflow perturbations

    NASA Astrophysics Data System (ADS)

    Konstantinidis, E.; Balabani, S.; Yianneskis, M.

    2005-10-01

    The interaction of vortex shedding from a circular cylinder with an inflow which has low-amplitude periodic velocity oscillations (perturbations) superimposed upon it, was investigated experimentally by means of particle image velocimetry. The experiments were made at three perturbation frequencies across the lock-on range in which the vortex shedding frequency is synchronized with the subharmonic of the imposed frequency. The basic wake pattern in this range is antisymmetric vortex shedding, i.e. the familiar 2S mode. The timing of vortex shedding is defined with respect to the cross-flow oscillation of the wake which is found to play a critical role. Quantitative analysis of the phase-referenced patterns of vorticity distribution in the wake shows that a vortex is actually shed from the cylinder when the cross-flow oscillation of the wake is strongest, marked by a sudden drop in the computed vortex strength. At the middle of the lock-on range, shedding occurs near the minimum inflow velocity in the cycle or, equivalently, during the forward stroke of a cylinder oscillating in-line with the flow. It is argued that the imposed timing of vortex shedding relative to the cylinder motion induces a negative excitation from the fluid, which might explain why the in-line response of a freely vibrating cylinder exhibits two positive excitation regions separated by the lock-on region found in forced oscillations.

  1. The qSD12 Locus Controls Offspring Tissue-Imposed Seed Dormancy in Rice

    PubMed Central

    Gu, Xing-You; Turnipseed, E. Brent; Foley, Michael E.

    2008-01-01

    Seed component structures were grouped into maternal and offspring (embryo and endosperm) tissues to characterize a dormancy quantitative trait locus (QTL) for tissue-specific function using a marker-assisted genetic approach. The approach was devised to test if genotypic/allelic frequencies of a marker tightly linked to the QTL deviate from Mendelian expectations in germinated and nongerminated subpopulations derived from a segregation population of partially after-ripened seeds and was applied to the dormancy QTL qSD12 and qSD7-1 in a nearly isogenic background of rice. Experimental results unambiguously demonstrated that qSD12 functions in the offspring tissue(s) and suggested that qSD7-1 may control dormancy through the maternal tissues. These experiments also provide the first solid evidence that an offspring tissue-imposed dormancy gene contributes to the segregation distortion in a mapping population developed from partially after-ripened seeds and, in part, to the germination heterogeneity of seeds from hybrid plants. Offspring and maternal tissue-imposed dormancy genes express in very early and late stages of the life cycle, respectively, and interact to provide the species with complementary adaptation strategies. The qSD12 locus was narrowed to the region of ∼600 kbp on a high-resolution map to facilitate cloning and marker-assisted selection of the major dormancy gene. PMID:18711220

  2. Aging increases flexibility of postural reactive responses based on constraints imposed by a manual task

    PubMed Central

    de Lima-Pardini, Andrea Cristina; Coelho, Daniel Boari; Silva, Marina Brito; Azzi, Nametala Maia; Martinelli, Alessandra Rezende; Horak, Fay Bahling; Teixeira, Luis Augusto

    2014-01-01

    This study compared the effect of stability constraints imposed by a manual task on the adaptation of postural responses between 16 healthy elderly (mean age = 71.56 years, SD = 7.38) and 16 healthy young (mean age = 22.94 years, SD = 4.82) individuals. Postural stability was perturbed through unexpected release of a load attached to the participant’s trunk while performing two versions of a voluntary task: holding a tray with a cylinder placed with its flat side down (low constraint) or with its rolling round side down (high constraint). Low and high constraint tasks were performed in alternate blocks of trials. Results showed that young participants adapted muscular activation and kinematics of postural responses in association with previous experience with the first block of manual task constraint, whereas the elderly modulated postural responses based on the current manual constraint. This study provides evidence for flexibility of postural strategies in the elderly to deal with constraints imposed by a manual task. PMID:25520656

  3. a Euclidean Formulation of Interior Orientation Costraints Imposed by the Fundamental Matrix

    NASA Astrophysics Data System (ADS)

    Kalisperakis, I.; Karras, G.; Petsa, E.

    2016-06-01

    Epipolar geometry of a stereopair can be expressed either in 3D, as the relative orientation (i.e. translation and rotation) of two bundles of optical rays in case of calibrated cameras or, in case of unclalibrated cameras, in 2D as the position of the epipoles on the image planes and a projective transformation that maps points in one image to corresponding epipolar lines on the other. The typical coplanarity equation describes the first case; the Fundamental matrix describes the second. It has also been proven in the Computer Vision literature that 2D epipolar geometry imposes two independent constraints on the parameters of camera interior orientation. In this contribution these constraints are expressed directly in 3D Euclidean space by imposing the equality of the dihedral angle of epipolar planes defined by the optical axes of the two cameras or by suitably chosen corresponding epipolar lines. By means of these constraints, new closed form algorithms are proposed for the estimation of a variable or common camera constant value given the fundamental matrix and the principal point position of a stereopair.

  4. Imposing Constraints from the Source Tree on ITG Constraints for SMT

    NASA Astrophysics Data System (ADS)

    Yamamoto, Hirofumi; Okuma, Hideo; Sumita, Eiichiro

    In the current statistical machine translation (SMT), erroneous word reordering is one of the most serious problems. To resolve this problem, many word-reordering constraint techniques have been proposed. Inversion transduction grammar (ITG) is one of these constraints. In ITG constraints, target-side word order is obtained by rotating nodes of the source-side binary tree. In these node rotations, the source binary tree instance is not considered. Therefore, stronger constraints for word reordering can be obtained by imposing further constraints derived from the source tree on the ITG constraints. For example, for the source word sequence { a b c d }, ITG constraints allow a total of twenty-two target word orderings. However, when the source binary tree instance ((a b) (c d)) is given, our proposed “imposing source tree on ITG” (IST-ITG) constraints allow only eight word orderings. The reduction in the number of word-order permutations by our proposed stronger constraints efficiently suppresses erroneous word orderings. In our experiments with IST-ITG using the NIST MT08 English-to-Chinese translation track's data, the proposed method resulted in a 1.8-points improvement in character BLEU-4 (35.2 to 37.0) and a 6.2% lower CER (74.1 to 67.9%) compared with our baseline condition.

  5. Mutations in man

    SciTech Connect

    Obe, G.

    1984-01-01

    This book contains 13 selections that cover some of the following topics: DNA repair, gene or point mutations, aspects of nondisjunction, origin and significance of chromosomal alterations, structure and organization of the human genome, and mutagenic activity of cigarette smoke.

  6. Diploid yeast cells yield homozygous spontaneous mutations

    NASA Technical Reports Server (NTRS)

    Esposito, M. S.; Bruschi, C. V.; Brushi, C. V. (Principal Investigator)

    1993-01-01

    A leucine-requiring hybrid of Saccharomyces cerevisiae, homoallelic at the LEU1 locus (leu1-12/leu1-12) and heterozygous for three chromosome-VII genetic markers distal to the LEU1 locus, was employed to inquire: (1) whether spontaneous gene mutation and mitotic segregation of heterozygous markers occur in positive nonrandom association and (2) whether homozygous LEU1/LEU1 mutant diploids are generated. The results demonstrate that gene mutation of leu1-12 to LEU1 and mitotic segregation of heterozygous chromosome-VII markers occur in strong positive nonrandom association, suggesting that the stimulatory DNA lesion is both mutagenic and recombinogenic. In addition, genetic analysis of diploid Leu+ revertants revealed that approximately 3% of mutations of leu1-12 to LEU1 result in LEU1/LEU1 homozygotes. Red-white sectored Leu+ colonies exhibit genotypes that implicate post-replicational chromatid breakage and exchange near the site of leu1-12 reversion, chromosome loss, and subsequent restitution of diploidy, in the sequence of events leading to mutational homozygosis. By analogy, diploid cell populations can yield variants homozygous for novel recessive gene mutations at biologically significant rates. Mutational homozygosis may be relevant to both carcinogenesis and the evolution of asexual diploid organisms.

  7. No reduction of metabolic rate in food restricted Caenorhabditis elegans.

    PubMed

    Houthoofd, Koen; Braeckman, Bart P; Lenaerts, Isabelle; Brys, Kristel; De Vreese, Annemie; Van Eygen, Sylvie; Vanfleteren, Jacques R

    2002-12-01

    Dietary restriction (DR) is the most consistent means of extending life span throughout the animal kingdom. Multiple mechanisms by which DR may act have been proposed but none are clearly predominant. We asked whether metabolic rate and stress resistance is altered in Caenorhabditis elegans in response to DR. DR was imposed in two complementary ways: by growing wild-type worms in liquid medium supplemented with reduced concentrations of bacteria and by using eat-2 mutants, which have a feeding defect. Metabolic rate was not reduced when we fed wild-type worms reduced food and was up-regulated in the eat-2 mutants in liquid culture, as assessed by oxygen consumption rate and heat production. The specific activity levels of the antioxidant enzymes superoxide dismutase (SOD) and catalase showed small increases when we reduced food in wild-type worms, but restricted worms acquired no elevated protection against paraquat and hydrogen peroxide. eat-2 mutants showed elevated specific activities of SOD and catalase relative to wild type in liquid culture. These results indicate that the effects imparted by DR and the eat-2 mutation are not identical, and they contradict, at least in C. elegans, the widespread belief that CR acts by lowering the rate of metabolism. PMID:12559405

  8. Experiments on the role of deleterious mutations as stepping stones in adaptive evolution.

    PubMed

    Covert, Arthur W; Lenski, Richard E; Wilke, Claus O; Ofria, Charles

    2013-08-20

    Many evolutionary studies assume that deleterious mutations necessarily impede adaptive evolution. However, a later mutation that is conditionally beneficial may interact with a deleterious predecessor before it is eliminated, thereby providing access to adaptations that might otherwise be inaccessible. It is unknown whether such sign-epistatic recoveries are inconsequential events or an important factor in evolution, owing to the difficulty of monitoring the effects and fates of all mutations during experiments with biological organisms. Here, we used digital organisms to compare the extent of adaptive evolution in populations when deleterious mutations were disallowed with control populations in which such mutations were allowed. Significantly higher fitness levels were achieved over the long term in the control populations because some of the deleterious mutations served as stepping stones across otherwise impassable fitness valleys. As a consequence, initially deleterious mutations facilitated the evolution of complex, beneficial functions. We also examined the effects of disallowing neutral mutations, of varying the mutation rate, and of sexual recombination. Populations evolving without neutral mutations were able to leverage deleterious and compensatory mutation pairs to overcome, at least partially, the absence of neutral mutations. Substantially raising or lowering the mutation rate reduced or eliminated the long-term benefit of deleterious mutations, but introducing recombination did not. Our work demonstrates that deleterious mutations can play an important role in adaptive evolution under at least some conditions. PMID:23918358

  9. Comparing Mutational Variabilities

    PubMed Central

    Houle, D.; Morikawa, B.; Lynch, M.

    1996-01-01

    We have reviewed the available data on V(M), the amount of genetic variation in phenotypic traits produced each generation by mutation. We use these data to make several qualitative tests of the mutation-selection balance hypothesis for the maintenance of genetic variance (MSB). To compare V(M) values, we use three dimensionless quantities: mutational heritability, V(M)/V(E); the mutational coefficient of variation, CV(M); and the ratio of the standing genetic variance to V(M), V(G)/V(M). Since genetic coefficients of variation for life history traits are larger than those for morphological traits, we predict that under MSB, life history traits should also have larger CV(M). This is confirmed; life history traits have a median CV(M) value more than six times higher than that for morphological traits. V(G)/V(M) approximates the persistence time of mutations under MSB in an infinite population. In order for MSB to hold, V(G)/V(M) must be small, substantially less than 1000, and life history traits should have smaller values than morphological traits. V(G)/V(M) averages about 50 generations for life history traits and 100 generations for morphological traits. These observations are all consistent with the predictions of a mutation-selection balance model. PMID:8807316

  10. Low Genetic Quality Alters Key Dimensions of the Mutational Spectrum.

    PubMed

    Sharp, Nathaniel P; Agrawal, Aneil F

    2016-03-01

    Mutations affect individual health, population persistence, adaptation, diversification, and genome evolution. There is evidence that the mutation rate varies among genotypes, but the causes of this variation are poorly understood. Here, we link differences in genetic quality with variation in spontaneous mutation in a Drosophila mutation accumulation experiment. We find that chromosomes maintained in low-quality genetic backgrounds experience a higher rate of indel mutation and a lower rate of gene conversion in a manner consistent with condition-based differences in the mechanisms used to repair DNA double strand breaks. These aspects of the mutational spectrum were also associated with body mass, suggesting that the effect of genetic quality on DNA repair was mediated by overall condition, and providing a mechanistic explanation for the differences in mutational fitness decline among these genotypes. The rate and spectrum of substitutions was unaffected by genetic quality, but we find variation in the probability of substitutions and indels with respect to several aspects of local sequence context, particularly GC content, with implications for models of molecular evolution and genome scans for signs of selection. Our finding that the chances of mutation depend on genetic context and overall condition has important implications for how sequences evolve, the risk of extinction, and human health. PMID:27015430

  11. Low Genetic Quality Alters Key Dimensions of the Mutational Spectrum

    PubMed Central

    Sharp, Nathaniel P.; Agrawal, Aneil F.

    2016-01-01

    Mutations affect individual health, population persistence, adaptation, diversification, and genome evolution. There is evidence that the mutation rate varies among genotypes, but the causes of this variation are poorly understood. Here, we link differences in genetic quality with variation in spontaneous mutation in a Drosophila mutation accumulation experiment. We find that chromosomes maintained in low-quality genetic backgrounds experience a higher rate of indel mutation and a lower rate of gene conversion in a manner consistent with condition-based differences in the mechanisms used to repair DNA double strand breaks. These aspects of the mutational spectrum were also associated with body mass, suggesting that the effect of genetic quality on DNA repair was mediated by overall condition, and providing a mechanistic explanation for the differences in mutational fitness decline among these genotypes. The rate and spectrum of substitutions was unaffected by genetic quality, but we find variation in the probability of substitutions and indels with respect to several aspects of local sequence context, particularly GC content, with implications for models of molecular evolution and genome scans for signs of selection. Our finding that the chances of mutation depend on genetic context and overall condition has important implications for how sequences evolve, the risk of extinction, and human health. PMID:27015430

  12. Fitness evolution and the rise of mutator alleles in experimental Escherichia coli populations.

    PubMed Central

    Shaver, Aaron C; Dombrowski, Peter G; Sweeney, Joseph Y; Treis, Tania; Zappala, Renata M; Sniegowski, Paul D

    2002-01-01

    We studied the evolution of high mutation rates and the evolution of fitness in three experimental populations of Escherichia coli adapting to a glucose-limited environment. We identified the mutations responsible for the high mutation rates and show that their rate of substitution in all three populations was too rapid to be accounted for simply by genetic drift. In two of the populations, large gains in fitness relative to the ancestor occurred as the mutator alleles rose to fixation, strongly supporting the conclusion that mutator alleles fixed by hitchhiking with beneficial mutations at other loci. In one population, no significant gain in fitness relative to the ancestor occurred in the population as a whole while the mutator allele rose to fixation, but a substantial and significant gain in fitness occurred in the mutator subpopulation as the mutator neared fixation. The spread of the mutator allele from rarity to fixation took >1000 generations in each population. We show that simultaneous adaptive gains in both the mutator and wild-type subpopulations (clonal interference) retarded the mutator fixation in at least one of the populations. We found little evidence that the evolution of high mutation rates accelerated adaptation in these populations. PMID:12399371

  13. Quantum Error-Correction-Enhanced Magnetometer Overcoming the Limit Imposed by Relaxation

    NASA Astrophysics Data System (ADS)

    Herrera-Martí, David A.; Gefen, Tuvia; Aharonov, Dorit; Katz, Nadav; Retzker, Alex

    2015-11-01

    When incorporated in quantum sensing protocols, quantum error correction can be used to correct for high frequency noise, as the correction procedure does not depend on the actual shape of the noise spectrum. As such, it provides a powerful way to complement usual refocusing techniques. Relaxation imposes a fundamental limit on the sensitivity of state of the art quantum sensors which cannot be overcome by dynamical decoupling. The only way to overcome this is to utilize quantum error correcting codes. We present a superconducting magnetometry design that incorporates approximate quantum error correction, in which the signal is generated by a two qubit Hamiltonian term. This two-qubit term is provided by the dynamics of a tunable coupler between two transmon qubits. For fast enough correction, it is possible to lengthen the coherence time of the device beyond the relaxation limit.

  14. Analytic and subjective assessments of operator workload imposed by communications tasks in transport aircraft

    NASA Technical Reports Server (NTRS)

    Eckel, J. S.; Crabtree, M. S.

    1984-01-01

    Analytical and subjective techniques that are sensitive to the information transmission and processing requirements of individual communications-related tasks are used to assess workload imposed on the aircrew by A-10 communications requirements for civilian transport category aircraft. Communications-related tasks are defined to consist of the verbal exchanges between crews and controllers. Three workload estimating techniques are proposed. The first, an information theoretic analysis, is used to calculate bit values for perceptual, manual, and verbal demands in each communication task. The second, a paired-comparisons technique, obtains subjective estimates of the information processing and memory requirements for specific messages. By combining the results of the first two techniques, a hybrid analytical scale is created. The third, a subjective rank ordering of sequences of communications tasks, provides an overall scaling of communications workload. Recommendations for future research include an examination of communications-induced workload among the air crew and the development of simulation scenarios.

  15. Photophysics of GFP-related chromophores imposed by a scaffold design.

    PubMed

    Dolgopolova, E A; Moore, T M; Fellows, W B; Smith, M D; Shustova, N B

    2016-06-14

    In this paper, a rigid scaffold imposes the photophysics of chromophores with a benzylidene imidazolidinone core by mimicking the β-barrel structure of the green fluorescent protein (GFP) and its analogs. The designed artificial frameworks maintain fluorescence responses and, therefore, conformational rigidity of typically non-emissive GFP-related chromophores. To replicate a small weight percent of the chromophore inside the natural GFP, two synthetic approaches were utilized: coordinative immobilization and non-coordinative inclusion. Despite low chromophore loading in the rigid matrix, both approaches resulted in formation of photoluminescent hybrid materials. Furthermore, the rigid scaffold dictates chromophore fluorescence by replicating its behavior in solution or the solid state. The presented results open an avenue for utilization of rigid scaffolds in the engineering of materials with tunable photoluminescence profiles for a variety of practical applications. PMID:26927627

  16. Pathways of information transmission among wild songbirds follow experimentally imposed changes in social foraging structure.

    PubMed

    Firth, Josh A; Sheldon, Ben C; Farine, Damien R

    2016-06-01

    Animals regularly use information from others to shape their decisions. Yet, determining how changes in social structure affect information flow and social learning strategies has remained challenging. We manipulated the social structure of a large community of wild songbirds by controlling which individuals could feed together at automated feeding stations (selective feeders). We then provided novel ephemeral food patches freely accessible to all birds and recorded the spread of this new information. We demonstrate that the discovery of new food patches followed the experimentally imposed social structure and that birds disproportionately learnt from those whom they could forage with at the selective feeders. The selective feeders reduced the number of conspecific information sources available and birds subsequently increased their use of information provided by heterospecifics. Our study demonstrates that changes to social systems carry over into pathways of information transfer and that individuals learn from tutors that provide relevant information in other contexts. PMID:27247439

  17. Performance limitations of bilateral force reflection imposed by operator dynamic characteristics

    NASA Technical Reports Server (NTRS)

    Chapel, Jim D.

    1989-01-01

    A linearized, single-axis model is presented for bilateral force reflection which facilitates investigation into the effects of manipulator, operator, and task dynamics, as well as time delay and gain scaling. Structural similarities are noted between this model and impedance control. Stability results based upon this model impose requirements upon operator dynamic characteristics as functions of system time delay and environmental stiffness. An experimental characterization reveals the limited capabilities of the human operator to meet these requirements. A procedure is presented for determining the force reflection gain scaling required to provide stability and acceptable operator workload. This procedure is applied to a system with dynamics typical of a space manipulator, and the required gain scaling is presented as a function of environmental stiffness.

  18. Pathways of information transmission among wild songbirds follow experimentally imposed changes in social foraging structure

    PubMed Central

    Sheldon, Ben C.

    2016-01-01

    Animals regularly use information from others to shape their decisions. Yet, determining how changes in social structure affect information flow and social learning strategies has remained challenging. We manipulated the social structure of a large community of wild songbirds by controlling which individuals could feed together at automated feeding stations (selective feeders). We then provided novel ephemeral food patches freely accessible to all birds and recorded the spread of this new information. We demonstrate that the discovery of new food patches followed the experimentally imposed social structure and that birds disproportionately learnt from those whom they could forage with at the selective feeders. The selective feeders reduced the number of conspecific information sources available and birds subsequently increased their use of information provided by heterospecifics. Our study demonstrates that changes to social systems carry over into pathways of information transfer and that individuals learn from tutors that provide relevant information in other contexts. PMID:27247439

  19. Altered ion channel conductance and ionic selectivity induced by large imposed membrane potential pulse.

    PubMed Central

    Chen, W; Lee, R C

    1994-01-01

    The effects of large magnitude transmembrane potential pulses on voltage-gated Na and K channel behavior in frog skeletal muscle membrane were studied using a modified double vaseline-gap voltage clamp. The effects of electroconformational damage to ionic channels were separated from damage to lipid bilayer (electroporation). A 4 ms transmembrane potential pulse of -600 mV resulted in a reduction of both Na and K channel conductivities. The supraphysiologic pulses also reduced ionic selectivity of the K channels against Na+ ions, resulting in a depolarization of the membrane resting potential. However, TTX and TEA binding effects were unaltered. The kinetics of spontaneous reversal of the electroconformational damage of channel proteins was found to be dependent on the magnitude of imposed membrane potential pulse. These results suggest that muscle and nerve dysfunction after electrical shock may be in part caused by electroconformational damage to voltage-gated ion channels. PMID:7948676

  20. A New Approach for Imposing Artificial Viscosity for Explicit Discontinuous Galerkin Scheme

    NASA Astrophysics Data System (ADS)

    See, Yee Chee; Lv, Yu; Ihme, Matthias

    2014-11-01

    The development of high-order numerical methods for unstructured meshes has been a significant area of research, and the discontinuous Galerkin (DG) method has found considerable interest. However, the DG-method exhibits robustness issues in application to flows with discontinuities and shocks. To address this issue, an artificial viscosity method was proposed by Persson et al. for steady flows. Its extension to time-dependent flows introduces substantial time-step restrictions. By addressing this issue, a novel method, which is based on an entropy formulation, is proposed. The resulting scheme doesn't impose restrictions on the CFL-constraint. Following a description of the formulation and the evaluation of the stability, this newly developed artificial viscosity scheme is demonstrated in application to different test cases.

  1. Host-imposed manganese starvation of invading pathogens: two routes to the same destination

    PubMed Central

    Morey, Jacqueline R.; McDevitt, Christopher A.; Kehl-Fie, Thomas E.

    2015-01-01

    During infection invading pathogens must acquire all essential nutrients, including first row transition metals, from the host. To combat invaders, the host exploits this fact and restricts the availability of these nutrients using a defense mechanism known as nutritional immunity. While iron sequestration is the most well-known aspect of this defense, recent work has revealed that the host restricts the availability of other essential elements, notably manganese, during infection. Furthermore, these studies have revealed that the host utilizes multiple strategies that extend beyond metal sequestration to prevent bacteria from obtaining these metals. This review will discuss the mechanisms by which bacteria attempt to obtain the essential first row transition metal ion manganese during infection, and the approaches utilized by the host to prevent this occurrence. In addition, this review will discuss the impact of host-imposed manganese starvation on invading bacteria. PMID:25836716

  2. Imposed magnetic field and hot electron propagation in inertial fusion hohlraums

    DOE PAGESBeta

    Strozzi, David J.; Perkins, L. J.; Marinak, M. M.; Larson, D. J.; Koning, J. M.; Logan, B. G.

    2015-12-02

    The effects of an imposed, axial magnetic fieldmore » $$B_{z0}$$ on hydrodynamics and energetic electrons in inertial confinement fusion indirect-drive hohlraums are studied. We present simulations from the radiation-hydrodynamics code HYDRA of a low-adiabat ignition design for the National Ignition Facility, with and without $$B_{z0}=70~\\text{T}$$. The field’s main hydrodynamic effect is to significantly reduce electron thermal conduction perpendicular to the field. This results in hotter and less dense plasma on the equator between the capsule and hohlraum wall. The inner laser beams experience less inverse bremsstrahlung absorption before reaching the wall. The X-ray drive is thus stronger from the equator with the imposed field. We study superthermal, or ‘hot’, electron dynamics with the particle-in-cell code ZUMA, using plasma conditions from HYDRA. During the early-time laser picket, hot electrons based on two-plasmon decay in the laser entrance hole (Regan et al., Phys. Plasmas, vol. 17(2), 2010, 020703) are guided to the capsule by a 70 T field. Twelve times more energy deposits in the deuterium–tritium fuel. For plasma conditions early in peak laser power, we present mono-energetic test-case studies with ZUMA as well as sources based on inner-beam stimulated Raman scattering. Furthermore, the effect of the field on deuterium–tritium deposition depends strongly on the source location, namely whether hot electrons are generated on field lines that connect to the capsule.« less

  3. Imposed magnetic field and hot electron propagation in inertial fusion hohlraums

    SciTech Connect

    Strozzi, David J.; Perkins, L. J.; Marinak, M. M.; Larson, D. J.; Koning, J. M.; Logan, B. G.

    2015-12-02

    The effects of an imposed, axial magnetic field $B_{z0}$ on hydrodynamics and energetic electrons in inertial confinement fusion indirect-drive hohlraums are studied. We present simulations from the radiation-hydrodynamics code HYDRA of a low-adiabat ignition design for the National Ignition Facility, with and without $B_{z0}=70~\\text{T}$. The field’s main hydrodynamic effect is to significantly reduce electron thermal conduction perpendicular to the field. This results in hotter and less dense plasma on the equator between the capsule and hohlraum wall. The inner laser beams experience less inverse bremsstrahlung absorption before reaching the wall. The X-ray drive is thus stronger from the equator with the imposed field. We study superthermal, or ‘hot’, electron dynamics with the particle-in-cell code ZUMA, using plasma conditions from HYDRA. During the early-time laser picket, hot electrons based on two-plasmon decay in the laser entrance hole (Regan et al., Phys. Plasmas, vol. 17(2), 2010, 020703) are guided to the capsule by a 70 T field. Twelve times more energy deposits in the deuterium–tritium fuel. For plasma conditions early in peak laser power, we present mono-energetic test-case studies with ZUMA as well as sources based on inner-beam stimulated Raman scattering. Furthermore, the effect of the field on deuterium–tritium deposition depends strongly on the source location, namely whether hot electrons are generated on field lines that connect to the capsule.

  4. 28 CFR 522.13 - Relationship between existing civil contempt commitment orders and new criminal sentences imposed...

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    .... Code. (a) Except as stated in (b), if a civil contempt commitment order is in effect when a criminal... contempt commitment order is in effect when a criminal sentence of imprisonment is imposed, the...

  5. A resolution of the mutation load paradox in humans.

    PubMed

    Lesecque, Yann; Keightley, Peter D; Eyre-Walker, Adam

    2012-08-01

    Current information on the rate of mutation and the fraction of sites in the genome that are subject to selection suggests that each human has received, on average, at least two new harmful mutations from its parents. These mutations were subsequently removed by natural selection through reduced survival or fertility. It has been argued that the mutation load, the proportional reduction in population mean fitness relative to the fitness of an idealized mutation-free individual, allows a theoretical prediction of the proportion of individuals in the population that fail to reproduce as a consequence of these harmful mutations. Application of this theory to humans implies that at least 88% of individuals should fail to reproduce and that each female would need to have more than 16 offspring to maintain population size. This prediction is clearly at odds with the low reproductive excess of human populations. Here, we derive expressions for the fraction of individuals that fail to reproduce as a consequence of recurrent deleterious mutation () for a model in which selection occurs via differences in relative fitness, such as would occur through competition between individuals. We show that is much smaller than the value predicted by comparing fitness to that of a mutation-free genotype. Under the relative fitness model, we show that depends jointly on U and the selective effects of new deleterious mutations and that a species could tolerate 10's or even 100's of new deleterious mutations per genome each generation. PMID:22661324

  6. Age-related mutations and chronic myelomonocytic leukemia.

    PubMed

    Mason, C C; Khorashad, J S; Tantravahi, S K; Kelley, T W; Zabriskie, M S; Yan, D; Pomicter, A D; Reynolds, K R; Eiring, A M; Kronenberg, Z; Sherman, R L; Tyner, J W; Dalley, B K; Dao, K-H; Yandell, M; Druker, B J; Gotlib, J; O'Hare, T; Deininger, M W

    2016-04-01

    Chronic myelomonocytic leukemia (CMML) is a hematologic malignancy nearly confined to the elderly. Previous studies to determine incidence and prognostic significance of somatic mutations in CMML have relied on candidate gene sequencing, although an unbiased mutational search has not been conducted. As many of the genes commonly mutated in CMML were recently associated with age-related clonal hematopoiesis (ARCH) and aged hematopoiesis is characterized by a myelomonocytic differentiation bias, we hypothesized that CMML and aged hematopoiesis may be closely related. We initially established the somatic mutation landscape of CMML by whole exome sequencing followed by gene-targeted validation. Genes mutated in ⩾10% of patients were SRSF2, TET2, ASXL1, RUNX1, SETBP1, KRAS, EZH2, CBL and NRAS, as well as the novel CMML genes FAT4, ARIH1, DNAH2 and CSMD1. Most CMML patients (71%) had mutations in ⩾2 ARCH genes and 52% had ⩾7 mutations overall. Higher mutation burden was associated with shorter survival. Age-adjusted population incidence and reported ARCH mutation rates are consistent with a model in which clinical CMML ensues when a sufficient number of stochastically acquired age-related mutations has accumulated, suggesting that CMML represents the leukemic conversion of the myelomonocytic-lineage-biased aged hematopoietic system. PMID:26648538

  7. Mutation Profile of Well-Differentiated Thyroid Cancer in Asians

    PubMed Central

    Song, Young Shin; Lim, Jung Ah

    2015-01-01

    Recent advances in molecular diagnostics have led to significant insights into the genetic basis of thyroid tumorigenesis. Among the mutations commonly seen in thyroid cancers, the vast majority are associated with the mitogen-activated protein kinase pathway. B-Raf proto-oncogene (BRAF) mutations are the most common mutations observed in papillary thyroid cancers (PTCs), followed by RET/PTC rearrangements and RAS mutations, while follicular thyroid cancers are more likely to harbor RAS mutations or PAX8/peroxisome proliferator-activated receptor γ (PPARγ) rearrangements. Beyond these more common mutations, alterations in the telomerase reverse transcriptase (TERT) promoter have recently been associated with clinicopathologic features, disease prognosis, and tumorigenesis in thyroid cancer. While the mutations underlying thyroid tumorigenesis are well known, the frequency of these mutations is strongly associated with geography, with clear differences reported between Asian and Western countries. Of particular interest is the prevalence of BRAF mutations, with Korean patients exhibiting the highest rate of BRAF-associated thyroid cancers in the world. Here, we review the prevalence of each of the most common mutations in Asian and Western countries, and identify the characteristics of well-differentiated thyroid cancer in Asians. PMID:26435130

  8. The mutational spectrum in Treacher Collins syndrome reveals a predominance of mutations that create a premature-termination codon

    SciTech Connect

    Edwards, S.J.; Gladwin, A.J.; Dixon, M.J.

    1997-03-01

    Treacher Collins syndrome (TCS) is an autosomal dominant disorder of craniofacial development, the features of which include conductive hearing loss and cleft palate. The TCS locus has been mapped to human chromosome 5q31.3-32 and the mutated gene identified. In the current investigation, 25 previously undescribed mutations, which are spread throughout the gene, are presented. This brings the total reported to date to 35, which represents a detection rate of 60%. Of the mutations that have been reported to date, all but one result in the introduction of a premature-termination codon into the predicted protein, treacle. Moreover, the mutations are largely family specific, although a common 5-bp deletion in exon 24 (seven different families) and a recurrent splicing mutation in intron 3 (two different families) have been identified. This mutational spectrum supports the hypothesis that TCS results from haploin-sufficiency. 49 refs., 4 figs., 3 tabs.

  9. Parkinson disease (PARK) genes are somatically mutated in cutaneous melanoma

    PubMed Central

    Samuels, Yardena; Azizi, Esther; Qutob, Nouar; Inzelberg, Lilah; Domany, Eytan; Schechtman, Edna; Friedman, Eitan

    2016-01-01

    Objective: To assess whether Parkinson disease (PD) genes are somatically mutated in cutaneous melanoma (CM) tissue, because CM occurs in patients with PD at higher rates than in the general population and PD is more common than expected in CM cohorts. Methods: We cross-referenced somatic mutations in metastatic CM detected by whole-exome sequencing with the 15 known PD (PARK) genes. We computed the empirical distribution of the sum of mutations in each gene (Smut) and of the number of tissue samples in which a given gene was mutated at least once (SSampl) for each of the analyzable genes, determined the 90th and 95th percentiles of the empirical distributions of these sums, and verified the location of PARK genes in these distributions. Identical analyses were applied to adenocarcinoma of lung (ADENOCA-LUNG) and squamous cell carcinoma of lung (SQUAMCA-LUNG). We also analyzed the distribution of the number of mutated PARK genes in CM samples vs the 2 lung cancers. Results: Somatic CM mutation analysis (n = 246) detected 315,914 mutations in 18,758 genes. Somatic CM mutations were found in 14 of 15 PARK genes. Forty-eight percent of CM samples carried ≥1 PARK mutation and 25% carried multiple PARK mutations. PARK8 mutations occurred above the 95th percentile of the empirical distribution for SMut and SSampl. Significantly more CM samples harbored multiple PARK gene mutations compared with SQUAMCA-LUNG (p = 0.0026) and with ADENOCA-LUNG (p < 0.0001). Conclusions: The overrepresentation of somatic PARK mutations in CM suggests shared dysregulated pathways for CM and PD. PMID:27123489

  10. Biallelic BRCA2 Mutations Shape the Somatic Mutational Landscape of Aggressive Prostate Tumors.

    PubMed

    Decker, Brennan; Karyadi, Danielle M; Davis, Brian W; Karlins, Eric; Tillmans, Lori S; Stanford, Janet L; Thibodeau, Stephen N; Ostrander, Elaine A

    2016-05-01

    To identify clinically important molecular subtypes of prostate cancer (PCa), we characterized the somatic landscape of aggressive tumors via deep, whole-genome sequencing. In our discovery set of ten tumor/normal subject pairs with Gleason scores of 8-10 at diagnosis, coordinated analysis of germline and somatic variants, including single-nucleotide variants, indels, and structural variants, revealed biallelic BRCA2 disruptions in a subset of samples. Compared to the other samples, the PCa BRCA2-deficient tumors exhibited a complex and highly specific mutation signature, featuring a 2.88-fold increased somatic mutation rate, depletion of context-specific C>T substitutions, and an enrichment for deletions, especially those longer than 10 bp. We next performed a BRCA2 deficiency-targeted reanalysis of 150 metastatic PCa tumors, and each of the 18 BRCA2-mutated samples recapitulated the BRCA2 deficiency-associated mutation signature, underscoring the potent influence of these lesions on somatic mutagenesis and tumor evolution. Among all 21 individuals with BRCA2-deficient tumors, only about half carried deleterious germline alleles. Importantly, the somatic mutation signature in tumors with one germline and one somatic risk allele was indistinguishable from those with purely somatic mutations. Our observations clearly demonstrate that BRCA2-disrupted tumors represent a unique and clinically relevant molecular subtype of aggressive PCa, highlighting both the promise and utility of this mutation signature as a prognostic and treatment-selection biomarker. Further, any test designed to leverage BRCA2 status as a biomarker for PCa must consider both germline and somatic mutations and all types of deleterious mutations. PMID:27087322

  11. Multi-institutional oncogenic driver mutation analysis in lung adenocarcinoma: The Lung Cancer Mutation Consortium experience

    PubMed Central

    Dias-Santagata, Dora; Wistuba, Ignacio I.; Chen, Heidi; Fujimoto, Junya; Kugler, Kelly; Franklin, Wilbur A.; Iafrate, A. John; Ladanyi, Marc; Kris, Mark G.; Johnson, Bruce E.; Bunn, Paul A.; Minna, John D.; Kwiatkowski, David J.

    2015-01-01

    Introduction Molecular genetic analyses of lung adenocarcinoma have recently become standard of care for treatment selection. The Lung Cancer Mutation Consortium was formed to enable collaborative multi-institutional analyses of 10 potential oncogenic driver mutations. Technical aspects of testing, and clinicopathologic correlations are presented. Methods Mutation testing in at least one of 8 genes (EGFR, KRAS, ERBB2, AKT1, BRAF, MEK1, NRAS, PIK3CA) using SNaPshot, mass spectrometry, Sanger sequencing +/− PNA and/or sizing assays, along with ALK and/or MET FISH were performed in 6 labs on 1007 patients from 14 institutions. Results 1007 specimens had mutation analysis performed, and 733 specimens had all 10 genes analyzed. Mutation identification rates did not vary by analytic method. Biopsy and cytology specimens were inadequate for testing in 26% and 35% of cases compared to 5% of surgical specimens. Among the 1007 cases with mutation analysis performed, EGFR, KRAS, ALK, and ERBB2 alterations were detected in 22, 25, 8.5, and 2.4% of cases, respectively. EGFR mutations were highly associated with female sex, Asian race, and never smoking status; and less strongly associated with stage IV disease, presence of bone metastases, and absence of adrenal metastases. ALK rearrangements were strongly associated with never smoking status, and more weakly associated with presence of liver metastases. ERBB2 mutations were strongly associated with Asian race and never smoking status. Two mutations were seen in 2.7% of samples, all but one of which involved one or more of PIK3CA, ALK or MET. Conclusion Multi-institutional molecular analysis across multiple platforms, sample types, and institutions can yield consistent results and novel clinicopathological observations. PMID:25738220

  12. Marcus model of spontaneous point mutation in DNA

    NASA Astrophysics Data System (ADS)

    Turaeva, N.; Brown-Kennerly, V.

    2015-11-01

    The theoretical model of Löwdin's mechanism of spontaneous mutation based on 2D Marcus theory of DPT has been proposed in this work. The equation for the kinetics of DPT during DNA replication has been established, and the expression for the probability of spontaneous mutation has been received. The probability of spontaneous mutation formation has been estimated for tautomeric G∗-C∗ complexes, which is in the range of experimental results. The probability of spontaneous mutation as a function of temperature, replication rate, and solvent effect has been discussed. It increases with temperature and decreases with replication rate. The solvent and pH effects on the probability of spontaneous mutation can also be discussed within the framework of the model.

  13. Mutations in lettuce improvement.

    PubMed

    Mou, Beiquan

    2011-01-01

    Lettuce is a major vegetable in western countries. Mutations generated genetic variations and played an important role in the domestication of the crop. Many traits derived from natural and induced mutations, such as dwarfing, early flowering, male sterility, and chlorophyll deficiency, are useful in physiological and genetic studies. Mutants were also used to develop new lettuce products including miniature and herbicide-tolerant cultivars. Mutant analysis was critical in lettuce genomic studies including identification and cloning of disease-resistance genes. Mutagenesis combined with genomic technology may provide powerful tools for the discovery of novel gene alleles. In addition to radiation and chemical mutagens, unconventional approaches such as tissue or protoplast culture, transposable elements, and space flights have been utilized to generate mutants in lettuce. Since mutation breeding is considered nontransgenic, it is more acceptable to consumers and will be explored more in the future for lettuce improvement. PMID:22287955

  14. Mutations in Lettuce Improvement

    PubMed Central

    Mou, Beiquan

    2011-01-01

    Lettuce is a major vegetable in western countries. Mutations generated genetic variations and played an important role in the domestication of the crop. Many traits derived from natural and induced mutations, such as dwarfing, early flowering, male sterility, and chlorophyll deficiency, are useful in physiological and genetic studies. Mutants were also used to develop new lettuce products including miniature and herbicide-tolerant cultivars. Mutant analysis was critical in lettuce genomic studies including identification and cloning of disease-resistance genes. Mutagenesis combined with genomic technology may provide powerful tools for the discovery of novel gene alleles. In addition to radiation and chemical mutagens, unconventional approaches such as tissue or protoplast culture, transposable elements, and space flights have been utilized to generate mutants in lettuce. Since mutation breeding is considered nontransgenic, it is more acceptable to consumers and will be explored more in the future for lettuce improvement. PMID:22287955

  15. BRAF V600 mutations and pathological features in Japanese melanoma patients

    PubMed Central

    Tanaka, Ryota; Tsutsumida, Arata; Namikawa, Kenjiro; Eguchi, Hironobu; Omata, Wataru; Oashi, Kohei; Ogawa, Toru; Hayashi, Amiko; Nakamura, Noriyuki; Tsuta, Koji

    2015-01-01

    Ultraviolet radiation is a risk factor for BRAF V600 mutations frequently found in melanomas that cause constitutive BRAF activation. Primary sites of melanoma and the frequency of BRAF mutations might differ between races. Melanoma is rare in Japan (1500–2000 cases/year compared with 132 000/year worldwide) and the frequency and distribution of BRAF V600 mutations are unknown. We aimed to investigate the frequency of BRAF V600 mutations in a cohort of Japanese patients with melanoma and determine the relationship between mutations and clinical/pathologic features. DNA was extracted from 80 formalin-fixed, paraffin-embedded tumours from individuals diagnosed with melanoma. BRAF V600 mutations were detected using the Cobas 4800 System with z480 Analyzer and Cobas 4800 BRAF V600 Mutation Test reagents. BRAF V600 mutations were detected in 41.8% of tested tumours, with an invalid rate of 1.3%. The mutation rate was more than 60% in patients aged less than 60 years and more than 36% in patients with stage III/IV disease. No sex difference in the mutation rate was observed. BRAF V600 mutations were detected in 18.8% of acral lentiginous melanomas (ALMs), 64.7% of superficial spreading melanomas, 50.0% of lentigo maligna melanomas and 20.0% of nodular melanomas. Although the mutation rate was low in ALMs, 36.4% were mutation positive at stage III/IV compared with 9.5% at stage I/II. This study confirmed associations among BRAF V600 mutations, pathological features and subtypes of melanoma. BRAF V600 mutations were more frequent in late-stage ALMs than in early-stage ALMs. Superficial spreading melanomas had similar mutation rates at all stages. These insights suggest improved treatment predictions for stage III/IV melanoma patients. PMID:25051202

  16. BRAF V600 mutations and pathological features in Japanese melanoma patients.

    PubMed

    Yamazaki, Naoya; Tanaka, Ryota; Tsutsumida, Arata; Namikawa, Kenjiro; Eguchi, Hironobu; Omata, Wataru; Oashi, Kohei; Ogawa, Toru; Hayashi, Amiko; Nakamura, Noriyuki; Tsuta, Koji

    2015-02-01

    Ultraviolet radiation is a risk factor for BRAF V600 mutations frequently found in melanomas that cause constitutive BRAF activation. Primary sites of melanoma and the frequency of BRAF mutations might differ between races. Melanoma is rare in Japan (1500-2000 cases/year compared with 132 000/year worldwide) and the frequency and distribution of BRAF V600 mutations are unknown. We aimed to investigate the frequency of BRAF V600 mutations in a cohort of Japanese patients with melanoma and determine the relationship between mutations and clinical/pathologic features. DNA was extracted from 80 formalin-fixed, paraffin-embedded tumours from individuals diagnosed with melanoma. BRAF V600 mutations were detected using the Cobas 4800 System with z480 Analyzer and Cobas 4800 BRAF V600 Mutation Test reagents. BRAF V600 mutations were detected in 41.8% of tested tumours, with an invalid rate of 1.3%. The mutation rate was more than 60% in patients aged less than 60 years and more than 36% in patients with stage III/IV disease. No sex difference in the mutation rate was observed. BRAF V600 mutations were detected in 18.8% of acral lentiginous melanomas (ALMs), 64.7% of superficial spreading melanomas, 50.0% of lentigo maligna melanomas and 20.0% of nodular melanomas. Although the mutation rate was low in ALMs, 36.4% were mutation positive at stage III/IV compared with 9.5% at stage I/II. This study confirmed associations among BRAF V600 mutations, pathological features and subtypes of melanoma. BRAF V600 mutations were more frequent in late-stage ALMs than in early-stage ALMs. Superficial spreading melanomas had similar mutation rates at all stages. These insights suggest improved treatment predictions for stage III/IV melanoma patients. PMID:25051202

  17. Radiation-induced mutations and plant breeding

    SciTech Connect

    Naqvi, S.H.M.

    1985-01-01

    Ionizing radiation could cause genetic changes in an organism and could modify gene linkages. The induction of mutation through radiation is random and the probability of getting the desired genetic change is low but can be increased by manipulating different parameters such as dose rate, physical conditions under which the material has been irradiated, etc. Induced mutations have been used as a supplement to conventional plant breeding, particularly for creating genetic variability for specific characters such as improved plant structure, pest and disease resistance, and desired changes in maturity period; more than 200 varieties of crop plants have been developed by this technique. The Pakistan Atomic Energy Commission has used this technique fruitfully to evolve better germplasm in cotton, rice, chickpea, wheat and mungbean; some of the mutants have become popular commercial varieties. This paper describes some uses of radiation induced mutations and the results achieved in Pakistan so far.

  18. Pax5 loss imposes a reversible differentiation block in B-progenitor acute lymphoblastic leukemia

    PubMed Central

    Liu, Grace J.; Cimmino, Luisa; Jude, Julian G.; Hu, Yifang; Witkowski, Matthew T.; McKenzie, Mark D.; Kartal-Kaess, Mutlu; Best, Sarah A.; Tuohey, Laura; Liao, Yang; Shi, Wei; Mullighan, Charles G.; Farrar, Michael A.; Nutt, Stephen L.; Smyth, Gordon K.; Zuber, Johannes; Dickins, Ross A.

    2014-01-01

    Loss-of-function mutations in hematopoietic transcription factors including PAX5 occur in most cases of B-progenitor acute lymphoblastic leukemia (B-ALL), a disease characterized by the accumulation of undifferentiated lymphoblasts. Although PAX5 mutation is a critical driver of B-ALL development in mice and humans, it remains unclear how its loss contributes to leukemogenesis and whether ongoing PAX5 deficiency is required for B-ALL maintenance. Here we used transgenic RNAi to reversibly suppress endogenous Pax5 expression in the hematopoietic compartment of mice, which cooperates with activated signal transducer and activator of transcription 5 (STAT5) to induce B-ALL. In this model, restoring endogenous Pax5 expression in established B-ALL triggers immunophenotypic maturation and durable disease remission by engaging a transcriptional program reminiscent of normal B-cell differentiation. Notably, even brief Pax5 restoration in B-ALL cells causes rapid cell cycle exit and disables their leukemia-initiating capacity. These and similar findings in human B-ALL cell lines establish that Pax5 hypomorphism promotes B-ALL self-renewal by impairing a differentiation program that can be re-engaged despite the presence of additional oncogenic lesions. Our results establish a causal relationship between the hallmark genetic and phenotypic features of B-ALL and suggest that engaging the latent differentiation potential of B-ALL cells may provide new therapeutic entry points. PMID:24939936

  19. Health economic burden that wounds impose on the National Health Service in the UK

    PubMed Central

    Guest, Julian F; Ayoub, Nadia; McIlwraith, Tracey; Uchegbu, Ijeoma; Gerrish, Alyson; Weidlich, Diana; Vowden, Kathryn; Vowden, Peter

    2015-01-01

    Objective To estimate the prevalence of wounds managed by the UK's National Health Service (NHS) in 2012/2013 and the annual levels of healthcare resource use attributable to their management and corresponding costs. Methods This was a retrospective cohort analysis of the records of patients in The Health Improvement Network (THIN) Database. Records of 1000 adult patients who had a wound in 2012/2013 (cases) were randomly selected and matched with 1000 patients with no history of a wound (controls). Patients’ characteristics, wound-related health outcomes and all healthcare resource use were quantified and the total NHS cost of patient management was estimated at 2013/2014 prices. Results Patients’ mean age was 69.0 years and 45% were male. 76% of patients presented with a new wound in the study year and 61% of wounds healed during the study year. Nutritional deficiency (OR 0.53; p<0.001) and diabetes (OR 0.65; p<0.001) were independent risk factors for non-healing. There were an estimated 2.2 million wounds managed by the NHS in 2012/2013. Annual levels of resource use attributable to managing these wounds and associated comorbidities included 18.6 million practice nurse visits, 10.9 million community nurse visits, 7.7 million GP visits and 3.4 million hospital outpatient visits. The annual NHS cost of managing these wounds and associated comorbidities was £5.3 billion. This was reduced to between £5.1 and £4.5 billion after adjusting for comorbidities. Conclusions Real world evidence highlights wound management is predominantly a nurse-led discipline. Approximately 30% of wounds lacked a differential diagnosis, indicative of practical difficulties experienced by non-specialist clinicians. Wounds impose a substantial health economic burden on the UK's NHS, comparable to that of managing obesity (£5.0 billion). Clinical and economic benefits could accrue from improved systems of care and an increased awareness of the impact that wounds impose on patients

  20. Deafness gene mutations in newborns in Beijing.

    PubMed

    Han, Shujing; Yang, Xiaojian; Zhou, Yi; Hao, Jinsheng; Shen, Adong; Xu, Fang; Chu, Ping; Jin, Yaqiong; Lu, Jie; Guo, Yongli; Shi, Jin; Liu, Haihong; Ni, Xin

    2016-05-01

    Objective To determine the incidence of congenital hearing loss (HL) in newborns by the rate of deafness-related genetic mutations. Design Clinical study of consecutive newborns in Beijing using allele-specific polymerase chain reaction-based universal array. Study sample This study tested 37 573 newborns within 3 days after birth, including nine sites in four genes: GJB2 (35 del G, 176 del 16, 235 del C, 299 del AT), SLC26A4 (IVS7-2 A > G, 2168 A > G), MTRNR1 (1555 A > G, 1494 C > T), and GJB3 (538 C > T). The birth condition of infants was also recorded. Results Of 37 573 newborns, 1810 carried pathogenic mutations, or 4.817%. The carrier rates of GJB2 (35 del G, 176 del 16, 235 del C, 299 del AT), GJB3 (538 C > T), SLC26A4 (IVS7-2 A > G, 2168 A > G), and MTRNR1 (1555 A > G, 1494 C > T) mutations were 0.005%, 0.104%, 1.924%, 0.551%, 0.295%, 0.253%, 1.387%, 0.024%, and 0.274%, respectively. Logistic regression analysis indicated no statistically significant relationship between mutations and infant sex, premature delivery, twin status, or birth weight. Conclusions The 235delC GJB2 mutation was the most frequent deafness-related mutation in the Chinese population. Genetic screening for the deafness gene will help detect more cases of newborn congenital HL than current screening practices. PMID:26766211