Science.gov

Sample records for imposed mutation rate

  1. 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

  2. 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.

  3. Mutation rate evolution in replicator dynamics.

    PubMed

    Allen, Benjamin; Rosenbloom, Daniel I Scholes

    2012-11-01

    The mutation rate of an organism is itself evolvable. In stable environments, if faithful replication is costless, theory predicts that mutation rates will evolve to zero. However, positive mutation rates can evolve in novel or fluctuating environments, as analytical and empirical studies have shown. Previous work on this question has focused on environments that fluctuate independently of the evolving population. Here we consider fluctuations that arise from frequency-dependent selection in the evolving population itself. We investigate how the dynamics of competing traits can induce selective pressure on the rates of mutation between these traits. To address this question, we introduce a theoretical framework combining replicator dynamics and adaptive dynamics. We suppose that changes in mutation rates are rare, compared to changes in the traits under direct selection, so that the expected evolutionary trajectories of mutation rates can be obtained from analysis of pairwise competition between strains of different rates. Depending on the nature of frequency-dependent trait dynamics, we demonstrate three possible outcomes of this competition. First, if trait frequencies are at a mutation-selection equilibrium, lower mutation rates can displace higher ones. Second, if trait dynamics converge to a heteroclinic cycle-arising, for example, from "rock-paper-scissors" interactions-mutator strains succeed against non-mutators. Third, in cases where selection alone maintains all traits at positive frequencies, zero and nonzero mutation rates can coexist indefinitely. Our second result suggests that relatively high mutation rates may be observed for traits subject to cyclical frequency-dependent dynamics.

  4. 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.

  5. Elevated germline mutation rate in teenage fathers

    PubMed Central

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

    2015-01-01

    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

  6. Aeolian dune field geomorphology modulates the stabilization rate imposed by climate

    NASA Astrophysics Data System (ADS)

    Barchyn, Thomas E.; Hugenholtz, Chris H.

    2012-06-01

    The activity of inland aeolian dune fields is typically related to the external forcing imposed by climate: active (bare) dunes are associated with windy and/or arid settings, and inactive (vegetated) dunes are associated with humid and/or calm environments. When a climate shifts the dune field reacts; however, the behavior, rate, and potential impact of diverse dune geomorphologies on these transitions are poorly understood. Here, we use a numerical model to systematically investigate the influence of dune field geomorphology (dune height, organization and collisions) on the time a dune field takes to stabilize. To generate diverse initial un-vegetated dune field geomorphologies under unidirectional winds, we varied pre-stabilization growth time and initial sediment thickness (termed equivalent sediment thickness: EST). Following dune field development from a flat bed, we introduced vegetation (simulating a climate shift) and transport-vegetation feedbacks slowly stabilized the dune fields. Qualitatively, very young and immature dune fields stabilized quickly, whereas older dune fields took longer. Dune fields with greater EST stabilized quicker than those with less EST. Larger dunes stabilized quicker because of low celerity, which facilitated higher vegetation growth rates. Extended stabilization times were associated with the extension of parabolic dunes. Dune-dune collisions resulted in premature stabilization; the frequency of collisions was related to dune spacing. Quantitatively comparing the distribution of deposition rates in a dune field to the deposition tolerance of vegetation provides a promising predictor of relative stabilization time. Dune fields with deposition rates dominantly above the deposition tolerance of vegetation advanced unimpeded and prolonged stabilization as parabolic dunes. Paleoenvironmental reconstructions or predictions of dune field activity should not assume that dune activity directly translates to climate, considerable lags to

  7. Why Are Phenotypic Mutation Rates Much Higher Than Genotypic Mutation Rates?

    PubMed Central

    Bürger, Reinhard; Willensdorfer, Martin; Nowak, Martin A.

    2006-01-01

    The evolution of genotypic mutation rates has been investigated in numerous theoretical and experimental studies. Mutations, however, occur not only when copying DNA, but also when building the phenotype, especially when translating and transcribing DNA to RNA and protein. Here we study the effect of such phenotypic mutations. We find a maximum phenotypic mutation rate, umax, that is compatible with maintaining a certain function of the organism. This may be called a phenotypic error threshold. In particular, we find a minimum phenotypic mutation rate, umin, with the property that there is (nearly) no selection pressure to reduce the rate of phenotypic mutations below this value. If there is a cost for lowering the phenotypic mutation rate, then umin is close to the optimum phenotypic mutation rate that maximizes the fitness of the organism. In our model, there is selective pressure to decrease the rate of genotypic mutations to zero, but to decrease the rate of phenotypic mutations only to a positive value. Despite its simplicity, our model can explain part of the huge difference between genotypic and phenotypic mutation rates that is observed in nature. The relevant data are summarized. PMID:16143614

  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. 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.

  10. 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.

  11. The evolution of bacterial mutation rates under simultaneous selection by interspecific and social parasitism.

    PubMed

    O'Brien, Siobhán; Rodrigues, Antonio M M; Buckling, Angus

    2013-12-22

    Many bacterial populations harbour substantial numbers of hypermutable bacteria, in spite of hypermutation being associated with deleterious mutations. One reason for the persistence of hypermutators is the provision of novel mutations, enabling rapid adaptation to continually changing environments, for example coevolving virulent parasites. However, hypermutation also increases the rate at which intraspecific parasites (social cheats) are generated. Interspecific and intraspecific parasitism are therefore likely to impose conflicting selection pressure on mutation rate. Here, we combine theory and experiments to investigate how simultaneous selection from inter- and intraspecific parasitism affects the evolution of bacterial mutation rates in the plant-colonizing bacterium Pseudomonas fluorescens. Both our theoretical and experimental results suggest that phage presence increases and selection for public goods cooperation (the production of iron-scavenging siderophores) decreases selection for mutator bacteria. Moreover, phages imposed a much greater growth cost than social cheating, and when both selection pressures were imposed simultaneously, selection for cooperation did not affect mutation rate evolution. Given the ubiquity of infectious phages in the natural environment and clinical infections, our results suggest that phages are likely to be more important than social interactions in determining mutation rate evolution.

  12. The evolution of bacterial mutation rates under simultaneous selection by interspecific and social parasitism.

    PubMed

    O'Brien, Siobhán; Rodrigues, Antonio M M; Buckling, Angus

    2013-12-22

    Many bacterial populations harbour substantial numbers of hypermutable bacteria, in spite of hypermutation being associated with deleterious mutations. One reason for the persistence of hypermutators is the provision of novel mutations, enabling rapid adaptation to continually changing environments, for example coevolving virulent parasites. However, hypermutation also increases the rate at which intraspecific parasites (social cheats) are generated. Interspecific and intraspecific parasitism are therefore likely to impose conflicting selection pressure on mutation rate. Here, we combine theory and experiments to investigate how simultaneous selection from inter- and intraspecific parasitism affects the evolution of bacterial mutation rates in the plant-colonizing bacterium Pseudomonas fluorescens. Both our theoretical and experimental results suggest that phage presence increases and selection for public goods cooperation (the production of iron-scavenging siderophores) decreases selection for mutator bacteria. Moreover, phages imposed a much greater growth cost than social cheating, and when both selection pressures were imposed simultaneously, selection for cooperation did not affect mutation rate evolution. Given the ubiquity of infectious phages in the natural environment and clinical infections, our results suggest that phages are likely to be more important than social interactions in determining mutation rate evolution. PMID:24197408

  13. Measurements of mutation rates in B lymphocytes.

    PubMed

    Wabl, M; Jäck, H M; Meyer, J; Beck-Engeser, G; von Borstel, R C; Steinberg, C M

    1987-04-01

    It is established that somatic mutation is an important source of antibody diversity in vivo. It is also established that Igh-V gene segments are hypermutable in vitro. This is not a completely satisfactory situation. While there is no reason to believe that Igh-V genes are not hypermutable in vivo as well, direct experimental evidence is lacking. Perhaps experiments with transgenic mice will soon fill this gap. It is not so clear how much higher than normal the rate of hypermutation is. As far as we are aware, there are no direct measurements of mutation rates per base pair per cell generation in mammals, certainly not for lymphocyte cell lines. For a variety of reasons, it is difficult to measure very low mutation rates. The general consensus is that the normal rate should be somewhere between 10(-10) and 10(-12) mutations per base pair per cell generation. Therefore, an experiment designed to directly determine a rate using the compartmentalization test would involve hundreds of cultures, each containing at least 10(9) cells. It is not a trivial problem to find one or a few mutants among so many cells. It is simple to study mutation to resistance to a drug, for example, ouabain or azaguanine, but, as we discussed, there are technical and conceptual pitfalls. The vast excess of dead cells influences the growth of a few mutant cells, particularly in lymphocyte cell lines. Even if this problem could be solved, the mutation rate so obtained would be "per gene(s)" and not "per base pair". The problems associated with cytotoxic agents can be avoided by immunofluorescence methods in conjunction with selective cloning or cell sorting. Using these techniques, we have carried out extensive experiments to determine whether the immunoglobulin mutator system acts, at least partially, on genetic elements other than those in or near the heavy chain variable region gene segment. For an opal termination codon in a heavy chain constant region gene segment, the rate of reversion

  14. 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

  15. Constraints on the Martian cratering rate imposed by the SNC meteorites and Vallis Marineris layered deposits

    NASA Astrophysics Data System (ADS)

    Brandenburg, J. E.

    Following two independent lines of evidence -- estimates of the age and formation time of a portion of the Martian geologic column exposed in the layered deposits and the crystallization and ejection ages of the SNC meteorites -- it appears that the Martian cratering rate must be double the lunar rate or even higher. This means models such as NHII or NHIII (Neukum and Hiller models II and III), which estimate the Martian cratering rate as being several times lunar are probably far closer to reality on Mars than lunar rates. The effect of such a shift is profound: Mars is transformed from a rather Moon-like place into a planet with vigorous dynamics, multiple large impacts, erosion, floods, and volcanism throughout its history. A strong shift upward in cratering rates on Mars apparently solves some glaring problems; however, it creates others. The period of time during which Earth-like atmospheric conditions existed, the liquid water era on Mars, persists in NHIII up to only 0.5 b.y. ago. Scenarios of extended Earth-like conditions on Mars have been discounted in the past because they would have removed many of the craters from the early bombardment era found in the south. It does appear that some process of crater removal was quite vigorous in the north during Mars' past. Evidence exists that the northern plains may have been the home of long-lived seas or perhaps even a paleo-ocean, so models exist for highly localized destruction of craters in the north. However, the question of how the ancient crater population could be preserved in the south under a long liquid-water era found in any high-cratering-rate models is a serious question that must be addressed. It does appear to be a higher-order problem because it involves low-energy dynamics acting in localized areas, i.e., erosion of craters in the south of Mars, whereas the two problems with the low-cratering-rate models involve high-energy events acting over large areas: the formation of the Vallis Marineris

  16. From molecular genetics to phylodynamics: evolutionary relevance of mutation rates across viruses.

    PubMed

    Sanjuán, Rafael

    2012-01-01

    Although evolution is a multifactorial process, theory posits that the speed of molecular evolution should be directly determined by the rate at which spontaneous mutations appear. To what extent these two biochemical and population-scale processes are related in nature, however, is largely unknown. Viruses are an ideal system for addressing this question because their evolution is fast enough to be observed in real time, and experimentally-determined mutation rates are abundant. This article provides statistically supported evidence that the mutation rate determines molecular evolution across all types of viruses. Properties of the viral genome such as its size and chemical composition are identified as major determinants of these rates. Furthermore, a quantitative analysis reveals that, as expected, evolution rates increase linearly with mutation rates for slowly mutating viruses. However, this relationship plateaus for fast mutating viruses. A model is proposed in which deleterious mutations impose an evolutionary speed limit and set an extinction threshold in nature. The model is consistent with data from replication kinetics, selection strength and chemical mutagenesis studies.

  17. The evolution of low mutation rates in experimental mutator populations of Saccharomyces cerevisiae.

    PubMed

    McDonald, Michael J; Hsieh, Yu-Ying; Yu, Yen-Hsin; Chang, Shang-Lin; Leu, Jun-Yi

    2012-07-10

    Mutation is the source of both beneficial adaptive variation and deleterious genetic load, fueling the opposing selective forces than shape mutation rate evolution. This dichotomy is well illustrated by the evolution of the mutator phenotype, a genome-wide 10- to 100-fold increase in mutation rate. This phenotype has often been observed in clonally expanding populations exposed to novel or frequently changing conditions. Although studies of both experimental and natural populations have shed light on the evolutionary forces that lead to the spread of the mutator allele through a population, significant gaps in our understanding of mutator evolution remain. Here we use an experimental evolution approach to investigate the conditions required for the evolution of a reduction in mutation rate and the mechanisms by which populations tolerate the accumulation of deleterious mutations. We find that after ∼6,700 generations, four out of eight experimental mutator lines had evolved a decreased mutation rate. We provide evidence that the accumulation of deleterious mutations leads to selection for reduced mutation rate clones in populations of mutators. Finally, we test the long-term consequences of the mutator phenotype, finding that mutator lines follow different evolutionary trajectories, some of which lead to drug resistance.

  18. 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

  19. MUTATION RATES OF BACTERIA IN STEADY STATE POPULATIONS

    PubMed Central

    Fox, Maurice S.

    1955-01-01

    The breeder and the chemostat have been used to measure mutation rates for two mutations under a variety of steady state growth conditions. These rates have been found to be higher in complex medium than in minimal (F) medium. The effects of changes in nutritional conditions on these high rates have been described. In addition, the mutation rates at short generation times, in complex medium, have been shown to decrease with increasing generation time. PMID:13271726

  20. 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.

  1. 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

  2. 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

  3. 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

  4. Genomic mutation rates that neutralize adaptive evolution and natural selection.

    PubMed

    Gerrish, Philip J; Colato, Alexandre; Sniegowski, Paul D

    2013-08-01

    When mutation rates are low, natural selection remains effective, and increasing the mutation rate can give rise to an increase in adaptation rate. When mutation rates are high to begin with, however, increasing the mutation rate may have a detrimental effect because of the overwhelming presence of deleterious mutations. Indeed, if mutation rates are high enough: (i) adaptive evolution may be neutralized, resulting in a zero (or negative) adaptation rate despite the continued availability of adaptive and/or compensatory mutations, or (ii) natural selection may be neutralized, because the fitness of lineages bearing adaptive and/or compensatory mutations--whether established or newly arising--is eroded by excessive mutation, causing such lineages to decline in frequency. We apply these two criteria to a standard model of asexual adaptive evolution and derive mathematical expressions--some new, some old in new guise--delineating the mutation rates under which either adaptive evolution or natural selection is neutralized. The expressions are simple and require no a priori knowledge of organism- and/or environment-specific parameters. Our discussion connects these results to each other and to previous theory, showing convergence or equivalence of the different results in most cases.

  5. Genomic mutation rates that neutralize adaptive evolution and natural selection.

    PubMed

    Gerrish, Philip J; Colato, Alexandre; Sniegowski, Paul D

    2013-08-01

    When mutation rates are low, natural selection remains effective, and increasing the mutation rate can give rise to an increase in adaptation rate. When mutation rates are high to begin with, however, increasing the mutation rate may have a detrimental effect because of the overwhelming presence of deleterious mutations. Indeed, if mutation rates are high enough: (i) adaptive evolution may be neutralized, resulting in a zero (or negative) adaptation rate despite the continued availability of adaptive and/or compensatory mutations, or (ii) natural selection may be neutralized, because the fitness of lineages bearing adaptive and/or compensatory mutations--whether established or newly arising--is eroded by excessive mutation, causing such lineages to decline in frequency. We apply these two criteria to a standard model of asexual adaptive evolution and derive mathematical expressions--some new, some old in new guise--delineating the mutation rates under which either adaptive evolution or natural selection is neutralized. The expressions are simple and require no a priori knowledge of organism- and/or environment-specific parameters. Our discussion connects these results to each other and to previous theory, showing convergence or equivalence of the different results in most cases. PMID:23720539

  6. Normal mutation rate variants arise in a Mutator (Mut S) Escherichia coli population.

    PubMed

    Turrientes, María-Carmen; Baquero, Fernando; Levin, Bruce R; Martínez, José-Luis; Ripoll, Aida; González-Alba, José-María; Tobes, Raquel; Manrique, Marina; Baquero, Maria-Rosario; Rodríguez-Domínguez, Mario-José; Cantón, Rafael; Galán, Juan-Carlos

    2013-01-01

    The rate at which mutations are generated is central to the pace of evolution. Although this rate is remarkably similar amongst all cellular organisms, bacterial strains with mutation rates 100 fold greater than the modal rates of their species are commonly isolated from natural sources and emerge in experimental populations. Theoretical studies postulate and empirical studies teort the hypotheses that these "mutator" strains evolved in response to selection for elevated rates of generation of inherited variation that enable bacteria to adapt to novel and/or rapidly changing environments. Less clear are the conditions under which selection will favor reductions in mutation rates. Declines in rates of mutation for established populations of mutator bacteria are not anticipated if such changes are attributed to the costs of augmented rates of generation of deleterious mutations. Here we report experimental evidence of evolution towards reduced mutation rates in a clinical isolate of Escherichia coli with an hyper-mutable phenotype due a deletion in a mismatch repair gene, (ΔmutS). The emergence in a ΔmutS background of variants with mutation rates approaching those of the normal rates of strains carrying wild-type MutS was associated with increase in fitness with respect to ancestral strain. We postulate that such an increase in fitness could be attributed to the emergence of mechanisms driving a permanent "aerobic style of life", the negative consequence of this behavior being regulated by the evolution of mechanisms protecting the cell against increased endogenous oxidative radicals involved in DNA damage, and thus reducing mutation rate. Gene expression assays and full sequencing of evolved mutator and normo-mutable variants supports the hypothesis. In conclusion, we postulate that the observed reductions in mutation rate are coincidental to, rather than, the selective force responsible for this evolution.

  7. 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

  8. 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.

  9. 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.

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

    PubMed Central

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

    2015-01-01

    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

  11. 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.

  12. Elevated Mutation Rate during Meiosis in Saccharomyces cerevisiae

    PubMed Central

    Rattray, Alison; Santoyo, Gustavo; Shafer, Brenda; Strathern, Jeffrey N.

    2015-01-01

    Mutations accumulate during all stages of growth, but only germ line mutations contribute to evolution. While meiosis contributes to evolution by reassortment of parental alleles, we show here that the process itself is inherently mutagenic. We have previously shown that the DNA synthesis associated with repair of a double-strand break is about 1000-fold less accurate than S-phase synthesis. Since the process of meiosis involves many programmed DSBs, we reasoned that this repair might also be mutagenic. Indeed, in the early 1960′s Magni and Von Borstel observed elevated reversion of recessive alleles during meiosis, and found that the revertants were more likely to be associated with a crossover than non-revertants, a process that they called “the meiotic effect.” Here we use a forward mutation reporter (CAN1 HIS3) placed at either a meiotic recombination coldspot or hotspot near the MAT locus on Chromosome III. We find that the increased mutation rate at CAN1 (6 to 21 –fold) correlates with the underlying recombination rate at the locus. Importantly, we show that the elevated mutation rate is fully dependent upon Spo11, the protein that introduces the meiosis specific DSBs. To examine associated recombination we selected for random spores with or without a mutation in CAN1. We find that the mutations isolated this way show an increased association with recombination (crossovers, loss of crossover interference and/or increased gene conversion tracts). Polζ appears to contribute about half of the mutations induced during meiosis, but is not the only source of mutations for the meiotic effect. We see no difference in either the spectrum or distribution of mutations between mitosis and meiosis. The correlation of hotspots with elevated mutagenesis provides a mechanism for organisms to control evolution rates in a gene specific manner. PMID:25569256

  13. Elevated mutation rate during meiosis in Saccharomyces cerevisiae.

    PubMed

    Rattray, Alison; Santoyo, Gustavo; Shafer, Brenda; Strathern, Jeffrey N

    2015-01-01

    Mutations accumulate during all stages of growth, but only germ line mutations contribute to evolution. While meiosis contributes to evolution by reassortment of parental alleles, we show here that the process itself is inherently mutagenic. We have previously shown that the DNA synthesis associated with repair of a double-strand break is about 1000-fold less accurate than S-phase synthesis. Since the process of meiosis involves many programmed DSBs, we reasoned that this repair might also be mutagenic. Indeed, in the early 1960's Magni and Von Borstel observed elevated reversion of recessive alleles during meiosis, and found that the revertants were more likely to be associated with a crossover than non-revertants, a process that they called "the meiotic effect." Here we use a forward mutation reporter (CAN1 HIS3) placed at either a meiotic recombination coldspot or hotspot near the MAT locus on Chromosome III. We find that the increased mutation rate at CAN1 (6 to 21 -fold) correlates with the underlying recombination rate at the locus. Importantly, we show that the elevated mutation rate is fully dependent upon Spo11, the protein that introduces the meiosis specific DSBs. To examine associated recombination we selected for random spores with or without a mutation in CAN1. We find that the mutations isolated this way show an increased association with recombination (crossovers, loss of crossover interference and/or increased gene conversion tracts). Polζ appears to contribute about half of the mutations induced during meiosis, but is not the only source of mutations for the meiotic effect. We see no difference in either the spectrum or distribution of mutations between mitosis and meiosis. The correlation of hotspots with elevated mutagenesis provides a mechanism for organisms to control evolution rates in a gene specific manner.

  14. 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

  15. 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

  16. Rate of spontaneous mutation at human loci encoding protein structure.

    PubMed Central

    Neel, J V; Mohrenweiser, H W; Meisler, M H

    1980-01-01

    The techniques of electrophoresis were used in a search for evidence of mutation affecting protein structure, the indicators being hemoglobin and a set of serum proteins and erythrocyte enzymes. Among 94,796 locus tests on Amerindians from Central and South America, there was no evidence for mutation. Among 105,649 locus tests on newborn infants in Ann Arbor, Michigan, there was also no evidence for mutation. We have previously failed to encounter any mutations in a series of 208,196 locus tests involving Japanese children [Neel, J. V., Satoh, C., Hamilton, H. B., Otake, M., Goriki, K., Kageoka, T., Fugita, M., Neriishi, S & Asakawa,J. (1980) Proc. Natl. Acad. Sci. USA 77, 4221-4225], and H. Harris, D. A. Hopkinson, and E. B. Robson [(1974) Ann. Hum. Genet. 37, 237-253] found no mutations in 113,478 locus tests on inhabitants of the United Kingdom. This failure to demonstrate any mutations of this type in a total of 522,119 locus tests excludes, at the 95% level of probability, a mutation rate greater than 0.6 X 10(-5)/locus per generation in this combination of populations. PMID:6934530

  17. Selection of a Mutant of Escherichia coli Which Has High Mutation Rates

    PubMed Central

    Helling, Robert B.

    1968-01-01

    A mutation which causes high mutation rates in all other loci tested was induced with nitrosoguanidine and was selected through the ability of the progeny of such mutant cells to mutate to streptomycin resistance at a higher rate than the wild-type cells. This mutation (mut-2) and the Treffers' mutation (mutT1) mapped at approximately the same position to the right of leu. Specificity studies showed that the two mutations differ in rates of mutation produced. PMID:4879569

  18. Unbiased Estimation of Mutation Rates under Fluctuating Final Counts

    PubMed Central

    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

  19. A revised indirect estimate of mutation rates in Amerindians.

    PubMed Central

    Neel, J V; Mohrenweiser, H W; Rothman, E D; Naidu, J M

    1986-01-01

    We have previously raised the possibility that the mutation rate resulting in rare electrophoretic variants is higher in tribal/tropical-dwelling/nonindustrialized societies than in civilized/temperate-dwelling/industrialized societies. Here, we report the results of examining 11 additional proteins for the occurrence of rare electrophoretic variants in 10 Amerindian tribes, for a total of 8,968 determinations and a total of 17,648 locus tests. When these data are combined with the results of all our previous similar studies of Amerindians, a total of 272,298 polypeptides, the products of 43 different loci, have been examined for the occurrence of rare electrophoretic variants. On the assumption that these variants are maintained by mutation pressure and are essentially neutral in their phenotypic effects, we have calculated by three different approaches that it requires an average mutation rate of 1.3 X 10(-5)/locus per generation to maintain the observed variant frequency. Concurrently, we are reporting elsewhere that a direct estimate of the mutation rate resulting in electromorphs in various studies of civilized industrialized populations is 0.3 X 10(-5)/locus per generation. Although this difference appears to have statistical significance, the nonquantifiable uncertainties to both approaches are such that our enthusiasm for a true difference in mutation rates between the two types of populations has diminished. However, even the lower of these estimates, when corrected for all the types of genetic variation that electrophoresis does not detect, implies total locus and gametic mutation rates well above those which in the past have dominated genetic thinking. PMID:3459353

  20. Nucleotide sequence determines the accelerated rate of point mutations.

    PubMed

    Kini, R Manjunatha; Chinnasamy, Arunkumar

    2010-09-01

    Although the theory of evolution was put forth about 150 years ago our understanding of how molecules drive evolution remains poor. It is well-established that proteins evolve at different rates, essentially based on their functional role and three-dimensional structure. However, the highly variable rates of evolution of different proteins - especially the rapidly evolving ones - within a single organism are poorly understood. Using examples of genes for fast-evolving toxins and human hereditary diseases, we show for the first time that specific nucleotide sequences appear to determine point mutation rates. Based on mutation rates, we have classified triplets (not just codons) into stable, unstable and intermediate groups. Toxin genes contain a relatively higher percentage of unstable triplets in their exons compared to introns, whereas non-toxin genes contain a higher percentage of unstable triplets in their introns. Thus the distribution of stable and unstable triplets is correlated with and may explain the accelerated evolution of point mutations in toxins. Similarly, at the genomic level, lower organisms with genes that evolve faster contain a higher percentage of unstable triplets compared to higher organisms. These findings show that mutation rates of proteins, and hence of the organisms, are DNA sequence-dependent and thus provide a proximate mechanism of evolution at the molecular level. PMID:20362603

  1. Germline mutation rates and the long-term phenotypic effects of mutation accumulation in wild-type laboratory mice and mutator mice.

    PubMed

    Uchimura, Arikuni; Higuchi, Mayumi; Minakuchi, Yohei; Ohno, Mizuki; Toyoda, Atsushi; Fujiyama, Asao; Miura, Ikuo; Wakana, Shigeharu; Nishino, Jo; Yagi, Takeshi

    2015-08-01

    The germline mutation rate is an important parameter that affects the amount of genetic variation and the rate of evolution. However, neither the rate of germline mutations in laboratory mice nor the biological significance of the mutation rate in mammalian populations is clear. Here we studied genome-wide mutation rates and the long-term effects of mutation accumulation on phenotype in more than 20 generations of wild-type C57BL/6 mice and mutator mice, which have high DNA replication error rates. We estimated the base-substitution mutation rate to be 5.4 × 10(-9) (95% confidence interval = 4.6 × 10(-9)-6.5 × 10(-9)) per nucleotide per generation in C57BL/6 laboratory mice, about half the rate reported in humans. The mutation rate in mutator mice was 17 times that in wild-type mice. Abnormal phenotypes were 4.1-fold more frequent in the mutator lines than in the wild-type lines. After several generations, the mutator mice reproduced at substantially lower rates than the controls, exhibiting low pregnancy rates, lower survival rates, and smaller litter sizes, and many of the breeding lines died out. These results provide fundamental information about mouse genetics and reveal the impact of germline mutation rates on phenotypes in a mammalian population.

  2. Germline mutation rates and the long-term phenotypic effects of mutation accumulation in wild-type laboratory mice and mutator mice

    PubMed Central

    Uchimura, Arikuni; Higuchi, Mayumi; Minakuchi, Yohei; Ohno, Mizuki; Toyoda, Atsushi; Fujiyama, Asao; Miura, Ikuo; Wakana, Shigeharu; Nishino, Jo; Yagi, Takeshi

    2015-01-01

    The germline mutation rate is an important parameter that affects the amount of genetic variation and the rate of evolution. However, neither the rate of germline mutations in laboratory mice nor the biological significance of the mutation rate in mammalian populations is clear. Here we studied genome-wide mutation rates and the long-term effects of mutation accumulation on phenotype in more than 20 generations of wild-type C57BL/6 mice and mutator mice, which have high DNA replication error rates. We estimated the base-substitution mutation rate to be 5.4 × 10−9 (95% confidence interval = 4.6 × 10−9–6.5 × 10−9) per nucleotide per generation in C57BL/6 laboratory mice, about half the rate reported in humans. The mutation rate in mutator mice was 17 times that in wild-type mice. Abnormal phenotypes were 4.1-fold more frequent in the mutator lines than in the wild-type lines. After several generations, the mutator mice reproduced at substantially lower rates than the controls, exhibiting low pregnancy rates, lower survival rates, and smaller litter sizes, and many of the breeding lines died out. These results provide fundamental information about mouse genetics and reveal the impact of germline mutation rates on phenotypes in a mammalian population. PMID:26129709

  3. Dynamic fitness landscapes: expansions for small mutation rates

    NASA Astrophysics Data System (ADS)

    Wilke, Claus O.; Ronnewinkel, Christopher

    2001-02-01

    We study the evolution of asexual microorganisms with small mutation rate in fluctuating environments, and develop techniques that allow us to expand the formal solution of the evolution equations to first order in the mutation rate. Our method can be applied to both discrete time and continuous time systems. While the behavior of continuous time systems is dominated by the average fitness landscape for small mutation rates, in discrete time systems it is instead the geometric mean fitness that determines the system's properties. In both cases, we find that in situations in which the arithmetic (resp. geometric) mean of the fitness landscape is degenerate, regions in which the fitness fluctuates around the mean value present a selective advantage over regions in which the fitness stays at the mean. This effect is caused by the vanishing genetic diffusion at low mutation rates. In the absence of strong diffusion, a population can stay close to a fluctuating peak when the peak's height is below average, and take advantage of the peak when its height is above average.

  4. Prospects for DNA methods to measure human heritable mutation rates

    SciTech Connect

    Mendelsohn, M.L.

    1985-06-14

    A workshop cosponsored by ICPEMC and the US Department of Energy was held in Alta, Utah, December 9-13, 1984 to examine the extent to which DNA-oriented methods might provide new approaches to the important but intractable problem of measuring mutation rates in control and exposed human populations. The workshop identified and analyzed six DNA methods for detection of human heritable mutation, including several created at the meeting, and concluded that none of the methods combine sufficient feasibility and efficiency to be recommended for general application. 8 refs.

  5. Estimation of the RNU2 macrosatellite mutation rate by BRCA1 mutation tracing

    PubMed Central

    Tessereau, Chloé; Lesecque, Yann; Monnet, Nastasia; Buisson, Monique; Barjhoux, Laure; Léoné, Mélanie; Feng, Bingjian; Goldgar, David E.; Sinilnikova, Olga M.; Mousset, Sylvain; Duret, Laurent; Mazoyer, Sylvie

    2014-01-01

    Large tandem repeat sequences have been poorly investigated as severe technical limitations and their frequent absence from the genome reference hinder their analysis. Extensive allelotyping of this class of variation has not been possible until now and their mutational dynamics are still poorly known. In order to estimate the mutation rate of a macrosatellite, we analysed in detail the RNU2 locus, which displays at least 50 different alleles containing 5-82 copies of a 6.1 kb repeat unit. Mining data from the 1000 Genomes Project allowed us to precisely estimate copy numbers of the RNU2 repeat unit using read depth of coverage. This further revealed significantly different mean values in various recent modern human populations, favoring a scenario of fast evolution of this locus. Its proximity to a disease gene with numerous founder mutations, BRCA1, within the same linkage disequilibrium block, offered the unique opportunity to trace RNU2 arrays over a large timescale. Analysis of the transmission of RNU2 arrays associated with one ‘private’ mutation in an extended kindred and four founder mutations in multiple kindreds gave an estimation by maximum likelihood of 5 × 10−3 mutations per generation, which is close to that of microsatellites. PMID:25034697

  6. 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

  7. Estimation of the Spontaneous Mutation Rate in Heliconius melpomene

    PubMed Central

    Keightley, Peter D.; Pinharanda, Ana; Ness, Rob W.; Simpson, Fraser; Dasmahapatra, Kanchon K.; Mallet, James; Davey, John W.; Jiggins, Chris D.

    2015-01-01

    We estimated the spontaneous mutation rate in Heliconius melpomene by genome sequencing of a pair of parents and 30 of their offspring, based on the ratio of number of de novo heterozygotes to the number of callable site-individuals. We detected nine new mutations, each one affecting a single site in a single offspring. This yields an estimated mutation rate of 2.9 × 10−9 (95% confidence interval, 1.3 × 10−9–5.5 × 10−9), which is similar to recent estimates in Drosophila melanogaster, the only other insect species in which the mutation rate has been directly estimated. We infer that recent effective population size of H. melpomene is about 2 million, a substantially lower value than its census size, suggesting a role for natural selection reducing diversity. We estimate that H. melpomene diverged from its Müllerian comimic H. erato about 6 Ma, a somewhat later date than estimates based on a local molecular clock. PMID:25371432

  8. 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

  9. 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

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

    PubMed

    Møller, Anders Pape; Mousseau, Timothy A

    2015-02-10

    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.

  11. 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.

  12. Historical mutation rates predict susceptibility to radiation in Chernobyl birds.

    PubMed

    Møller, A P; Erritzøe, J; Karadas, F; Mousseau, T A

    2010-10-01

    Extreme environmental perturbations are rare, but may have important evolutionary consequences. Responses to current perturbations may provide important information about the ability of living organisms to cope with similar conditions in the evolutionary past. Radioactive contamination from Chernobyl constitutes one such extreme perturbation, with significant but highly variable impact on local population density and mutation rates of different species of animals and plants. We explicitly tested the hypothesis that species with strong impacts of radiation on abundance were those with high rates of historical mutation accumulation as reflected by cytochrome b mitochondrial DNA base-pair substitution rates during past environmental perturbations. Using a dataset of 32 species of birds, we show higher historical mitochondrial substitution rates in species with the strongest negative impact of local levels of radiation on local population density. These effects were robust to different estimates of impact of radiation on abundance, weighting of estimates of abundance by sample size, statistical control for similarity in the response among species because of common phylogenetic descent, and effects of population size and longevity. Therefore, species that respond strongly to the impact of radiation from Chernobyl are also the species that in the past have been most susceptible to factors that have caused high substitution rates in mitochondrial DNA.

  13. 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

  14. 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.

  15. 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

  16. A highly unexpected strong correlation between fixation probability of nonsynonymous mutations and mutation rate.

    PubMed

    Wyckoff, Gerald J; Malcom, Christine M; Vallender, Eric J; Lahn, Bruce T

    2005-07-01

    Under prevailing theories, the nonsynonymous-to-synonymous substitution ratio (i.e. K(a)/K(s)), which measures the fixation probability of nonsynonymous mutations, is correlated with the strength of selection. In this article, we report that K(a)/K(s) is also strongly correlated with the mutation rate as measured by K(s), and that this correlation appears to have a similar magnitude as the correlation between K(a)/K(s) and selective strength. This finding cannot be reconciled with current theories. It suggests that we should re-evaluate the current paradigms of coding-sequence evolution, and that the wide use of K(a)/K(s) as a measure of selective strength needs reassessment.

  17. 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.

  18. Whole genome sequencing of mutation accumulation lines reveals a low mutation rate in the social amoeba Dictyostelium discoideum.

    PubMed

    Saxer, Gerda; Havlak, Paul; Fox, Sara A; Quance, Michael A; Gupta, Sharu; Fofanov, Yuriy; Strassmann, Joan E; Queller, David C

    2012-01-01

    Spontaneous mutations play a central role in evolution. Despite their importance, mutation rates are some of the most elusive parameters to measure in evolutionary biology. The combination of mutation accumulation (MA) experiments and whole-genome sequencing now makes it possible to estimate mutation rates by directly observing new mutations at the molecular level across the whole genome. We performed an MA experiment with the social amoeba Dictyostelium discoideum and sequenced the genomes of three randomly chosen lines using high-throughput sequencing to estimate the spontaneous mutation rate in this model organism. The mitochondrial mutation rate of 6.76×10(-9), with a Poisson confidence interval of 4.1×10(-9) - 9.5×10(-9), per nucleotide per generation is slightly lower than estimates for other taxa. The mutation rate estimate for the nuclear DNA of 2.9×10(-11), with a Poisson confidence interval ranging from 7.4×10(-13) to 1.6×10(-10), is the lowest reported for any eukaryote. These results are consistent with low microsatellite mutation rates previously observed in D. discoideum and low levels of genetic variation observed in wild D. discoideum populations. In addition, D. discoideum has been shown to be quite resistant to DNA damage, which suggests an efficient DNA-repair mechanism that could be an adaptation to life in soil and frequent exposure to intracellular and extracellular mutagenic compounds. The social aspect of the life cycle of D. discoideum and a large portion of the genome under relaxed selection during vegetative growth could also select for a low mutation rate. This hypothesis is supported by a significantly lower mutation rate per cell division in multicellular eukaryotes compared with unicellular eukaryotes. PMID:23056439

  19. Purifying selection, drift, and reversible mutation with arbitrarily high mutation rates.

    PubMed

    Charlesworth, Brian; Jain, Kavita

    2014-12-01

    Some species exhibit very high levels of DNA sequence variability; there is also evidence for the existence of heritable epigenetic variants that experience state changes at a much higher rate than sequence variants. In both cases, the resulting high diversity levels within a population (hyperdiversity) mean that standard population genetics methods are not trustworthy. We analyze a population genetics model that incorporates purifying selection, reversible mutations, and genetic drift, assuming a stationary population size. We derive analytical results for both population parameters and sample statistics and discuss their implications for studies of natural genetic and epigenetic variation. In particular, we find that (1) many more intermediate-frequency variants are expected than under standard models, even with moderately strong purifying selection, and (2) rates of evolution under purifying selection may be close to, or even exceed, neutral rates. These findings are related to empirical studies of sequence and epigenetic variation.

  20. Escherichia coli frameshift mutation rate depends on the chromosomal context but not on the GATC content near the mutation site.

    PubMed

    Martina, Mariana A; Correa, Elisa M E; Argaraña, Carlos E; Barra, José L

    2012-01-01

    Different studies have suggested that mutation rate varies at different positions in the genome. In this work we analyzed if the chromosomal context and/or the presence of GATC sites can affect the frameshift mutation rate in the Escherichia coli genome. We show that in a mismatch repair deficient background, a condition where the mutation rate reflects the fidelity of the DNA polymerization process, the frameshift mutation rate could vary up to four times among different chromosomal contexts. Furthermore, the mismatch repair efficiency could vary up to eight times when compared at different chromosomal locations, indicating that detection and/or repair of frameshift events also depends on the chromosomal context. Also, GATC sequences have been proved to be essential for the correct functioning of the E. coli mismatch repair system. Using bacteriophage heteroduplexes molecules it has been shown that GATC influence the mismatch repair efficiency in a distance- and number-dependent manner, being almost nonfunctional when GATC sequences are located at 1 kb or more from the mutation site. Interestingly, we found that in E. coli genomic DNA the mismatch repair system can efficiently function even if the nearest GATC sequence is located more than 2 kb away from the mutation site. The results presented in this work show that even though frameshift mutations can be efficiently generated and/or repaired anywhere in the genome, these processes can be modulated by the chromosomal context that surrounds the mutation site.

  1. 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)

  2. Direct estimation of the mitochondrial DNA mutation rate in Drosophila melanogaster.

    PubMed

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

    2008-08-19

    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 x 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 10x higher than the nuclear mutation rate, but the mitochondrial major strand G-->A mutation rate is about 70x 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 the

  3. 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.

  4. Evolution of high mutation rates in experimental populations of E. coli

    NASA Astrophysics Data System (ADS)

    Sniegowski, Paul D.; Gerrish, Philip J.; Lenski, Richard E.

    1997-06-01

    Most mutations are likely to be deleterious, and so the spontaneous mutation rate is generally held at a very low value. Nonetheless, evolutionary theory predicts that high mutation rates can evolve under certain circumstances. Empirical observations have previously been limited to short-term studies of the fates of mutator strains deliberately introduced into laboratory populations of Escherichia coli, and to the effects of intense selective events on mutator frequencies in E. coli. Here we report the rise of spontaneously originated mutators in populations of E. coli undergoing long-term adaptation to a new environment. Our results corroborate computer simulations of mutator evolution in adapting clonal populations, and may help to explain observations that associate high mutation rates with emerging pathogens and with certain cancers.

  5. 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

  6. 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.

  7. The application of a linear algebra to the analysis of mutation rates.

    PubMed

    Jones, M E; Thomas, S M; Clarke, K

    1999-07-01

    Cells and bacteria growing in culture are subject to mutation, and as this mutation is the ultimate substrate for selection and evolution, the factors controlling the mutation rate are of some interest. The mutational event is not observed directly, but is inferred from the phenotype of the original mutant or of its descendants; the rate of mutation is inferred from the number of such mutant phenotypes. Such inference presumes a knowledge of the probability distribution for the size of a clone arising from a single mutation. We develop a mathematical formulation that assists in the design and analysis of experiments which investigate mutation rates and mutant clone size distribution, and we use it to analyse data for which the classical Luria-Delbrück clone-size distribution must be rejected.

  8. Direct estimate of the rate of germline mutation in a bird

    PubMed Central

    Smeds, Linnéa; Qvarnström, Anna; Ellegren, Hans

    2016-01-01

    The fidelity of DNA replication together with repair mechanisms ensure that the genetic material is properly copied from one generation to another. However, on extremely rare occasions when damages to DNA or replication errors are not repaired, germline mutations can be transmitted to the next generation. Because of the rarity of these events, studying the rate at which new mutations arise across organisms has been a great challenge, especially in multicellular nonmodel organisms with large genomes. We sequenced the genomes of 11 birds from a three-generation pedigree of the collared flycatcher (Ficedula albicollis) and used highly stringent bioinformatic criteria for mutation detection and used several procedures to validate mutations, including following the stable inheritance of new mutations to subsequent generations. We identified 55 de novo mutations with a 10-fold enrichment of mutations at CpG sites and with only a modest male mutation bias. The estimated rate of mutation per site per generation was 4.6 × 10−9, which corresponds to 2.3 × 10−9 mutations per site per year. Compared to mammals, this is similar to mouse but about half of that reported for humans, which may be due to the higher frequency of male mutations in humans. We confirm that mutation rate scales positively with genome size and that there is a strong negative relationship between mutation rate and effective population size, in line with the drift-barrier hypothesis. Our study illustrates that it should be feasible to obtain direct estimates of the rate of mutation in essentially any organism from which family material can be obtained. PMID:27412854

  9. Measuring the Rates of Spontaneous Mutation From Deep and Large-Scale Polymorphism Data

    PubMed Central

    Messer, Philipp W.

    2009-01-01

    The rates and patterns of spontaneous mutation are fundamental parameters of molecular evolution. Current methodology either tries to measure such rates and patterns directly in mutation-accumulation experiments or tries to infer them indirectly from levels of divergence or polymorphism. While experimental approaches are constrained by the low rate at which new mutations occur, indirect approaches suffer from their underlying assumption that mutations are effectively neutral. Here I present a maximum-likelihood approach to estimate mutation rates from large-scale polymorphism data. It is demonstrated that the method is not sensitive to demography and the distribution of selection coefficients among mutations when applied to mutations at sufficiently low population frequencies. With the many large-scale sequencing projects currently underway, for instance, the 1000 genomes project in humans, plenty of the required low-frequency polymorphism data will shortly become available. My method will allow for an accurate and unbiased inference of mutation rates and patterns from such data sets at high spatial resolution. I discuss how the assessment of several long-standing problems of evolutionary biology would benefit from the availability of accurate mutation rate estimates. PMID:19528323

  10. Fidelity drive: a mechanism for chaperone proteins to maintain stable mutation rates in prokaryotes over evolutionary time.

    PubMed

    Xue, Julian Z; Kaznatcheev, Artem; Costopoulos, Andre; Guichard, Frederic

    2015-01-01

    We show a mechanism by which chaperone proteins can play a key role in maintaining the long-term evolutionary stability of mutation rates in prokaryotes with perfect genetic linkage. Since chaperones can reduce the phenotypic effects of mutations, higher mutation rate, by affecting chaperones, can increase the phenotypic effects of mutations. This in turn leads to greater mutation effect among the proteins that control mutation repair and DNA replication, resulting in large changes in mutation rate. The converse of this is that when mutation rate is low and chaperones are functioning well, then the rate of change in mutation rate will also be low, leading to low mutation rates being evolutionarily frozen. We show that the strength of this recursion is critical to determining the long-term evolutionary patterns of mutation rate among prokaryotes. If this recursion is weak, then mutation rates can grow without bound, leading to the extinction of the lineage. However, if this recursion is strong, then we can reproduce empirical patterns of prokaryotic mutation rates, where mutation rates remain stable over evolutionary time, and where most mutation rates are low, but with a significant fraction of high mutators.

  11. 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).

  12. 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.

  13. 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

  14. 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

  15. An ABC method for estimating the rate and distribution of effects of beneficial mutations.

    PubMed

    Moura de Sousa, Jorge A; Campos, Paulo R A; Gordo, Isabel

    2013-01-01

    Determining the distribution of adaptive mutations available to natural selection is a difficult task. These are rare events and most of them are lost by chance. Some theoretical works propose that the distribution of newly arising beneficial mutations should be close to exponential. Empirical data are scarce and do not always support an exponential distribution. Analysis of the dynamics of adaptation in asexual populations of microorganisms has revealed that these can be summarized by two effective parameters, the effective mutation rate, Ue, and the effective selection coefficient of a beneficial mutation, Se. Here, we show that these effective parameters will not always reflect the rate and mean effect of beneficial mutations, especially when the distribution of arising mutations has high variance, and the mutation rate is high. We propose a method to estimate the distribution of arising beneficial mutations, which is motivated by a common experimental setup. The method, which we call One Biallelic Marker Approximate Bayesian Computation, makes use of experimental data consisting of periodic measures of neutral marker frequencies and mean population fitness. Using simulations, we find that this method allows the discrimination of the shape of the distribution of arising mutations and that it provides reasonable estimates of their rates and mean effects in ranges of the parameter space that may be of biological relevance.

  16. 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

  17. Conditional Coalescent Trees With Two Mutation Rates and Their Application to Genomic Instability

    PubMed Central

    Emily, Mathieu; François, Olivier

    2006-01-01

    Humans have invested several genes in DNA repair and fidelity replication. To account for the disparity between the rarity of mutations in normal cells and the large number of mutations present in cancer, an hypothesis is that cancer cells must exhibit a mutator phenotype (genomic instability) during tumor progression, with the initiation of abnormal mutation rates caused by the loss of mismatch repair. In this study we introduce a stochastic model of mutation in tumor cells with the aim of estimating the amount of genomic instability due to the alteration of DNA repair genes. Our approach took into account the difficulties generated by sampling within tumoral clones and the fact that these clones must be difficult to isolate. We provide corrections to two classical statistics to obtain unbiased estimators of the raised mutation rate, and we show that large statistical errors may be associated with such estimators. The power of these new statistics to reject genomic instability is assessed and proved to increase with the intensity of mutation rates. In addition, we show that genomic instability cannot be detected unless the raised mutation rates exceed the normal rates by a factor of at least 1000. PMID:16387889

  18. The effects of chromatin organization on variation in mutation rates in the genome

    PubMed Central

    Makova, Kateryna D.; Hardison, Ross C.

    2015-01-01

    The variation in local rates of mutations can affect both the evolution of genes and their function in normal and cancer cells. Deciphering the molecular determinants of this variation will be aided by resolving distinct types of mutation, since they differ in regional preferences and in associations with genomic features. Chromatin organization contributes to regional variation in mutation rate, but differently among mutation types. In both germ-line mutations and somatic mutations, base substitutions are more abundant in regions of closed chromatin, perhaps reflecting error accumulation late in replication. In contrast, a distinctive mutational state with very high levels of indels and substitutions is enriched in regions of open chromatin. These associations illuminate an intricate interplay between the nucleotide sequence of DNA and its dynamic packaging into c inhromatin, and they have important implications for current biomedical research. This review focuses on the recent studies showing associations between chromatin state and mutation rates, including pairwise and multivariate investigations of germ-line and somatic (particularly cancer) mutations. PMID:25732611

  19. The rate with which spontaneous mutation alters the electrophoretic mobility of polypeptides.

    PubMed Central

    Neel, J V; Satoh, C; Goriki, K; Fujita, M; Takahashi, N; Asakawa, J; Hazama, R

    1986-01-01

    Studies of a Japanese population, involving a total of 539,170 locus tests distributed over 36 polypeptides, yielded three presumptive spontaneous mutations altering the electrophoretic mobility of the polypeptide. This corresponds to a mutation rate of 0.6 X 10(-5) per locus per generation. The a priori probability that undetected discrepancies between legal and biological parentage might in our test system result in an apparent electrophoretic mutation in this population is calculated to be only 0.3 X 10(-7) per locus per generation. Since electrophoresis only detects about half of the amino acid substitutions due to mutations of nucleotides, the corrected rate for mutations causing amino acid substitutions in polypeptides is 1.2 X 10(-5) per locus per generation. With allowance for synonymous mutations and those resulting in stop codons, the total mutation rate for nucleotide changes in the exons encoding a polypeptide becomes approximately equal to 1.8 X 10(-5) per locus per generation. When the present observations are combined with all of the other available data concerning mutation resulting in electrophoretic variants, the electrophoretic rate drops to 0.3 X 10(-5) per locus per generation, the total locus rate drops to roughly 1.0 X 10(-5), and the nucleotide rate drops to 1 X 10(-8). Even with this lower estimate, given approximately equal to 2 X 10(9) nucleotides in the haploid genome and an average of 10(3) exon nucleotides per polypeptide encoded, the implication, if these exon rates can be generalized, is of approximately equal to 20 nucleotide mutations per gamete per generation. This estimate of the frequency of "point" mutations does not include small duplications, rearrangements, or deletions resulting from unequal crossing-over, transcription errors, etc. PMID:3455776

  20. 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.

  1. 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

  2. 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

  3. Association of intron loss with high mutation rate in Arabidopsis: implications for genome size evolution.

    PubMed

    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.

  4. 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

  5. CpG dinucleotides and the mutation rate of non-CpG DNA.

    PubMed

    Walser, Jean-Claude; Ponger, Loïc; Furano, Anthony V

    2008-09-01

    The neutral mutation rate is equal to the base substitution rate when the latter is not affected by natural selection. Differences between these rates may reveal that factors such as natural selection, linkage, or a mutator locus are affecting a given sequence. We examined the neutral base substitution rate by measuring the sequence divergence of approximately 30,000 pairs of inactive orthologous L1 retrotransposon sequences interspersed throughout the human and chimpanzee genomes. In contrast to other studies, we related ortholog divergence to the time (age) that the L1 sequences resided in the genome prior to the chimpanzee and human speciation. As expected, the younger orthologs contained more hypermutable CpGs than the older ones because of their conversion to TpGs (and CpAs). Consequently, the younger orthologs accumulated more CpG mutations than the older ones during the approximately 5 million years since the human and chimpanzee lineages separated. But during this same time, the younger orthologs also accumulated more non-CpG mutations than the older ones. In fact, non-CpG and CpG mutations showed an almost perfect (R2 = 0.98) correlation for approximately 97% of the ortholog pairs. The correlation is independent of G + C content, recombination rate, and chromosomal location. Therefore, it likely reflects an intrinsic effect of CpGs, or mutations thereof, on non-CpG DNA rather than the joint manifestation of the chromosomal environment. The CpG effect is not uniform for all regions of non-CpG DNA. Therefore, the mutation rate of non-CpG DNA is contingent to varying extents on local CpG content. Aside from their implications for mutational mechanisms, these results indicate that a precise determination of a uniform genome-wide neutral mutation rate may not be attainable. PMID:18550801

  6. Rate of FKS Mutations among Consecutive Candida Isolates Causing Bloodstream Infection.

    PubMed

    Shields, Ryan K; Nguyen, M Hong; Press, Ellen G; Cumbie, Richard; Driscoll, Eileen; Pasculle, A William; Clancy, Cornelius J

    2015-12-01

    Precise FKS mutation rates among Candida species are undefined because studies have not systematically screened consecutive, disease-causing isolates. The Sensititre YeastOne (SYO) assay measures echinocandin MICs against Candida with less variability than reference broth microdilution methods. However, clinical breakpoint MICs may overstate caspofungin nonsusceptibility compared to other agents. Our objectives were to determine Candida FKS mutation rates by studying consecutive bloodstream isolates and to determine if discrepant susceptibility results were associated with FKS mutations. FKS hot spots were sequenced in echinocandin-intermediate and -resistant isolates and those from patients with breakthrough candidemia or ≥ 3 days of prior echinocandin exposure. Overall, 453 isolates from 384 patients underwent susceptibility testing; 16% were echinocandin intermediate or resistant. Intermediate susceptibility rates were higher for Candida glabrata than for other species (P < 0.0001) and higher for caspofungin than for other agents (P < 0.0001). Resistance rates were similar between agents. FKS mutations were detected in 5% of sequenced isolates and 2% of isolates overall. Corresponding rates among C. glabrata isolates were 8% and 4%, respectively. Among Candida albicans isolates, rates were 5% and <1%, respectively. Mutations occurred exclusively with prior echinocandin exposure and were not detected in other species. Isolates with discrepant susceptibility results did not harbor FKS mutations. Mutation rates among isolates resistant to ≥ 2, 1, and 0 agents were 75%, 13%, and 0%, respectively. In conclusion, FKS mutations were uncommon among non-C. glabrata species, even with prior echinocandin exposure. Discrepancies in echinocandin susceptibility by SYO testing were not driven by mutations and likely reflect imprecise caspofungin clinical breakpoints.

  7. 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

  8. 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

  9. Mutation rates at the glycophorin A and HPRT loci in uranium miners exposed to radon progeny.

    PubMed Central

    Shanahan, E M; Peterson, D; Roxby, D; Quintana, J; Morely, A A; Woodward, A

    1996-01-01

    OBJECTIVES--To find whether a relation exists between estimated levels of exposure to radon and its progeny and mutations in hypoxanthine phosphoribosyl transferase (HPRT) and glycophorin A in a cohort of former uranium miners. METHODS--A cohort study involving a sample of miners from the Radium Hill uranium mine in South Australia, which operated from 1952 to 1961. Radiation exposures underground at Radium Hill were estimated from historical radon gas measures with a job exposure matrix. Workers from the mine who worked exclusively above ground according to mine records were selected as controls. In 1991-2 miners were interviewed and blood taken for measurement of somatic mutations. Mutation rates for HPRT and glycophorin A were estimated with standard assay techniques. RESULTS--Homozygous mutations of glycophorin A were increased in underground miners (P = 0.0027) and the mutation rate tended to rise with increasing exposure with the exception of the highest exposure (> 10 working level months). However, there was no association between place of work and either the hemizygous mutations of glycophorin A or the HPRT mutation. CONCLUSIONS--There may be an association between glycophorin A mutations and previous occupational exposure to ionising radiation. However, not enough is known at present to use these assays as biomarkers for historical exposure in underground mining cohorts. PMID:8704866

  10. Prognostic significance of K-Ras mutation rate in metastatic colorectal cancer patients

    PubMed Central

    Vincenzi, Bruno; Cremolini, Chiara; Sartore-Bianchi, Andrea; Russo, Antonio; Mannavola, Francesco; Perrone, Giuseppe; Pantano, Francesco; Loupakis, Fotios; Rossini, Daniele; Ongaro, Elena; Bonazzina, Erica; Dell'Aquila, Emanuela; Imperatori, Marco; Zoccoli, Alice; Bronte, Giuseppe; De Maglio, Giovanna; Fontanini, Gabriella; Natoli, Clara; Falcone, Alfredo; Santini, Daniele; Onetti-Muda, Andrea; Siena, Salvatore; Tonini, Giuseppe; Aprile, Giuseppe

    2015-01-01

    Introduction: Activating mutations of K-Ras gene have a well-established role as predictors of resistance to anti-EGFR monoclonal antibodies in metastatic colorectal cancer (mCRC) patients. Their prognostic value is controversial, and no data regarding the prognostic value of mutation rate, defined as the percentage of mutated alleles/tumor sample, are available. We aimed to evaluate the prognostic value of K-Rasmutation rate in a homogenous cohort of mCRC patients receiving first-line doublet plus bevacizumab. Patients and Methods: This retrospective study enrolled 397 K-Ras mutant mCRC patients from 6 Italian centers, and 263 patients were fully evaluable for our analysis. K-Ras mutation rate was assessed by pyrosequencing. Patients with less than 60% of cancer cells in tumor tissue were excluded. No patients received anti-EGFR containing anticancer therapy, at any time. Median mutation rate was 40% and was adopted as cut-off. The primary and secondary endpoints were PFS and OS respectively. Results: At univariate analysis, K-Ras mutation rate higher than 40% was significantly associated with lower PFS (7.3 vs 9.1 months; P < 0.0001) and OS (21 vs 31 months; P = 0.004). A multivariate model adjusted for age at diagnosis, site of origin of tumor tissue (primary vs metastases), referral center, number of metastatic sites, and first-line chemotherapy backbone, showed that K-Ras mutation rate remained a significant predictor of PFS and OS in the whole population. Discussion: Our data demonstrate an association between K-Ras mutation rate and prognosis in mCRC patients treated with bevacizumab-containing first-line therapy. These data deserve to be verified in an independent validation set. PMID:26384309

  11. 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

  12. 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

  13. Predicting protein folding rate change upon point mutation using residue-level coevolutionary information.

    PubMed

    Mallik, Saurav; Das, Smita; Kundu, Sudip

    2016-01-01

    Change in folding kinetics of globular proteins upon point mutation is crucial to a wide spectrum of biological research, such as protein misfolding, toxicity, and aggregations. Here we seek to address whether residue-level coevolutionary information of globular proteins can be informative to folding rate changes upon point mutations. Generating residue-level coevolutionary networks of globular proteins, we analyze three parameters: relative coevolution order (rCEO), network density (ND), and characteristic path length (CPL). A point mutation is considered to be equivalent to a node deletion of this network and respective percentage changes in rCEO, ND, CPL are found linearly correlated (0.84, 0.73, and -0.61, respectively) with experimental folding rate changes. The three parameters predict the folding rate change upon a point mutation with 0.031, 0.045, and 0.059 standard errors, respectively.

  14. 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

  15. 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

    2011-06-12

    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.

  16. A stochastic model for estimation of mutation rates in multiple-replication proliferation processes.

    PubMed

    Xiong, Xiaoping; Boyett, James M; Webster, Robert G; Stech, Juergen

    2009-08-01

    In this paper we propose a stochastic model based on the branching process for estimation and comparison of the mutation rates in proliferation processes of cells or microbes. We assume in this model that cells or microbes (the elements of a population) are reproduced by generations and thus the model is more suitably applicable to situations in which the new elements in a population are produced by older elements from the previous generation rather than by newly created elements from the same current generation. Cells and bacteria proliferate by binary replication, whereas the RNA viruses proliferate by multiple replication. The model is in terms of multiple replications, which includes the special case of binary replication. We propose statistical procedures for estimation and comparison of the mutation rates from data of multiple cultures with divergent culture sizes. The mutation rate is defined as the probability of mutation per replication per genome and thus can be assumed constant in the entire proliferation process. We derive the number of cultures for planning experiments to achieve desired accuracy for estimation or desired statistical power for comparing the mutation rates of two strains of microbes. We establish the efficiency of the proposed method by demonstrating how the estimation of mutation rates would be affected when the culture sizes were assumed similar but actually diverge. PMID:18846374

  17. Lamivudine/Adefovir Treatment Increases the Rate of Spontaneous Mutation of Hepatitis B Virus in Patients

    PubMed Central

    Pereira-Gómez, Marianoel; Bou, Juan-Vicente; Andreu, Iván; Sanjuán, Rafael

    2016-01-01

    The high levels of genetic diversity shown by hepatitis B virus (HBV) are commonly attributed to the low fidelity of its polymerase. However, the rate of spontaneous mutation of human HBV in vivo is currently unknown. Here, based on the evolutionary principle that the population frequency of lethal mutations equals the rate at which they are produced, we have estimated the mutation rate of HBV in vivo by scoring premature stop codons in 621 publicly available, full-length, molecular clone sequences derived from patients. This yielded an estimate of 8.7 × 10−5 spontaneous mutations per nucleotide per cell infection in untreated patients, which should be taken as an upper limit estimate because PCR errors and/or lack of effective lethality may inflate observed mutation frequencies. We found that, in patients undergoing lamivudine/adefovir treatment, the HBV mutation rate was elevated by more than sixfold, revealing a mutagenic effect of this treatment. Genome-wide analysis of single-nucleotide polymorphisms indicated that lamivudine/adefovir treatment increases the fraction of A/T-to-G/C base substitutions, consistent with recent work showing similar effects of lamivudine in cellular DNA. Based on these data, the rate at which HBV produces new genetic variants in treated patients is similar to or even higher than in RNA viruses. PMID:27649318

  18. Lamivudine/Adefovir Treatment Increases the Rate of Spontaneous Mutation of Hepatitis B Virus in Patients.

    PubMed

    Pereira-Gómez, Marianoel; Bou, Juan-Vicente; Andreu, Iván; Sanjuán, Rafael

    2016-01-01

    The high levels of genetic diversity shown by hepatitis B virus (HBV) are commonly attributed to the low fidelity of its polymerase. However, the rate of spontaneous mutation of human HBV in vivo is currently unknown. Here, based on the evolutionary principle that the population frequency of lethal mutations equals the rate at which they are produced, we have estimated the mutation rate of HBV in vivo by scoring premature stop codons in 621 publicly available, full-length, molecular clone sequences derived from patients. This yielded an estimate of 8.7 × 10-5 spontaneous mutations per nucleotide per cell infection in untreated patients, which should be taken as an upper limit estimate because PCR errors and/or lack of effective lethality may inflate observed mutation frequencies. We found that, in patients undergoing lamivudine/adefovir treatment, the HBV mutation rate was elevated by more than sixfold, revealing a mutagenic effect of this treatment. Genome-wide analysis of single-nucleotide polymorphisms indicated that lamivudine/adefovir treatment increases the fraction of A/T-to-G/C base substitutions, consistent with recent work showing similar effects of lamivudine in cellular DNA. Based on these data, the rate at which HBV produces new genetic variants in treated patients is similar to or even higher than in RNA viruses. PMID:27649318

  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.

  1. High mitochondrial mutation rates estimated from deep-rooting Costa Rican pedigrees

    PubMed Central

    Madrigal, Lorena; Melendez-Obando, Mauricio; Villegas-Palma, Ramon; Barrantes, Ramiro; Raventos, Henrieta; Pereira, Reynaldo; Luiselli, Donata; Pettener, Davide; Barbujani, Guido

    2012-01-01

    Estimates of mutation rates for the noncoding hypervariable Region I (HVR-I) of mitochondrial DNA (mtDNA) vary widely, depending on whether they are inferred from phylogenies (assuming that molecular evolution is clock-like) or directly from pedigrees. All pedigree-based studies so far were conducted on populations of European origin. In this paper we analyzed 19 deep-rooting pedigrees in a population of mixed origin in Costa Rica. We calculated two estimates of the HVR-I mutation rate, one considering all apparent mutations, and one disregarding changes at sites known to be mutational hot spots and eliminating genealogy branches which might be suspected to include errors, or unrecognized adoptions along the female lines. At the end of this procedure, we still observed a mutation rate equal to 1.24 × 10−6, per site per year, i.e., at least three-fold as high as estimates derived from phylogenies. Our results confirm that mutation rates observed in pedigrees are much higher than estimated assuming a neutral model of long-term HVRI evolution. We argue that, until the cause of these discrepancies will be fully understood, both lower estimates (i.e., those derived from phylogenetic comparisons) and higher, direct estimates such as those obtained in this study, should be considered when modeling evolutionary and demographic processes. PMID:22460349

  2. 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

  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. 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

  5. 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.

  6. Both microsatellite length and sequence context determine frameshift mutation rates in defective DNA mismatch repair.

    PubMed

    Chung, Heekyung; Lopez, Claudia G; Holmstrom, Joy; Young, Dennis J; Lai, Jenny F; Ream-Robinson, Deena; Carethers, John M

    2010-07-01

    It is generally accepted that longer microsatellites mutate more frequently in defective DNA mismatch repair (MMR) than shorter microsatellites. Indeed, we have previously observed that the A10 microsatellite of transforming growth factor beta type II receptor (TGFBR2) frameshifts -1 bp at a faster rate than the A8 microsatellite of activin type II receptor (ACVR2), although both genes become frameshift-mutated in >80% of MMR-defective colorectal cancers. To experimentally determine the effect of microsatellite length upon frameshift mutation in gene-specific sequence contexts, we altered the microsatellite length within TGFBR2 exon 3 and ACVR2 exon 10, generating A7, A10 and A13 constructs. These constructs were cloned 1 bp out of frame of EGFP, allowing a -1 bp frameshift to drive EGFP expression, and stably transfected into MMR-deficient cells. Subsequent non-fluorescent cells were sorted, cultured for 7-35 days and harvested for EGFP analysis and DNA sequencing. Longer microsatellites within TGFBR2 and ACVR2 showed significantly higher mutation rates than shorter ones, with TGFBR2 A13, A10 and A7 frameshifts measured at 22.38x10(-4), 2.17x10(-4) and 0.13x10(-4), respectively. Surprisingly, shorter ACVR2 constructs showed three times higher mutation rates at A7 and A10 lengths than identical length TGFBR2 constructs but comparably lower at the A13 length, suggesting influences from both microsatellite length as well as the sequence context. Furthermore, the TGFBR2 A13 construct mutated into 33% A11 sequences (-2 bp) in addition to expected A12 (-1 bp), indicating that this construct undergoes continual subsequent frameshift mutation. These data demonstrate experimentally that both the length of a mononucleotide microsatellite and its sequence context influence mutation rate in defective DNA MMR.

  7. 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

    2016-04-01

    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.

  8. A novel multiplex assay amplifying 13 Y-STRs characterized by rapid and moderate mutation rate.

    PubMed

    Rogalla, Urszula; Woźniak, Marcin; Swobodziński, Jacek; Derenko, Miroslava; Malyarchuk, Boris A; Dambueva, Irina; Koziński, Marek; Kubica, Jacek; Grzybowski, Tomasz

    2015-03-01

    As microsatellites located on Y chromosome mutate with different rates, they may be exploited in evolutionary studies, genealogical testing of a variety of populations and even, as proven recently, aid individual identification. Currently available commercial Y-STR kits encompass mostly low to moderately mutating loci, making them a perfect choice for the first two applications. Some attempts have been made so far to utilize Y-STRs to provide a discriminatory tool for forensic purposes. Although all 13 rapidly mutating Y-STRs were already multiplexed, no single assay based on single-copy markers allowing at least a portion of close male relatives to be differentiated from one another is available. To fill in the blanks, we constructed and validated an assay comprised of single-copy Y-STR markers only with a mutation rate ranging from 8×10(-3) to 1×10(-2). Performance of the resulting combination of nine RM Y-STRs and four moderately mutating ones was tested on 361 father-son pairs and 1326 males from 9 populations revealing an overall mutation rate of 1.607×10(-1) for the assay as a whole. Application of the proposed 13 Y-STR set to differentiation of haplotypes present among homogenous population of Buryats resulted in a threefold increase of discrimination as compared with 10 Y-STRs from the PowerPlex(®) Y.

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

    PubMed

    Greenspoon, Philip B; M'Gonigle, Leithen K

    2013-06-22

    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.

  10. Validating viral quasispecies with digital organisms: a re-examination of the critical mutation rate

    PubMed Central

    Comas, Iñaki; Moya, Andrés; González-Candelas, Fernando

    2005-01-01

    Background In this report we re-examine some recent experiments with digital organisms to test some predictions of quasispecies theory. These experiments revealed that under high mutation rates populations of less fit organisms previously adapted to such high mutation rates were able to outcompete organisms with higher average fitness but adapted to low mutation rates. Results We have verified that these results do hold in the original conditions and, by extending the set of initial parameters, we have also detected that the critical mutation rate was independent of population size, a result that we have found to be dependent on a different, contingent factor, the initial fitness vector. Furthermore, in all but one case, the critical mutation rate is higher than the error threshold, a key parameter in quasispecies theory, which prevents its extrapolation to natural viral populations. Conclusion From these results we conclude that digital organisms are useful tools for investigating evolutionary patterns and processes including some predictions from the quasispecies theory. PMID:15651995

  11. 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

  12. p53 mutations associated with aging-related rise in cancer incidence rates.

    PubMed

    Richardson, Richard B

    2013-08-01

    TP53's role as guardian of the genome diminishes with age, as the probability of mutation increases. Previous studies have shown an association between p53 gene mutations and cancer. However, the role of somatic TP53 mutations in the steep rise in cancer rates with aging has not been investigated at a population level. This relationship was quantified using the International Agency for Research on Cancer (IARC) TP53 and GLOBOCAN cancer databases. The power function exponent of the cancer rate was calculated for 5-y age-standardized incidence or mortality rates for up to 25 cancer sites occurring in adults of median age 42 to 72 y. Linear regression analysis of the mean percentage of a cancer's TP53 mutations and the corresponding cancer exponent was conducted for four populations: worldwide, Japan, Western Europe, and the United States. Significant associations (P ≤ 0.05) were found for incidence rates but not mortality rates. Regardless of the population studied, positive associations were found for all cancer sites, with more significant associations for solid tumors, excluding the outlier prostate cancer or sex-related tumors. Worldwide and Japanese populations yielded P values as low as 0.002 and 0.005, respectively. For the United States, a significant association was apparent only when analysis utilized the Surveillance, Epidemiology, and End Results (SEER) database. This study found that TP53 mutations accounts for approximately one-quarter and one-third of the aging-related rise in the worldwide and Japanese incidence of all cancers, respectively. These significant associations between TP53 mutations and the rapid rise in cancer incidence with aging, considered with previously published literature, support a causal role for TP53 according to the Bradford-Hill criteria. However, questions remain concerning the contribution of TP53 mutations to neoplastic development and the role of factors such as genetic instability, obesity, and gene deficiencies other

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

    NASA Astrophysics Data System (ADS)

    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 [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

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

    PubMed Central

    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. 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

  16. Host-parasite coevolution and optimal mutation rates for semiconservative quasispecies

    NASA Astrophysics Data System (ADS)

    Brumer, Yisroel; Shakhnovich, Eugene I.

    2004-06-01

    In this paper, we extend a model of host-parasite coevolution to incorporate the semiconservative nature of DNA replication for both the host and the parasite. We find that the optimal mutation rate for the semiconservative and conservative hosts converge for realistic genome lengths, thus maintaining the admirable agreement between theory and experiment found previously for the conservative model and justifying the conservative approximation in some cases. We demonstrate that, while the optimal mutation rate for a conservative and semiconservative parasite interacting with a given immune system is similar to that of a conservative parasite, the properties away from this optimum differ significantly. We suspect that this difference, coupled with the requirement that a parasite optimize survival in a range of viable hosts, may help explain why semiconservative viruses are known to have significantly lower mutation rates than their conservative counterparts.

  17. 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.

  18. The causes of synonymous rate variation in the rodent genome. Can substitution rates be used to estimate the sex bias in mutation rate?

    PubMed Central

    Smith, N G; Hurst, L D

    1999-01-01

    Miyata et al. have suggested that the male-to-female mutation rate ratio (alpha) can be estimated by comparing the neutral substitution rates of X-linked (X), Y-linked (Y), and autosomal (A) genes. Rodent silent site X/A comparisons provide very different estimates from X/Y comparisons. We examine three explanations for this discrepancy: (1) statistical biases and artifacts, (2) nonneutral evolution, and (3) differences in mutation rate per germline replication. By estimating errors and using a variety of methodologies, we tentatively reject explanation 1. Our analyses of patterns of codon usage, synonymous rates, and nonsynonymous rates suggest that silent sites in rodents are evolving neutrally, and we can therefore reject explanation 2. We find both base composition and methylation differences between the different sets of chromosomes, a result consistent with explanation 3, but these differences do not appear to explain the observed discrepancies in estimates of alpha. Our finding of significantly low synonymous substitution rates in genomically imprinted genes suggests a link between hemizygous expression and an adaptive reduction in the mutation rate, which is consistent with explanation 3. Therefore our results provide circumstantial evidence in favor of the hypothesis that the discrepancies in estimates of alpha are due to differences in the mutation rate per germline replication between different parts of the genome. This explanation violates a critical assumption of the method of Miyata et al., and hence we suggest that estimates of alpha, obtained using this method, need to be treated with caution. PMID:10353908

  19. 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.

  20. 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

  1. The rate of mutation and the homozygous and heterozygous mutational effects for competitive viability: a long-term experiment with Drosophila melanogaster.

    PubMed Central

    Chavarrías, D; López-Fanjul, C; García-Dorado, A

    2001-01-01

    The effect of 250 generations of mutation accumulation (MA) on the second chromosome competitive viability of Drosophila melanogaster was analyzed both in homozygous and heterozygous conditions. We used full-sib MA lines, where selection hampers the accumulation of severely deleterious mutations but is ineffective against mildly deleterious ones. A large control population was simultaneously evaluated. Competitive viability scores, unaffected by the expression of mutations in heterozygosis, were obtained relative to a Cy/L(2) genotype. The rate of decline in mean DeltaM approximately 0.1% was small. However, that of increase in variance DeltaV approximately 0.08 x 10(-3) was similar to the values obtained in previous experiments when severely deleterious mutations were excluded. The corresponding estimates of the mutation rate lambda > or = 0.01 and the average effect of mutations E(s) < or = 0.08 are in good agreement with Bateman-Mukai and minimum distance estimates for noncompetitive viability obtained from the same MA lines after 105 generations. Thus, competitive and noncompetitive viability show similar mutational properties. The regression estimate of the degree of dominance for mild-to-moderate deleterious mutations was approximately 0.3, suggesting that the pertinent value for new unselected mutations should be somewhat smaller. PMID:11404332

  2. 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

  3. 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

  4. Hybridization Alters Spontaneous Mutation Rates in a Parent-of-Origin-Dependent Fashion in Arabidopsis1[W

    PubMed Central

    Bashir, Tufail; Sailer, Christian; Gerber, Florian; Loganathan, Nitin; Bhoopalan, Hemadev; Eichenberger, Christof; Grossniklaus, Ueli; Baskar, Ramamurthy

    2014-01-01

    Over 70 years ago, increased spontaneous mutation rates were observed in Drosophila spp. hybrids, but the genetic basis of this phenomenon is not well understood. The model plant Arabidopsis (Arabidopsis thaliana) offers unique opportunities to study the types of mutations induced upon hybridization and the frequency of their occurrence. Understanding the mutational effects of hybridization is important, as many crop plants are grown as hybrids. Besides, hybridization is important for speciation and its effects on genome integrity could be critical, as chromosomal rearrangements can lead to reproductive isolation. We examined the rates of hybridization-induced point and frameshift mutations as well as homologous recombination events in intraspecific Arabidopsis hybrids using a set of transgenic mutation detector lines that carry mutated or truncated versions of a reporter gene. We found that hybridization alters the frequency of different kinds of mutations. In general, Columbia (Col) × Cape Verde Islands and Col × C24 hybrid progeny had decreased T→G and T→A transversion rates but an increased C→T transition rate. Significant changes in frameshift mutation rates were also observed in some hybrids. In Col × C24 hybrids, there is a trend for increased homologous recombination rates, except for the hybrids from one line, while in Col × Cape Verde Islands hybrids, this rate is decreased. The overall genetic distance of the parents had no influence on mutation rates in the progeny, as closely related accessions on occasion displayed higher mutation rates than accessions that are separated farther apart. However, reciprocal hybrids had significantly different mutation rates, suggesting parent-of-origin-dependent effects on the mutation frequency. PMID:24664208

  5. Comparisons of mutation rate variation at genome-wide microsatellites: evolutionary insights from two cultivated rice and their wild relatives

    PubMed Central

    2008-01-01

    Background Mutation rate (μ) per generation per locus is an important parameter in the models of population genetics. Studies on mutation rate and its variation are of significance to elucidate the extent and distribution of genetic variation, further infer evolutionary relationships among closely related species, and deeply understand genetic variation of genomes. However, patterns of rate variation of microsatellite loci are still poorly understood in plant species. Furthermore, how their mutation rates vary in di-, tri-, and tetra-nucleotide repeats within the species is largely uninvestigated across related plant genomes. Results Genome-wide variation of mutation rates was first investigated by means of the composite population parameter θ (θ = 4Nμ, where N is the effective population size and μ is the mutation rate per locus per generation) in four subspecies of Asian cultivated rice O. sativa and its three related species, O. rufipogon, O. glaberrima, and O. officinalis. On the basis of three data sets of microsatellite allele frequencies throughout the genome, population mutation rate (θ) was estimated for each locus. Our results reveal that the variation of population mutation rates at microsatellites within each studied species or subspecies of cultivated rice can be approximated with a gamma distribution. The mean population mutation rates of microsatellites do not significantly differ in motifs of di-, tri-, and tetra-nucleotide repeats for the studied rice species. The shape parameter was also estimated for each subspecies of rice as well as other related rice species. Of them, different subspecies of O. sativa possesses similar shape parameters (α) of the gamma distribution, while other species extensively vary in their population mutation rates. Conclusion Through the analysis of genome-wide microsatellite data, the population mutation rate can be approximately fitted with a gamma distribution in most of the studied species. In general

  6. 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

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

    PubMed Central

    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

  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. p53 mutations associated with aging-related rise in cancer incidence rates

    PubMed Central

    Richardson, Richard B

    2013-01-01

    TP53’s role as guardian of the genome diminishes with age, as the probability of mutation increases. Previous studies have shown an association between p53 gene mutations and cancer. However, the role of somatic TP53 mutations in the steep rise in cancer rates with aging has not been investigated at a population level. This relationship was quantified using the International Agency for Research on Cancer (IARC) TP53 and GLOBOCAN cancer databases. The power function exponent of the cancer rate was calculated for 5-y age-standardized incidence or mortality rates for up to 25 cancer sites occurring in adults of median age 42 to 72 y. Linear regression analysis of the mean percentage of a cancer’s TP53 mutations and the corresponding cancer exponent was conducted for four populations: worldwide, Japan, Western Europe, and the United States. Significant associations (P ≤ 0.05) were found for incidence rates but not mortality rates. Regardless of the population studied, positive associations were found for all cancer sites, with more significant associations for solid tumors, excluding the outlier prostate cancer or sex-related tumors. Worldwide and Japanese populations yielded P values as low as 0.002 and 0.005, respectively. For the United States, a significant association was apparent only when analysis utilized the Surveillance, Epidemiology, and End Results (SEER) database. This study found that TP53 mutations accounts for approximately one-quarter and one-third of the aging-related rise in the worldwide and Japanese incidence of all cancers, respectively. These significant associations between TP53 mutations and the rapid rise in cancer incidence with aging, considered with previously published literature, support a causal role for TP53 according to the Bradford-Hill criteria. However, questions remain concerning the contribution of TP53 mutations to neoplastic development and the role of factors such as genetic instability, obesity, and gene deficiencies

  11. 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.

  12. 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

  13. 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.

  14. Estimating the spontaneous mutation rate of loss of sex in the human pathogenic fungus Cryptococcus neoformans.

    PubMed Central

    Xu, Jianping

    2002-01-01

    Few events have evolutionary consequences as pervasive as changes in reproductive behavior. Among those changes, the loss of the ability to undergo sexual reproduction is probably the most profound. However, little is known about the rate of loss of sex. Here I describe an experimental system using the fungus Cryptococcus neoformans and provide the first empirical estimate of the spontaneous mutation rate of loss of sex in fungi. Two critical steps in sexual reproduction in C. neoformans were examined: mating and filamentation. Mating, the fusion of cells of opposite sexes, is a universal first step in eukaryotic sexual reproduction. In contrast, filamentation, a prerequisite process preceding meiosis and sexual spore development, is restricted to C. neoformans and a few other fungal species. After approximately 600 mitotic divisions under favorable asexual growth conditions, mean abilities for mating and filamentation decreased significantly by >67 and 24%, respectively. Similarly, though statistically not significant, the mean vegetative growth rates also decreased and among the mutation accumulation lines, the vegetative growth rates were negatively correlated to the mating ability. The estimated mutation rates to decreases in mating ability and filamentation were in excess of 0.0172 and 0.0036, respectively. The results show that C. neoformans can be a highly attractive model for analyses of reproductive system evolution in fungi. PMID:12454063

  15. A germ-line-selective advantage rather than an increased mutation rate can explain some unexpectedly common human disease mutations.

    PubMed

    Choi, Soo-Kyung; Yoon, Song-Ro; Calabrese, Peter; Arnheim, Norman

    2008-07-22

    Two nucleotide substitutions in the human FGFR2 gene (C755G or C758G) are responsible for virtually all sporadic cases of Apert syndrome. This condition is 100-1,000 times more common than genomic mutation frequency data predict. Here, we report on the C758G de novo Apert syndrome mutation. Using data on older donors, we show that spontaneous mutations are not uniformly distributed throughout normal testes. Instead, we find foci where C758G mutation frequencies are 3-4 orders of magnitude greater than the remaining tissue. We conclude this nucleotide site is not a mutation hot spot even after accounting for possible Luria-Delbruck "mutation jackpots." An alternative explanation for such foci involving positive selection acting on adult self-renewing Ap spermatogonia experiencing the rare mutation could not be rejected. Further, the two youngest individuals studied (19 and 23 years old) had lower mutation frequencies and smaller foci at both mutation sites compared with the older individuals. This implies that the mutation frequency of foci increases as adults age, and thus selection could explain the paternal age effect for Apert syndrome and other genetic conditions. Our results, now including the analysis of two mutations in the same set of testes, suggest that positive selection can increase the relative frequency of premeiotic germ cells carrying such mutations, although individuals who inherit them have reduced fitness. In addition, we compared the anatomical distribution of C758G mutation foci with both new and old data on the C755G mutation in the same testis and found their positions were not correlated with one another. PMID:18632557

  16. Detecting recent selective sweeps while controlling for mutation rate and background selection.

    PubMed

    Huber, Christian D; DeGiorgio, Michael; Hellmann, Ines; Nielsen, Rasmus

    2016-01-01

    A composite likelihood ratio test implemented in the program sweepfinder is a commonly used method for scanning a genome for recent selective sweeps. sweepfinder uses information on the spatial pattern (along the chromosome) of the site frequency spectrum around the selected locus. To avoid confounding effects of background selection and variation in the mutation process along the genome, the method is typically applied only to sites that are variable within species. However, the power to detect and localize selective sweeps can be greatly improved if invariable sites are also included in the analysis. In the spirit of a Hudson-Kreitman-Aguadé test, we suggest adding fixed differences relative to an out-group to account for variation in mutation rate, thereby facilitating more robust and powerful analyses. We also develop a method for including background selection, modelled as a local reduction in the effective population size. Using simulations, we show that these advances lead to a gain in power while maintaining robustness to mutation rate variation. Furthermore, the new method also provides more precise localization of the causative mutation than methods using the spatial pattern of segregating sites alone. PMID:26290347

  17. Identification of common cystic fibrosis mutations in African-Americans with cystic fibrosis increases the detection rate to 75%.

    PubMed Central

    Macek, M; Mackova, A; Hamosh, A; Hilman, B C; Selden, R F; Lucotte, G; Friedman, K J; Knowles, M R; Rosenstein, B J; Cutting, G R

    1997-01-01

    Cystic fibrosis (CF)--an autosomal recessive disorder caused by mutations in CF transmembrane conductance regulator (CFTR) and characterized by abnormal chloride conduction across epithelial membranes, leading to chronic lung and exocrine pancreatic disease--is less common in African-Americans than in Caucasians. No large-scale studies of mutation identification and screening in African-American CF patients have been reported, to date. In this study, the entire coding and flanking intronic sequence of the CFTR gene was analyzed by denaturing gradient-gel electrophoresis and sequencing in an index group of 82 African-American CF chromosomes to identify mutations. One novel mutation, 3120+1G-->A, occurred with a frequency of 12.3% and was also detected in a native African patient. To establish frequencies, an additional group of 66 African-American CF chromosomes were screened for mutations identified in two or more African-American patients. Screening for 16 "common Caucasian" mutations identified 52% of CF alleles in African-Americans, while screening for 8 "common African" mutations accounted for an additional 23%. The combined detection rate of 75% was comparable to the sensitivity of mutation analysis in Caucasian CF patients. These results indicate that African-Americans have their own set of "common" CF mutations that originate from the native African population. Inclusion of these "common" mutations substantially improves CF mutation detection rates in African-Americans. PMID:9150159

  18. 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

  19. Is there a difference among human populations in the rate with which mutation produces electrophoretic variants?

    PubMed Central

    Neel, J V; Rothman, E

    1981-01-01

    Data are summarized that suggest that tropical-zone/tribal/nonindustrialized populations have higher frequencies of certain types of protein variants than temperate-zone/civilized/industrial populations, and it is demonstrated that these differences are not an artifact produced by the contagious type of sampling used with respect to tribal populations. Evidence is reviewed that suggests that a possible explanation of this difference is higher mutation rates in the tribal populations studied. PMID:6942419

  20. 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

  1. 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.

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

    PubMed Central

    Harris, Kelley

    2015-01-01

    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

  3. 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.

  4. 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

  5. Mutation Rate, Spectrum, Topology, and Context-Dependency in the DNA Mismatch Repair-Deficient Pseudomonas fluorescens ATCC948

    PubMed Central

    Long, Hongan; Sung, Way; Miller, Samuel F.; Ackerman, Matthew S.; Doak, Thomas G.; Lynch, Michael

    2015-01-01

    High levels of genetic diversity exist among natural isolates of the bacterium Pseudomonas fluorescens, and are especially elevated around the replication terminus of the genome, where strain-specific genes are found. In an effort to understand the role of genetic variation in the evolution of Pseudomonas, we analyzed 31,106 base substitutions from 45 mutation accumulation lines of P. fluorescens ATCC948, naturally deficient for mismatch repair, yielding a base-substitution mutation rate of 2.34 × 10−8 per site per generation (SE: 0.01 × 10−8) and a small-insertion-deletion mutation rate of 1.65 × 10−9 per site per generation (SE: 0.03 × 10−9). We find that the spectrum of mutations in prophage regions, which often contain virulence factors and antibiotic resistance, is highly similar to that in the intergenic regions of the host genome. Our results show that the mutation rate varies around the chromosome, with the lowest mutation rate found near the origin of replication. Consistent with observations from other studies, we find that site-specific mutation rates are heavily influenced by the immediately flanking nucleotides, indicating that mutations are context dependent. PMID:25539726

  6. Minimum of Information Distance Criterion for Optimal Control of Mutation Rate in Evolutionary Systems

    NASA Astrophysics Data System (ADS)

    Belavkin, Roman V.

    2013-01-01

    Evolutionary dynamics studies changes in populations of species, which occur due to various processes such as replication and mutation. Here we consider this dynamics as an example of Markov evolution on a simplex of probability measures describing the populations, and then define optimality of this evolution with respect to constraints on information distance between these measures. We show how this convex programming problem is related to a variational problem of optimizing Markov transition kernel subject to a constraint on Shannon's mutual information. This relation is represented by the Pythagorean theorem in information geometry considered on the simplex of joint probability measures. We discuss the application of this variational approach to optimization of a stochastic search in metric spaces, and in particular to optimization of mutation rate parameter during the search for optimal DNA sequences in evolutionary systems.

  7. Rates of mutation and host transmission for an Escherichia coli clone over 3 years.

    PubMed

    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.

  8. 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

  9. 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

  10. 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

  11. Evolution of Mutation Rates: Phylogenomic Analysis of the Photolyase/Cryptochrome Family

    PubMed Central

    Lucas-Lledó, José Ignacio; Lynch, Michael

    2009-01-01

    Photoreactivation, one of the first DNA repair pathways to evolve, is the direct reversal of premutagenic lesions caused by ultraviolet (UV) irradiation, catalyzed by photolyases in a light-dependent, single-enzyme reaction. It has been experimentally shown that photoreactivation prevents UV mutagenesis in a broad range of species. In the absence of photoreactivation, UV-induced photolesions are repaired by the more complex and much less efficient nucleotide excision repair pathway. Despite their obvious beneficial effects, several lineages, including placental mammals, lost photolyase genes during evolution. In this study, we ask why photolyase genes have been lost in those lineages and discuss the significance of these losses in the context of the evolution of the genomic mutation rates. We first perform an extensive phylogenomic analysis of the photolyase/cryptochrome family, to assess what species lack each kind of photolyase gene. Then, we estimate the ratio of nonsynonymous to synonymous substitution rates in several groups of photolyase genes, as a proxy of the strength of purifying natural selection, and we ask whether less evolutionarily constrained photolyase genes are more likely lost. We also review functional data and compare the efficiency of different kinds of photolyases. We find that eukaryotic photolyases are, on average, less evolutionarily constrained than eubacterial ones and that the strength of natural selection is correlated with the affinity of photolyases for their substrates. We propose that the loss of photolyase genes in eukaryotic species may be due to weak natural selection and may result in a deleterious increase of their genomic mutation rates. In contrast, the loss of photolyase genes in prokaryotes may not cause an increase in the mutation rate and be neutral in most cases. PMID:19228922

  12. Mutation rates in plastid genomes: they are lower than you might think.

    PubMed

    Smith, David Roy

    2015-05-01

    Within plastid-bearing species, the mutation rate of the plastid genome is often assumed to be greater than that of the mitochondrial genome. This assumption is based on early, pioneering studies of land plant molecular evolution, which uncovered higher rates of synonymous substitution in plastid versus mitochondrial DNAs. However, much of the plastid-containing eukaryotic diversity falls outside of land plants, and the patterns of plastid DNA evolution for embryophytes do not necessarily reflect those of other groups. Recent analyses of plastid and mitochondrial substitution rates in diverse lineages have uncovered very different trends than those recorded for land plants. Here, I explore these new data and argue that for many protists the plastid mutation rate is lower than that of the mitochondrion, including groups with primary or secondary plastids as well as nonphotosynthetic algae. These findings have far-reaching implications for how we view plastid genomes and how their sequences are used for evolutionary analyses, and might ultimately reflect a general tendency toward more efficient DNA repair mechanisms in plastids than in mitochondria.

  13. 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

  14. 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

  15. 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

  16. Increased episomal replication accounts for the high rate of adaptive mutation in recD mutants of Escherichia coli.

    PubMed Central

    Foster, P L; Rosche, W A

    1999-01-01

    Adaptive mutation has been studied extensively in FC40, a strain of Escherichia coli that cannot metabolize lactose (Lac-) because of a frameshift mutation affecting the lacZ gene on its episome. recD mutants of FC40, in which the exonuclease activity of RecBCD (ExoV) is abolished but its helicase activity is retained, have an increased rate of adaptive mutation. The results presented here show that, in several respects, adaptive mutation to Lac+ involves different mechanisms in recD mutant cells than in wild-type cells. About half of the apparent increase in the adaptive mutation rate of recD mutant cells is due to a RecA-dependent increase in episomal copy number and to growth of the Lac- cells on the lactose plates. The remaining increase appears to be due to continued replication of the episome, with the extra copies being degraded or passed to recD+ recipients. In addition, the increase in adaptive mutation rate in recD mutant cells is (i) dependent on activities of the single-stranded exonucleases, RecJ and ExoI, which are not required for (in fact, slightly inhibit) adaptive mutation in wild-type cells, and (ii) enhanced by RecG, which opposes adaptive mutation in wild-type cells. PMID:10224241

  17. Increasing Nucleosome Occupancy Is Correlated with an Increasing Mutation Rate so Long as DNA Repair Machinery Is Intact.

    PubMed

    Yazdi, Puya G; Pedersen, Brian A; Taylor, Jared F; Khattab, Omar S; Chen, Yu-Han; Chen, Yumay; Jacobsen, Steven E; Wang, Ping H

    2015-01-01

    Deciphering the multitude of epigenomic and genomic factors that influence the mutation rate is an area of great interest in modern biology. Recently, chromatin has been shown to play a part in this process. To elucidate this relationship further, we integrated our own ultra-deep sequenced human nucleosomal DNA data set with a host of published human genomic and cancer genomic data sets. Our results revealed, that differences in nucleosome occupancy are associated with changes in base-specific mutation rates. Increasing nucleosome occupancy is associated with an increasing transition to transversion ratio and an increased germline mutation rate within the human genome. Additionally, cancer single nucleotide variants and microindels are enriched within nucleosomes and both the coding and non-coding cancer mutation rate increases with increasing nucleosome occupancy. There is an enrichment of cancer indels at the theoretical start (74 bp) and end (115 bp) of linker DNA between two nucleosomes. We then hypothesized that increasing nucleosome occupancy decreases access to DNA by DNA repair machinery and could account for the increasing mutation rate. Such a relationship should not exist in DNA repair knockouts, and we thus repeated our analysis in DNA repair machinery knockouts to test our hypothesis. Indeed, our results revealed no correlation between increasing nucleosome occupancy and increasing mutation rate in DNA repair knockouts. Our findings emphasize the linkage of the genome and epigenome through the nucleosome whose properties can affect genome evolution and genetic aberrations such as cancer.

  18. 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

  19. 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.

  20. Minisatellite DNA mutation rate in dandelions increases with leaf-tissue concentrations of Cr, Fe, Mn, and Ni.

    PubMed

    Rogstad, Steven H; Keane, Brian; Collier, Matthew H

    2003-09-01

    We have examined whether mutation rates at minisatellite DNA loci in dandelions (Taraxacum officinale Weber, sensu lato: Asteraceae) increase with increasing exposure to metal pollution. From 16 sites (Colorado to Pennsylvania, USA) covering a range of airborne particulate-matter exposures, soil metal concentrations, and leaf-tissue metal concentrations, we grew an average of 7.9 offspring from each of 10 parent plants, and we analyzed the parent-offspring transmission of 82,715 minisatellite DNA markers to 1,258 offspring for rates of mutation. The mean number of markers examined per individual (using six minisatellite probes) was 65.8. Detection of mutations is facilitated by agamospermous reproduction (clonal seed production) in dandelions. Across sites, the average single-event, parent-offspring marker transmission mutation rate was 0.0067, ranging from 0.002 to 0.015 (a 7.5-fold difference). No significant correlation was detected between site single-event mutation rates and either airborne particulate-matter or soil concentrations for any of the metals. However, across sites, mutation rates were significantly (p < 0.05) and positively correlated to increasing leaf-tissue concentrations of Cr, Fe, Mn, and Ni (Cd, Cu, Pb, and Zn exhibited no correlation). Multiple-regression analyses suggest that a model including three metals--in order of importance: Cr (p = 0.002), Fe (p = 0.02), and Ni (p = 0.005); overall, p = 0.001--may improve the ability to predict mutation rate relative to leaf metal concentrations in dandelions. Mutations at minisatellite DNA loci in sexually apomictic organisms may thus provide convenient biomarkers by which to assess the mutagen stressor risk in environments.

  1. Distributions of selectively constrained sites and deleterious mutation rates in the hominid and murid genomes.

    PubMed

    Eory, Lél; Halligan, Daniel L; Keightley, Peter D

    2010-01-01

    Protein-coding sequences make up only about 1% of the mammalian genome. Much of the remaining 99% has been long assumed to be junk DNA, with little or no functional significance. Here, we show that in hominids, a group with historically low effective population sizes, all classes of noncoding DNA evolve more slowly than ancestral transposable elements and so appear to be subject to significant evolutionary constraints. Under the nearly neutral theory, we expected to see lower levels of selective constraints on most sequence types in hominids than murids, a group that is thought to have a higher effective population size. We found that this is the case for many sequence types examined, the most extreme example being 5'UTRs, for which constraint in hominids is only about one-third that of murids. Surprisingly, however, we observed higher constraints for some sequence types in hominids, notably 4-fold sites, where constraint is more than twice as high as in murids. This implies that more than about one-fifth of mutations at 4-fold sites are effectively selected against in hominids. The higher constraint at 4-fold sites in hominids suggests a more complex protein-coding gene structure than murids and indicates that methods for detecting selection on protein-coding sequences (e.g., using the d(N)/d(S) ratio), with 4-fold sites as a neutral standard, may lead to biased estimates, particularly in hominids. Our constraint estimates imply that 5.4% of nucleotide sites in the human genome are subject to effective negative selection and that there are three times as many constrained sites within noncoding sequences as within protein-coding sequences. Including coding and noncoding sites, we estimate that the genomic deleterious mutation rate U = 4.2. The mutational load predicted under a multiplicative model is therefore about 99% in hominids.

  2. 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.

  3. 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.

  4. Age-related increase in the rate of spontaneou and {gamma}-ray-induced hprt mutations in mouse spleen lymphocytes

    SciTech Connect

    Gazlev, A.I.; Podlutskii, A.Ya.; Bradbury, R.

    1994-11-01

    Endogenous and exogenous factors continually afflict DNA of cells of organisms. A certain amount of the damage is accumulated causing mutations, increasing the risk of malignacies, impairing cell functions, and upsetting the body`s homeostasis. The research reported here studies the rates of spontaneous hprt nmutationsand those induced you ggammairradiation in the splenocytes of mice at various ages. The rate of spontaneous and induced hprt gene mutations increases with aging. In gamma irradiated mice the rate of radiation-induced mutations depended on the absorbed dose and age, with the rate 2.3-3.0 fold higher in 104-110 week old mice than in younger pups. 15 refs., 1 tab.

  5. 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

  6. Rates of BRCA1/2 mutation testing among young survivors of breast cancer.

    PubMed

    Kehl, Kenneth L; Shen, Chan; Litton, Jennifer K; Arun, Banu; Giordano, Sharon H

    2016-01-01

    Guidelines in the United States recommend consideration of testing for mutations in the BRCA1 and BRCA2 genes for women diagnosed with breast cancer under age 45. Identification of mutations among survivors has implications for secondary prevention and familial risk reduction. Although only 10 % of breast cancers are diagnosed under age 45, there are approximately 2.8 million breast cancer survivors in the United States, such that the young survivor population likely numbers in the hundreds of thousands. However, little is known about genetic testing rates in this population. We assessed trends in BRCA1/2 testing among breast cancer survivors who were under age 45 at diagnosis and were treated from 2005 to 2012. Using insurance claims from a national database (MarketScan), we identified incident breast cancer cases among (1) women aged ≤40 and (2) women aged 41-45. We measured BRCA1/2 testing using Kaplan-Meier analysis and Cox proportional hazards models. Among 26,985 patients analyzed, BRCA1/2 testing rates increased with each year of diagnosis from 2005 to 2012 (P < 0.001). However, among women treated in earlier years, testing rates did not approach those of patients treated later, even after extended follow-up (median time from surgery to testing among patients treated in 2005, not reached; median time to testing among patients treated in 2012, 0.2 months for women aged ≤40 and 1.0 month for women aged 41-45). Women aged 41-45 had lower rates than women aged ≤40 throughout the analysis period (P < 0.001 for each year). BRCA1/2 testing rates among young women with incident breast cancer increased substantially in the last decade. However, most survivors treated in earlier years have never been tested. Our results demonstrate a need to better incorporate genetic counseling into survivorship and primary care for this population.

  7. A novel LQT-3 mutation disrupts an inactivation gate complex with distinct rate-dependent phenotypic consequences.

    PubMed

    Bankston, John R; Sampson, Kevin J; Kateriya, Suneel; Glaaser, Ian W; Malito, David L; Chung, Wendy K; Kass, Robert S

    2007-01-01

    Inherited mutations of SCN5A, the gene that encodes Na(V)1.5, the alpha subunit of the principle voltage-gated Na(+) channel in the heart, cause congenital Long QT Syndrome variant 3 (LQT-3) by perturbation of channel inactivation. LQT-3 mutations induce small, but aberrant, inward current that prolongs the ventricular action potential and subjects mutation carriers to arrhythmia risk dictated in part by the biophysical consequences of the mutations. Most previously investigated LQT-3 mutations are associated with increased arrhythmia risk during rest or sleep. Here we report a novel LQT-3 mutation discovered in a pediatric proband diagnosed with LQTS but who experienced cardiac events during periods of mild exercise as well as rest. The mutation, which changes a single amino acid (S1904L) in the Na(V)1.5 carboxy terminal domain, disrupts the channel inactivation gate complex and promotes late Na(+) channel currents, not by promoting a bursting mode of gating, but by increasing the propensity of the channel to reopen during prolonged depolarization. Incorporating a modified version of the Markov model of the Na(V)1.5 channel into a mathematical model of the human ventricular action potential predicts that the biophysical consequences of the S1904L mutation result in action potential prolongation that is seen for all heart rates but, in contrast to other previously-investigated LQT-3 mutant channels, is most pronounced at fast rates resulting in a drastic reduction in the cells ability to adapt APD to heart rate.

  8. 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.

  9. 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

  10. 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

  11. 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

  12. 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

  13. Incidence and mutation rates of Huntington's disease in Spain: experience of 9 years of direct genetic testing

    PubMed Central

    Ramos-Arroyo, M; Moreno, S; Valiente, A

    2005-01-01

    Background: Prior to the discovery of the Huntington's disease (HD) mutation, the prevalence, incidence, and new mutation rates for this disease were based on the presence of progressive choreic movements and a positive family history. Objective: To evaluate the uptake of the HD genetic analysis in Spain, and to provide additional information on the epidemiology of this disease from the experience of 9 years of direct genetic testing. Methods: From 1994 to 2002, CAG repeat length was determined in 317 patients with symptoms compatible with HD. In all cases, demographic, clinical, and family data were carefully reviewed. Results: HD diagnosis (CAG repeat length ⩾36) was confirmed in 166 (52%) symptomatic cases. Of these, 76 (45.8%) reported a positive family history and in 21 cases (12.7%) family history was negative. New mutation events were genetically proven in three families and highly suspected in another, estimating that the minimum new mutation rate for HD in our population is >4%, with a potential mutation rate of 8%. More than 16% of all HD cases had late onset (>59 years) of symptoms, and in three quarters of these the family history was negative. The incidence rate for the autonomous communities of Navarra and the Basque country, based on the number of newly diagnosed cases by genetic testing, was 4.7 per million per year. Conclusions: Direct HD genetic testing shows that the incidence and mutation rates of the disease are 2–3 times higher than previously reported. We also demonstrated the relevance of CAG repeat length assessment in diagnosing patients with late onset of symptoms and negative family history for HD. PMID:15716522

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

    PubMed

    Bershtein, Shimon; Serohijos, Adrian W R; Bhattacharyya, Sanchari; Manhart, Michael; Choi, Jeong-Mo; Mu, Wanmeng; Zhou, Jingwen; Shakhnovich, Eugene I

    2015-10-01

    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 (kcat/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

  15. 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

  16. The fundamental theorem of neutral evolution: rates of substitution and mutation should factor in premeiotic clusters.

    PubMed

    Woodruff, R C; Thomson, J N

    2005-11-01

    Mutations do not always arise as single events. Many new mutations actually occur in the cell lineage before germ cell formation or meiosis and are therefore replicated pre-meiotically. The increased likelihood of substitutions caused by these clusters of new mutant alleles can change the fundamental theorem of neutral evolution.

  17. Nonequivalence of updating rules in evolutionary games under high mutation rates

    NASA Astrophysics Data System (ADS)

    Kaiping, G. A.; Jacobs, G. S.; Cox, S. J.; Sluckin, T. J.

    2014-10-01

    Moran processes are often used to model selection in evolutionary simulations. The updating rule in Moran processes is a birth-death process, i. e., selection according to fitness of an individual to give birth, followed by the death of a random individual. For well-mixed populations with only two strategies this updating rule is known to be equivalent to selecting unfit individuals for death and then selecting randomly for procreation (biased death-birth process). It is, however, known that this equivalence does not hold when considering structured populations. Here we study whether changing the updating rule can also have an effect in well-mixed populations in the presence of more than two strategies and high mutation rates. We find, using three models from different areas of evolutionary simulation, that the choice of updating rule can change model results. We show, e. g., that going from the birth-death process to the death-birth process can change a public goods game with punishment from containing mostly defectors to having a majority of cooperative strategies. From the examples given we derive guidelines indicating when the choice of the updating rule can be expected to have an impact on the results of the model.

  18. Do mutator mutations fuel tumorigenesis?

    PubMed

    Fox, Edward J; Prindle, Marc J; Loeb, Lawrence A

    2013-12-01

    The mutator phenotype hypothesis proposes that the mutation rate of normal cells is insufficient to account for the large number of mutations found in human cancers. Consequently, human tumors exhibit an elevated mutation rate that increases the likelihood of a tumor acquiring advantageous mutations. The hypothesis predicts that tumors are composed of cells harboring hundreds of thousands of mutations, as opposed to a small number of specific driver mutations, and that malignant cells within a tumor therefore constitute a highly heterogeneous population. As a result, drugs targeting specific mutated driver genes or even pathways of mutated driver genes will have only limited anticancer potential. In addition, because the tumor is composed of such a diverse cell population, tumor cells harboring drug-resistant mutations will exist prior to the administration of any chemotherapeutic agent. We present recent evidence in support of the mutator phenotype hypothesis, major arguments against this concept, and discuss the clinical consequences of tumor evolution fueled by an elevated mutation rate. We also consider the therapeutic possibility of altering the rate of mutation accumulation. Most significantly, we contend that there is a need to fundamentally reconsider current approaches to personalized cancer therapy. We propose that targeting cellular pathways that alter the rate of mutation accumulation in tumors will ultimately prove more effective than attempting to identify and target mutant driver genes or driver pathways.

  19. 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

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

    PubMed

    Behringer, Megan G; Hall, David W

    2015-11-12

    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.

  1. 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

  2. Direct Evidence on the Contribution of a Missense Mutation in GDF9 to Variation in Ovulation Rate of Finnsheep

    PubMed Central

    Mullen, Michael P.; Hanrahan, James P.

    2014-01-01

    The Finnish Landrace (Finnsheep) is a well known high-prolificacy sheep breed and has been used in many countries as a source of genetic material to increase fecundity of local breeds. Analyses to date have indicated that mutations with a large effect on ovulation rate are not responsible for the exceptional prolificacy of Finnsheep. The objectives of this study were to ascertain if: 1) any of 12 known mutations with large effects on ovulation rate in sheep, or 2) any other DNA sequence variants within the candidate genes GDF9 and BMP15 are implicated in the high prolificacy of the Finnish Landrace breed; using material from lines developed by divergent selection on ovulation rate. Genotyping results showed that none of 12 known mutations (FecBB, FecXB, FecXG, FecXGR, FecXH, FecXI, FecXL, FecXO, FecXR, FecGE, FecGH, or FecGT) were present in a sample of 108 Finnsheep and, thus, do not contribute to the exceptional prolificacy of the breed. However, DNA sequence analysis of GDF9 identified a previously known mutation, V371M, whose frequency differed significantly (P<0.001) between High and Low ovulation rate lines. While analysis of ovulation rate data for Finnsheep failed to establish a significant association between this trait and V371M, analysis of data on Belclare sheep revealed a significant association between V371M and ovulation rate (P<0.01). Ewes that were heterozygous for V371M exhibited increased ovulation rate (+0.17, s.e. 0.080; P<0.05) compared to wild type and the effect was non-additive (ovulation rate of heterozygotes was significantly lower (P<0.01) than the mean of the homozygotes). This finding brings to 13 the number of mutations that have large effects on ovulation rate in sheep and to 5, including FecBB, FecGE, FecXO and FecXGR, the number of mutations within the TGFβ superfamily with a positive effect on prolificacy in the homozygous state. PMID:24751660

  3. Direct evidence on the contribution of a missense mutation in GDF9 to variation in ovulation rate of Finnsheep.

    PubMed

    Mullen, Michael P; Hanrahan, James P

    2014-01-01

    The Finnish Landrace (Finnsheep) is a well known high-prolificacy sheep breed and has been used in many countries as a source of genetic material to increase fecundity of local breeds. Analyses to date have indicated that mutations with a large effect on ovulation rate are not responsible for the exceptional prolificacy of Finnsheep. The objectives of this study were to ascertain if: 1) any of 12 known mutations with large effects on ovulation rate in sheep, or 2) any other DNA sequence variants within the candidate genes GDF9 and BMP15 are implicated in the high prolificacy of the Finnish Landrace breed; using material from lines developed by divergent selection on ovulation rate. Genotyping results showed that none of 12 known mutations (FecBB, FecXB, FecXG, FecXGR, FecXH, FecXI, FecXL, FecXO, FecXR, FecGE, FecGH, or FecGT) were present in a sample of 108 Finnsheep and, thus, do not contribute to the exceptional prolificacy of the breed. However, DNA sequence analysis of GDF9 identified a previously known mutation, V371M, whose frequency differed significantly (P<0.001) between High and Low ovulation rate lines. While analysis of ovulation rate data for Finnsheep failed to establish a significant association between this trait and V371M, analysis of data on Belclare sheep revealed a significant association between V371M and ovulation rate (P<0.01). Ewes that were heterozygous for V371M exhibited increased ovulation rate (+0.17, s.e. 0.080; P<0.05) compared to wild type and the effect was non-additive (ovulation rate of heterozygotes was significantly lower (P<0.01) than the mean of the homozygotes). This finding brings to 13 the number of mutations that have large effects on ovulation rate in sheep and to 5, including FecBB, FecGE, FecXO and FecXGR, the number of mutations within the TGFβ superfamily with a positive effect on prolificacy in the homozygous state.

  4. 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

  5. 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

  6. A trade-off between oxidative stress resistance and DNA repair plays a role in the evolution of elevated mutation rates in bacteria.

    PubMed

    Torres-Barceló, Clara; Cabot, Gabriel; Oliver, Antonio; Buckling, Angus; Maclean, R Craig

    2013-04-22

    The dominant paradigm for the evolution of mutator alleles in bacterial populations is that they spread by indirect selection for linked beneficial mutations when bacteria are poorly adapted. In this paper, we challenge the ubiquity of this paradigm by demonstrating that a clinically important stressor, hydrogen peroxide, generates direct selection for an elevated mutation rate in the pathogenic bacterium Pseudomonas aeruginosa as a consequence of a trade-off between the fidelity of DNA repair and hydrogen peroxide resistance. We demonstrate that the biochemical mechanism underlying this trade-off in the case of mutS is the elevated secretion of catalase by the mutator strain. Our results provide, to our knowledge, the first experimental evidence that direct selection can favour mutator alleles in bacterial populations, and pave the way for future studies to understand how mutation and DNA repair are linked to stress responses and how this affects the evolution of bacterial mutation rates.

  7. The effects of sex and mutation rate on adaptation in test tubes and to mouse hosts by Saccharomyces cerevisiae.

    PubMed

    Grimberg, Brian; Zeyl, Clifford

    2005-02-01

    Some hypotheses for the evolution of sex focus on adaptation to changing or heterogeneous environments, but these hypotheses have rarely been tested. We tested for advantages of sex and of increased mutation rates in yeast strains in two contrasting environments: a standard and relatively homogeneous laboratory environment of minimal medium in test tubes, and the variable environment of a mouse brain experienced by pathogenic strains. Evolving populations were founded as equal mixtures of sexual and obligately asexual genotypes. In the sexuals, cycles of sporulation, meiosis, and mating were induced approximately every 50 mitotic generations, with the asexuals undergoing sporulation but not ploidy cycles or recombination. In both environments, replicate negative control populations established with the same pair of strains were propagated with neither mating nor meiosis. In test tubes with no sex induced, sexuals were fixed in all five replicates within 250 mitotic generations, whereas in mice with no sex induced, asexuals were fixed in all four replicates by 170 generations. Inducing sex altered these outcomes in opposite directions in test tubes and mice, decreasing the fixation frequencies of sexuals in test tubes but increasing them in mice. These contrasts with asexual controls suggest an advantage for sex in mice but not in test tubes, although there was no difference between test tubes and mice in the numbers of populations fixed-for sexuals. In analogous experiments testing for an advantage of increased mutation rates, wild-type genotypes became fixed at the expense of mutators in every replicate of both test tube and mouse populations, indicating a disadvantage for mutators in both environments. Increased rates of point mutation do not appear to accelerate adaptation.

  8. The rate of the founder Jewish mutations in BRCA1 and BRCA2 in prostate cancer patients in Israel

    PubMed Central

    Vazina, A; Baniel, J; Yaacobi, Y; Shtriker, A; Engelstein, D; Leibovitz, I; Zehavi, M; Sidi, A A; Ramon, Y; Tischler, T; Livne, P M; Friedman, E

    2000-01-01

    Inherited predisposition occurs in 5–10% of all prostate cancer (CaP) patients, but the genes involved in conferring genetic susceptibility remain largely unknown. Several lines of evidence indicate that germline mutations in BRCA1 and BRCA2 might be associated with an increased risk for CaP. Three mutations in these two genes (185delAG and 5382InsC (BRCA1) and 6174delT (BRCA2) occur in about 2.5% of the general Ashkenazi population, and the 185delAG BRCA1 mutation, in up to 1% of non-Ashkenazi Jews. In order to assess the contribution of these germline mutations to prostate cancer in Jewish Israeli patients, we tested 174 unselected prostate cancer patients (95 of Ashkenazi origin) for these mutations by PCR amplification and modified restriction enzyme digests. Patient’s age range was 45–81 years (median 66), and in 24 (14.4%) the disease was diagnosed prior to 55 years of age. Nineteen (11%) and 12 (6.9%) patients had a first or second degree relative with CaP or breast cancer, respectively. Overall, five mutation carriers were detected: 2/152 (1.3%) 185delAG, 2/104 (2%) 5382InsC, and 1/158 (0.6%) 6174delT. In all carriers, the disease was diagnosed after the age of 55, and only one of them had a family history of breast and CaP. In addition, no allelic losses at the BRCA1 locus were demonstrated in 17 patients with a family history of CaP, using seven microsatellite markers. We conclude that the rate of the predominant Jewish BRCA1 and BRCA2 mutations in CaP patients does not significantly differ from that of the general population, and that mutational inactivation of the BRCA1 is rare in familial CaP. Thus, germline BRCA1 and BRCA2 mutations probably contribute little to CaP occurrence, to inherited predisposition, and to early onset disease in Jewish individuals. © 2000 Cancer Research Campaign PMID:10945492

  9. 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.

  10. Imbalanced deoxyribonucleoside triphosphate pools and spontaneous mutation rates determined during dCMP deaminase-defective bacteriophage T4 infections.

    PubMed

    Sargent, R G; Mathews, C K

    1987-04-25

    DNA precursor imbalances are known to be mutagenic in both eukaryotic and prokaryotic systems. Almost certainly, such mutagenesis involves competition between correctly and incorrectly base-paired precursors at replication sites. Since other factors may be involved, it is important to identify specific mutations induced by specific pool imbalances. Using bacteriophage T4, we have developed a system for such analysis. We prepare double mutants of T4; one mutation affects a phage-coded enzyme of deoxyribonucleoside triphosphate (dNTP) metabolism, while the second is an rII mutation known to revert along a specific pathway. We determine dNTP pools in infection by such a mutant and measure both the spontaneous reversion rate of the rII mutation and, in some cases, the nucleotide sequence at the mutant site. In this paper we analyze mutations induced by a deficiency of T4-encoded deoxycytidylate deaminase. This causes pools of 5-hydroxymethyl-dCTP to expand some 30-fold, while dTTP pools contract. This specifically stimulates AT-to-GC reversion. One of the four AT-to-GC reverters tested, rIIUV215, increases its reversion rate at least 1000-fold under these pool-imbalance conditions, while the other mutants tested show increases of only about 10-fold. Therefore, factors other than dNTP competition, including local DNA sequence environment, must be invoked to fully explain mechanisms of dNTP pool imbalance-induced mutagenesis. We discuss models for this, and we also report unexpected effects of the dCMP deaminase deficiency upon pools of ribonucleoside triphosphates. PMID:3553179

  11. 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

  12. Description and validation of a method for simultaneous estimation of effective population size and mutation rate from human population data.

    PubMed Central

    Chakraborty, R; Neel, J V

    1989-01-01

    A method is presented for utilizing population data on electrophoretic variants of proteins to estimate simultaneously the effective sizes (Ne values) of the populations in question and the rate of mutation resulting in electromorphs at the loci whose products were surveyed. The method is applied to data from 12 relatively unacculturated Amerindian tribes for whom census data and independent estimates of the number of different electrophoretic variants at 27 loci are available. Because of tribal demographic structure, Ne should be less than the current number of reproductive-aged adults. In fact, it is substantially greater for 7 tribes, most likely due to intertribal migration and a recent decrease in tribal size. Estimates of locus mutation rates for the 27 loci vary by more than a factor of 20, with an average of 1.1 x 10(-5) per locus per generation. This latter estimate is in satisfactory agreement with the results of other indirect approaches to the estimation of mutation rates in these tribes but about two times higher than the results of direct estimates based on these same loci in studies on civilized populations. This discrepancy could be due to the above-hypothesized migration and to decreases in tribal size. PMID:2594777

  13. Force-induced on-rate switching and modulation by mutations in gain-of-function von Willebrand diseases

    PubMed Central

    Kim, Jongseong; Hudson, Nathan E.; Springer, Timothy A.

    2015-01-01

    Mutations in the ultralong vascular protein von Willebrand factor (VWF) cause the common human bleeding disorder, von Willebrand disease (VWD). The A1 domain in VWF binds to glycoprotein Ibα (GPIbα) on platelets, in a reaction triggered, in part, by alterations in flow during bleeding. Gain-of-function mutations in A1 and GPIbα in VWD suggest conformational regulation. We report that force application switches A1 and/or GPIbα to a second state with faster on-rate, providing a mechanism for activating VWF binding to platelets. Switching occurs near 10 pN, a force that also induces a state of the receptor−ligand complex with slower off-rate. Force greatly increases the effects of VWD mutations, explaining pathophysiology. Conversion of single molecule kon (s−1) to bulk phase kon (s−1M−1) and the kon and koff values extrapolated to zero force for the low-force pathways show remarkably good agreement with bulk-phase measurements. PMID:25810255

  14. Force-induced on-rate switching and modulation by mutations in gain-of-function von Willebrand diseases.

    PubMed

    Kim, Jongseong; Hudson, Nathan E; Springer, Timothy A

    2015-04-14

    Mutations in the ultralong vascular protein von Willebrand factor (VWF) cause the common human bleeding disorder, von Willebrand disease (VWD). The A1 domain in VWF binds to glycoprotein Ibα (GPIbα) on platelets, in a reaction triggered, in part, by alterations in flow during bleeding. Gain-of-function mutations in A1 and GPIbα in VWD suggest conformational regulation. We report that force application switches A1 and/or GPIbα to a second state with faster on-rate, providing a mechanism for activating VWF binding to platelets. Switching occurs near 10 pN, a force that also induces a state of the receptor-ligand complex with slower off-rate. Force greatly increases the effects of VWD mutations, explaining pathophysiology. Conversion of single molecule kon (s(-1)) to bulk phase kon (s(-1)M(-1)) and the kon and koff values extrapolated to zero force for the low-force pathways show remarkably good agreement with bulk-phase measurements.

  15. 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.

  16. Paternal Age Explains a Major Portion of De Novo Germline Mutation Rate Variability in Healthy Individuals

    PubMed Central

    Bourassa, Cynthia V.; Lemieux Perreault, Louis-Philippe; Legault, Marc-André; Barhdadi, Amina; Ambalavanan, Amirthagowri; Brendgen, Mara; Vitaro, Frank; Noreau, Anne; Dionne, Ginette; Tremblay, Richard E.; Dion, Patrick A.; Boivin, Michel; Dubé, Marie-Pierre; Rouleau, Guy A.

    2016-01-01

    De novo mutations (DNM) are an important source of rare variants and are increasingly being linked to the development of many diseases. Recently, the paternal age effect has been the focus of a number of studies that attempt to explain the observation that increasing paternal age increases the risk for a number of diseases. Using disease-free familial quartets we show that there is a strong positive correlation between paternal age and germline DNM in healthy subjects. We also observed that germline CNVs do not follow the same trend, suggesting a different mechanism. Finally, we observed that DNM were not evenly distributed across the genome, which adds support to the existence of DNM hotspots. PMID:27723766

  17. 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

  18. 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

  19. 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

  20. 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

  1. The Effective Mutation Rate at Y Chromosome Short Tandem Repeats, with Application to Human Population-Divergence Time

    PubMed Central

    Zhivotovsky, Lev A.; Underhill, Peter A.; Cinnioğlu, Cengiz; Kayser, Manfred; Morar, Bharti; Kivisild, Toomas; Scozzari, Rosaria; Cruciani, Fulvio; Destro-Bisol, Giovanni; Spedini, Gabriella; Chambers, Geoffrey K.; Herrera, Rene J.; Yong, Kiau Kiun; Gresham, David; Tournev, Ivailo; Feldman, Marcus W.; Kalaydjieva, Luba

    2004-01-01

    We estimate an effective mutation rate at an average Y chromosome short-tandem repeat locus as 6.9×10-4 per 25 years, with a standard deviation across loci of 5.7×10-4, using data on microsatellite variation within Y chromosome haplogroups defined by unique-event polymorphisms in populations with documented short-term histories, as well as comparative data on worldwide populations at both the Y chromosome and various autosomal loci. This value is used to estimate the times of the African Bantu expansion, the divergence of Polynesian populations (the Maoris, Cook Islanders, and Samoans), and the origin of Gypsy populations from Bulgaria. PMID:14691732

  2. 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.

  3. 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

  4. 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.

  5. Quantitative determination of decitabine incorporation into DNA and its effect on mutation rates in human cancer cells.

    PubMed

    Öz, Simin; Raddatz, Günter; Rius, Maria; Blagitko-Dorfs, Nadja; Lübbert, Michael; Maercker, Christian; Lyko, Frank

    2014-10-29

    Decitabine (5-aza-2'-deoxycytidine) is a DNA methyltransferase inhibitor and an archetypal epigenetic drug for the therapy of myeloid leukemias. The mode of action of decitabine strictly depends on the incorporation of the drug into DNA. However, DNA incorporation and ensuing genotoxic effects of decitabine have not yet been investigated in human cancer cell lines or in models related to the approved indication of the drug. Here we describe a robust assay for the quantitative determination of decitabine incorporation rates into DNA from human cancer cells. Using a panel of human myeloid leukemia cell lines we show appreciable amounts of decitabine incorporation that closely correlated with cellular drug uptake. Decitabine incorporation was also detectable in primary cells from myeloid leukemia patients, indicating that the assay is suitable for biomarker analyses to predict drug responses in patients. Finally, we also used next-generation sequencing to comprehensively analyze the effects of decitabine incorporation on the DNA sequence level. Interestingly, this approach failed to reveal significant changes in the rates of point mutations and genome rearrangements in myeloid leukemia cell lines. These results indicate that standard rates of decitabine incorporation are not genotoxic in myeloid leukemia cells.

  6. Imposed-Dynamo Current Drive (IDCD)

    NASA Astrophysics Data System (ADS)

    Jarboe, Thomas; Victor, Brian; Nelson, Brian; Hansen, Chris; Akcay, Cihan; Ennis, David; Hossack, Aaron; Marklin, George; Smith, Roger

    2012-10-01

    A mechanism for Steady Inductive Helicity Injection (SIHI) current drive has been discovered where the current driving fluctuations are not generated by the plasma but rather are imposed by the injectors.[T.R. Jarboe et al., accepted for publication in Nuclear Fusion] Sheared flow of the electron fluid distorts the imposed fluctuations to drive current. The model accurately predicts the time dependent toroidal current, the injector impedance scaling, and the profile produced in the HIT-SI experiment. These results show that a stable equilibrium can be efficiently sustained with imposed fluctuations and the current profile can, in principle, be controlled. Both are large steps for controlled fusion. Some of the effects of the fluctuations on the confinement of tokamak and spheromak reactors are assessed and the degradation may be tolerable since the required fluctuations, in a reactor, are low (deltaB/B about 0.0001). A larger experiment (HIT-PoP) designed to test the confinement properties of a plasma sustained by IDCD is discussed. Since these very low fluctuation levels can provide current drive for the entire plasma the effect of random fluctuations on the plasma current profile is extremely important. The mechanism is also of interest to plasma self-organization, fast reconnection and plasma physics in general.

  7. Epistasis, pleiotropy, and the mutation load in sexual and asexual populations.

    PubMed

    Roze, Denis; Blanckaert, Alexandre

    2014-01-01

    Mutation may impose a substantial load on populations, which varies according to the reproductive mode of organisms. Over the past years, various authors used adaptive landscape models to predict the long-term effect of mutation on mean fitness; however, many of these studies assumed very weak mutation rates, so that at most one mutation segregates in the population. In this article, we derive several simple approximations (confirmed by simulations) for the mutation load at high mutation rate (U), using a general model that allows us to play with the number of selected traits (n), the degree of pleiotropy of mutations, and the shape of the fitness function (which affects the average sign and magnitude of epistasis among mutations). When mutations have strong fitness effects, the equilibrium fitness W¯ of sexuals and asexuals is close to e(-U); under weaker mutational effects, sexuals reach a different regime where W¯ is a simple function of U and of a parameter describing the shape of the fitness function. Contrarily to weak mutation results showing that W¯ is an increasing function of population size and a decreasing function of n, these parameters may have opposite effects in sexual populations at high mutation rate.

  8. 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

  9. Impact of BRCA1/2 mutation on young women's 5-year parenthood rates: a prospective comparative study (GENEPSO-PS cohort).

    PubMed

    Mancini, Julien; Mouret-Fourme, Emmanuelle; Noguès, Catherine; Julian-Reynier, Claire

    2015-06-01

    Previous qualitative and intentions surveys have shown that the disclosure of a BRCA1/2 mutation might deter young women from becoming pregnant. However, to our knowledge, no comparative studies have ever documented the possibility that positive genetic test results might affect these women's future reproductive rates. Our aim was therefore to quantify the impact of BRCA1/2 mutation disclosure on long-term relationships between partners and childbearing rates. Participants were cancer-free women belonging to families in which a deleterious BRCA1/2 mutation had been identified, who had attended one of the 29 participating cancer genetic clinics for BRCA1/2 testing between 2000 and 2006. Logistic regression models were used to determine predictors of the 5-year self-reported parenthood rate. The sample consisted of 271 women aged 18-45 years (126 BRCA1/2 mutation carriers and 145 non-carriers). Couples had separated more frequently among BRCA1/2 carriers than non-carriers (10 vs. 3%, p = .040), especially among nulliparous carriers (13%). Among the 104 women who were childless at disclosure, disclosure of a BRCA1/2 mutation was not significantly associated with childbearing during the 5-year follow-up period [adjusted odds ratio .64, 95% confidence interval (CI) (.26, 1.57), p = .334]. Among the 167 women with at least one child at disclosure of a BRCA1/2 mutation had no conspicuous effect on the childbearing trends [adjOR .88, 95% CI (.35, 2.21), p = .787]. The disclosure of a BRCA1/2 mutation might impact couples' relationships and future mothering rates, particularly among nulliparous women. Studies on larger populations are now required to confirm these findings.

  10. 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.

  11. The effect of low-dose exposure on germline microsatellite mutation rates in humans accidentally exposed to caesium-137 in Goiânia.

    PubMed

    Costa, Emília Oliveira Alves; de Melo e Silva, Daniela; de Melo, Aldaires Vieira; Godoy, Fernanda Ribeiro; Nunes, Hugo Freire; Pedrosa, Eduardo Rocha; Flores, Braúlio Cançado; Rodovalho, Ricardo Goulart; da Silva, Cláudio Carlos; da Cruz, Aparecido Divino

    2011-09-01

    A serious radiological accident occurred in 1987 in Goiânia, Brazil, which lead to extensive human and environmental contamination as a result of ionising radiation (IR) from caesium-137. Among the exposed were those in direct contact with caesium-137, their relatives, neighbours, liquidators and health personnel involved in the handling of the radioactive material and the clean-up of the radioactive sites. The exposed group consisted of 10 two-generation families, totalling 34 people. For each exposed family, at least one of the progenitors was directly exposed to very low doses of γ-IR. The control group consisted of 215 non-irradiated families, composed of a father, mother and child, all of them from Goiânia, Brazil. Genomic DNA was purified using 100 μl of whole blood. The amplification reactions were prepared according to PowerPlex® 16, following the manufacturer's instructions. Genetic profiles were obtained from a single polymerase chain reaction amplification. The exposed group had only one germline mutation of a paternal origin in the 'locus' D8S1179 and the observed mutation presented a gain of only one repeat unit. In the control group, 11 mutations were observed and the mutational events were distributed in five loci D16S539, D3S1358, FGA, Penta E and D21S11. The mutation rates for the exposed and control groups were 0.006 and 0.002, respectively. There was no statistically significant difference (P = 0.09) between the mutation rate of the exposed and control groups. In conclusion, the quantification of mutational events in short tandem repeats can provide a useful system for detecting induced mutations in a relatively small population.

  12. Mutation rate in Velvet tobacco mottle virus varies between genomic region and virus variant but is not influenced by obligatory mirid transmission.

    PubMed

    Arthur, K; Collins, N C; Randles, J W

    2012-12-01

    Genomic mutation in plant viruses of cultivated plants is known to be influenced by virus, host and vector, but the factors influencing mutation in viruses of native plants in natural ecosystems are rarely studied. We have tested the effect of mode of transmission on mutation in Velvet tobacco mottle virus (VTMoV), a mirid-vectored sobemovirus associated with Nicotiana velutina, an Australian native xerophyte growing in a region isolated from anthropogenic influences. Two variants of VTMoV (K1 and R17) were passaged monthly in the alternative experimental plant host, N. clevelandii, for 2 years, either by mechanical inoculation or by transmission with the mirid Cyrtopeltis nicotianae. Sequence variations were scored after 24 passages in regions of the genome containing the open reading frames (ORFs) for the P1 and coat protein (CP). The mean mutation rate was 6.83 × 10(-4) nt/site year, but a higher overall rate was observed for the K1 (satellite -) than the R17 (satellite +) variant. The P1 ORF showed a higher frequency of non-synonymous mutations than the CP. No clear association was found between either mutation site or mutation rate and the mode of transmission, indicating that obligatory mirid transmission had not exerted a specific bottle-neck effect on sequence variation during the experimental time frame. Failure to detect any sequence motifs linked to vector transmission suggests that a specific capsid-stylet interaction is not required for transmission by mirids. PMID:22983896

  13. 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

  14. 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

  15. Mutation accumulation and fitness in mutator subpopulations of Escherichia coli.

    PubMed

    Maharjan, Ram P; Liu, Bin; Li, Yang; Reeves, Peter R; Wang, Lei; Ferenci, Thomas

    2013-02-23

    Bacterial populations in clinical and laboratory settings contain a significant proportion of mutants with elevated mutation rates (mutators). Mutators have a particular advantage when multiple beneficial mutations are needed for fitness, as in antibiotic resistance. Nevertheless, high mutation rates potentially lead to increasing numbers of deleterious mutations and subsequently to the decreased fitness of mutators. To test how fitness changed with mutation accumulation, genome sequencing and fitness assays of nine Escherichia coli mutY mutators were undertaken in an evolving chemostat population at three time points. Unexpectedly, the fitness in members of the mutator subpopulation became constant despite a growing number of mutations over time. To test if the accumulated mutations affected fitness, we replaced each of the known beneficial mutations with wild-type alleles in a mutator isolate. We found that the other 25 accumulated mutations were not deleterious. Our results suggest that isolates with deleterious mutations are eliminated by competition in a continuous culture, leaving mutators with mostly neutral mutations. Interestingly, the mutator-non-mutator balance in the population reversed after the fitness plateau of mutators was reached, suggesting that the mutator-non-mutator ratio in populations has more to do with competition between members of the population than the accumulation of deleterious mutations.

  16. 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

  17. 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

  18. A genetic study of von Recklinghausen neurofibromatosis in south east Wales. I. Prevalence, fitness, mutation rate, and effect of parental transmission on severity.

    PubMed Central

    Huson, S M; Compston, D A; Clark, P; Harper, P S

    1989-01-01

    A population based study of von Recklinghausen neurofibromatosis in south east Wales (population 668,100) identified 69 families with 135 affected members (prevalence 1/4950 of the population). In these families penetrance of the NF-1 gene was 100% by the age of five years. The genetic fitness of NF-1 sufferers was found to be reduced to 0.47, the effect being more marked in males than females (f = 0.31 and 0.60, respectively). Forty-one of 135 cases were judged to represent new disease mutations and the mutation rate was estimated to lie between 3.1 x 10(-5) and 10.4 x 10(-5). A parental age effect for new mutations was not found, nor was a maternal effect on disease severity. PMID:2511318

  19. Population data and mutation rate of nine Y-STRs in a mestizo Mexican population from Guadalajara, Jalisco, México.

    PubMed

    Padilla-Gutiérrez, Jorge Ramón; Valle, Yeminia; Quintero-Ramos, Antonio; Hernández, Guillermo; Rodarte, Katya; Ortiz, Rocío; Olivares, Norma; Rivas, Fernando

    2008-11-01

    Nine Y-STR (DYS19, DYS390, DYS391, DYS392, DYS446, DYS447, DYS448, DYS456 and DYS458) were analyzed in a male sample of 285 unrelated individuals from Guadalajara, Jalisco, México. The haplotype diversity (0.996) and discrimination capacity (0.986) were calculated. A family study of around 200 father/son pairs and among 1828 meiosis showed five mutational events. All mutations were single step. The overall mutation rate estimated across the nine Y-STRs was 2.7 x 10(-3) (95% CI 1.2-6.4 x 10(-3))/locus/meiosis. The results indicate that these nine loci are useful Y-linked markers for forensic applications.

  20. Imposing deviant immunity on the presensitized state.

    PubMed

    Kosiewicz, M M; Okamoto, S; Miki, S; Ksander, B R; Shimizu, T; Streilein, J W

    1994-10-01

    Delayed hypersensitivity (DH) is an important immune effector modality that successfully wards off intracellular pathogens and many parasites, but also causes immunopathogenic injury to vital tissues. Particularly in the eye, DH has devastating effects that can lead to blindness. Ags injected into the anterior chamber of the eye of naive mice elicit a deviant form of systemic immunity in which DH is selectively down-regulated. Expression of DH in this model system is curtailed by regulatory CD8+ T cells. At present, we have determined whether injection of Ag into the anterior chamber of eyes of specifically sensitized mice also impairs DH expression. Our results indicate that DH is blunted or eliminated in previously primed mice when heterologous proteins, retinal autoantigens, or minor histocompatibility Ags are injected into the anterior chamber. Suppression is achieved in this system by Ag-specific CD8+ T cells, and failed DH can be imposed on immunized mice by i.v. injections of peritoneal exudate cells pulsed with Ag in vitro in the presence of TGF-beta. Thus, the immune regulatory mechanisms that operate to protect the eye from immunogenic inflammation can be invoked in previously sensitized mice. In addition, tolerance could not be generated in presensitized mice by either i.v. injection of soluble Ag or painting of hapten on UVB-exposed skin. It seems that the strategies used by the eye to create a deviant state of immunity in the face of pre-existing conventional immunity may be unique.

  1. Prevention of avoidable mutational diseases: Memorandum from a WHO Meeting*

    PubMed Central

    1986-01-01

    About 1% of children are born with a serious disorder which is the direct result of a mutational event in a parent or a more distant ancestor. These disorders, of which several thousand are known, mainly afflict the blood, bone, brain, ear, eye or muscle and the changes are usually irrevocable by the time of diagnosis. Another 1% of individuals will develop a serious genetic disease some time after birth. In addition to these direct consequences of a mutant event, far higher proportions will suffer from the indirect effects of one or several mutations. In view of their chronic and severe nature most of these disorders impose a burden disproportionate to their frequency, and it is sound public health policy to avoid the birth of babies known to have the established mutations and prevent further cases in the immediate or distant future by minimizing the exposure of people at risk to known mutagens. The advantages in permitting certain mutagenic exposures must be assessed against the later costs. Owing to the natural mutation rate and the vast backlog of previous mutations, the prospects of prevention are limited to preventing an increase, rather than to achieving any substantial decrease. This Memorandum describes progress in the ability to dissect and interpret the mutational process, to identify populations at risk, and to evaluate the consequences of the various types of mutational event and emphasizes that the current approach to prevention of mutational disease must involve improving our ability to study populations that appear to be at increased risk. PMID:3488837

  2. Mutation rates for unbalanced Robertsonian translocations associated with Down syndrome. Evidence for a temporal change in New York State live births 1968--1977.

    PubMed Central

    Hook, E B; Albright, S G

    1981-01-01

    The mutation rate for translocation Down syndrome was investigated for New York State live births for each of the years 1968--1977 using data from the New York State Chromosome Registry. The overall rate was 2.5 X 10(-5) per gamete (1.4 X 10(-5) for G/21 and 1.0 X 10(-5) for D/21 rearrangements), about 20% higher than rates previously reported by two other studies. For the first 5-year period, 1968--1972, the rate was 1.8 X 10(-5), and for the second 5-year period, 3.1 X 10(-5); there was an abrupt change in 1973 and 1974 to rates more than twice that in the 3 preceding years. These rates were derived by applying completeness estimates for all cases of Down syndrome, mostly 47,trisomy 21, in the jurisdiction to cases with translocation Down syndrome mutations. If completeness corrections are ignored and only the minimum boundaries of rates are considered, however, the increase in 1973 and 1974 was even greater compared with the previous 3 years. The trends, if not attributable to an undetected artifact, may have been caused by an increased frequency of mutant zygotes and/or enhanced intrauterine survival of mutant translocations. PMID:6454341

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

    DOE PAGES

    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

  4. 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

  5. Lower carrier rate of GJB2 W24X ancestral Indian mutation in Roma samples from Hungary: implication for public health intervention.

    PubMed

    Sipeky, Csilla; Matyas, Petra; Melegh, Marton; Janicsek, Ingrid; Szalai, Renata; Szabo, Istvan; Varnai, Reka; Tarlos, Greta; Ganczer, Alma; Melegh, Bela

    2014-09-01

    The purpose of this work was to characterise the W24X mutation of the GJB2 gene in order to provide more representative and geographicaly relevant carrier rates of healthy Roma subisolates and the Hungarian population. 493 Roma and 498 Hungarian healthy subjects were genotyped for the GJB2 c.71G>A (rs104894396, W24X) mutation by PCR-RFLP assay and direct sequencing. This is the first report on GJB2 W24X mutation in geographically subisolated Roma population of Hungary compared to local Hungarians. Comparing the genotype and allele frequencies of GJB2 rs104894396 mutation, significant difference was found in GG (98.4 vs. 99.8 %), GA (1.62 vs. 0.20 %) genotypes and A (0.8 vs. 0.1 %) allele between the Roma and Hungarian populations, respectively (p < 0.02). None of the subjects of Roma and Hungarian samples carried the GJB2 W24X AA genotype. Considerable result of our study, that the proportion of GJB2 W24X GA heterozygotes and the A allele frequency was eight times higher in Roma than in Hungarians. Considering the results, the mutant allele frequency both in Roma (0.8 %) and in Hungarian (0.1 %) populations is lower than expected from previous results, likely reflecting local differentiated subisolates of these populations and a suspected lower risk for GJB2 mutation related deafness. However, the significant difference in GJB2 W24X carrier rates between the Roma and Hungarians may initiate individual diagnostic investigations and effective public health interventions. PMID:24969484

  6. 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.

  7. 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.

  8. Altered promoter recycling rates contribute to dominant-negative activity of human peroxisome proliferator-activated receptor-gamma mutations associated with diabetes.

    PubMed

    Li, Gang; Leff, Todd

    2007-04-01

    The transcription factor peroxisome proliferator-activated receptor-gamma (PPARgamma) plays an important role in regulating lipid and glucose metabolism and improves insulin sensitivity in diabetic patients when activated by thiazolidinedione drugs. Several loss-of-function mutations in PPARgamma have been identified that cause lipodystrophy and diabetes in humans. Because affected individuals are heterozygotes and have one normal PPARgamma allele, it is of interest to know whether these mutations act in a dominant-negative fashion to inhibit the activity of the wild-type (WT) receptor. Here we compare the molecular phenotypes of two previously identified PPARgamma mutations: P467L, reported to be dominant negative; and F388L, reported to be devoid of dominant-negative activity. We developed a competitive chromatin immunoprecipitation assay to measure the relative ability of mutant PPARgamma to compete with WT receptor for binding to a PPAR regulatory element (PPRE)-containing promoter. By determining the ratio of mutant and WT receptors bound to a PPRE over time, we estimated the relative promoter turnover rate of each receptor. This assay demonstrated that PPARgamma bearing the P467L had a reduced promoter turnover rate compared with the F388L receptor, and over time out-competed the WT receptor for promoter binding sites. We propose that the P467L receptor is dominant negative because in a cell containing both WT and mutant receptors, the majority of the PPAR-regulated promoters will be occupied by the transcriptionally defective mutant receptor. In contrast, the F388L mutation lacks dominant-negative activity because its more rapid promoter turnover rate prevented it from out-competing the WT receptor for promoter binding sites.

  9. Reversion of somatic mutations of the respiratory syncytial virus-specific human monoclonal antibody Fab19 reveal a direct relationship between association rate and neutralizing potency.

    PubMed

    Bates, John T; Keefer, Christopher J; Utley, Thomas J; Correia, Bruno E; Schief, William R; Crowe, James E

    2013-04-01

    The role of affinity in determining neutralizing potency of mAbs directed against viruses is not well understood. We investigated the kinetic, structural, and functional advantage conferred by individual naturally occurring somatic mutations in the Ab H chain V region of Fab19, a well-described neutralizing human mAb directed to respiratory syncytial virus. Comparison of the affinity-matured Ab Fab19 with recombinant Fab19 Abs that were variants containing reverted amino acids from the inferred unmutated ancestor sequence revealed the molecular basis for affinity maturation of this Ab. Enhanced binding was achieved through mutations in the third H chain CDR (HCDR3) that conferred a markedly faster on-rate and a desirable increase in antiviral neutralizing activity. In contrast, most somatic mutations in the HCDR1 and HCDR2 regions did not significantly enhance Ag binding or antiviral activity. We observed a direct relationship between the measured association rate (Kon) for F protein and antiviral activity. Modeling studies of the structure of the Ag-Ab complex suggested the HCDR3 loop interacts with the antigenic site A surface loop of the respiratory syncytial virus F protein, previously shown to contain the epitope for this Ab by experimentation. These studies define a direct relationship of affinity and neutralizing activity for a viral glycoprotein-specific human mAb.

  10. 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

  11. 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

  12. Self-imposed length limits in recreational fisheries

    USGS Publications Warehouse

    Chizinski, Christopher J.; Martin, Dustin R.; Hurley, Keith L.; Pope, Kevin L.

    2014-01-01

    A primary motivating factor on the decision to harvest a fish among consumptive-orientated anglers is the size of the fish. There is likely a cost-benefit trade-off for harvest of individual fish that is size and species dependent, which should produce a logistic-type response of fish fate (release or harvest) as a function of fish size and species. We define the self-imposed length limit as the length at which a captured fish had a 50% probability of being harvested, which was selected because it marks the length of the fish where the probability of harvest becomes greater than the probability of release. We assessed the influences of fish size, catch per unit effort, size distribution of caught fish, and creel limit on the self-imposed length limits for bluegill Lepomis macrochirus, channel catfish Ictalurus punctatus, black crappie Pomoxis nigromaculatus and white crappie Pomoxis annularis combined, white bass Morone chrysops, and yellow perch Perca flavescens at six lakes in Nebraska, USA. As we predicted, the probability of harvest increased with increasing size for all species harvested, which supported the concept of a size-dependent trade-off in costs and benefits of harvesting individual fish. It was also clear that probability of harvest was not simply defined by fish length, but rather was likely influenced to various degrees by interactions between species, catch rate, size distribution, creel-limit regulation and fish size. A greater understanding of harvest decisions within the context of perceived likelihood that a creel limit will be realized by a given angler party, which is a function of fish availability, harvest regulation and angler skill and orientation, is needed to predict the influence that anglers have on fish communities and to allow managers to sustainable manage exploited fish populations in recreational fisheries.

  13. 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

  14. Disentangling the effects of mating systems and mutation rates on cytoplasmic [correction of cytoplamic] diversity in gynodioecious Silene nutans and dioecious Silene otites.

    PubMed

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

    2013-08-01

    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.

  15. Effect of an E461G mutation of beta-galactosidase (Escherichia coli, lac Z) on pL rate profiles and solvent deuterium isotope effects.

    PubMed

    Richard, J P; Huber, R E; McCall, D A

    2001-06-01

    An E461G mutation of beta-galactosidase results in the disappearance of the high pL (L = H, D) downward break in the rate profiles for k(cat)/K(m) for wild-type enzyme-catalyzed hydrolysis of 4-nitrophenyl beta-D-galactopyranoside (Gal-OPNP) and a decrease from (k(cat))(HOH)/(k(cat))(DOD) = 1.7 to (k(cat))(HOH)/(k(cat))(DOD) = 1.2 in the solvent deuterium isotope effect. These observations provide evidence that the propionic acid side chain of Glu 461 is protonated at catalytically active free beta-galactosidase and they are consistent with a role for this residue in Brønsted acid catalysis at the leaving group. The earlier observation that this same E461G mutation results in the loss of a downward break at high pH in the rate profile for k(s) for transfer of the beta-D-galactopyranosyl group from beta-galactosidase to water cannot be simply explained by a mechanism in which the single side chain of Glu 461 functions to provide general acid catalysis in the rate limiting step for formation of the beta-D-galactopyranosyl intermediate and general base catalysis of breakdown of this intermediate. Evidence is presented that there may be different catalytic mechanisms, with different roles for the side chain for Glu-461, for nucleophilic addition of water and of small alkyl alcohols to the beta-D-galactopyranosyl reaction intermediate.

  16. 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

  17. 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

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

    PubMed

    Bauch, Chris T; McElreath, Richard

    2016-04-05

    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.

  19. 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.

  20. 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

  1. 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

  2. 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.

  3. 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.

  4. Evolution of Imposed Vortices Over Concave Surfaces in Hypervelocity Flow

    NASA Astrophysics Data System (ADS)

    Flaherty, William; Austin, Joanna

    2012-11-01

    Steamwise oriented vortices in the boundary layer of a hypersonic flow have the potential to affect heat transfer and skin friction significantly. These effects can be exacerbated by the addition of extra strain rates associated with concave surface curvature. Vortices can either occur naturally (in the form of Goertler vortices), or be introduced by some form of mechanical distortion (such as a protuberance). In this work we experimentally investigate the effect of concave surface curvature on the propagation of imposed vortices. These experiments are carried out in the Hypervelocity Expansion Tube at the University of Illinois. This facility is capable of generating flows with high enthalpies (4-9MJ/kg) and Mach numbers (3-7). Using a novel, fast-response pressure sensitive paint we are able to observe the development of vortices which are induced using diamond-shaped vortex generators. Models with varying amount of surface curvature (encompassing Goertler numbers between 10-22) are used to investigate the dynamics of vortex propagation and interaction. Our results show that the vortices remain attached and of constant strength for 10-12cm (80 boundary layer thicknesses) along the curved surfaces, while on flat plates the vortices are no longer apparent within 6 cm downstream.

  5. 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.

  6. 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.

  7. 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

  8. The L76V drug resistance mutation decreases the dimer stability and rate of autoprocessing of HIV-1 protease by reducing internal hydrophobic contacts.

    PubMed

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

    2011-05-31

    The mature HIV-1 protease (PR) bearing the L76V drug resistance mutation (PR(L76V)) is significantly less stable, with a >7-fold higher dimer dissociation constant (K(d)) of 71 ± 24 nM and twice the sensitivity to urea denaturation (UC(50) = 0.85 M) relative to those of PR. Differential scanning calorimetry showed decreases in T(m) of 12 °C for PR(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, ∼160-fold higher than that of PR, consistent with DRV resistance. Crystal structures of PR(L76V) in complexes with DRV and SQV were determined at resolutions of 1.45-1.46 Å. 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(L76V) relative to PR, possibly accounting for the resistance to DRV. SQV shows slightly improved polar interactions with PR(L76V) compared to those with PR. Although the L76V mutation significantly slows the N-terminal autoprocessing of the precursor TFR-PR(L76V) to give rise to the mature PR(L76V), the coselected M46I mutation counteracts the effect by enhancing this rate but renders the TFR-PR(M46I/L76V) precursor less responsive to inhibition by 6 μM LPV while preserving inhibition by SQV and DRV. The correlation of lowered stability, higher K(d), and impaired autoprocessing with reduced internal hydrophobic contacts suggests a novel molecular mechanism for drug resistance.

  9. 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.

  10. Estimation of the deamidation rates of major deamidation sites in a Fab fragment of mouse IgG1-κ by capillary isoelectric focusing of mutated Fab fragments.

    PubMed

    Shimura, Kiyohito; Hoshino, Makoto; Kamiya, Keiichiro; Enomoto, Manabu; Hisada, Sunao; Matsumoto, Hiroyuki; Novotny, Mark; Kasai, Ken-ichi

    2013-02-01

    The deamidation of asparagine (Asn or N) residues in proteins is a common post-translational chemical modification. The identification of deamidation sites and determination of the degree of deamidation have been carried out by the combination of peptide mapping and mass spectrometry. However, when a peptide fragment contains multiple amides, such analysis becomes difficult and sometimes impossible. In this report, a quantitative method for estimating the deamidation rate of a specific amide in a protein is presented without using peptide mapping. Five Asn residues of a recombinant fragment antigen binding (rFab) (mouse IgG1, κ) were mutated to a serine (Ser) residue, one by one, through site-directed mutagenesis, and the single-residue deamidation rates of the original rFab and the mutants were determined using capillary isoelectric focusing. The difference of the rate between the original rFab and the mutant was assumed to be equal to the deamidation rate of the specific Asn residue, which had been mutated. Among five mutants established, three major deamidation sites-H chain Asn135, L chain Asn157, and L chain Asn161, using the Kabat numbering system-were identified, accounting for 66%, 29%, and 7% of the single-residue deamidation of the original rFab, respectively. Although the former two have been known by peptide mapping, the last one, which resides on the same tryptic peptide that carries one of the former two, previously has not been identified. For the first time, the deamidation rate constants of the three sites were estimated to be 10.5 × 10(-3) h(-1), 4.6 × 10(-3) h(-1), and 1.1 × 10(-3) h(-1) in 0.1 M phosphate buffer, pH 7.5 at 37 °C, respectively, with corresponding half-life of 2.8 days, 6.3 days, and 27 days. The method should be applicable to any recombinant proteins. PMID:23278172

  11. Mutation in bone morphogenetic protein receptor-IB is associated with increased ovulation rate in Booroola Mérino ewes

    PubMed Central

    Mulsant, Philippe; Lecerf, Frédéric; Fabre, Stéphane; Schibler, Laurent; Monget, Philippe; Lanneluc, Isabelle; Pisselet, Claudine; Riquet, Juliette; Monniaux, Danielle; Callebaut, Isabelle; Cribiu, Edmond; Thimonier, Jacques; Teyssier, Jacques; Bodin, Loys; Cognié, Yves; Chitour, Nour; Elsen, Jean-Michel

    2001-01-01

    Ewes from the Booroola strain of Australian Mérino sheep are characterized by high ovulation rate and litter size. This phenotype is due to the action of the FecBB allele of a major gene named FecB, as determined by statistical analysis of phenotypic data. By genetic analysis of 31 informative half-sib families from heterozygous sires, we showed that the FecB locus is situated in the region of ovine chromosome 6 corresponding to the human chromosome 4q22–23 that contains the bone morphogenetic protein receptor IB (BMPR-IB) gene encoding a member of the transforming growth factor-β (TGF-β) receptor family. A nonconservative substitution (Q249R) in the BMPR-IB coding sequence was found to be associated fully with the hyperprolificacy phenotype of Booroola ewes. In vitro, ovarian granulosa cells from FecBB/FecBB ewes were less responsive than granulosa cells from FecB+/FecB+ ewes to the inhibitory effect on steroidogenesis of GDF-5 and BMP-4, natural ligands of BMPR-IB. It is suggested that in FecBB/FecBB ewes, BMPR-IB would be inactivated partially, leading to an advanced differentiation of granulosa cells and an advanced maturation of ovulatory follicles. PMID:11320249

  12. Law & psychiatry: imposed insanity defenses and political crimes.

    PubMed

    Appelbaum, Paul S

    2013-01-01

    Anders Breivik's murder of 77 people in Norway in 2011 led to an unusual clash of interests. With conflicting psychiatric reports regarding his sanity, prosecutors argued that Breivik should be found not guilty by reason of insanity, whereas the defense strongly maintained that he was sane and responsible for his actions. Imposing an insanity defense on an unwilling defendant pits societal interests in fair adjudications against the right of defendants to control their defense. For crimes with political motivations, an imposed insanity verdict discredits the perpetrator and may distract the public from the threats posed by extreme political views.

  13. 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.

  14. Labeling exercise fat-burning increases post-exercise food consumption in self-imposed exercisers.

    PubMed

    Fenzl, Navina; Bartsch, Katja; Koenigstorfer, Joerg

    2014-10-01

    The goal of the study was to determine whether the label given to an exercise bout affects immediate post-exercise food intake. The authors hypothesized that explicitly labeling an exercise bout 'fat-burning' (vs. labeling an exercise bout 'endurance' exercise) would increase post-exercise food intake in individuals who self-impose physical activity, because they are more likely to see the label as signal of activated fat metabolism and license to reward oneself. No such effect was expected for individuals who do not self-impose physical activity but consider exercise enjoyable. Ninety-six participants took part in an experiment manipulating the label given to an exercise bout (fat-burning exercise or endurance exercise) between participants. They cycled on an ergometer for 20 minutes at a consistent work rate (55-65% of predicted VO2 max) and were offered ad libitum food (i.e., pretzel pieces) after the exercise bout. The results showed that self-imposed exercisers, that is, individuals with low behavioral regulation and individuals with high psychological distress, high fatigue levels, and low positive well-being when exercising, ate more food after exercise when the bout was labeled fat-burning exercise rather than endurance exercise. The results help develop health interventions, indicating that the tendency to compensate for energy expended following physical activity depends on both the label given to the exercise bout and the degree to which individuals self-impose physical activity.

  15. 50 CFR 270.18 - Method of imposing assessments.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 50 Wildlife and Fisheries 11 2013-10-01 2013-10-01 false Method of imposing assessments. 270.18 Section 270.18 Wildlife and Fisheries NATIONAL MARINE FISHERIES SERVICE, NATIONAL OCEANIC AND ATMOSPHERIC ADMINISTRATION, DEPARTMENT OF COMMERCE FISH AND SEAFOOD PROMOTION SPECIES-SPECIFIC SEAFOOD MARKETING...

  16. 36 CFR 1256.42 - Who imposes general restrictions?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 36 Parks, Forests, and Public Property 3 2010-07-01 2010-07-01 false Who imposes general restrictions? 1256.42 Section 1256.42 Parks, Forests, and Public Property NATIONAL ARCHIVES AND RECORDS ADMINISTRATION PUBLIC AVAILABILITY AND USE ACCESS TO RECORDS AND DONATED HISTORICAL MATERIALS...

  17. 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.

  18. A generalized-secant homogenization scheme for viscoplastic polycrystalline solids under imposed deformations

    NASA Astrophysics Data System (ADS)

    Idiart, Martín I.; Vincent, Pierre-Guy

    2015-03-01

    Homogenization estimates for viscoplastic polycrystals are derived by applying the generalized-secant linearization scheme of Liu and Ponte Castañeda (2004) [1] to the constitutive description with strain rates as primary variables. The resulting estimates are thus particularly suitable for simulating mechanical processes where deformations are imposed and where the material softens. Their accuracy is preliminarily assessed in the context of a model material system. Good agreement with previous estimates is found.

  19. Sexual selection and maintenance of sex: evidence from comparisons of rates of genomic accumulation of mutations and divergence of sex-related genes in sexual and hermaphroditic species of Caenorhabditis.

    PubMed

    Artieri, Carlo G; Haerty, Wilfried; Gupta, Bhagwati P; Singh, Rama S

    2008-05-01

    Several hypotheses have been proposed to explain the persistence of dioecy despite the reproductive advantages conferred to hermaphrodites, including greater efficiency at purging deleterious mutations in the former. Dioecy can benefit from both mutation purging and accelerated evolution by bringing together beneficial mutations in the same individual via recombination and shuffling of genotypes. In addition, mathematical treatment has shown that sexual selection is also capable of mitigating the cost of maintaining separate sexes by increasing the overall fitness of sexual populations, and genomic comparisons have shown that sexual selection can lead to accelerated evolution. Here, we examine the advantages of dioecy versus hermaphroditism by comparing the rate of evolution in sex-related genes and the rate of accumulation of deleterious mutations using a large number of orthologs (11,493) in the dioecious Caenorhabditis remanei and the hermaphroditic Caenorhabditis briggsae. We have used this data set to estimate the deleterious mutation rate per generation, U, in both species and find that although it is significantly higher in hermaphrodites, both species are at least 2 orders of magnitude lower than the value required to explain the persistence of sex by efficiency at purging deleterious mutations alone. We also find that genes expressed in sperm are evolving rapidly in both species; however, they show a greater increase in their rate of evolution relative to genes expressed in other tissues in C. remanei, suggesting stronger sexual selection pressure acting on these genes in dioecious species. Interestingly, the persistence of a signal of rapid evolution of sperm genes in C. briggsae suggests a recent evolutionary origin of hermaphrodism in this lineage. Our results provide empirical evidence of increased sexual selection pressure in dioecious animals, supporting the possibility that sexual selection may play an important role in the maintenance of sexual

  20. Mutational spectrum drives the rise of mutator bacteria.

    PubMed

    Couce, Alejandro; Guelfo, Javier R; Blázquez, Jesús

    2013-01-01

    Understanding how mutator strains emerge in bacterial populations is relevant both to evolutionary theory and to reduce the threat they pose in clinical settings. The rise of mutator alleles is understood as a result of their hitchhiking with linked beneficial mutations, although the factors that govern this process remain unclear. A prominent but underappreciated fact is that each mutator allele increases only a specific spectrum of mutational changes. This spectrum has been speculated to alter the distribution of fitness effects of beneficial mutations, potentially affecting hitchhiking. To study this possibility, we analyzed the fitness distribution of beneficial mutations generated from different mutator and wild-type Escherichia coli strains. Using antibiotic resistance as a model system, we show that mutational spectra can alter these distributions substantially, ultimately determining the competitive ability of each strain across environments. Computer simulation showed that the effect of mutational spectrum on hitchhiking dynamics follows a non-linear function, implying that even slight spectrum-dependent fitness differences are sufficient to alter mutator success frequency by several orders of magnitude. These results indicate an unanticipated central role for the mutational spectrum in the evolution of bacterial mutation rates. At a practical level, this study indicates that knowledge of the molecular details of resistance determinants is crucial for minimizing mutator evolution during antibiotic therapy.

  1. Mutator Dynamics on a Smooth Evolutionary Landscape

    NASA Astrophysics Data System (ADS)

    Kessler, David A.; Levine, Herbert

    1998-03-01

    We investigate a model of evolutionary dynamics on a smooth landscape which features a ``mutator'' allele which increases the mutation rate. We show that when the fitness is far from its equilibrium value the expected proportion of mutators approaches a value governed solely by the transition rates into and out of the mutator state, resulting in a much faster fitness increase than would be the case without the mutator allele. Near the fitness equilibrium, the mutators are severely suppressed, due to the detrimental effects of a large mutation rate near the fitness maximum. We discuss the results of a recent experiment on natural selection of E. coli in the light of our model.

  2. Genome destabilizing mutator alleles drive specific mutational trajectories in Saccharomyces cerevisiae.

    PubMed

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

    2014-02-01

    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.

  3. 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

  4. The rate of recurrent BRCA1, BRCA2, and TP53 mutations in the general population, and unselected ovarian cancer cases, in Belo Horizonte, Brazil.

    PubMed

    Schayek, Hagit; De Marco, Luiz; Starinsky-Elbaz, Sigal; Rossette, Mariana; Laitman, Yael; Bastos-Rodrigues, Luciana; da Silva Filho, Agnaldo Lopes; Friedman, Eitan

    2016-01-01

    In Brazil, several recurring mutations in BRCA1 and BRCA2 and a TP53 mutation (R337H) have been reported in high risk breast cancer cases. We hypothesized that these recurring mutations may also be detected in the general population and ovarian cancer cases in the state of Minas Gerais. To test this notion, participants were recruited from the outpatient and the Gynecological clinic in the UFMG Medical Center in Belo Horizonte, Minas Gerais, Brazil. BRCA1 (c.68_69delAG, c.5266dupC, c.181T>G, c.4034delA, c.5123C>A), BRCA2 (c.5946delT, c.8537_8538delAG, 4936_4939delGAAA), the c.156_157insAlu* BRCA2 and the c.1010G>A *TP53 mutation were genotyped using validated techniques. Overall, 513 cancer free participants (273 men) (mean age 47.7 ± 15.1 years) and 103 ovarian cancer cases (mean age at diagnosis 58.7 ± 9.6 years) were studied. None of the participants were found to carry any of the genotyped mutations. We conclude that the recurring mutations in BRCA1, BRCA2 and TP53 cannot be detected in the general population or consecutive ovarian cancer cases in this geographical region in Brazil.

  5. Mutation in the protease cleavage site of GDF9 increases ovulation rate and litter size in heterozygous ewes and causes infertility in homozygous ewes.

    PubMed

    Souza, C J H; McNeilly, A S; Benavides, M V; Melo, E O; Moraes, J C F

    2014-10-01

    Litter size (LS) in sheep is determined mainly by ovulation rate (OR). Several polymorphisms have been identified in the growth differentiation factor 9 (GDF9) gene that result in an increase in OR and prolificacy of sheep. Screening the databank of the Brazilian Sheep Breeders Association for triplet delivery, we identified flocks of prolific Ile de France ewes. After resequencing of GDF9, a point mutation (c.943C>T) was identified, resulting in a non-conservative amino acid change (p.Arg315Cys) in the cleavage site of the propeptide. This new allele was called Vacaria (FecG(v) ). A flock of half-sib ewes was evaluated for OR in the first three breeding seasons, and Vacaria heterozygotes had higher OR (P < 0.001), averaging 2.1 ± 0.1 when compared to 1.2 ± 0.1 in wild-type ewes. The OR was also influenced by age, increasing in the second and third breeding seasons (P < 0.001). In flocks segregating this allele, the LS was higher in mutant sheep (P < 0.001), averaging 1.61 ± 0.07 in heterozygotes and 1.29 ± 0.03 in wild-type ewes. Analysis of homozygote reproductive tract morphology revealed uterine and ovarian hypoplasia. Ovarian follicles continue to develop up to small antral stages, although with abnormal oocyte morphology and altered arrangement of granulosa cells. After the collapse of the oocyte in most follicles, the remaining cells formed clusters that persisted in the ovary. This SNP is useful to improve selection for dam prolificacy and also as a model to investigate GDF9 post-translation processing and the fate of the follicular cells that remain after the oocyte demise.

  6. 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

  7. 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.

  8. Quasi-two-dimensional Turing patterns in an imposed gradient

    NASA Astrophysics Data System (ADS)

    Lengyel, István; Kádár, Sándor; Epstein, Irving R.

    1992-11-01

    In experiments on quasi-two-dimensional Turing structures, patterns form perpendicular to a concentration gradient imposed by the boundary conditions. Using linear stability analysis, with the ClO2-I2-MA (malonic acid) reaction as an example, we obtain conditions on the position along the gradient direction and possible three dimensionality of the structures. Experiments on the effects of MA and starch concentrations on the position of the structures support the theory. Simulations taking into account the starch indicator yield Turing patterns even with equal diffusion coefficients for the activator and inhibitor species.

  9. Observational constraints imposed by Brans-Dicke cosmologies.

    NASA Technical Reports Server (NTRS)

    Morganstern, R. E.

    1973-01-01

    Flat-space Brans-Dicke (BD) cosmologies previously found are analyzed in more detail. It is shown that the observed values of the matter density, the Hubble age, the ages of objects in the universe, the deceleration parameter, and the bound on the (unobserved) fractional time variation of the gravitational constant are too inaccurate to distinguish between the BD and Einstein-Friedmann cosmologies. An attempt is made to argue that because of the great degree of latitude in the observational constraints imposed by the BD cosmologies, efforts to improve the bound on the fractional time variation of G alone are not sufficient to rule out the BD theory.

  10. 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.

  11. 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.

  12. 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.

  13. 26 CFR 52.4681-1 - Taxes imposed with respect to ozone-depleting chemicals.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 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 taxes with respect to ozone-depleting chemicals (ODCs): (1) Tax on ODCs. Section 4681(a)(1) imposes a tax...

  14. 26 CFR 52.4681-1 - Taxes imposed with respect to ozone-depleting chemicals.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 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 taxes with respect to ozone-depleting chemicals (ODCs): (1) Tax on ODCs. Section 4681(a)(1) imposes a tax...

  15. 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...

  16. 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...

  17. 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... 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...

  18. 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

    2016-09-12

    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.

  19. The fitness burden imposed by synthesising quorum sensing signals

    PubMed Central

    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

  20. 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

  1. A loss-of-function mutation in the PAS kinase Rim15p is related to defective quiescence entry and high fermentation rates of Saccharomyces cerevisiae sake yeast strains.

    PubMed

    Watanabe, Daisuke; Araki, Yuya; Zhou, Yan; Maeya, Naoki; Akao, Takeshi; Shimoi, Hitoshi

    2012-06-01

    Sake yeast cells have defective entry into the quiescent state, allowing them to sustain high fermentation rates. To reveal the underlying mechanism, we investigated the PAS kinase Rim15p, which orchestrates initiation of the quiescence program in Saccharomyces cerevisiae. We found that Rim15p is truncated at the carboxyl terminus in modern sake yeast strains as a result of a frameshift mutation. Introduction of this mutation or deletion of the full-length RIM15 gene in a laboratory strain led to a defective stress response, decreased synthesis of the storage carbohydrates trehalose and glycogen, and impaired G(1) arrest, which together closely resemble the characteristic phenotypes of sake yeast. Notably, expression of a functional RIM15 gene in a modern sake strain suppressed all of these phenotypes, demonstrating that dysfunction of Rim15p prevents sake yeast cells from entering quiescence. Moreover, loss of Rim15p or its downstream targets Igo1p and Igo2p remarkably improved the fermentation rate in a laboratory strain. This finding verified that Rim15p-mediated entry into quiescence plays pivotal roles in the inhibition of ethanol fermentation. Taken together, our results suggest that the loss-of-function mutation in the RIM15 gene may be the key genetic determinant of the increased ethanol production rates in modern sake yeast strains.

  2. Synchronization of Eukaryotic Flagella with an Imposed Periodic Flow

    NASA Astrophysics Data System (ADS)

    Quaranta, Greta; Aubin-Tam, Marie-Eve; Tam, Daniel

    2015-11-01

    The eukaryotic cilia and flagella are subcellular structures able to beat in synchrony for long periods of time. Recent studies have characterized the dynamics of flagellar locomotion and have focused on the physical mechanisms driving synchronous beating and especially on the importance of hydrodynamic interactions. We explored the possibility to control the beating of the two flagella of a single C. reinhardtii cell by imposing an external periodic hydrodynamic force. We do so by generating an oscillatory background flow around a single cell. Our study shows that flagellar beating can be phase locked to an external hydrodynamic forcing of non-biological origin and the synchronization transition is well represented by a low-order stochastic model. Remarkably, the hydrodynamic forces needed to synchronize the flagella and the background flow are considerably larger than the forces typically experienced in physiological conditions. Our results suggest that the importance of hydrodynamics in flagellar synchronization may be limited.

  3. Accelerating Mutational Load Is Not Due to Synergistic Epistasis or Mutator Alleles in Mutation Accumulation Lines of Yeast.

    PubMed

    Jasmin, Jean-Nicolas; Lenormand, Thomas

    2016-02-01

    Much of our knowledge about the fitness effects of new mutations has been gained from mutation accumulation (MA) experiments. Yet the fitness effect of single mutations is rarely measured in MA experiments. This raises several issues, notably for inferring epistasis for fitness. The acceleration of fitness decline in MA lines has been taken as evidence for synergistic epistasis, but establishing the role of epistasis requires measuring the fitness of genotypes carrying known numbers of mutations. Otherwise, accelerating fitness loss could be explained by increased genetic mutation rates. Here we segregated mutations accumulated over 4800 generations in haploid and diploid MA lines of the yeast Saccharomyces cerevisiae. We found no correspondence between an accelerated fitness decline and synergistic epistasis among deleterious mutations in haploid lines. Pairs of mutations showed no overall epistasis. Furthermore, several lines of evidence indicate that genetic mutation rates did not increase in the MA lines. Crucially, segregant fitness analyses revealed that MA accelerated in both haploid and diploid lines, even though the fitness of diploid lines was nearly constant during the MA experiment. This suggests that the accelerated fitness decline in haploids was caused by cryptic environmental factors that increased mutation rates in all lines during the last third of the lines' transfers. In addition, we provide new estimates of deleterious mutation rates, including lethal mutations, and highlight that nearly all the mutational load we observed was due to one or two mutations having a large effect on fitness.

  4. 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.

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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.

  12. 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.

  13. 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

  14. 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.

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

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ...) and section 6663 are imposed: Step 1 Determine the portion, if any, of the underpayment on which no... of underpayment on which no penalty is imposed $150 Step 2 Determine the portion, if any, of the underpayment on which a penalty of 20 percent is imposed: “Adjusted” taxable income from step 1...

  16. 42 CFR 460.40 - Violations for which CMS may impose sanctions.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 4 2011-10-01 2011-10-01 false Violations for which CMS may impose sanctions. 460... for which CMS may impose sanctions. In addition to other remedies authorized by law, CMS may impose any of the sanctions specified in §§ 460.42 and 460.46 if CMS determines that a PACE...

  17. 42 CFR 460.40 - Violations for which CMS may impose sanctions.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 4 2010-10-01 2010-10-01 false Violations for which CMS may impose sanctions. 460... for which CMS may impose sanctions. In addition to other remedies authorized by law, CMS may impose any of the sanctions specified in §§ 460.42 and 460.46 if CMS determines that a PACE...

  18. 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...

  19. 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...

  20. 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...

  1. 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...

  2. 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...

  3. 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

  4. 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.

  5. 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.

  6. 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.

  7. Current-limited imposed-potential technique for inducing and monitoring metastable pitting events

    SciTech Connect

    Wall, F.D.

    1999-11-24

    A technique has been developed to selectively induce metastable pitting while preventing the transition to stable pit growth. The current-limited imposed-potential (CLIP) technique limits available cathodic current to an initiated site using a resistor in series with the working electrode to form a voltage divider. Potentiodynamic CLIP testing yields a distribution of breakdown potentials from a single experiment. Potentiostatic CLIP testing yields induction time data, which can be used as input to a calculation of germination rate. Initial data indicate that a one-to-one correlation exists between electrochemical transients and observed pitting sites. The CLIP technique provides a consistent means of gathering quantitative potential and current transients associated with localized oxide breakdown.

  8. 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.

  9. Effects of single and double mutations in plastocyanin on the rate constant and activation parameters for the rearrangement gating the electron-transfer reaction between the triplet state of zinc cytochrome c and cupriplastocyanin.

    PubMed

    Ivković-Jensen, M M; Ullmann, G M; Young, S; Hansson, O; Crnogorac, M M; Ejdebäck, M; Kostić, N M

    1998-06-30

    The unimolecular rate constant for the photoinduced electron-transfer reaction 3Zncyt/pc(II) --> Zncyt+/pc(I) within the electrostatic complex of zinc cytochrome c and spinach cupriplastocyanin is kF. We report the effects on kF of the following factors, all at pH 7.0: 12 single mutations on the plastocyanin surface (Leu12Asn, Leu12Glu, Leu12Lys, Asp42Asn, Asp42Lys, Glu43Asn, Glu59Gln, Glu59Lys, Glu60Gln, Glu60Lys, Gln88Glu, and Gln88Lys), the double mutation Glu59Lys/Glu60Gln, temperature (in the range 273.3-302.9 K), and solution viscosity (in the range 1. 00-116.0 cP) at 283.2 and 293.2 K. We also report the effects of the plastocyanin mutations on the association constant (Ka) and the corresponding free energy of association (DeltaGa) with zinc cytochrome c at 298.2 K. Dependence of kF on temperature yielded the activation parameters DeltaH, DeltaS, and DeltaG. Dependence of kF on solution viscosity yielded the protein friction and confirmed the DeltaG values determined from the temperature dependence. The aforementioned intracomplex reaction is not a simple electron-transfer reaction because donor-acceptor electronic coupling (HAB) and reorganizational energy (lambda), obtained by fitting of the temperature dependence of kF to the Marcus equation, deviate from the expectations based on precedents and because kF greatly depends on viscosity. This last dependence and the fact that certain mutations affect Ka but not kF are two lines of evidence against the mechanism in which the electron-transfer step is coupled with the faster, but thermodynamically unfavorable, rearrangement step. The electron-transfer reaction is gated by the slower, and thus rate determining, structural rearrangement of the diprotein complex; the rate constant kF corresponds to this rearrangement. Isokinetic correlation of DeltaH and DeltaS parameters and Coulombic energies of the various configurations of the Zncyt/pc(II) complex consistently show that the rearrangement is a facile

  10. Volatility of Mutator Phenotypes at Single Cell Resolution.

    PubMed

    Kennedy, Scott R; Schultz, Eric M; Chappell, Thomas M; Kohrn, Brendan; Knowels, Gary M; Herr, Alan J

    2015-04-01

    Mutator phenotypes accelerate the evolutionary process of neoplastic transformation. Historically, the measurement of mutation rates has relied on scoring the occurrence of rare mutations in target genes in large populations of cells. Averaging mutation rates over large cell populations assumes that new mutations arise at a constant rate during each cell division. If the mutation rate is not constant, an expanding mutator population may contain subclones with widely divergent rates of evolution. Here, we report mutation rate measurements of individual cell divisions of mutator yeast deficient in DNA polymerase ε proofreading and base-base mismatch repair. Our data are best fit by a model in which cells can assume one of two distinct mutator states, with mutation rates that differ by an order of magnitude. In error-prone cell divisions, mutations occurred on the same chromosome more frequently than expected by chance, often in DNA with similar predicted replication timing, consistent with a spatiotemporal dimension to the hypermutator state. Mapping of mutations onto predicted replicons revealed that mutations were enriched in the first half of the replicon as well as near termination zones. Taken together, our findings show that individual genome replication events exhibit an unexpected volatility that may deepen our understanding of the evolution of mutator-driven malignancies.

  11. Sponsor-Imposed Publication Restrictions Disclosed on ClinicalTrials.gov.

    PubMed

    Stretton, Serina; Lew, Rebecca A; Ely, Julie A; Snape, Mark J; Carey, Luke C; Haley, Cassandra; Woolley, Mark J; Woolley, Karen L

    2016-01-01

    We investigated whether sponsor-imposed publication restrictions for ClinicalTrials.gov trials were reasonable, based on consistency with Good Publication Practice 2 (GPP2). ClinicalTrials.gov trial record data were electronically imported (October 7, 2012) and screened for eligibility (phase 2-4, interventional, recruitment closed, results available, first received for registration after November 10, 2009, any sponsor type, investigators not sponsor employees). Two authors categorized restrictions information as consistent or not consistent with GPP2, resolving discrepancies by consensus. Of the eligible trials (388/484, n = 81,768 participants), 80.7% (313/388) had restrictions disclosed, and 92.5% (311/388) were industry-sponsored. Significantly more trials had restrictions that were consistent with GPP2 than not (74.1% [232/313], n = 55,280 participants vs. 25.9% [81/313], n = 19,677 participants; P < .001). Reasons for inconsistency were insufficient, unclear, or ambiguous information (48.1%, 39/81), sponsor-required approval for publication (35.8%, 29/81), sponsor-required text changes (8.6%, 7/81), and outright bans (7.4%, 6/81). Follow-up of trials with insufficient information and a contact email (response rate, 46.9% [15/32]) revealed 2 additional bans. A total of 776 participants had consented to trials that had publication bans. Many, but not all, sponsor-imposed publication restrictions disclosed on ClinicalTrials.gov may be considered reasonable. Sponsors should ensure restrictions are appropriately disclosed. Volunteers should be alerted to any restrictions before consenting to participate in a clinical trial.

  12. 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

  13. 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.

  14. Additional work of breathing imposed by endotracheal tubes, breathing circuits, and intensive care ventilators.

    PubMed

    Bersten, A D; Rutten, A J; Vedig, A E; Skowronski, G A

    1989-07-01

    A disadvantage of spontaneous breathing through an endotracheal tube (ETT) and connector attached to a breathing circuit and/or ventilator (breathing device) is an increase in the work of breathing. The work of breathing associated with ETT of 6 to 9-mm diameter and eight breathing devices was determined, using a lung simulator to mimic spontaneous inspiration at flow rates of 20 to 100 L/min and a tidal volume of 500 ml, at both zero end-expiratory pressure (ZEEP) and 10 cm H2O continuous positive airway pressure (CPAP). Work associated with the breathing devices alone (WCIR) ranged from -0.002 kg.m/L (Servo 900-C ventilator, 7-mm ETT, 20 L/min, ZEEP) to 0.1 kg.m/L (continuous flow circuit, 7-mm ETT, 100 L/min, CPAP), the latter representing 196% of the work of normal breathing. When the devices were attached to ETT, total apparatus work (WAPP) ranged from 0.009 kg.m/L (Mapleson-D circuit, 9-mm ETT, 20 L/min, ZEEP) to 0.25 kg.m/L (Drager EV-A, 6-mm ETT, 100 L/min, ZEEP), the latter representing 490% of the work of normal breathing. This additional work imposed by the ETT varied considerably among devices. Spontaneous breathing through modern ventilators, circuits and ETT imposes a burden of increased work, most of which is associated with the presence of the ETT and connector. Whether this burden represents an impediment to the weaning patient, or has training value for the ultimate resumption of unassisted spontaneous ventilation, remains to be determined.

  15. The physiological load imposed on basketball players during competition.

    PubMed

    McInnes, S E; Carlson, J S; Jones, C J; McKenna, M J

    1995-10-01

    In this study, the intensities of activity and movement patterns during men's basketball were investigated by videoing the movements and monitoring the heart rate and blood lactate responses of eight elite players during competition. The results are expressed according to 'live time', which is actual playing time, and 'total time', which includes live time as well as all stoppages in play. The mean (+/- S.D.) frequency of all activities was 997 +/- 183, with a change in movement category every 2.0 s. A mean total of 105 +/- 52 high-intensity runs (mean duration 1.7 s) was recorded for each game, resulting in one high-intensity run every 21 s during live time. Sixty percent of live time was spent engaged in low-intensity activity, while 15% was spent in high-intensity activity. The mean heart rate (HR) during live time was 169 +/- 9 beats min-1 (89 +/- 2% peak HR attained during laboratory testing); 75% of live time was spent with a HR response of greater than 85% peak HR. The mean blood lactate concentration was 6.8 +/- 2.8 mM, indicating the involvement of glycolysis in the energy demands of basketball. It is concluded that the physiological requirements of men's basketball are high, placing considerable demands on the cardiovascular and metabolic capacities of players.

  16. 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.

  17. 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

  18. 5 CFR 890.1062 - Deciding whether to impose penalties and assessments.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... Imposed Against Health Care Providers Civil Monetary Penalties and Financial Assessments § 890.1062... assessment by any Federal or State agency, whether or not any sanction was actually imposed; (6) The monetary amount of any damages, losses, and costs, as described in § 890.1064(c), attributable to the...

  19. 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

    ...; Increase in Fees Imposed AGENCY: Financial Management Service, Fiscal Service, Department of the Treasury... Management Service, is increasing the fees it imposes on and collects from surety companies and reinsuring... fees are determined in accordance with the Office of Management and Budget Circular A-25, as...

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

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 3 2011-10-01 2011-10-01 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, 2011 CFR

    2011-10-01

    ... 42 Public Health 3 2011-10-01 2011-10-01 false Collection of civil money penalties imposed by CMS... 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 penalty following...

  2. 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...

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

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Tax imposed on life insurance companies. 1.802-3... TAX (CONTINUED) INCOME TAXES Life Insurance Companies § 1.802-3 Tax imposed on life insurance... tax on the life insurance company taxable income (as defined in section 802(b) and paragraph (a)...

  4. 24 CFR 266.120 - Actions for which sanctions may be imposed.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... HOUSING AND URBAN DEVELOPMENT MORTGAGE AND LOAN INSURANCE PROGRAMS UNDER NATIONAL HOUSING ACT AND OTHER.... Violations for which sanctions may be imposed include, but are not limited to: (a) Commission of fraud or... which sanctions may be imposed against the HFA by HUD's Mortgagee Review Board under 24 CFR 25.9....

  5. 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....

  6. 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...

  7. 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...

  8. 34 CFR 30.61 - What penalties does the Secretary impose on delinquent debtors?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 34 Education 1 2010-07-01 2010-07-01 false What penalties does the Secretary impose on delinquent debtors? 30.61 Section 30.61 Education Office of the Secretary, Department of Education DEBT COLLECTION What Costs and Penalties Does the Secretary Impose on Delinquent Debtors? § 30.61 What penalties...

  9. 34 CFR 30.60 - What costs does the Secretary impose on delinquent debtors?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 34 Education 1 2010-07-01 2010-07-01 false What costs does the Secretary impose on delinquent debtors? 30.60 Section 30.60 Education Office of the Secretary, Department of Education DEBT COLLECTION What Costs and Penalties Does the Secretary Impose on Delinquent Debtors? § 30.60 What costs does...

  10. The influence of imposed normal vibrations on the frictional sliding along the fault

    NASA Astrophysics Data System (ADS)

    Karachevtseva, Iuliia; Dyskin, Arcady; Pasternak, Elena

    2016-04-01

    Sliding over discontinuities (faults, fractures) in the stable state is prevented by friction. However, the faults are continuously subjected to variations in normal stress and can produce sliding over initially stable fractures/interfaces. In the Earth's crust the normal oscillations can be produced by tidal stresses or by the seismic waves generated by other seismic events. This is associated with the earthquake triggering and leading to a stick-slip sliding. It is conventionally assumed that the mechanism of stick-slip over geomaterials lies in intermittent change between static and kinetic friction and the rate dependence of the friction coefficient. The formulation of the friction law on geological faults is the key element in the modelling of earthquakes. We investigate the effects of imposed normal vibrations on steady sliding and stick-slip regimes and analyse the dynamics of system with different friction modelling. For this purpose we consider a simple spring-block model introduced by Burridge and Knopoff. The results show that a model exhibits different behaviour in the frictional sliding with constant and nonlinear friction. It is important to note, that a block-spring model can produce oscillations in the velocity of sliding that is the stick-slip like behaviour even when the friction coefficient is constant. The effect of force reduction is observed under the influence of harmonic vertical vibrations. The rate-dependent friction creates more complex pattern of oscillations.

  11. How mutation affects evolutionary games on graphs.

    PubMed

    Allen, Benjamin; Traulsen, Arne; Tarnita, Corina E; Nowak, Martin A

    2012-04-21

    Evolutionary dynamics are affected by population structure, mutation rates and update rules. Spatial or network structure facilitates the clustering of strategies, which represents a mechanism for the evolution of cooperation. Mutation dilutes this effect. Here we analyze how mutation influences evolutionary clustering on graphs. We introduce new mathematical methods to evolutionary game theory, specifically the analysis of coalescing random walks via generating functions. These techniques allow us to derive exact identity-by-descent (IBD) probabilities, which characterize spatial assortment on lattices and Cayley trees. From these IBD probabilities we obtain exact conditions for the evolution of cooperation and other game strategies, showing the dual effects of graph topology and mutation rate. High mutation rates diminish the clustering of cooperators, hindering their evolutionary success. Our model can represent either genetic evolution with mutation, or social imitation processes with random strategy exploration.

  12. 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

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

    PubMed

    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

    2016-09-29

    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

  14. Mutation of EMG1 causing Bowen-Conradi syndrome results in reduced cell proliferation rates concomitant with G2/M arrest and 18S rRNA processing delay.

    PubMed

    Armistead, Joy; Hemming, Richard; Patel, Nehal; Triggs-Raine, Barbara

    2014-06-01

    Bowen-Conradi syndrome (BCS) is a lethal autosomal recessive disorder caused by a D86G substitution in the protein, Essential for Mitotic Growth 1 (EMG1). EMG1 is essential for 18S rRNA maturation and 40S ribosome biogenesis in yeast, but no studies of its role in ribosome biogenesis have been done in mammals. To assess the effect of the EMG1 mutation on cell growth and ribosomal biogenesis in humans, we employed BCS patient cells. The D86G substitution did not interfere with EMG1 nucleolar localization. In BCS patient lymphoblasts, cells accumulated in G2/M, resulting in reduced proliferation rates; however, patient fibroblasts showed normal proliferation. The rate of 18S rRNA processing was consistently delayed in patient cells, although this did not lead to a difference in the levels of 40S ribosomes, or a change in protein synthesis rates. These results demonstrate that as in yeast, EMG1 in mammals has a role in ribosome biogenesis. The obvious phenotype in lymphoblasts compared to fibroblasts suggests a greater need for EMG1 in rapidly dividing cells. Tissue-specific effects have been seen in other ribosomal biogenesis disorders, and it seems likely that the impact of EMG1 deficiency would be larger in the rapidly proliferating cells of the developing embryo.

  15. 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

    2014-06-09

    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

  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, 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...

  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, 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...

  19. 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...

  20. 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... 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...

  1. Vulnerabilities of Residential Buildings In England To The Physical Forces Imposed By Floods

    NASA Astrophysics Data System (ADS)

    Kelman, I.; Spence, R.

    Floods cause extensive damage to residential properties in the U.K. as illustrated by the 10,000 homes flooded during Autumn 2000. Flood damage prediction in the U.K., though, rarely uses more than depth-damage curves. This study analyses the physical forces imposed on residential properties by floods. A force typology and the relative importance of each force are presented. Residential buildings are analysed by com- ponent to determine the relative importance of different failure modes under applied forces. This analysis illustrates that the three most relevant failure modes for mod- ern English dwellings are window and door glass breaking, cavity brickwork walls collapsing, and the infiltration rate of floodwater from outside the property to inside. These three modes are quantified by applying techniques from, respectively, materials science, structural engineering, and fluid mechanics plus building ventilation. Com- bining these results with detailed field surveys of more than 1,000 residential build- ings over two case study sites in eastern England, a methodology for profiling the flood vulnerability of individual residences and entire communities is developed. Im- plications and recommendations for reducing building and community vulnerability are interpreted in the context of other natural hazards threatening the same areas.

  2. 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.

  3. Plasma membrane NADH oxidase of maize roots responds to gravity and imposed centrifugal forces.

    PubMed

    Bacon, E; Morre, D J

    2001-06-01

    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. PMID:12033222

  4. Mutations in domain I interhelical loops affect the rate of pore formation by the Bacillus thuringiensis Cry1Aa toxin in insect midgut brush border membrane vesicles.

    PubMed

    Lebel, Geneviève; Vachon, Vincent; Préfontaine, Gabrielle; Girard, Frédéric; Masson, Luke; Juteau, Marc; Bah, Aliou; Larouche, Geneviève; Vincent, Charles; Laprade, Raynald; Schwartz, Jean-Louis

    2009-06-01

    Pore formation in the apical membrane of the midgut epithelial cells of susceptible insects constitutes a key step in the mode of action of Bacillus thuringiensis insecticidal toxins. In order to study the mechanism of toxin insertion into the membrane, at least one residue in each of the pore-forming-domain (domain I) interhelical loops of Cry1Aa was replaced individually by cysteine, an amino acid which is normally absent from the activated Cry1Aa toxin, using site-directed mutagenesis. The toxicity of most mutants to Manduca sexta neonate larvae was comparable to that of Cry1Aa. The ability of each of the activated mutant toxins to permeabilize M. sexta midgut brush border membrane vesicles was examined with an osmotic swelling assay. Following a 1-h preincubation, all mutants except the V150C mutant were able to form pores at pH 7.5, although the W182C mutant had a weaker activity than the other toxins. Increasing the pH to 10.5, a procedure which introduces a negative charge on the thiol group of the cysteine residues, caused a significant reduction in the pore-forming abilities of most mutants without affecting those of Cry1Aa or the I88C, T122C, Y153C, or S252C mutant. The rate of pore formation was significantly lower for the F50C, Q151C, Y153C, W182C, and S252C mutants than for Cry1Aa at pH 7.5. At the higher pH, all mutants formed pores significantly more slowly than Cry1Aa, except the I88C mutant, which formed pores significantly faster, and the T122C mutant. These results indicate that domain I interhelical loop residues play an important role in the conformational changes leading to toxin insertion and pore formation.

  5. 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

  6. 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

  7. Sentence imposed.

    PubMed

    1999-04-30

    The New York Supreme Court sentenced [name removed] to 4 to 12 years in prison on charges of exposing a woman to HIV through unprotected sex. [Name removed] pleaded guilty to a charge of reckless endangerment in the first degree, and to another count of statutory rape for having sex with a 13-year-old girl. Public health officials say [name removed] has exposed at least 48 women and girls to HIV, infecting 13 of them. He was sentenced 3 days later, to 2 to 6 years for having unprotected sex with a 15-year-old in the Bronx. The sentences will run concurrently. PMID:11366531

  8. 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

  9. 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

  10. Sex and deleterious mutations.

    PubMed

    Gordo, Isabel; Campos, Paulo R A

    2008-05-01

    The evolutionary advantage of sexual reproduction has been considered as one of the most pressing questions in evolutionary biology. While a pluralistic view of the evolution of sex and recombination has been suggested by some, here we take a simpler view and try to quantify the conditions under which sex can evolve given a set of minimal assumptions. Since real populations are finite and also subject to recurrent deleterious mutations, this minimal model should apply generally to all populations. We show that the maximum advantage of recombination occurs for an intermediate value of the deleterious effect of mutations. Furthermore we show that the conditions under which the biggest advantage of sex is achieved are those that produce the fastest fitness decline in the corresponding asexual population and are therefore the conditions for which Muller's ratchet has the strongest effect. We also show that the selective advantage of a modifier of the recombination rate depends on its strength. The quantification of the range of selective effects that favors recombination then leads us to suggest that, if in stressful environments the effect of deleterious mutations is enhanced, a connection between sex and stress could be expected, as it is found in several species.

  11. Mutator and MULE Transposons.

    PubMed

    Lisch, Damon

    2015-04-01

    The Mutator system of transposable elements (TEs) is a highly mutagenic family of transposons in maize. Because they transpose at high rates and target genic regions, these transposons can rapidly generate large numbers of new mutants, which has made the Mutator system a favored tool for both forward and reverse mutagenesis in maize. Low copy number versions of this system have also proved to be excellent models for understanding the regulation and behavior of Class II transposons in plants. Notably, the availability of a naturally occurring locus that can heritably silence autonomous Mutator elements has provided insights into the means by which otherwise active transposons are recognized and silenced. This chapter will provide a review of the biology, regulation, evolution and uses of this remarkable transposon system, with an emphasis on recent developments in our understanding of the ways in which this TE system is recognized and epigenetically silenced as well as recent evidence that Mu-like elements (MULEs) have had a significant impact on the evolution of plant genomes.

  12. 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

  13. Regular systems of inbreeding with mutation.

    PubMed

    Campbell, R B

    1988-08-01

    Probability of identity by type is studied for regular systems of inbreeding in the presence of mutation. Analytic results are presented for half-sib mating, first cousin mating, and half nth cousin mating under both infinite allele and two allele (back mutation) models. Reasonable rates of mutation do not provide significantly different results from probability of identity by descent in the absence of mutation. Homozygosity is higher under half-sib mating than under first cousin mating, but the expected number of copies of a gene in the population is higher under first cousin mating than under half-sib mating.

  14. Leaf morphological and physiological adjustments to the spectrally selective shade imposed by anthocyanins in Prunus cerasifera.

    PubMed

    Kyparissis, A; Grammatikopoulos, G; Manetas, Y

    2007-06-01

    Prunus domestica L. has green leaves, whereas Prunus cerasifera Ehrh. var. atropurpurea has red leaves due to the presence of mesophyll anthocyanins. We compared morphological and photosynthetic characteristics of leaves of these species, which were sampled from shoots grafted in pairs on P. domestica rootstocks, each pair comprising one shoot of each species. Two hypotheses were tested: (1) anthocyanins protect red leaves against photoinhibition; and (2) red leaves display shade characteristics because of light attenuation by anthocyanins. Parameters were measured seasonally, during a period of increasing water stress, which caused a similar drop in shoot water potential in each species. As judged by predawn measurements of maximum PSII yield, chronic photoinhibition did not develop in either species and, despite the anthocyanic screen, the red leaves of P. cerasifera displayed lower light-adapted PSII yields and higher non-photochemical quenching than the green leaves of P. domestica. Thus, it appears that, in this system, anthocyanins afford little photoprotection. As predicted by the shade acclimation hypothesis, red leaves were thinner and had a lower stomatal frequency, area- based CO2 assimilation rate, apparent carboxylation efficiency and chlorophyll a:b ratio than green leaves. However, red leaves were similar to green leaves in conductivity to water vapor diffusion, dry-mass-based chlorophyll concentrations and carotenoid:chlorophyll ratios. The data for red leaves indicate adaptations to a green-depleted, red-enriched shade, rather than a neutral or canopy-like shade. Thus, green light attenuation by anthocyanins may impose a limitation on leaf thickness. Moreover, the selective depletion of light at wavelengths that are preferentially absorbed by PSII and chlorophyll b may lead to adjustments in chlorophyll pigment ratios to compensate for the uneven spectral distribution of internal light. The apparent photosynthetic cost associated with lost photons

  15. Repair-Resistant Mutation in Neurospora

    PubMed Central

    Stadler, David; Macleod, Helen; Loo, Melanie

    1987-01-01

    Chronic UV treatment produces severalfold fewer mutations in Neurospora conidia than does the same total dose of acute UV. Experiments were designed to determine the conditions required for chronic UV mutagenesis. Measurement of the coincidence frequency for two independent mutations revealed the existence of a subset of cells which are mutable by chronic UV. Analysis of forward mutation at the mtr locus showed that the genetic alterations produced by chronic UV were virtually all point mutants, even though the assay system could detect alterations or deletions extending into neighboring genes. A significant fraction of the mutants produced by acute UV were multigenic deletions. The size of the dose-rate effect (acute UV mutation frequency divided by chronic UV mutation frequency) was compared for several different mutation assay systems. Forward mutations (recessive lethals and mtr) gave values ranging from four to nine. For events which were restricted to specific molecular sites (specific reversions and nonsense suppressor mutations), there was a wider range of dose-rate ratios. This suggests that chronic UV mutation may be restricted to certain molecular sequences or configurations. PMID:3609724

  16. 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

  17. Genomic confirmation of nutrient-dependent mutability of mutators in Escherichia coli.

    PubMed

    Tsuru, Saburo; Ishizawa, Yuuka; Shibai, Atsushi; Takahashi, Yusuke; Motooka, Daisuke; Nakamura, Shota; Yomo, Tetsuya

    2015-12-01

    Mutators with increased mutation rates are prevalent in various environments and have important roles in accelerating adaptive evolution. Previous studies on mutator strains of microorganisms have shown that some mutators have constant mutation rates, whereas others exhibit switchable mutation rates depending on nutritional conditions. This suggests that the contributions of mutators on evolution vary with fluctuating nutritional conditions. However, such conditional mutability has been unclear at the genomic level. In addition, it is still unknown why mutation rates change with nutritional condition. Here, we used two mutator strains of Escherichia coli to explore the nutrient dependence of mutation rates at the genomic level. These strains were transferred repeatedly under different nutritional conditions for hundreds of generations to accumulate mutations. Whole-genome sequencing of the offspring showed that the nutrient dependence of the mutation rates was pervasive at the genomic scale. Neutrality in the mutation accumulation processes and constancy in the mutational bias suggested that nutrient dependence was not derived from conditional selective purges or from shifts of mutational bias. Some mutators could simply switch their mutation rates for both transitions and transversions in response to nutritional shifts.

  18. Clock-like mutational processes in human somatic cells

    DOE PAGES

    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

  19. 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

    2016-07-19

    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.

  20. 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

  1. 42 CFR 423.760 - Determinations regarding the amount of civil money penalties and assessment imposed by CMS.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... penalties and assessment imposed by CMS. 423.760 Section 423.760 Public Health CENTERS FOR MEDICARE... penalties and assessment imposed by CMS. (a) Determining the appropriate amount of any penalty. In determining the amount of penalty imposed under 423.752(c)(1), CMS will consider as appropriate: (1)...

  2. 42 CFR 422.760 - Determinations regarding the amount of civil money penalties and assessment imposed by CMS.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... penalties and assessment imposed by CMS. 422.760 Section 422.760 Public Health CENTERS FOR MEDICARE... assessment imposed by CMS. (a) Determining the appropriate amount of any penalty. In determining the amount of penalty imposed under 422.752(c)(1), CMS will consider as appropriate: (1) The nature of...

  3. 26 CFR 1.1375-1 - Tax imposed when passive investment income of corporation having subchapter C earnings and...

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 11 2014-04-01 2014-04-01 false Tax imposed when passive investment income of... imposed when passive investment income of corporation having subchapter C earnings and profits exceed 25...) imposes a tax on the income of certain S corporations that have passive investment income. In the case...

  4. 26 CFR 1.1375-1 - Tax imposed when passive investment income of corporation having subchapter C earnings and...

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 11 2013-04-01 2013-04-01 false Tax imposed when passive investment income of... imposed when passive investment income of corporation having subchapter C earnings and profits exceed 25...) imposes a tax on the income of certain S corporations that have passive investment income. In the case...

  5. 26 CFR 1.1375-1 - Tax imposed when passive investment income of corporation having subchapter C earnings and...

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 11 2011-04-01 2011-04-01 false Tax imposed when passive investment income of... imposed when passive investment income of corporation having subchapter C earnings and profits exceed 25...) imposes a tax on the income of certain S corporations that have passive investment income. In the case...

  6. 26 CFR 1.1375-1 - Tax imposed when passive investment income of corporation having subchapter C earnings and...

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 11 2012-04-01 2012-04-01 false Tax imposed when passive investment income of... imposed when passive investment income of corporation having subchapter C earnings and profits exceed 25...) imposes a tax on the income of certain S corporations that have passive investment income. In the case...

  7. 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.

  8. 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

  9. Gene mutations in chronic lymphocytic leukemia.

    PubMed

    Amin, Nisar A; Malek, Sami N

    2016-04-01

    The recent discovery of genes mutated in chronic lymphocytic leukemia (CLL) has stimulated new research into the role of these genes in CLL pathogenesis. CLL cases carry approximately 5-20 mutated genes per exome, a lower number than detected in many human tumors. Of the recurrently mutated genes in CLL, all are mutated in 10% or less of patients when assayed in unselected CLL cohorts at diagnosis. Mutations in TP53 are of major clinical relevance, are often associated with del17p and gain in frequency over time. TP53 mutated and associated del17p states substantially lower response rates, remission duration, and survival in CLL. Mutations in NOTCH1 and SF3B1 are recurrent, often associated with progressive CLL that is also IgVH unmutated and ZAP70-positive and are under investigation as targets for novel therapies and as factors influencing CLL outcome. There are an estimated 20-50 additional mutated genes with frequencies of 1%-5% in CLL; more work is needed to identify these and to study their significance. Finally, of the major biological aberration categories influencing CLL as a disease, gene mutations will need to be placed into context with regard to their ultimate role and importance. Such calibrated appreciation necessitates studies incorporating multiple CLL driver aberrations into biological and clinical analyses. PMID:27040699

  10. 45 CFR 261.65 - Under what circumstances will we impose a work verification penalty?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... internal controls to ensure a consistent measurement of work participation, we will reduce the adjusted... 45 Public Welfare 2 2010-10-01 2010-10-01 false Under what circumstances will we impose a work... AND HUMAN SERVICES ENSURING THAT RECIPIENTS WORK How Do We Ensure the Accuracy of Work...

  11. 43 CFR 5.6 - What type of permit conditions may the agency impose?

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 43 Public Lands: Interior 1 2014-10-01 2014-10-01 false What type of permit conditions may the agency impose? 5.6 Section 5.6 Public Lands: Interior Office of the Secretary of the Interior COMMERCIAL FILMING AND SIMILAR PROJECTS AND STILL PHOTOGRAPHY ON CERTAIN AREAS UNDER DEPARTMENT JURISDICTION...

  12. 43 CFR 5.6 - What type of permit conditions may the agency impose?

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 43 Public Lands: Interior 1 2013-10-01 2013-10-01 false What type of permit conditions may the agency impose? 5.6 Section 5.6 Public Lands: Interior Office of the Secretary of the Interior COMMERCIAL FILMING AND SIMILAR PROJECTS AND STILL PHOTOGRAPHY ON CERTAIN AREAS UNDER DEPARTMENT JURISDICTION...

  13. 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…

  14. 42 CFR 422.752 - Basis for imposing intermediate sanctions and civil money penalties.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... money penalties. 422.752 Section 422.752 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES... Sanctions § 422.752 Basis for imposing intermediate sanctions and civil money penalties. (a) All... sanctions at 422.750(a)(1) and (a)(3). (c) Civil Money Penalties. (1) CMS. In addition to, or in place...

  15. 42 CFR 422.756 - Procedures for imposing intermediate sanctions and civil money penalties.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... civil money penalties. 422.756 Section 422.756 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES... Sanctions § 422.756 Procedures for imposing intermediate sanctions and civil money penalties. (a) Notice of... money penalties—(1) CMS notice to OIG. If CMS determines that an MA organization has failed to...

  16. Identities of Young Korean English Language Learners at School: Imposed or Achieved?

    ERIC Educational Resources Information Center

    Ro, Jennifer Moon

    2010-01-01

    Gee's (2000-2001) analytical framework was used to describe the constructed identities of two young Korean ELLs (English language learners) within the school context and were considered to gain insight into their academic success. The author argues that the "model minority" stereotype was influential in shaping the imposed identities created by…

  17. When Will They Ever Learn? Another Failure of Centrally-Imposed Change.

    ERIC Educational Resources Information Center

    Bishop, Pam; Mulford, Bill

    1999-01-01

    Shows how the relationship between (Australian) secondary teachers and their highly respected, collegial principal changed when he was perceived as "doer of the center's bidding." The principal's efforts to comply with a ministerial directive to impose a statewide curriculum undermined trust in his leadership. (12 references) (MLH)

  18. 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...

  19. 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…

  20. 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...

  1. 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...

  2. 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...

  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. 13 CFR 127.700 - 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? 127.700 Section 127.700 Business Credit and Assistance SMALL BUSINESS ADMINISTRATION WOMEN-OWNED SMALL BUSINESS FEDERAL CONTRACT ASSISTANCE PROCEDURES Penalties § 127.700 What penalties...

  6. 42 CFR 423.756 - Procedures for imposing intermediate sanctions and civil money penalties.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... civil money penalties. 423.756 Section 423.756 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICARE PROGRAM VOLUNTARY MEDICARE PRESCRIPTION DRUG BENEFIT Intermediate Sanctions § 423.756 Procedures for imposing intermediate sanctions and civil...

  7. 42 CFR 423.758 - 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. 423.758 Section 423.758 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICARE PROGRAM VOLUNTARY MEDICARE PRESCRIPTION DRUG...

  8. 42 CFR 423.752 - Basis for imposing intermediate sanctions and civil money penalties.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 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 Basis for imposing intermediate sanctions and civil...

  9. 13 CFR 125.29 - What penalties may be imposed under this part?

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... GOVERNMENT CONTRACTING PROGRAMS Penalties and Retention of Records § 125.29 What penalties may be imposed... person or concern pursuant to the procedures set forth in part 145 of this chapter. The contracting... Regulation, 48 CFR Part 9, subpart 9.4. (b) Civil penalties. Persons or concerns are subject to severe...

  10. 13 CFR 125.29 - What penalties may be imposed under this part?

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... GOVERNMENT CONTRACTING PROGRAMS Penalties and Retention of Records § 125.29 What penalties may be imposed... person or concern pursuant to the procedures set forth in part 145 of this chapter. The contracting... Regulation, 48 CFR Part 9, subpart 9.4. (b) Civil penalties. Persons or concerns are subject to severe...

  11. 13 CFR 125.29 - What penalties may be imposed under this part?

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... GOVERNMENT CONTRACTING PROGRAMS Penalties and Retention of Records § 125.29 What penalties may be imposed... person or concern pursuant to the procedures set forth in part 145 of this chapter. The contracting... Regulation, 48 CFR Part 9, subpart 9.4. (b) Civil penalties. Persons or concerns are subject to severe...

  12. 13 CFR 125.29 - What penalties may be imposed under this part?

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... GOVERNMENT CONTRACTING PROGRAMS Penalties and Retention of Records § 125.29 What penalties may be imposed... person or concern pursuant to the procedures set forth in part 145 of this chapter. The contracting... Regulation, 48 CFR Part 9, subpart 9.4. (b) Civil penalties. Persons or concerns are subject to severe...

  13. 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...

  14. 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...

  15. 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...

  16. 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...

  17. 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...

  18. 26 CFR 1.802-3 - Tax imposed on life insurance companies.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ...) imposes a tax on the life insurance company taxable income (as defined in section 802(b) and paragraph (a... net long-term capital gain (as defined in section 1222(7)) of any life insurance company exceeds its... the net long-term capital gain (as defined in section 1222(7)) of any life insurance company...

  19. 26 CFR 1.802-3 - Tax imposed on life insurance companies.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ...) imposes a tax on the life insurance company taxable income (as defined in section 802(b) and paragraph (a... net long-term capital gain (as defined in section 1222(7)) of any life insurance company exceeds its... the net long-term capital gain (as defined in section 1222(7)) of any life insurance company...

  20. 26 CFR 1.802-3 - Tax imposed on life insurance companies.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ...) imposes a tax on the life insurance company taxable income (as defined in section 802(b) and paragraph (a... net long-term capital gain (as defined in section 1222(7)) of any life insurance company exceeds its... the net long-term capital gain (as defined in section 1222(7)) of any life insurance company...

  1. 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

    ... in Fees Imposed AGENCY: Financial Management Service, Fiscal Service, Department of the Treasury..., Financial Management Service, Department of the Treasury, 3700 East West Highway, Room 6F01, Hyattsville, MD... for Management (CFO), Financial Management Service. BILLING CODE 4810-35-M...

  2. 34 CFR 30.61 - What penalties does the Secretary impose on delinquent debtors?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... debtors? 30.61 Section 30.61 Education Office of the Secretary, Department of Education DEBT COLLECTION... the Secretary impose on delinquent debtors? (a) If a debtor does not make a payment on a debt, or portion of a debt, within 90 days after the date specified in the first demand for payment sent to...

  3. Stress-directed adaptive mutations and evolution.

    PubMed

    Wright, Barbara E

    2004-05-01

    Comparative biochemistry demonstrates that the metabolites, complex biochemical networks, enzymes and regulatory mechanisms essential to all living cells are conserved in amazing detail throughout evolution. Thus, in order to evolve, an organism must overcome new adverse conditions without creating different but equally dangerous alterations in its ongoing successful metabolic relationship with its environment. Evidence suggests that stable long-term acquisitive evolution results from minor increases in mutation rates of genes related to a particular stress, with minimal disturbance to the balanced and resilient metabolism critical for responding to an unpredictable environment. Microorganisms have evolved specific biochemical feedback mechanisms that direct mutations to genes derepressed by starvation or other stressors in their environment. Transcription of the activated genes creates localized supercoiling and DNA secondary structures with unpaired bases vulnerable to mutation. The resulting mutants provide appropriate variants for selection by the stress involved, thus accelerating evolution with minimal random damage to the genome. This model has successfully predicted mutation frequencies in genes of E. coli and humans. Stressed cells observed in the laboratory over hundreds of generations accumulate mutations that also arise by this mechanism. When this occurs in repair-deficient mutator strains with high rates of random mutation, the specific stress-directed mutations are also enhanced.

  4. Comparison of the genetic effects of equimolar doses of ENU and MNU: While the chemicals differ dramatically in their mutagenicity in stem-cell spermatogonia, both elicit very high mutation rates in differentiating spermatogonia

    SciTech Connect

    Russell, Liane B; Hunsicker, Patricia R; Russell, William

    2007-03-01

    Mutagenoic, reproductive, and toxicity effects of two closely related chemicals, ethylnitrosourea (ENU) and methylnitrosourea (MNU), were compared at equimolar and near-equimolar doses in the mouse specific-locus test in a screen of all stages of spermatogenesis and spermiogenesis. In stem cell spermatogonial (SG), ENU is more than an order of magnitude more mutagenic than MNU. During post-SG stages, both chemicals exhibit high peaks in mutation yield when differentiating spermatogonial (DG) and preleptotene spermatocytes are exposed. The mutation frequency induced by 75 mg MNU/kg during this peak interval is, to date, the highest induced by any single- xposure mutagenic treatment chemical or radiation that allows survival of the exposed animal and its germ cells, producing an estimated 10 new mutations per genome. There is thus a vast difference between stem cell and differentiating spermatogonial in their sensitivity to MNU, but little difference between these stages in their sensitivity to ENU. During stages following meiotic metaphase, the highest mutation yield is obtained from exposed spermatids, but for both chemicals, that yield is less than one-quarter that obtained from the peak interval. Large-lesion (LL) mutations were induced only in spermatids. Although only a few of the remaining mutations were analyzed molecularly, there is considerable evidence from recent molecular characterizations of the marker genes and their flanking chromosomal regions that most, if not all, mutations induced during the peak-sensitive period did not involve lesions outside the marked loci. Both ENU and MNU treatments of post-SG stages yielded significant numbers of mutants that were recovered as mosaics, with the proportion being higher for ENU than for MNU. Comparing the chemicals for the endpoints studied and additional ones (e.g., chromosome aberrations, toxicity to germ cells and to animals, teratogenicity) revealed that while MNU is generally more effective, the opposite

  5. Mutational landscape of yeast mutator strains.

    PubMed

    Serero, Alexandre; Jubin, Claire; Loeillet, Sophie; Legoix-Né, Patricia; Nicolas, Alain G

    2014-02-01

    The acquisition of mutations is relevant to every aspect of genetics, including cancer and evolution of species on Darwinian selection. Genome variations arise from rare stochastic imperfections of cellular metabolism and deficiencies in maintenance genes. Here, we established the genome-wide spectrum of mutations that accumulate in a WT and in nine Saccharomyces cerevisiae mutator strains deficient for distinct genome maintenance processes: pol32Δ and rad27Δ (replication), msh2Δ (mismatch repair), tsa1Δ (oxidative stress), mre11Δ (recombination), mec1Δ tel1Δ (DNA damage/S-phase checkpoints), pif1Δ (maintenance of mitochondrial genome and telomere length), cac1Δ cac3Δ (nucleosome deposition), and clb5Δ (cell cycle progression). This study reveals the diversity, complexity, and ultimate unique nature of each mutational spectrum, composed of punctual mutations, chromosomal structural variations, and/or aneuploidies. The mutations produced in clb5Δ/CCNB1, mec1Δ/ATR, tel1Δ/ATM, and rad27Δ/FEN1 strains extensively reshape the genome, following a trajectory dependent on previous events. It comprises the transmission of unstable genomes that lead to colony mosaicisms. This comprehensive analytical approach of mutator defects provides a model to understand how genome variations might accumulate during clonal evolution of somatic cell populations, including tumor cells.

  6. 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

  7. Fluoroquinolone resistance does not impose a cost on the fitness of Clostridium difficile in vitro.

    PubMed

    Wasels, François; Kuehne, Sarah A; Cartman, Stephen T; Spigaglia, Patrizia; Barbanti, Fabrizio; Minton, Nigel P; Mastrantonio, Paola

    2015-03-01

    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

  8. 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

  9. Tailoring the metabolism against mutations

    NASA Astrophysics Data System (ADS)

    Gulbahce, Natali; Motter, Adilson E.; Almaas, Eivind; Barabasi, Albert Laszlo

    2008-03-01

    In the post-genomic era, organisms can be modelled at the whole-cell level in silico via steady state methods to describe their metabolic capabilities. We use two such methods, Flux Balance Analysis and Minimization of Metabolic Adjustment to explore the behavior of cells (of E. coli and S. cerevisiae) after severe mutations. We propose experimentally feasible ways of modifying the underlying biochemical reaction network of a mutant cell such that cell functionality, in particular growth rate, is significantly improved.

  10. 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.

  11. Self-interest without selfishness: the hedonic benefit of imposed self-interest.

    PubMed

    Berman, Jonathan Z; Small, Deborah A

    2012-10-01

    Despite commonsense appeal, the link between self-interest and happiness remains elusive. One reason why individuals may not feel satisfied with self-interest is that they feel uneasy about sacrificing the needs of others for their own gain. We propose that externally imposing self-interest allows individuals to enjoy self-benefiting outcomes that are untainted by self-reproach for failing to help others. Study 1 demonstrated that an imposed self-interested option (a reward) leads to greater happiness than does choosing between a self-interested option and a prosocial option (a charity donation). Study 2 demonstrated that this effect is not driven by choice in general; rather, it is the specific trade-off between benefiting the self and benefiting others that inhibits happiness gained from self-interest. We theorize that the agency inherent in choice reduces the hedonic value of self-interest. Results of Study 3 find support for this mechanism.

  12. 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

  13. 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

  14. Recurrent Somatic Mutations in Regulatory Regions of Human Cancer Genomes

    PubMed Central

    Melton, Collin; Reuter, Jason A.; Spacek, Damek V.; Snyder, Michael

    2015-01-01

    Aberrant regulation of gene expression in cancer can promote survival and proliferation of cancer cells. Here we integrate TCGA whole genome sequencing data of 436 patients from eight cancer subtypes with ENCODE and other regulatory annotations to identify point mutations in regulatory regions. We find evidence for positive selection of mutations in transcription factor binding sites, consistent with these sites regulating important cancer cell functions. Using a novel method that adjusts for sample- and genomic locus-specific mutation rate, we identify recurrently mutated sites across cancer patients. Mutated regulatory sites include known sites in the TERT promoter and many novel sites, including a subset in proximity to cancer genes. In reporter assays, two novel sites display decreased enhancer activity upon mutation. These data demonstrate that many regulatory regions contain mutations under selective pressure and suggest a larger role for regulatory mutations in cancer than previously appreciated. PMID:26053494

  15. 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.

  16. Quantifying the mutational meltdown in diploid populations.

    PubMed

    Coron, Camille; Méléard, Sylvie; Porcher, Emmanuelle; Robert, Alexandre

    2013-05-01

    Mutational meltdown, in which demographic and genetic processes mutually reinforce one another to accelerate the extinction of small populations, has been poorly quantified despite its potential importance in conservation biology. Here we present a model-based framework to study and quantify the mutational meltdown in a finite diploid population that is evolving continuously in time and subject to resource competition. We model slightly deleterious mutations affecting the population demographic parameters and study how the rate of mutation fixation increases as the genetic load increases, a process that we investigate at two timescales: an ecological scale and a mutational scale. Unlike most previous studies, we treat population size as a random process in continuous time. We show that as deleterious mutations accumulate, the decrease in mean population size accelerates with time relative to a null model with a constant mean fixation time. We quantify this mutational meltdown via the change in the mean fixation time after each new mutation fixation, and we show that the meltdown appears less severe than predicted by earlier theoretical work. We also emphasize that mean population size alone can be a misleading index of the risk of population extinction, which could be better evaluated with additional information on demographic parameters.

  17. Human Germline Mutation and the Erratic Evolutionary Clock

    PubMed Central

    Przeworski, Molly

    2016-01-01

    Our understanding of the chronology of human evolution relies on the “molecular clock” provided by the steady accumulation of substitutions on an evolutionary lineage. Recent analyses of human pedigrees have called this understanding into question by revealing unexpectedly low germline mutation rates, which imply that substitutions accrue more slowly than previously believed. Translating mutation rates estimated from pedigrees into substitution rates is not as straightforward as it may seem, however. We dissect the steps involved, emphasizing that dating evolutionary events requires not “a mutation rate” but a precise characterization of how mutations accumulate in development in males and females—knowledge that remains elusive. PMID:27760127

  18. Differential Persistence of Transmitted HIV-1 Drug Resistance Mutation Classes

    PubMed Central

    Jain, Vivek; Sucupira, Maria C.; Bacchetti, Peter; Hartogensis, Wendy; Diaz, Ricardo S.; Kallas, Esper G.; Janini, Luiz M.; Liegler, Teri; Pilcher, Christopher D.; Grant, Robert M.; Cortes, Rodrigo; Deeks, Steven G.

    2011-01-01

    Background. Transmitted human immunodeficiency virus type 1 (HIV-1) drug resistance (TDR) mutations can become replaced over time by emerging wild-type viral variants with improved fitness. The impact of class-specific mutations on this rate of mutation replacement is uncertain. Methods. We studied participants with acute and/or early HIV infection and TDR in 2 cohorts (San Francisco, California, and São Paulo, Brazil). We followed baseline mutations longitudinally and compared replacement rates between mutation classes with use of a parametric proportional hazards model. Results. Among 75 individuals with 195 TDR mutations, M184V/I became undetectable markedly faster than did nonnucleoside reverse-transcriptase inhibitor (NNRTI) mutations (hazard ratio, 77.5; 95% confidence interval [CI], 14.7–408.2; P < .0001), while protease inhibitor and NNRTI replacement rates were similar. Higher plasma HIV-1 RNA level predicted faster mutation replacement, but this was not statistically significant (hazard ratio, 1.71 log10 copies/mL; 95% CI, .90–3.25 log10 copies/mL; P = .11). We found substantial person-to-person variability in mutation replacement rates not accounted for by viral load or mutation class (P < .0001). Conclusions. The rapid replacement of M184V/I mutations is consistent with known fitness costs. The long-term persistence of NNRTI and protease inhibitor mutations suggests a risk for person-to-person propagation. Host and/or viral factors not accounted for by viral load or mutation class are likely influencing mutation replacement and warrant further study. PMID:21451005

  19. Mutations in Escherichia coli that relieve catabolite repression of tryptophanase synthesis. Tryptophanase promoter-like mutations.

    PubMed

    Ward, D F; Yudkin, M D

    1976-01-01

    From a strain lacking adenyl cyclase and the catabolite-sensitive gene activator protein, two mutants were isolated that can synthesize tryptophanase. Each mutation is extremely closely linked to the tryptophanase structural gene. The mutations differ from one another in the rate of synthesis of tryptophanase that they permit in the genetic background in which they were isolated; they differ from one another and also from the wild type in the maximum rate of synthesis of tryptophanase that they permit in a genetic background with intact adenyl cyclase and catabolite-sensitive gene activator protein. Both mutations appear to lie in the tryptophanase promoter.

  20. The directed mutation controversy and neo-Darwinism.

    PubMed

    Lenski, R E; Mittler, J E

    1993-01-01

    According to neo-Darwinian theory, random mutation produces genetic differences among organisms whereas natural selection tends to increase the frequency of advantageous alleles. However, several recent papers claim that certain mutations in bacteria and yeast occur at much higher rates specifically when the mutant phenotypes are advantageous. Various molecular models have been proposed that might explain these directed mutations, but the models have not been confirmed. Critics contend that studies purporting to demonstrate directed mutation lack certain controls and fail to account adequately for population dynamics. Further experiments that address these criticisms do not support the existence of directed mutations.

  1. Persistence of HIV-1 transmitted drug resistance mutations.

    PubMed

    Castro, Hannah; Pillay, Deenan; Cane, Patricia; Asboe, David; Cambiano, Valentina; Phillips, Andrew; Dunn, David T

    2013-11-01

    There are few data on the persistence of individual human immunodeficiency virus type 1 (HIV-1) transmitted drug resistance (TDR) mutations in the absence of selective drug pressure. We studied 313 patients in whom TDR mutations were detected at their first resistance test and who had a subsequent test performed while ART-naive. The rate at which mutations became undetectable was estimated using exponential regression accounting for interval censoring. Most thymidine analogue mutations (TAMs) and T215 revertants (but not T215F/Y) were found to be highly stable, with NNRTI and PI mutations being relatively less persistent. Our estimates are important for informing HIV transmission models.

  2. Role of epistasis on the fixation probability of a non-mutator in an adapted asexual population.

    PubMed

    James, Ananthu

    2016-10-21

    The mutation rate of a well adapted population is prone to reduction so as to have a lower mutational load. We aim to understand the role of epistatic interactions between the fitness affecting mutations in this process. Using a multitype branching process, the fixation probability of a single non-mutator emerging in a large asexual mutator population is analytically calculated here. The mutator population undergoes deleterious mutations at constant, but at a much higher rate than that of the non-mutator. We find that antagonistic epistasis lowers the chances of mutation rate reduction, while synergistic epistasis enhances it. Below a critical value of epistasis, the fixation probability behaves non-monotonically with variation in the mutation rate of the background population. Moreover, the variation of this critical value of the epistasis parameter with the strength of the mutator is discussed in the appendix. For synergistic epistasis, when selection is varied, the fixation probability reduces overall, with damped oscillations.

  3. Nonadaptive mutations occur on the F' episome during adaptive mutation conditions in Escherichia coli.

    PubMed Central

    Foster, P L

    1997-01-01

    One of the most studied examples of adaptive mutation is a strain of Escherichia coli, FC40, that cannot utilize lactose (Lac-) but that readily reverts to lactose utilization (Lac+) when lactose is its sole carbon source. Adaptive reversion to Lac+ occurs at a high rate when the Lac- allele is on an F' episome and conjugal functions are expressed. It was previously shown that nonselected mutations on the chromosome did not appear in the Lac- population while episomal Lac+ mutations accumulated, but it remained possible that nonselected mutations might occur on the episome. To investigate this possibility, a second mutational target was created on the Lac- episome by mutation of a Tn1O element, which encodes tetracycline resistance (Tetr), to tetracycline sensitivity (Tets). Reversion rates to Tetr during normal growth and during lactose selection were measured. The results show that nonselected Tetr mutations do accumulate in Lac- cells when those cells are under selection to become Lac+. Thus, reversion to Lac+ in FC40 does not appear to be adaptive in the narrow sense of the word. In addition, the results suggest that during lactose selection, both Lac+ and Tetr mutations are created or preserved by the same recombination-dependent mechanism. PMID:9045812

  4. The mutational spectrum of non-CpG DNA varies with CpG content.

    PubMed

    Walser, Jean-Claude; Furano, Anthony V

    2010-07-01

    The accumulation of base substitutions (mutations) not subject to natural selection is the neutral mutation rate. Because this rate reflects the in vivo processes involved in maintaining the integrity of genetic information, the factors that affect the neutral mutation rate are of considerable interest. Mammals exhibit two dramatically different neutral mutation rates: the CpG mutation rate, wherein the C of most CpGs (i.e., methyl-CpG) mutate at 10-50 times that of C in any other context or of any other base. The latter mutations constitute the non-CpG rate. The high CpG rate results from the spontaneous deamination of methyl-C to T and incomplete restoration of the ensuing T:G mismatches to C:Gs. Here, we determined the neutral non-CpG mutation rate as a function of CpG content by comparing sequence divergence of thousands of pairs of neutrally evolving chimpanzee and human orthologs that differ primarily in CpG content. Both the mutation rate and the mutational spectrum (transition/transversion ratio) of non-CpG residues change in parallel as sigmoidal (logistic) functions of CpG content. As different mechanisms generate transitions and transversions, these results indicate that both mutation rate and mutational processes are contingent on the local CpG content. We consider several possible mechanisms that might explain how CpG exerts these effects. PMID:20498119

  5. 49 CFR 236.567 - Restrictions imposed when device fails and/or is cut out en route.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 false Restrictions imposed when device fails and/or is cut out en route. 236.567 Section 236.567 Transportation Other Regulations Relating to Transportation...; Locomotives § 236.567 Restrictions imposed when device fails and/or is cut out en route. Where an...

  6. Imposed-Etic and Emic Measures of Intelligence as Predictors of Early School Performance of Rural Philippine Children.

    ERIC Educational Resources Information Center

    Church, A. Timothy; Katigbak, Marcia S.

    1988-01-01

    Emic (culture-specific) and Western-type (imposed-etic) strategies were applied to the assessment of intelligence in 67 rural Filipino children. Imposed-etic tests measured a concept of intelligence that only partially overlaps emic conceptions, and were better predictors of school performance, which was not predicted by indigenous (emic)…

  7. 28 CFR 1.10 - Procedures applicable to prisoners under a sentence of death imposed by a United States District...

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 28 Judicial Administration 1 2010-07-01 2010-07-01 false Procedures applicable to prisoners under a sentence of death imposed by a United States District Court. 1.10 Section 1.10 Judicial Administration DEPARTMENT OF JUSTICE EXECUTIVE CLEMENCY § 1.10 Procedures applicable to prisoners under a sentence of death imposed by a United States...

  8. 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...

  9. 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...

  10. 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...

  11. 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...

  12. 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...

  13. 42 CFR 488.433 - Civil money penalties: Uses and approval of civil money penalties imposed by CMS.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 5 2011-10-01 2011-10-01 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....

  14. 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....

  15. 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....

  16. 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...

  17. 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.

  18. Mitochondrial DNA exhibits resistance to induced point and deletion mutations

    PubMed Central

    Valente, William J.; Ericson, Nolan G.; Long, Alexandra S.; White, Paul A.; Marchetti, Francesco; Bielas, Jason H.

    2016-01-01

    The accumulation of somatic mitochondrial DNA (mtDNA) mutations contributes to the pathogenesis of human disease. Currently, mitochondrial mutations are largely considered results of inaccurate processing of its heavily damaged genome. However, mainly from a lack of methods to monitor mtDNA mutations with sufficient sensitivity and accuracy, a link between mtDNA damage and mutation has not been established. To test the hypothesis that mtDNA-damaging agents induce mtDNA mutations, we exposed MutaTMMouse mice to benzo[a]pyrene (B[a]P) or N-ethyl-N-nitrosourea (ENU), daily for 28 consecutive days, and quantified mtDNA point and deletion mutations in bone marrow and liver using our newly developed Digital Random Mutation Capture (dRMC) and Digital Deletion Detection (3D) assays. Surprisingly, our results demonstrate mutagen treatment did not increase mitochondrial point or deletion mutation frequencies, despite evidence both compounds increase nuclear DNA mutations and demonstrated B[a]P adduct formation in mtDNA. These findings contradict models of mtDNA mutagenesis that assert the elevated rate of mtDNA mutation stems from damage sensitivity and abridged repair capacity. Rather, our results demonstrate induced mtDNA damage does not readily convert into mutation. These findings suggest robust mitochondrial damage responses repress induced mutations after mutagen exposure. PMID:27550180

  19. Contrasting dynamics of a mutator allele in asexual populations of differing size.

    PubMed

    Raynes, Yevgeniy; Gazzara, Matthew R; Sniegowski, Paul D

    2012-07-01

    Mutators have been shown to hitchhike in asexual populations when the anticipated beneficial mutation supply rate of the mutator subpopulation, NU(b) (for subpopulation of size N and beneficial mutation rate U(b)) exceeds that of the wild-type subpopulation. Here, we examine the effect of total population size on mutator dynamics in asexual experimental populations of Saccharomyces cerevisiae. Although mutators quickly hitchhike to fixation in smaller populations, mutator fixation requires more and more time as population size increases; this observed delay in mutator hitchhiking is consistent with the expected effect of clonal interference. Interestingly, despite their higher beneficial mutation supply rate, mutators are supplanted by the wild type in very large populations. We postulate that this striking reversal in mutator dynamics is caused by an interaction between clonal interference, the fitness cost of the mutator allele, and infrequent large-effect beneficial mutations in our experimental populations. Our work thus identifies a potential set of circumstances under which mutator hitchhiking can be inhibited in natural asexual populations, despite recent theoretical predictions that such populations should have a net tendency to evolve ever-higher genomic mutation rates.

  20. Emerging asymmetric interactions between forage and predator fisheries impose management trade-offs.

    PubMed

    Houle, J E; Andersen, K H; Farnsworth, K D; Reid, D G

    2013-10-01

    A size and trait-based marine community model was used to investigate interactions, with potential implications for yields, when a fishery targeting forage fish species (whose main adult diet is zooplankton) co-occurs with a fishery targeting larger-sized predator species. Predicted effects on the size structure of the fish community, growth and recruitment of fishes, and yield from the fisheries were used to identify management trade-offs among the different fisheries. Results showed that moderate fishing on forage fishes imposed only small effects on predator fisheries, whereas predator fisheries could enhance yield from forage fisheries under some circumstances.

  1. 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.

  2. 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

  3. The molecular landscape of ASPM mutations in primary microcephaly

    PubMed Central

    Nicholas, A K; Swanson, E A; Cox, J J; Karbani, G; Malik, S; Springell, K; Hampshire, D; Ahmed, M; Bond, J; Di Benedetto, D; Fichera, M; Romano, C; Dobyns, W B; Woods, C G

    2009-01-01

    Background: Autosomal recessive primary microcephaly (MCPH) is a model disease to study human neurogenesis. In affected individuals the brain grows at a reduced rate during fetal life resulting in a small but structurally normal brain and mental retardation. The condition is genetically heterogeneous with mutations in ASPM being most commonly reported. Methods and results: We have examined this further by studying three cohorts of microcephalic children to extend both the phenotype and the mutation spectrum. Firstly, in 99 consecutively ascertained consanguineous families with a strict diagnosis of MCPH, 41 (41%) were homozygous at the MCPH5 locus and all but two families had mutations. Thus, 39% of consanguineous MCPH families had homozygous ASPM mutations. Secondly, in 27 non-consanguineous, predominantly Caucasian families with a strict diagnosis of MCPH, 11 (40%) had ASPM mutations. Thirdly, in 45 families with a less restricted phenotype including microcephaly and mental retardation, but regardless of other neurological features, only 3 (7%) had an ASPM mutation. This report contains 27 novel mutations and almost doubles the number of MCPH associated ASPM mutations known to 57. All but one of the mutations lead to the use of a premature termination codon, 23 were nonsense mutations, 28 deletions or insertions, 5 splicing, and 1 was a translocation. Seventeen of the 57 mutations were recurrent. There were no definitive missense mutations found nor was there any mutation/phenotype correlation. ASPM mutations were found in all ethnic groups studied. Conclusion: This study confirms that mutations in ASPM are the most common cause of MCPH, that ASPM mutations are restricted to individuals with an MCPH phenotype, and that ASPM testing in primary microcephaly is clinically useful. PMID:19028728

  4. New mutations affecting induced mutagenesis in yeast.

    PubMed

    Lawrence, C W; Krauss, B R; Christensen, R B

    1985-01-01

    Previously isolated mutations in baker's yeast, Saccharomyces cerevisiae, that impair induced mutagenesis were all identified with the aid of tests that either exclusively or predominantly detect base-pair substitutions. To avoid this bias, we have screened 11 366 potentially mutant clones for UV-induced reversion of the frameshift allele, his4-38, and have identified 10 mutants that give much reduced yields of revertants. Complementation and recombination tests show that 6 of these carry mutations at the previously known REV1, REV1 and REV3 loci, while the remaining 4 define 3 new genes, REV4 (2 mutations), REV5 and REV6. The rev4 mutations are readily suppressed in many genetic backgrounds and, like the rev5 mutation, impart only a limited deficiency for induced mutagenesis: it is likely, therefore that the REV4+ and REV5+ gene functions are only remotely concerned with this process. The rev6 mutants have a more general deficiency, however, as well as marked sensitivity to UV and an increased spontaneous mutation rate, properties that suggest the REV6 gene is directly involved in mutation induction. The REV5 gene is located about 1 cM proximal to CYC1 on chromosome X.

  5. 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.

  6. 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.

  7. Mutation and premating isolation.

    PubMed

    Woodruff, R C; Thompson, J N

    2002-11-01

    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. Multiplex detection of mutations.

    PubMed

    Perlin, David S; Balashov, Sergey; Park, Steven

    2008-01-01

    Rapid and reliable detection of mutations at the genetic level is an integral part of modern molecular diagnostics. These mutations can range from dominant single nucleotide polymorphisms within specific loci to codominant heterozygotic insertions and they present considerable challenges to investigators in developing rapid nucleic acid-based amplification assays that can distinguish wild-type from mutant alleles. The recent improvements of real-time polymerase chain reaction (PCR) using self-reporting fluorescence probes have given researchers a powerful tool in developing assays for mutation detection that can be multiplexed for high-throughput screening of multiple mutations and cost effectiveness. Here we describe an application of a multiplexed real-time PCR assay using Molecular Beacon probes for the detection of mutations in codon 54 of the CYP51A gene in Aspergillus fumigatus conferring triazole resistance.

  9. 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.

  10. Causality-imposed (Kramers-Kronig) relationships between attenuation and dispersion.

    PubMed

    Waters, Kendall R; Mobley, Joel; Miller, James G

    2005-05-01

    Causality imposes restrictions on both the time-domain and frequency-domain responses of a system. The Kramers-Kronig (K-K) relations relate the real and imaginary parts of the frequency-domain response. In ultrasonics, K-K relations often are used to link attenuation and dispersion. We review both integral and differential forms of the frequency-domain K-K relations that are relevant to theoretical models and laboratory measurements. We consider two methods for implementing integral K-K relations for the case of finite-bandwidth data, namely, extrapolation of data and restriction of integration limits. For the latter approach, we discuss the accuracy of K-K predictions for specific classes of system behavior and how the truncation of the integrals affects this accuracy. We demonstrate the accurate prediction of attenuation and dispersion using several forms of the K-K relations relevant to experimental measurements of media with attenuation coefficients obeying a frequency power law and media consisting of resonant scatterers. We also review the time-causal relations that describe the time-domain consequences of causality in the wave equation. These relations can be thought of as time-domain analogs of the (frequency-domain) K-K relations. Causality-imposed relations, such as the K-K and time-causal relations, provide useful tools for the analysis of measurements and models of acoustic systems.

  11. 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.

  12. 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.

  13. Magnetic Variability Imposed by the Quasi-16-Day Wave (Q16DW)

    NASA Astrophysics Data System (ADS)

    Elhawary, R.; Forbes, J. M.

    2015-12-01

    It is now well-accepted that vertically-propagating waves from the lower atmosphere exert significant variability on the ionosphere. The first interaction occurs within the so-called "dynamo region" (ca. 100-150 km), where winds, plasma and Earth's magnetic field interact to generate electric fields and currents. These electric fields map to higher altitudes and impose spatial-temporal variability on the F-region ionospheric plasma. The accompanying dynamo-region electric currents induce ground magnetic perturbations measured by magnetometers distributed over the globe, and thus provide important insights into the nature of this neutral-plasma interaction. For instance, one might ask: what kind of longitude variability is imposed by planetary waves? In this study, we analyze the northward component of geomagnetic solar quiet (Sq) variations in an attempt to identify the zonal wave number content of planetary-wave (PW) signals in the Sq field. Data from five northern-hemisphere mid-latitude ground-based magnetometer stations distributed in longitude around one latitudinal circle are analyzed for the solar minimum period of 2009. The Q16DW and its zonal wave number components 0, ± 1 and ±2 are extracted and form the focus of this particular study. Results are interpreted in terms of the longitude variation of the total Q16DW, its connection with the Q16DW in the neutral atmosphere, and possible influences of the longitude dependence of Earth's magnetic field.

  14. Whole-system responses of experimental plant communities to climate extremes imposed in different seasons.

    PubMed

    De Boeck, Hans J; Dreesen, Freja E; Janssens, Ivan A; Nijs, Ivan

    2011-02-01

    • Discrete climate events such as heat waves and droughts can have a disproportionate impact on ecosystems relative to the temporal scale over which they occur. Research oriented towards (extreme) events rather than (gradual) trends is therefore urgently needed. • Here, we imposed heat waves and droughts (50-yr return time) in a full factorial design on experimental plant communities in spring, summer or autumn. Droughts were created by removing the controlled water table (rainout shelters prevented precipitation), while heat waves were imposed with infrared heaters. • Measurements of whole-system CO(2) exchange, growth and biomass production revealed multiple interactions between treatments and the season in which they occurred. Heat waves had only small and transient effects, with infrared imaging showing little heat stress because of transpirational cooling. If heat waves were combined with drought, negative effects observed in single factor drought treatments were exacerbated through intensified soil drying, and heat stress in summer. Plant recovery from stress differed, affecting the biomass yield. • In conclusion, the timing of extreme events is critical regarding their impact, and synergisms between heat waves and drought aggravate the negative effects of these extremes on plant growth and functioning.

  15. Emerging patterns of somatic mutations in cancer

    PubMed Central

    Watson, Ian R.; Takahashi, Koichi; Futreal, P. Andrew; Chin, Lynda

    2014-01-01

    The advance in technological tools for massively parallel, high-throughput sequencing of DNA has enabled the comprehensive characterization of somatic mutations in large number of tumor samples. Here, we review recent cancer genomic studies that have assembled emerging views of the landscapes of somatic mutations through deep sequencing analyses of the coding exomes and whole genomes in various cancer types. We discuss the comparative genomics of different cancers, including mutation rates, spectrums, and roles of environmental insults that influence these processes. We highlight the developing statistical approaches used to identify significantly mutated genes, and discuss the emerging biological and clinical insights from such analyses as well as the challenges ahead translating these genomic data into clinical impacts. PMID:24022702

  16. Emerging patterns of somatic mutations in cancer.

    PubMed

    Watson, Ian R; Takahashi, Koichi; Futreal, P Andrew; Chin, Lynda

    2013-10-01

    Recent advances in technological tools for massively parallel, high-throughput sequencing of DNA have enabled the comprehensive characterization of somatic mutations in a large number of tumour samples. In this Review, we describe recent cancer genomic studies that have assembled emerging views of the landscapes of somatic mutations through deep-sequencing analyses of the coding exomes and whole genomes in various cancer types. We discuss the comparative genomics of different cancers, including mutation rates and spectra, as well as the roles of environmental insults that influence these processes. We highlight the developing statistical approaches that are used to identify significantly mutated genes, and discuss the emerging biological and clinical insights from such analyses, as well as the future challenges of translating these genomic data into clinical impacts.

  17. 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

  18. The Origin of Spontaneous Mutation in SACCHAROMYCES CEREVISIAE

    PubMed Central

    Quah, Siew-Keen; von Borstel, R. C.; Hastings, P. J.

    1980-01-01

    Characterization of two antimutator loci in yeast shows that both are members of the same mutagenic repair system known to be responsible for almost all induced mutation (Lawrence and Christensen 1976, 1979a,b; Prakash 1976). One of the these newly isolated antimutator mutations is an allele of rev3 (Lemontt 1971b). Two other alleles of rev3 were tested and were also found to be antimutators. Double mutants carrying rev3 and mutator mutations of rad3, rad51 or rad18 are like rev3 single mutants with respect to spontaneous mutation rate, supporting the hypothesis (Hastings, Quah and von Borstel 1976) that many mutators in yeast act by channelling spontaneous lesions from accurate to mutagenic repair. However, the enhanced mutation rate seen in a radiation-resistant mutator mutant mut1 is not dependent on REV3, but is dependent on another gene designated ANT1. An additive effect on the reduction in spontaneous mutation, seen in the ant1 rev3 double-mutant strain, leads to the conclusion that at least 90% of spontaneous mutations seen in the wild type are caused by mutagenic repair of spontaneous lesions. PMID:7021317

  19. The rich phase structure of a mutator model

    PubMed Central

    Saakian, David B.; Yakushkina, Tatiana; Hu, Chin-Kun

    2016-01-01

    We propose a modification of the Crow-Kimura and Eigen models of biological molecular evolution to include a mutator gene that causes both an increase in the mutation rate and a change in the fitness landscape. This mutator effect relates to a wide range of biomedical problems. There are three possible phases: mutator phase, mixed phase and non-selective phase. We calculate the phase structure, the mean fitness and the fraction of the mutator allele in the population, which can be applied to describe cancer development and RNA viruses. We find that depending on the genome length, either the normal or the mutator allele dominates in the mixed phase. We analytically solve the model for a general fitness function. We conclude that the random fitness landscape is an appropriate choice for describing the observed mutator phenomenon in the case of a small fraction of mutators. It is shown that the increase in the mutation rates in the regular and the mutator parts of the genome should be set independently; only some combinations of these increases can push the complex biomedical system to the non-selective phase, potentially related to the eradication of tumors. PMID:27721395

  20. Inference of directional selection and mutation parameters assuming equilibrium.

    PubMed

    Vogl, Claus; Bergman, Juraj

    2015-12-01

    In a classical study, Wright (1931) proposed a model for the evolution of a biallelic locus under the influence of mutation, directional selection and drift. He derived the equilibrium distribution of the allelic proportion conditional on the scaled mutation rate, the mutation bias and the scaled strength of directional selection. The equilibrium distribution can be used for inference of these parameters with genome-wide datasets of "site frequency spectra" (SFS). Assuming that the scaled mutation rate is low, Wright's model can be approximated by a boundary-mutation model, where mutations are introduced into the population exclusively from sites fixed for the preferred or unpreferred allelic states. With the boundary-mutation model, inference can be partitioned: (i) the shape of the SFS distribution within the polymorphic region is determined by random drift and directional selection, but not by the mutation parameters, such that inference of the selection parameter relies exclusively on the polymorphic sites in the SFS; (ii) the mutation parameters can be inferred from the amount of polymorphic and monomorphic preferred and unpreferred alleles, conditional on the selection parameter. Herein, we derive maximum likelihood estimators for the mutation and selection parameters in equilibrium and apply the method to simulated SFS data as well as empirical data from a Madagascar population of Drosophila simulans.

  1. Non-fatherhood or mutation? A probabilistic approach to parental exclusion in paternity testing.

    PubMed

    Dawid, A P; Mortera, J; Pascali, V L

    2001-12-15

    The occurrence of germline mutations at microsatellite loci poses problems in ascertaining non-fatherhood status in paternity testing. We describe the appropriate probabilistic analysis for computing the likelihood ratio in favour of paternity while allowing for mutation, for all 18 relevant combinations of seemingly incompatible parental genotypes. We allow arbitrary and possibly different mutation rates in paternal and maternal germlines. We describe a stationary mutation model for expressing the required allele-specific transition mutation rates in terms of overall mutation rates, and compare the likelihood ratios calculated from this and from other mutation models suggested in the literature. We also show how to derive an upper bound on the likelihood ratio, depending only on the overall mutation rate.

  2. 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

  3. 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.

  4. 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.

  5. Quantum Error-Correction-Enhanced Magnetometer Overcoming the Limit Imposed by Relaxation.

    PubMed

    Herrera-Martí, David A; Gefen, Tuvia; Aharonov, Dorit; Katz, Nadav; Retzker, Alex

    2015-11-13

    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. PMID:26613424

  6. Mixed finite element methods for linear elasticity with weakly imposed symmetry

    NASA Astrophysics Data System (ADS)

    Arnold, Douglas N.; Falk, Richard S.; Winther, Ragnar

    2007-12-01

    In this paper, we construct new finite element methods for the approximation of the equations of linear elasticity in three space dimensions that produce direct approximations to both stresses and displacements. The methods are based on a modified form of the Hellinger-Reissner variational principle that only weakly imposes the symmetry condition on the stresses. Although this approach has been previously used by a number of authors, a key new ingredient here is a constructive derivation of the elasticity complex starting from the de Rham complex. By mimicking this construction in the discrete case, we derive new mixed finite elements for elasticity in a systematic manner from known discretizations of the de Rham complex. These elements appear to be simpler than the ones previously derived. For example, we construct stable discretizations which use only piecewise linear elements to approximate the stress field and piecewise constant functions to approximate the displacement field.

  7. Improved Confinement due to Open Ergodic Field Lines Imposed by the Dynamic Ergodic Divertor in TEXTOR

    NASA Astrophysics Data System (ADS)

    Finken, K. H.; Abdullaev, S. S.; Jakubowski, M. W.; de Bock, M. F. M.; Bozhenkov, S.; Busch, C.; von Hellermann, M.; Jaspers, R.; Kikuchi, Y.; Krämer-Flecken, A.; Lehnen, M.; Schega, D.; Schmitz, O.; Spatschek, K. H.; Unterberg, B.; Wingen, A.; Wolf, R. C.; Zimmermann, O.

    2007-02-01

    The ergodization of the magnetic field lines imposed by the dynamic ergodic diverter (DED) in TEXTOR can lead both to confinement improvement and to confinement deterioration. The cases of substantial improvement are in resonant ways related to particular conditions in which magnetic flux tubes starting at the X points of induced islands are connected with the wall. This opening process is connected with a characteristic modification of the heat deposition pattern at the divertor target plate and leads to a substantial increase and steepening of the core plasma density and pressure. The improvement is tentatively attributed to a modification of the electric potential in the plasma carried by the open field lines. The confinement improvement bases on a spontaneous density built up due to the application of the DED and is primarily a particle confinement improvement.

  8. 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

  9. Quantum Error-Correction-Enhanced Magnetometer Overcoming the Limit Imposed by Relaxation.

    PubMed

    Herrera-Martí, David A; Gefen, Tuvia; Aharonov, Dorit; Katz, Nadav; Retzker, Alex

    2015-11-13

    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.

  10. 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

  11. 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

  12. Imposed magnetic field and hot electron propagation in inertial fusion hohlraums

    DOE PAGES

    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

  13. 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.

  14. 76 FR 70544 - OFAC Implementation of Certain Sanctions Imposed on Seven Persons by the Secretary of State...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-14

    .... The Secretary of State recently imposed ISA sanctions on eight persons. See 76 FR 56,866 (Sept. 14....), Gildo Pastor Center--Block C 4.20, 7 rue du Gabian, Fontvieille MC 98000, Monaco; Web site...

  15. 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.

  16. Mutational spectrum of adult T-ALL.

    PubMed

    Neumann, Martin; Vosberg, Sebastian; Schlee, Cornelia; Heesch, Sandra; Schwartz, Stefan; Gökbuget, Nicola; Hoelzer, Dieter; Graf, Alexander; Krebs, Stefan; Bartram, Isabelle; Blum, Helmut; Brüggemann, Monika; Hecht, Jochen; Bohlander, Stefan K; Greif, Philipp A; Baldus, Claudia D

    2015-02-20

    Novel target discovery is warranted to improve treatment in adult T-cell acute lymphoblastic leukemia (T-ALL) patients. We provide a comprehensive study on mutations to enhance the understanding of therapeutic targets and studied 81 adult T-ALL patients. NOTCH1 exhibitedthe highest mutation rate (53%). Mutation frequencies of FBXW7 (10%), WT1 (10%), JAK3 (12%), PHF6 (11%), and BCL11B (10%) were in line with previous reports. We identified recurrent alterations in transcription factors DNM2, and RELN, the WNT pathway associated cadherin FAT1, and in epigenetic regulators (MLL2, EZH2). Interestingly, we discovered novel recurrent mutations in the DNA repair complex member HERC1, in NOTCH2, and in the splicing factor ZRSR2. A frequently affected pathway was the JAK/STAT pathway (18%) and a significant proportion of T-ALL patients harboured mutations in epigenetic regulators (33%), both predominantly found in the unfavourable subgroup of early T-ALL. Importantly, adult T-ALL patients not only showed a highly heterogeneous mutational spectrum, but also variable subclonal allele frequencies implicated in therapy resistance and evolution of relapse. In conclusion, we provide novel insights in genetic alterations of signalling pathways (e.g. druggable by γ-secretase inhibitors, JAK inhibitors or EZH2 inhibitors), present in over 80% of all adult T-ALL patients, that could guide novel therapeutic approaches.

  17. Mutational spectrum of adult T-ALL.

    PubMed

    Neumann, Martin; Vosberg, Sebastian; Schlee, Cornelia; Heesch, Sandra; Schwartz, Stefan; Gökbuget, Nicola; Hoelzer, Dieter; Graf, Alexander; Krebs, Stefan; Bartram, Isabelle; Blum, Helmut; Brüggemann, Monika; Hecht, Jochen; Bohlander, Stefan K; Greif, Philipp A; Baldus, Claudia D

    2015-02-20

    Novel target discovery is warranted to improve treatment in adult T-cell acute lymphoblastic leukemia (T-ALL) patients. We provide a comprehensive study on mutations to enhance the understanding of therapeutic targets and studied 81 adult T-ALL patients. NOTCH1 exhibitedthe highest mutation rate (53%). Mutation frequencies of FBXW7 (10%), WT1 (10%), JAK3 (12%), PHF6 (11%), and BCL11B (10%) were in line with previous reports. We identified recurrent alterations in transcription factors DNM2, and RELN, the WNT pathway associated cadherin FAT1, and in epigenetic regulators (MLL2, EZH2). Interestingly, we discovered novel recurrent mutations in the DNA repair complex member HERC1, in NOTCH2, and in the splicing factor ZRSR2. A frequently affected pathway was the JAK/STAT pathway (18%) and a significant proportion of T-ALL patients harboured mutations in epigenetic regulators (33%), both predominantly found in the unfavourable subgroup of early T-ALL. Importantly, adult T-ALL patients not only showed a highly heterogeneous mutational spectrum, but also variable subclonal allele frequencies implicated in therapy resistance and evolution of relapse. In conclusion, we provide novel insights in genetic alterations of signalling pathways (e.g. druggable by γ-secretase inhibitors, JAK inhibitors or EZH2 inhibitors), present in over 80% of all adult T-ALL patients, that could guide novel therapeutic approaches. PMID:25595890

  18. 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.

  19. 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

  20. Experiments on the role of deleterious mutations as stepping stones in adaptive evolution

    PubMed Central

    Covert, Arthur W.; Lenski, Richard E.; Wilke, Claus O.; Ofria, Charles

    2013-01-01

    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

  1. 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.

  2. 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.

  3. 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

  4. 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

  5. DNA sequence evolution with neighbor-dependent mutation.

    PubMed

    Arndt, Peter F; Burge, Christopher B; Hwa, Terence

    2003-01-01

    We introduce a model of DNA sequence evolution which can account for biases in mutation rates that depend on the identity of the neighboring bases. An analytic solution for this class of models is developed by adopting well-known methods of nonlinear dynamics. Results are presented for the CpG-methylation-deamination process, which dominates point substitutions in vertebrates. The dinucleotide frequencies generated by the model (using empirically obtained mutation rates) match the overall pattern observed in noncoding DNA. A web-based tool has been constructed to compute single- and dinucleotide frequencies for arbitrary neighbor-dependent mutation rates. Also provided is the backward procedure to infer the mutation rates using maximum likelihood analysis given the observed single- and dinucleotide frequencies. Reasonable estimates of the mutation rates can be obtained very efficiently, using generic noncoding DNA sequences as input, after masking out long homonucleotide subsequences. Our method is much more convenient and versatile to use than the traditional method of deducing mutation rates by counting mutation events in carefully chosen sequences. More generally, our approach provides a more realistic but still tractable description of noncoding genomic DNA and may be used as a null model for various sequence analysis applications.

  6. System analysis of gene mutations and clinical phenotype in Chinese patients with autosomal-dominant polycystic kidney disease

    PubMed Central

    Jin, Meiling; Xie, Yuansheng; Chen, Zhiqiang; Liao, Yujie; Li, Zuoxiang; Hu, Panpan; Qi, Yan; Yin, Zhiwei; Li, Qinggang; Fu, Ping; Chen, Xiangmei

    2016-01-01

    Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder mainly caused by mutation in PKD1/PKD2. However, ethnic differences in mutations, the association between mutation genotype/clinical phenotype, and the clinical applicable value of mutation detection are poorly understood. We made systematically analysis of Chinese ADPKD patients based on a next-generation sequencing platform. Among 148 ADPKD patients enrolled, 108 mutations were detected in 127 patients (85.8%). Compared with mutations in Caucasian published previously, the PKD2 mutation detection rate was lower, and patients carrying the PKD2 mutation invariably carried the PKD1 mutation. The definite pathogenic mutation detection rate was lower, whereas the multiple mutations detection rate was higher in Chinese patients. Then, we correlated PKD1/PKD2 mutation data and clinical data: patients with mutation exhibited a more severe phenotype; patients with >1 mutations exhibited a more severe phenotype; patients with pathogenic mutations exhibited a more severe phenotype. Thus, the PKD1/PKD2 mutation status differed by ethnicity, and the PKD1/PKD2 genotype may affect the clinical phenotype of ADPKD. Furthermore, it makes sense to detect PKD1/PKD2 mutation status for early diagnosis and prognosis, perhaps as early as the embryo/zygote stage, to facilitate early clinical intervention and family planning. PMID:27782177

  7. 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

  8. Tissue-specific mutation accumulation in human adult stem cells during life

    NASA Astrophysics Data System (ADS)

    Blokzijl, Francis; de Ligt, Joep; Jager, Myrthe; Sasselli, Valentina; Roerink, Sophie; Sasaki, Nobuo; Huch, Meritxell; Boymans, Sander; Kuijk, Ewart; Prins, Pjotr; Nijman, Isaac J.; Martincorena, Inigo; Mokry, Michal; Wiegerinck, Caroline L.; Middendorp, Sabine; Sato, Toshiro; Schwank, Gerald; Nieuwenhuis, Edward E. S.; Verstegen, Monique M. A.; van der Laan, Luc J. W.; de Jonge, Jeroen; Ijzermans, Jan N. M.; Vries, Robert G.; van de Wetering, Marc; Stratton, Michael R.; Clevers, Hans; Cuppen, Edwin; van Boxtel, Ruben

    2016-10-01

    The gradual accumulation of genetic mutations in human adult stem cells (ASCs) during life is associated with various age-related diseases, including cancer. Extreme variation in cancer risk across tissues was recently proposed to depend on the lifetime number of ASC divisions, owing to unavoidable random mutations that arise during DNA replication. However, the rates and patterns of mutations in normal ASCs remain unknown. Here we determine genome-wide mutation patterns in ASCs of the small intestine, colon and liver of human donors with ages ranging from 3 to 87 years by sequencing clonal organoid cultures derived from primary multipotent cells. Our results show that mutations accumulate steadily over time in all of the assessed tissue types, at a rate of approximately 40 novel mutations per year, despite the large variation in cancer incidence among these tissues. Liver ASCs, however, have different mutation spectra compared to those of the colon and small intestine. Mutational signature analysis reveals that this difference can be attributed to spontaneous deamination of methylated cytosine residues in the colon and small intestine, probably reflecting their high ASC division rate. In liver, a signature with an as-yet-unknown underlying mechanism is predominant. Mutation spectra of driver genes in cancer show high similarity to the tissue-specific ASC mutation spectra, suggesting that intrinsic mutational processes in ASCs can initiate tumorigenesis. Notably, the inter-individual variation in mutation rate and spectra are low, suggesting tissue-specific activity of common mutational processes throughout life.

  9. 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

  10. 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

  11. Accelerated mutation accumulation in asexual lineages of a freshwater snail.

    PubMed

    Neiman, Maurine; Hehman, Gery; Miller, Joseph T; Logsdon, John M; Taylor, Douglas R

    2010-04-01

    Sexual reproduction is both extremely costly and widespread relative to asexual reproduction, meaning that it must also confer profound advantages in order to persist. One theorized benefit of sex is that it facilitates the clearance of harmful mutations, which would accumulate more rapidly in the absence of recombination. The extent to which ineffective purifying selection and mutation accumulation are direct consequences of asexuality and whether the accelerated buildup of harmful mutations in asexuals can occur rapidly enough to maintain sex within natural populations, however, remain as open questions. We addressed key components of these questions by estimating the rate of mutation accumulation in the mitochondrial genomes of multiple sexual and asexual representatives of Potamopyrgus antipodarum, a New Zealand snail characterized by mixed sexual/asexual populations. We found that increased mutation accumulation is associated with asexuality and occurs rapidly enough to be detected in recently derived asexual lineages of P. antipodarum. Our results demonstrate that increased mutation accumulation in asexuals can differentially affect coexisting and ecologically similar sexual and asexual lineages. The accelerated rate of mutation accumulation observed in asexual P. antipodarum provides some of the most direct evidence to date for a link between asexuality and mutation accumulation and implies that mutational buildup could be rapid enough to contribute to the short-term evolutionary mechanisms that favor sexual reproduction.

  12. The origins, determinants, and consequences of human mutations.

    PubMed

    Shendure, Jay; Akey, Joshua M

    2015-09-25

    Germline mutations are the principal cause of heritable disease and the ultimate source of evolutionary change. Similarly, somatic mutations are the primary cause of cancer and may contribute to the burden of human disease more broadly than previously appreciated. Here, we review recent insights into the rates, spectrum, and determinants of genomic mutations and how these parameters inform our understanding of both Mendelian and complex human diseases. We also consider models for conceptualizing mutational consequences and outline several key areas for future research, including the development of new technologies to access and quantify the full spectrum of mutations, as well as to better interpret the consequences of mutations with respect to molecular functionality, evolutionary fitness, and disease pathogenicity.

  13. Competition between transposable elements and mutator genes in bacteria.

    PubMed

    Fehér, Tamás; Bogos, Balázs; Méhi, Orsolya; Fekete, Gergely; Csörgo, Bálint; Kovács, Károly; Pósfai, György; Papp, Balázs; Hurst, Laurence D; Pál, Csaba

    2012-10-01

    Although both genotypes with elevated mutation rate (mutators) and mobilization of insertion sequence (IS) elements have substantial impact on genome diversification, their potential interactions are unknown. Moreover, the evolutionary forces driving gradual accumulation of these elements are unclear: Do these elements spread in an initially transposon-free bacterial genome as they enable rapid adaptive evolution? To address these issues, we inserted an active IS1 element into a reduced Escherichia coli genome devoid of all other mobile DNA. Evolutionary laboratory experiments revealed that IS elements increase mutational supply and occasionally generate variants with especially large phenotypic effects. However, their impact on adaptive evolution is small compared with mismatch repair mutator alleles, and hence, the latter impede the spread of IS-carrying strains. Given their ubiquity in natural populations, such mutator alleles could limit early phase of IS element evolution in a new bacterial host. More generally, our work demonstrates the existence of an evolutionary conflict between mutation-promoting mechanisms.

  14. Leaf Asymmetry as a Developmental Constraint Imposed by Auxin-Dependent Phyllotactic Patterning[OA

    PubMed Central

    Chitwood, Daniel H.; Headland, Lauren R.; Ranjan, Aashish; Martinez, Ciera C.; Braybrook, Siobhan A.; Koenig, Daniel P.; Kuhlemeier, Cris; Smith, Richard S.; Sinha, Neelima R.

    2012-01-01

    In a majority of species, leaf development is thought to proceed in a bilaterally symmetric fashion without systematic asymmetries. This is despite the left and right sides of an initiating primordium occupying niches that differ in their distance from sinks and sources of auxin. Here, we revisit an existing model of auxin transport sufficient to recreate spiral phyllotactic patterns and find previously overlooked asymmetries between auxin distribution and the centers of leaf primordia. We show that it is the direction of the phyllotactic spiral that determines the side of the leaf these asymmetries fall on. We empirically confirm the presence of an asymmetric auxin response using a DR5 reporter and observe morphological asymmetries in young leaf primordia. Notably, these morphological asymmetries persist in mature leaves, and we observe left-right asymmetries in the superficially bilaterally symmetric leaves of tomato (Solanum lycopersicum) and Arabidopsis thaliana that are consistent with modeled predictions. We further demonstrate that auxin application to a single side of a leaf primordium is sufficient to recapitulate the asymmetries we observe. Our results provide a framework to study a previously overlooked developmental axis and provide insights into the developmental constraints imposed upon leaf morphology by auxin-dependent phyllotactic patterning. PMID:22722959

  15. Host-Imposed Copper Poisoning Impacts Fungal Micronutrient Acquisition during Systemic Candida albicans Infections

    PubMed Central

    Mackie, Joanna; Ballou, Elizabeth R.; Childers, Delma S.; MacCallum, Donna M.; Feldmann, Joerg; Brown, Alistair J. P.

    2016-01-01

    Nutritional immunity is a process whereby an infected host manipulates essential micronutrients to defend against an invading pathogen. We reveal a dynamic aspect of nutritional immunity during infection that involves copper assimilation. Using a combination of laser ablation inductively coupled mass spectrometry (LA-ICP MS) and metal mapping, immunohistochemistry, and gene expression profiling from infected tissues, we show that readjustments in hepatic, splenic and renal copper homeostasis accompany disseminated Candida albicans infections in the mouse model. Localized host-imposed copper poisoning manifests itself as a transient increase in copper early in the kidney infection. Changes in renal copper are detected by the fungus, as revealed by gene expression profiling and fungal virulence studies. The fungus responds by differentially regulating the Crp1 copper efflux pump (higher expression during early infection and down-regulation late in infection) and the Ctr1 copper importer (lower expression during early infection, and subsequent up-regulation late in infection) to maintain copper homeostasis during disease progression. Both Crp1 and Ctr1 are required for full fungal virulence. Importantly, copper homeostasis influences other virulence traits—metabolic flexibility and oxidative stress resistance. Our study highlights the importance of copper homeostasis for host defence and fungal virulence during systemic disease. PMID:27362522

  16. Insights into the complex levels of regulation imposed on Escherichia coli DNA polymerase V.

    PubMed

    Goodman, Myron F; McDonald, John P; Jaszczur, Malgorzata M; Woodgate, Roger

    2016-08-01

    It is now close to 40 years since the isolation of non-mutable umu/uvm strains of Escherichia coli and the realization that damage induced mutagenesis in E.coli is not a passive process. Early models of mutagenesis envisioned the Umu proteins as accessory factors to the cell's replicase that not only reduced its normally high fidelity, but also allowed the enzyme to traverse otherwise replication-blocking lesions in the genome. However, these models underwent a radical revision approximately 15 years ago, with the discovery that the Umu proteins actually encode for a DNA polymerase, E.coli pol V. The polymerase lacks 3'→5' exonucleolytic proofreading activity and is inherently error-prone when replicating both undamaged and damage DNA. So as to limit any "gratuitous" mutagenesis, the activity of pol V is strictly regulated in the cell at multiple levels. This review will summarize our current understanding of the myriad levels of regulation imposed on pol V including transcriptional control, posttranslational modification, targeted proteolysis, activation of the catalytic activity of pol V through protein-protein interactions and the very recently described intracellular spatial regulation of pol V. Remarkably, despite the multiple levels at which pol V is regulated, the enzyme is nevertheless able to contribute to the genetic diversity and evolutionary fitness of E.coli. PMID:27236212

  17. How can Saturn impose its rotation period in a noncorotating magnetosphere?

    NASA Astrophysics Data System (ADS)

    Espinosa, StéPhane A.; Southwood, David J.; Dougherty, MichèLe K.

    2003-02-01

    A conceptual model is proposed, where Saturn can impose its rotation period in a noncorotating magnetosphere, as observed by Pioneer 11, Voyager 1 and 2. The fundamental hypothesis for this so-called "Camshaft model" is that Saturn has an equatorial anomaly, likely to be magnetic. It is restricted in longitude, and the source is yet to be detected. This longitudinal asymmetry is equivalent to a variation of pressure for the magnetospheric subcorotating plasma, and therefore as the planet rotates, a compressional wave is generated. That is, we use the MHD fast mode, which can propagate across the magnetic field, rather than the transverse mode for momentum transfer from the planet to the magnetospheric plasma. The wave propagates radially outward across the background magnetic field, inducing a motion in the plasma that is decoupled from and superposed on its azimuthal motion. Consequently, as the planet rotates, magnetic field observations fixed in an inertial frame would present a periodic signature with the planetary rotation period. This is true at each local time, independently of the level of plasma subcorotation. We then show that the Camshaft model accounts very well for the previously reported observations of spin-periodic perturbations in Saturn's magnetic field. Finally, we consider the perturbation magnetic field (obtained by subtracting only the model planetary field from the observations) measured by Pioneer 11 while outbound, and find its orientation consistent with the Camshaft model once the propagation delay of the compressional wave is included.

  18. Edge-Imposed Domain Ordering in Antiferromagnetic LaFeO3 Nanostructures

    NASA Astrophysics Data System (ADS)

    Grepstad, J. K.; Folven, E.; Tybell, T.; Scholl, A.; Young, A.; Retterer, S. T.; Takamura, Y.

    2011-03-01

    The antiferromagnetic (AFM) domain structure of submicron-sized LaFe O3 nanostructures was imaged with photoemission electron microscopy in combination with x-ray magnetic linear dichroism. These nanostructures were defined in epitaxial LaFe O3 thin films using e-beam lithography and Ar + ion implantation to locally destroy the magnetic order in the surrounding matrix. Extended domains were found to form along the perimeter of rectangular-shaped islands, when their edges were aligned with the in-plane < 100 > axes of the cubic SrTiO substrate. The AFM spin axis of these domains was confined to lie within the film plane, aligned with the edges of the nanostructures. This domain configuration predominated for nanoislands scaled down to 500x500 nm . However, no edge-imposed domain ordering was observed for rectangular islands rotated by 45 with respect to the in-plane crystalline axes, suggesting a magnetocrystalline origin of the extended edge-bound AFM domains. These findings may prove important to spintronic devices relying on exchange-biased nanostructures, where domain engineering in antiferromagnets remains relatively unexplored and has the potential to provide new device opportunities. This work was sponsored by the DoE BES and the Div. of Scientific User Facilities, US DoE, and by the Research Council of Norway.

  19. Nanosecond Motions in Proteins Impose Bounds on the Timescale Distributions of Local Dynamics

    PubMed Central

    Okan, Osman Burak; Atilgan, Ali Rana; Atilgan, Canan

    2009-01-01

    Abstract We elucidate the physics of protein dynamical transition via 10–100-ns molecular dynamics simulations at temperatures spanning 160–300 K. By tracking the energy fluctuations, we show that the protein dynamical transition is marked by a crossover from nonstationary to stationary processes that underlie the dynamics of protein motions. A two-timescale function captures the nonexponential character of backbone structural relaxations. One timescale is attributed to the collective segmental motions and the other to local relaxations. The former is well defined by a single-exponential, nanosecond decay, operative at all temperatures. The latter is described by a set of processes that display a distribution of timescales. Although their average remains on the picosecond timescale, the distribution is markedly contracted at the onset of the transition. It is shown that the collective motions impose bounds on timescales spanned by local dynamical processes. The nonstationary character below the transition implicates the presence of a collection of substates whose interactions are restricted. At these temperatures, a wide distribution of local-motion timescales, extending beyond that of nanoseconds, is observed. At physiological temperatures, local motions are confined to timescales faster than nanoseconds. This relatively narrow window makes possible the appearance of multiple channels for the backbone dynamics to operate. PMID:19804740

  20. Ion confinement and transport in a toroidal plasma with externally imposed radial electric fields

    NASA Technical Reports Server (NTRS)

    Roth, J. R.; Krawczonek, W. M.; Powers, E. J.; Kim, Y. C.; Hong, H. Y.

    1979-01-01

    Strong electric fields were imposed along the minor radius of the toroidal plasma by biasing it with electrodes maintained at kilovolt potentials. Coherent, low-frequency disturbances characteristic of various magnetohydrodynamic instabilities were absent in the high-density, well-confined regime. High, direct-current radial electric fields with magnitudes up to 135 volts per centimeter penetrated inward to at least one-half the plasma radius. When the electric field pointed radially toward, the ion transport was inward against a strong local density gradient; and the plasma density and confinement time were significantly enhanced. The radial transport along the electric field appeared to be consistent with fluctuation-induced transport. With negative electrode polarity the particle confinement was consistent with a balance of two processes: a radial infusion of ions, in those sectors of the plasma not containing electrodes, that resulted from the radially inward fields; and ion losses to the electrodes, each of the which acted as a sink and drew ions out of the plasma. A simple model of particle confinement was proposed in which the particle confinement time is proportional to the plasma volume. The scaling predicted by this model was consistent with experimental measurements.