Science.gov

Sample records for imposed mutation rate

  1. Hitting cancers' weak spots: vulnerabilities imposed by p53 mutation.

    PubMed

    Gurpinar, Evrim; Vousden, Karen H

    2015-08-01

    The tumor suppressor protein p53 plays a critical role in limiting malignant development and progression. Almost all cancers show loss of p53 function, through either mutation in the p53 gene itself or defects in the mechanisms that activate p53. While reactivation of p53 can effectively limit tumor growth, this is a difficult therapeutic goal to achieve in the many cancers that do not retain wild type p53. An alternative approach focuses on identifying vulnerabilities imposed on cancers by virtue of the loss of or alterations in p53, to identify additional pathways that can be targeted to specifically kill or inhibit the growth of p53 mutated cells. These indirect ways of exploiting mutations in p53 - which occur in more than half of all human cancers - provide numerous exciting therapeutic possibilities.

  2. Estimation of spontaneous mutation rates.

    PubMed

    Natarajan, Loki; Berry, Charles C; Gasche, Christoph

    2003-09-01

    Spontaneous or randomly occurring mutations play a key role in cancer progression. Estimation of the mutation rate of cancer cells can provide useful information about the disease. To ascertain these mutation rates, we need mathematical models that describe the distribution of mutant cells. In this investigation, we develop a discrete time stochastic model for a mutational birth process. We assume that mutations occur concurrently with mitosis so that when a nonmutant parent cell splits into two progeny, one of these daughter cells could carry a mutation. We propose an estimator for the mutation rate and investigate its statistical properties via theory and simulations. A salient feature of this estimator is the ease with which it can be computed. The methods developed herein are applied to a human colorectal cancer cell line and compared to existing continuous time models.

  3. Heterozygosity increases microsatellite mutation rate

    PubMed Central

    Amos, William

    2016-01-01

    Whole genome sequencing of families of Arabidopsis has recently lent strong support to the heterozygote instability (HI) hypothesis that heterozygosity locally increases mutation rate. However, there is an important theoretical difference between the impact on base substitutions, where mutation rate increases in regions surrounding a heterozygous site, and the impact of HI on sequences such as microsatellites, where mutations are likely to occur at the heterozygous site itself. At microsatellite loci, HI should create a positive feedback loop, with heterozygosity and mutation rate mutually increasing each other. Direct support for HI acting on microsatellites is limited and contradictory. I therefore analysed AC microsatellites in 1163 genome sequences from the 1000 genomes project. I used the presence of rare alleles, which are likely to be very recent in origin, as a surrogate measure of mutation rate. I show that rare alleles are more likely to occur at locus-population combinations with higher heterozygosity even when all populations carry exactly the same number of alleles. PMID:26740567

  4. TGFβ Receptor Mutations Impose a Strong Predisposition for Human Allergic Disease

    PubMed Central

    Frischmeyer-Guerrerio, Pamela A.; Guerrerio, Anthony L.; Oswald, Gretchen; Chichester, Kristin; Myers, Loretha; Halushka, Marc K.; Oliva-Hemker, Maria; Wood, Robert A.; Dietz, Harry C.

    2013-01-01

    Transforming growth factor–β (TGFβ) is a multifunctional cytokine that plays diverse roles in physiologic processes as well as human disease, including cancer, heart disease, and fibrotic disorders. In the immune system, TGFβ regulates regulatory T cell (Treg) maturation and immune homeostasis. Although genetic manipulation of the TGFβ pathway modulates immune tolerance in mouse models, the contribution of this pathway to human allergic phenotypes is not well understood. We demonstrate that patients with Loeys-Dietz syndrome (LDS), an autosomal dominant disorder caused by mutations in the genes encoding receptor subunits for TGFβ, TGFBR1 and TGFBR2, are strongly predisposed to develop allergic disease, including asthma, food allergy, eczema, allergic rhinitis, and eosinophilic gastrointestinal disease. LDS patients exhibited elevated immunoglobulin E levels, eosinophil counts, and T helper 2 (TH2) cytokines in their plasma. They had an increased frequency of CD4+ T cells that expressed both Foxp3 and interleukin-13, but retained the ability to suppress effector T cell proliferation. TH2 cytokine–producing cells accumulated in cultures of naïve CD4+ T cells from LDS subjects, but not controls, after stimulation with TGFβ, suggesting that LDS mutations support TH2 skewing in naïve lymphocytes in a cell-autonomous manner. The monogenic nature of LDS demonstrates that altered TGFβ signaling can predispose to allergic phenotypes in humans and underscores a prominent role for TGFβ in directing immune responses to antigens present in the environment and foods. This paradigm may be relevant to nonsyndromic presentations of allergic disease and highlights the potential therapeutic benefit of strategies that inhibit TGFβ signaling. PMID:23884466

  5. 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.

  6. Elevated germline mutation rate in teenage fathers.

    PubMed

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

    2015-03-22

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

  7. 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.

  8. 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.

  9. How small are small mutation rates?

    PubMed

    Wu, Bin; Gokhale, Chaitanya S; Wang, Long; Traulsen, Arne

    2012-04-01

    We consider evolutionary game dynamics in a finite population of size N. When mutations are rare, the population is monomorphic most of the time. Occasionally a mutation arises. It can either reach fixation or go extinct. The evolutionary dynamics of the process under small mutation rates can be approximated by an embedded Markov chain on the pure states. Here we analyze how small the mutation rate should be to make the embedded Markov chain a good approximation by calculating the difference between the real stationary distribution and the approximated one. While for a coexistence game, where the best reply to any strategy is the opposite strategy, it is necessary that the mutation rate μ is less than N (-1/2)exp[-N] to ensure that the approximation is good, for all other games, it is sufficient if the mutation rate is smaller than (N ln N)(-1). Our results also hold for a wide class of imitation processes under arbitrary selection intensity.

  10. Sex biases in the mutation rate.

    PubMed

    Hurst, L D; Ellegren, H

    1998-11-01

    Men have more germ-line cell divisions than women. Does this lead to a higher mutation rate in males? Most estimates of the proportion of mutations originating in men come either from direct observation of disease-inducing mutations or from analysis of the relative rate of evolution of sex-linked and autosomal genes in primates. The latter mode of analysis has also been applied to other mammals, birds and files. For unknown reasons, this method produces contradictory results. A majority of estimates using the best direct methods in humans indicate a male bias for point mutations, but the variance in estimates is high. It is unclear how the evolutionary and direct data correspond and a consensus as to the extent of any male bias is not presently possible. While the number of germ-line cell divisions might contribute to differences, this by no means accounts for all of the data.

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

    PubMed Central

    Lovitt, Thomas C.; Curtiss, Karen A.

    1969-01-01

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

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

    NASA Technical Reports Server (NTRS)

    Brandenburg, J. E.

    1993-01-01

    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

  13. 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

  14. Parent-progeny sequencing indicates higher mutation rates in heterozygotes.

    PubMed

    Yang, Sihai; Wang, Long; Huang, Ju; Zhang, Xiaohui; Yuan, Yang; Chen, Jian-Qun; Hurst, Laurence D; Tian, Dacheng

    2015-07-23

    Mutation rates vary within genomes, but the causes of this remain unclear. As many prior inferences rely on methods that assume an absence of selection, potentially leading to artefactual results, we call mutation events directly using a parent-offspring sequencing strategy focusing on Arabidopsis and using rice and honey bee for replication. Here we show that mutation rates are higher in heterozygotes and in proximity to crossover events. A correlation between recombination rate and intraspecific diversity is in part owing to a higher mutation rate in domains of high recombination/diversity. Implicating diversity per se as a cause, we find an ∼3.5-fold higher mutation rate in heterozygotes than in homozygotes, with mutations occurring in closer proximity to heterozygous sites than expected by chance. In a genome that is a patchwork of heterozygous and homozygous domains, mutations occur disproportionately more often in the heterozygous domains. If segregating mutations predispose to a higher local mutation rate, clusters of genes dominantly under purifying selection (more commonly homozygous) and under balancing selection (more commonly heterozygous), might have low and high mutation rates, respectively. Our results are consistent with this, there being a ten times higher mutation rate in pathogen resistance genes, expected to be under positive or balancing selection. Consequently, we do not necessarily need to evoke extremely weak selection on the mutation rate to explain why mutational hot and cold spots might correspond to regions under positive/balancing and purifying selection, respectively.

  15. Anaerobically Grown Escherichia coli Has an Enhanced Mutation Rate and Distinct Mutational Spectra

    PubMed Central

    Shewaramani, Sonal; Finn, Thomas J.; Kassen, Rees; Rainey, Paul B.

    2017-01-01

    Oxidative stress is a major cause of mutation but little is known about how growth in the absence of oxygen impacts the rate and spectrum of mutations. We employed long-term mutation accumulation experiments to directly measure the rates and spectra of spontaneous mutation events in Escherichia coli populations propagated under aerobic and anaerobic conditions. To detect mutations, whole genome sequencing was coupled with methods of analysis sufficient to identify a broad range of mutational classes, including structural variants (SVs) generated by movement of repetitive elements. The anaerobically grown populations displayed a mutation rate nearly twice that of the aerobic populations, showed distinct asymmetric mutational strand biases, and greater insertion element activity. Consistent with mutation rate and spectra observations, genes for transposition and recombination repair associated with SVs were up-regulated during anaerobic growth. Together, these results define differences in mutational spectra affecting the evolution of facultative anaerobes. PMID:28103245

  16. 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

  17. 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.

  18. 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

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

    PubMed

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

    2016-02-01

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

  20. 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.

  1. Optimal mutation rates in dynamic environments: The eigen model

    NASA Astrophysics Data System (ADS)

    Ancliff, Mark; Park, Jeong-Man

    2011-03-01

    We consider the Eigen quasispecies model with a dynamic environment. For an environment with sharp-peak fitness in which the most-fit sequence moves by k spin-flips each period T we find an asymptotic stationary state in which the quasispecies population changes regularly according to the regular environmental change. From this stationary state we estimate the maximum and the minimum mutation rates for a quasispecies to survive under the changing environment and calculate the optimum mutation rate that maximizes the population growth. Interestingly we find that the optimum mutation rate in the Eigen model is lower than that in the Crow-Kimura model, and at their optimum mutation rates the corresponding mean fitness in the Eigen model is lower than that in the Crow-Kimura model, suggesting that the mutation process which occurs in parallel to the replication process as in the Crow-Kimura model gives an adaptive advantage under changing environment.

  2. Optimal mutation rates in dynamic environments: The Eigen model

    NASA Astrophysics Data System (ADS)

    Ancliff, Mark; Park, Jeong-Man

    2010-08-01

    We consider the Eigen quasispecies model with a dynamic environment. For an environment with sharp-peak fitness in which the most-fit sequence moves by k spin-flips each period T we find an asymptotic stationary state in which the quasispecies population changes regularly according to the regular environmental change. From this stationary state we estimate the maximum and the minimum mutation rates for a quasispecies to survive under the changing environment and calculate the optimum mutation rate that maximizes the population growth. Interestingly we find that the optimum mutation rate in the Eigen model is lower than that in the Crow-Kimura model, and at their optimum mutation rates the corresponding mean fitness in the eigenmodel is lower than that in the Crow-Kimura model, suggesting that the mutation process which occurs in parallel to the replication process as in the Crow-Kimura model gives an adaptive advantage under changing environment.

  3. Rate of fixation of beneficial mutations in sexual populations

    NASA Astrophysics Data System (ADS)

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

    2009-06-01

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

  4. Biological basis of germline mutation: comparisons of spontaneous germline mutation rates among drosophila, mouse, and human.

    PubMed

    Drost, J B; Lee, W R

    1995-01-01

    Spontaneous mutation rates per generation are similar among the three species considered here--Drosophila, mouse, and human--and are not related to time, as is often assumed. Spontaneous germline mutation rates per generation averaged among loci are less variable among species than they are among loci and tests and between gender. Mutation rates are highly variable over time in diverse lineages. Recent estimates of the number of germ cell divisions per generation are: for humans, 401 (30-year generation) in males and 31 in females; for mice, 62 (9-month generation) in males and 25 in females; and for Drosophila melanogaster, 35.5 (18-day generation) in males and 36.5 (25-day generation) in females. The relationships between germ cell division estimates of the two sexes in the three species closely reflect those between mutation rates in the sexes, although mutation rates per cell division vary among species. Whereas the overall rate per generation is constant among species, this consistency must be achieved by diverse mechanisms. Modifiers of mutation rates, on which selection might act, include germline characteristics that contribute disproportionately to the total mutation rates. The germline mutation rates between the sexes within a species are largely influenced by germ cell divisions per generation. Also, a large portion of the total mutations occur during the interval between the beginning of meiosis and differentiation of the soma from the germline. Significant genetic events contributing to mutations during this time may include meiosis, lack of DNA repair in sperm cells, methylation of CpG dinucleotides in mammalian sperm and early embryo, gonomeric fertilization, and rapid cleavage divisions.

  5. 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

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

    SciTech Connect

    Crow, J.F. )

    1993-01-01

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

  7. 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.

  8. Variation in RNA Virus Mutation Rates across Host Cells

    PubMed Central

    Combe, Marine; Sanjuán, Rafael

    2014-01-01

    It is well established that RNA viruses exhibit higher rates of spontaneous mutation than DNA viruses and microorganisms. However, their mutation rates vary amply, from 10−6 to 10−4 substitutions per nucleotide per round of copying (s/n/r) and the causes of this variability remain poorly understood. In addition to differences in intrinsic fidelity or error correction capability, viral mutation rates may be dependent on host factors. Here, we assessed the effect of the cellular environment on the rate of spontaneous mutation of the vesicular stomatitis virus (VSV), which has a broad host range and cell tropism. Luria-Delbrück fluctuation tests and sequencing showed that VSV mutated similarly in baby hamster kidney, murine embryonic fibroblasts, colon cancer, and neuroblastoma cells (approx. 10−5 s/n/r). Cell immortalization through p53 inactivation and oxygen levels (1–21%) did not have a significant impact on viral replication fidelity. This shows that previously published mutation rates can be considered reliable despite being based on a narrow and artificial set of laboratory conditions. Interestingly, we also found that VSV mutated approximately four times more slowly in various insect cells compared with mammalian cells. This may contribute to explaining the relatively slow evolution of VSV and other arthropod-borne viruses in nature. PMID:24465205

  9. Effects of population size and mutation rate on the evolution of mutational robustness.

    PubMed

    Elena, Santiago F; Wilke, Claus O; Ofria, Charles; Lenski, Richard E

    2007-03-01

    It is often assumed that the efficiency of selection for mutational robustness would be proportional to mutation rate and population size, thus being inefficient in small populations. However, Krakauer and Plotkin (2002) hypothesized that selection in small populations would favor robustness mechanisms, such as redundancy, that mask the effect of deleterious mutations. In large populations, by contrast, selection is more effective at removing deleterious mutants and fitness would be improved by eliminating mechanisms that mask the effect of deleterious mutations and thus impede their removal. Here, we test whether these predictions are supported in experiments with evolving populations of digital organisms. Digital organisms are self-replicating programs that inhabit a virtual world inside a computer. Like their organic counterparts, digital organisms mutate, compete, evolve, and adapt by natural selection to their environment. In this study, 160 populations evolved at different combinations of mutation rate and population size. After 10(4) generations, we measured the mutational robustness of the most abundant genotype in each population. Mutational robustness tended to increase with mutation rate and to decline with population size, although the dependence with population size was in part mediated by a negative relationship between fitness and robustness. These results are independent of whether genomes were constrained to their original length or allowed to change in size.

  10. Statistical methods for analyzing Drosophila germline mutation rates.

    PubMed

    Fu, Yun-Xin

    2013-08-01

    Most studies of mutation rates implicitly assume that they remain constant throughout development of the germline. However, researchers recently used a novel statistical framework to reveal that mutation rates differ dramatically during sperm development in Drosophila melanogaster. Here a general framework is described for the inference of germline mutation patterns, generated from either mutation screening experiments or DNA sequence polymorphism data, that enables analysis of more than two mutations per family. The inference is made more rigorous and flexible by providing a better approximation of the probabilities of patterns of mutations and an improved coalescent algorithm within a single host with realistic assumptions. The properties of the inference framework, both the estimation and the hypothesis testing, were investigated by simulation. The refined inference framework is shown to provide (1) nearly unbiased maximum-likelihood estimates of mutation rates and (2) robust hypothesis testing using the standard asymptotic distribution of the likelihood-ratio tests. It is readily applicable to data sets in which multiple mutations in the same family are common.

  11. 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.

  12. Sexual selection does not influence minisatellite mutation rate

    PubMed Central

    Amos, William

    2009-01-01

    Background Moller and Cuervo report a significant trend between minisatellite mutation rate and the frequency of extra-pair copulations in birds. This is interpreted as evidence that the high rate of evolution demanded by sexual selection has itself selected for a higher mutation rate in species where selection is strongest. However, there are good a priori reasons for believing that their method of calculating minisatellite mutation rates will be highly error prone and a poor surrogate measure of the evolutionary rate of genes. I therefore attempted to replicate their results using both their data and an independent data set based on papers they failed to locate. Results I find that Moller and Cuervo's data set contains numerous errors that act somewhat to strengthen their key regression. More importantly, data from uncited papers fail to replicate their reported trend and one species in particular, Vireo olivaceus, is apparently deliberately omitted, yet its inclusion removes significance from the original correlation. Over the small number of cases were comparisons can be made, mutation rate estimates do not differ between species but do vary significantly depending on the laboratory/operator. Conclusion There appears to be no clear relationship between minisatellite mutation rate and EPC rate in birds. The previously reported trend can be attributed to data transcription errors and unfortunate data selection. My analysis highlights the importance of total methodological transparency when conducting meta-analyses. PMID:19133116

  13. Maximum, minimum, and optimal mutation rates in dynamic environments

    NASA Astrophysics Data System (ADS)

    Ancliff, Mark; Park, Jeong-Man

    2009-12-01

    We analyze the dynamics of the parallel mutation-selection quasispecies model with a changing environment. For an environment with the sharp-peak fitness function in which the most fit sequence changes by k spin flips every period T , we find analytical expressions for the minimum and maximum mutation rates for which a quasispecies can survive, valid in the limit of large sequence size. We find an asymptotic solution in which the quasispecies population changes periodically according to the periodic environmental change. In this state we compute the mutation rate that gives the optimal mean fitness over a period. We find that the optimal mutation rate per genome, k/T , is independent of genome size, a relationship which is observed across broad groups of real organisms.

  14. Sperm competition can drive a male-biased mutation rate.

    PubMed

    Blumenstiel, Justin P

    2007-12-07

    A pattern of male-biased mutation has been found in a wide range of species. The standard explanation for this bias is that there are greater numbers of mitotic cell divisions in the history of the average sperm, compared to the average egg, and that mutations typically result from errors made during replication. However, this fails to provide an ultimate evolutionary explanation for why the male germline would tolerate more mutations that are typically deleterious. One possibility is that if there is a tradeoff between producing large numbers of sperm and expending energetic resources in maintaining a lower mutation rate, sperm competition would select for males that produce larger numbers of sperm despite a higher resulting mutation rate. Here I describe a model that jointly considers the fitness consequences of deleterious mutation and mating success in the face of sperm competition. I show that a moderate level of sperm competition can account for the observation that the male germline tolerates a higher mutation rate than the female germline.

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

    PubMed

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

    2015-05-01

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

  16. 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

  17. Estimation of the upper limit of the mutation rate and mean heterozygous effect of deleterious mutations.

    PubMed

    Caballero, A

    2006-12-01

    Deng et al. have recently proposed that estimates of an upper limit to the rate of spontaneous mutations and their average heterozygous effect can be obtained from the mean and variance of a given fitness trait in naturally segregating populations, provided that allele frequencies are maintained at the balance between mutation and selection. Using simulations they show that this estimation method generally has little bias and is very robust to violations of the mutation-selection balance assumption. Here I show that the particular parameters and models used in these simulations generally reduce the amount of bias that can occur with this estimation method. In particular, the assumption of a large mutation rate in the simulations always implies a low bias of estimates. In addition, the specific model of overdominance used to check the violation of the mutation-selection balance assumption is such that there is not a dramatic decline in mean fitness from overdominant mutations, again implying a low bias of estimates. The assumption of lower mutation rates and/or other models of balancing selection may imply considerably larger biases of the estimates, making the reliability of the proposed method highly questionable.

  18. Mutation and mutation rates at Y chromosome specific Short Tandem Repeat Polymorphisms (STRs): a reappraisal.

    PubMed

    Pinto, Nádia; Gusmão, Leonor; Amorim, António

    2014-03-01

    Mutation is a topic of intense research and raises important problems in forensics. Since the markers of choice in current forensic genetics analyses are microsatellites or Short Tandem Repeat Polymorphisms (STRs), mutation is sufficiently common to cause difficulties in evaluating DNA evidence in a significant proportion of cases but at the same time rare enough to turn the estimation of the corresponding probability of occurrence into a hard task. We address these issues using the simplest model of transmission: the Y chromosome specific STRs. Within this model, and under an explicit set of definitions and involved assumptions, we developed the theoretical framework required for the study of allelic transitions in gametogenesis, identifying the required parameters and associated probabilities and finally we discuss the estimation of these parameters and their application in forensics. We conclude that (i) for forensic casework the relevant parameter for incorporation in a likelihood ratio is biallelic specific (i.e. the mutation rate estimate corresponds to the probability of the specific allelic transition observed) and (ii) for these estimates as well as in order to provide data for testing mutation models the absolute frequency of mutated and non-mutated transmissions per allele, along with the description of the observed mutations should be reported.

  19. High-throughput oncogene mutation profiling shows demographic differences in BRAF mutation rates among melanoma patients.

    PubMed

    van den Hurk, Karin; Balint, Balazs; Toomey, Sinead; O'Leary, Patrick C; Unwin, Louise; Sheahan, Kieran; McDermott, Enda W; Murphy, Ian; van den Oord, Joost J; Rafferty, Mairin; FitzGerald, Dara M; Moran, Julie; Cummins, Robert; MacEneaney, Owen; Kay, Elaine W; O'Brien, Cathal P; Finn, Stephen P; Heffron, Cynthia C B B; Murphy, Michelle; Yela, Ruben; Power, Derek G; Regan, Padraic J; McDermott, Clodagh M; O'Keeffe, Allan; Orosz, Zsolt; Donnellan, Paul P; Crown, John P; Hennessy, Bryan T; Gallagher, William M

    2015-06-01

    Because of advances in targeted therapies, the clinical evaluation of cutaneous melanoma is increasingly based on a combination of traditional histopathology and molecular pathology. Therefore, it is necessary to expand our knowledge of the molecular events that accompany the development and progression of melanoma to optimize clinical management. The central objective of this study was to increase our knowledge of the mutational events that complement melanoma progression. High-throughput genotyping was adapted to query 159 known single nucleotide mutations in 33 cancer-related genes across two melanoma cohorts from Ireland (n=94) and Belgium (n=60). Results were correlated with various clinicopathological characteristics. A total of 23 mutations in 12 genes were identified, that is--BRAF, NRAS, MET, PHLPP2, PIK3R1, IDH1, KIT, STK11, CTNNB1, JAK2, ALK, and GNAS. Unexpectedly, we discovered significant differences in BRAF, MET, and PIK3R1 mutations between the cohorts. That is, cases from Ireland showed significantly lower (P<0.001) BRAF(V600E) mutation rates (19%) compared with the mutation frequency observed in Belgian patients (43%). Moreover, MET mutations were detected in 12% of Irish cases, whereas none of the Belgian patients harbored these mutations, and Irish patients significantly more often (P=0.027) had PIK3R1-mutant (33%) melanoma versus 17% of Belgian cases. The low incidence of BRAF(V600E)(-) mutant melanoma among Irish patients was confirmed in five independent Irish cohorts, and in total, only 165 of 689 (24%) Irish cases carried mutant BRAF(V600E). Together, our data show that melanoma-driving mutations vary by demographic area, which has important implications for the clinical management of this disease.

  20. 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

  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. 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.

  3. 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

  4. Generation of rodent malaria parasites with a high mutation rate by destructing proofreading activity of DNA polymerase δ.

    PubMed

    Honma, Hajime; Hirai, Makoto; Nakamura, Shota; Hakimi, Hassan; Kawazu, Shin-Ichiro; Palacpac, Nirianne M Q; Hisaeda, Hajime; Matsuoka, Hiroyuki; Kawai, Satoru; Endo, Hiroyoshi; Yasunaga, Teruo; Ohashi, Jun; Mita, Toshihiro; Horii, Toshihiro; Furusawa, Mitsuru; Tanabe, Kazuyuki

    2014-08-01

    Plasmodium falciparum malaria imposes a serious public health concern throughout the tropics. Although genetic tools are principally important to fully investigate malaria parasites, currently available forward and reverse tools are fairly limited. It is expected that parasites with a high mutation rate can readily acquire novel phenotypes/traits; however, they remain an untapped tool for malaria biology. Here, we generated a mutator malaria parasite (hereinafter called a 'malaria mutator'), using site-directed mutagenesis and gene transfection techniques. A mutator Plasmodium berghei line with a defective proofreading 3' → 5' exonuclease activity in DNA polymerase δ (referred to as PbMut) and a control P. berghei line with wild-type DNA polymerase δ (referred to as PbCtl) were maintained by weekly passage in ddY mice for 122 weeks. High-throughput genome sequencing analysis revealed that two PbMut lines had 175-178 mutations and a 86- to 90-fold higher mutation rate than that of a PbCtl line. PbMut, PbCtl, and their parent strain, PbWT, showed similar course of infection. Interestingly, PbMut lost the ability to form gametocytes during serial passages. We believe that the malaria mutator system could provide a novel and useful tool to investigate malaria biology.

  5. 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

  6. 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.

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

    PubMed

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

    2015-09-02

    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.

  8. Mutation accumulation in real branches: fitness assays for genomic deleterious mutation rate and effect in large-statured plants.

    PubMed

    Schultz, Stewart T; Scofield, Douglas G

    2009-08-01

    The genomic deleterious mutation rate and mean effect are central to the biology and evolution of all species. Large-statured plants, such as trees, are predicted to have high mutation rates due to mitotic mutation and the absence of a sheltered germ line, but their size and generation time has hindered genetic study. We develop and test approaches for estimating deleterious mutation rates and effects from viability comparisons within the canopy of large-statured plants. Our methods, inspired by E. J. Klekowski, are a modification of the classic Bateman-Mukai mutation-accumulation experiment. Within a canopy, cell lineages accumulate mitotic mutations independently. Gametes or zygotes produced at more distal points by these cell lineages contain more mitotic mutations than those at basal locations, and within-flower selfs contain more homozygous mutations than between-flower selfs. The resulting viability differences allow demonstration of lethal mutation with experiments similar in size to assays of genetic load and allow estimates of the rate and effect of new mutations with moderate precision and bias similar to that of classic mutation-accumulation experiments in small-statured organisms. These methods open up new possibilities with the potential to provide valuable new insights into the evolutionary genetics of plants.

  9. Contributions of intrinsic mutation rate and selfish selection to levels of de novo HRAS mutations in the paternal germline.

    PubMed

    Giannoulatou, Eleni; McVean, Gilean; Taylor, Indira B; McGowan, Simon J; Maher, Geoffrey J; Iqbal, Zamin; Pfeifer, Susanne P; Turner, Isaac; Burkitt Wright, Emma M M; Shorto, Jennifer; Itani, Aysha; Turner, Karen; Gregory, Lorna; Buck, David; Rajpert-De Meyts, Ewa; Looijenga, Leendert H J; Kerr, Bronwyn; Wilkie, Andrew O M; Goriely, Anne

    2013-12-10

    The RAS proto-oncogene Harvey rat sarcoma viral oncogene homolog (HRAS) encodes a small GTPase that transduces signals from cell surface receptors to intracellular effectors to control cellular behavior. Although somatic HRAS mutations have been described in many cancers, germline mutations cause Costello syndrome (CS), a congenital disorder associated with predisposition to malignancy. Based on the epidemiology of CS and the occurrence of HRAS mutations in spermatocytic seminoma, we proposed that activating HRAS mutations become enriched in sperm through a process akin to tumorigenesis, termed selfish spermatogonial selection. To test this hypothesis, we quantified the levels, in blood and sperm samples, of HRAS mutations at the p.G12 codon and compared the results to changes at the p.A11 codon, at which activating mutations do not occur. The data strongly support the role of selection in determining HRAS mutation levels in sperm, and hence the occurrence of CS, but we also found differences from the mutation pattern in tumorigenesis. First, the relative prevalence of mutations in sperm correlates weakly with their in vitro activating properties and occurrence in cancers. Second, specific tandem base substitutions (predominantly GC>TT/AA) occur in sperm but not in cancers; genomewide analysis showed that this same mutation is also overrepresented in constitutional pathogenic and polymorphic variants, suggesting a heightened vulnerability to these mutations in the germline. We developed a statistical model to show how both intrinsic mutation rate and selfish selection contribute to the mutational burden borne by the paternal germline.

  10. Pattern of mutation rates in the germline of Drosophila melanogaster males from a large-scale mutation screening experiment.

    PubMed

    Gao, Jian-Jun; Pan, Xue-Rong; Hu, Jing; Ma, Li; Wu, Jian-Min; Shao, Ye-Lin; Ai, Shi-Meng; Liu, Shu-Qun; Barton, Sara A; Woodruff, Ronny C; Zhang, Ya-Ping; Fu, Yun-Xin

    2014-06-11

    The sperm or eggs of sexual organisms go through a series of cell divisions from the fertilized egg; mutations can occur at each division. Mutations in the lineage of cells leading to the sperm or eggs are of particular importance because many such mutations may be shared by somatic tissues and also may be inherited, thus having a lasting consequence. For decades, little has been known about the pattern of the mutation rates along the germline development. Recently it was shown from a small portion of data that resulted from a large-scale mutation screening experiment that the rates of recessive lethal or nearly lethal mutations differ dramatically during the germline development of Drosophila melanogaster males. In this paper the full data set from the experiment and its analysis are reported by taking advantage of a recent methodologic advance. By analyzing the mutation patterns with different levels of recessive lethality, earlier published conclusions based on partial data are found to remain valid. Furthermore, it is found that for most nearly lethal mutations, the mutation rate at the first cell division is even greater than previous thought compared with those at other divisions. There is also some evidence that the mutation rate at the second division decreases rapidly but is still appreciably greater than those for the rest of the cleavage stage. The mutation rate at spermatogenesis is greater than late cleavage and stem-cell stages, but there is no evidence that rates are different among the five cell divisions of the spermatogenesis. We also found that a modestly biased sampling, leading to slightly more primordial germ cells after the eighth division than those reported in the literature, provides the best fit to the data. These findings provide conceptual and numerical basis for exploring the consequences of differential mutation rates during individual development.

  11. Homeochaos: dynamics stability of a symbiotic network with population dynamics and evolving mutation rates

    NASA Astrophysics Data System (ADS)

    Kaneko, Kunihiko; Ikegami, Takashi

    1992-06-01

    Evolution of mutation rates is studied, in a population model with mutation of species coded by bit sequences and mutation rates. Even without interaction among species, the mutation rate is initially enhanced to search for fitted species and then is lowered towards zero. This enhancement opens a possibility of automatic simulated annealing. With the interaction among species (hosts versus parasites), high mutation rates are sustained. The rates go up with the interaction strength abruptly if the fitness landscape is rugged. A large cluster of species, connected by mutation, is formed by a sustained high mutation rate. With the formation of this symbiotic network resolved is the paradox of mutation rates; paradox on the stability of a rule to change itself. Population dynamics of each species shows high-dimensional chaos with small positive Lyapunov exponents. Stability of our symbiotic network is dynamically sustained through this weak high-dimensional chaos, termed “homeochaos”.

  12. Reaction rate theory of radiation exposure:Effects of dose rate on mutation frequency

    NASA Astrophysics Data System (ADS)

    Bando, Masako; Nakamura, Issei; Manabe, Yuichiro

    2014-03-01

    We revisit the linear no threshold (LNT) hypothesis deduced from the prominent works done by H. J. Muller for the DNA mutation induced by the artificial radiation and by W. L. Russell and E. M. Kelly for that of mega-mouse experiments, developing a new kinetic reaction theory. While the existing theoretical models primarily rely on the dependence of the total dose D on the mutation frequency, the key ingredient in our theory is the dose rate d(t) that accounts for decrease in the mutation rate during the time course of the cellular reactions. The general form for the mutation frequency with the constant dose rate d is simply expressed as, dFm(t)/dt = A - BFm(t) , with A =a0 +a1(d +deff) and B =b0 +b1(d +deff) . We discuss the solution for a most likely case with B > 0 ; Fm(t) = [A/B -Fm(0) ] (1 -e-Bt) +Fm(0) with the control value Fm(0) . We show that all the data of mega-mouse experiments by Russel with different dose rates fall on the universal scaling function Φ(τ) ≡ [Fm(τ) -Fm(0) ]/[ A / B -Fm(0) ] = 1 - exp(- τ) with scaled time τ = Bt . The concept of such a scaling rule provides us with a strong tool to study different species in a unified manner.

  13. 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.

  14. Purifying Selection, Drift, and Reversible Mutation with Arbitrarily High Mutation Rates

    PubMed Central

    Charlesworth, Brian; Jain, Kavita

    2014-01-01

    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. PMID:25230951

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

    PubMed

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

    2015-09-01

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

  16. Low pesticide rates may hasten the evolution of resistance by increasing mutation frequencies.

    PubMed

    Gressel, Jonathan

    2011-03-01

    At very low pesticide rates, a certain low proportion of pests may receive a sublethal dose, are highly stressed by the pesticide and yet survive. Stress is a general enhancer of mutation rates. Thus, the survivors are likely to have more than normal mutations, which might include mutations leading to pesticide resistance, both for multifactorial (polygenic, gene amplification, sequential allelic mutations) and for major gene resistance. Management strategies should consider how to eliminate the subpopulation of pests with the high mutation rates, but the best strategy is probably to avoid too low application rates of pesticides from the outset.

  17. 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)

  18. Coevolution of Quasispecies: B-Cell Mutation Rates Maximize Viral Error Catastrophes

    NASA Astrophysics Data System (ADS)

    Kamp, Christel; Bornholdt, Stefan

    2002-02-01

    Coevolution of two coupled quasispecies is studied, motivated by the competition between viral evolution and adapting immune response. In this coadaptive model, besides the classical error catastrophe for high virus mutation rates, a second ``adaptation'' catastrophe occurs, when virus mutation rates are too small to escape immune attack. Maximizing both regimes of viral error catastrophes is a possible strategy for an optimal immune response, reducing the range of allowed viral mutation rates to a minimum. From this requirement, one obtains constraints on B-cell mutation rates and receptor lengths, yielding an estimate of somatic hypermutation rates in the germinal center in accordance with observation.

  19. Mutation rate analysis via parent–progeny sequencing of the perennial peach. II. No evidence for recombination-associated mutation

    PubMed Central

    Zhang, Yanchun; Qin, Chao

    2016-01-01

    Mutation rates and recombination rates vary between species and between regions within a genome. What are the determinants of these forms of variation? Prior evidence has suggested that the recombination might be mutagenic with an excess of new mutations in the vicinity of recombination break points. As it is conjectured that domesticated taxa have higher recombination rates than wild ones, we expect domesticated taxa to have raised mutation rates. Here, we use parent–offspring sequencing in domesticated and wild peach to ask (i) whether recombination is mutagenic, and (ii) whether domesticated peach has a higher recombination rate than wild peach. We find no evidence that domesticated peach has an increased recombination rate, nor an increased mutation rate near recombination events. If recombination is mutagenic in this taxa, the effect is too weak to be detected by our analysis. While an absence of recombination-associated mutation might explain an absence of a recombination–heterozygozity correlation in peach, we caution against such an interpretation. PMID:27798307

  20. Comparison of EGFR mutation rates in lung adenocarcinoma tissue and pleural effusion samples.

    PubMed

    Guan, Y; Wang, Z J; Wang, L Q; Hua, D F; Liu, J

    2016-04-04

    The goal of the current study was to investigate the differences in epidermal growth factor receptor (EGFR) mutation rates in tumor tissue and pleural effusion specimens from patients with lung adenocarcinoma. PCR amplification and gene sequencing were used to detect EGFR mutations in exons 18, 19, 20, and 21 in tumor tissue and pleural effusion samples from 50 patients with advanced lung adenocarcinoma. The EGFR mutation rate was 34.0% in tissue samples from patients with advanced lung adenocarcinoma. There were 11 cases with exon 19 mutations and 6 cases with exon 21 mutations. The EGFR mutation rate was 30.0% in pleural effusion specimens, including 10 cases with exon 19 mutation and 5 cases with exon 21 mutations. Although the tissue samples had a slightly higher mutation rate compared to the pleural effusion samples, the difference was not statistically significant. These results indicate that the EGFR mutation rate detected in pleural effusion specimens from patients with advanced lung adenocarcinoma is similar to that detected in tumor tissue samples. Therefore, pleural effusion specimens can potentially be used for EGFR mutation detection in advanced lung adenocarcinoma.

  1. Chromatin organization is a major influence on regional mutation rates in human cancer cells.

    PubMed

    Schuster-Böckler, Benjamin; Lehner, Ben

    2012-08-23

    Cancer genome sequencing provides the first direct information on how mutation rates vary across the human genome in somatic cells. Testing diverse genetic and epigenetic features, here we show that mutation rates in cancer genomes are strikingly related to chromatin organization. Indeed, at the megabase scale, a single feature—levels of the heterochromatin-associated histone modification H3K9me3—can account for more than 40% of mutation-rate variation, and a combination of features can account for more than 55%. The strong association between mutation rates and chromatin organization is upheld in samples from different tissues and for different mutation types. This suggests that the arrangement of the genome into heterochromatin- and euchromatin-like domains is a dominant influence on regional mutation-rate variation in human somatic cells.

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

    PubMed

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

    1999-07-07

    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.

  3. Low Base-Substitution Mutation Rate in the Germline Genome of the Ciliate Tetrahymena thermophil.

    PubMed

    Long, Hongan; Winter, David J; Chang, Allan Y-C; Sung, Way; Wu, Steven H; Balboa, Mariel; Azevedo, Ricardo B R; Cartwright, Reed A; Lynch, Michael; Zufall, Rebecca A

    2016-09-15

    Mutation is the ultimate source of all genetic variation and is, therefore, central to evolutionary change. Previous work on Paramecium tetraurelia found an unusually low germline base-substitution mutation rate in this ciliate. Here, we tested the generality of this result among ciliates using Tetrahymena thermophila. We sequenced the genomes of 10 lines of T. thermophila that had each undergone approximately 1,000 generations of mutation accumulation (MA). We applied an existing mutation-calling pipeline and developed a new probabilistic mutation detection approach that directly models the design of an MA experiment and accommodates the noise introduced by mismapped reads. Our probabilistic mutation-calling method provides a straightforward way of estimating the number of sites at which a mutation could have been called if one was present, providing the denominator for our mutation rate calculations. From these methods, we find that T. thermophila has a germline base-substitution mutation rate of 7.61 × 10 (-)  (12) per-site, per cell division, which is consistent with the low base-substitution mutation rate in P. tetraurelia Over the course of the evolution experiment, genomic exclusion lines derived from the MA lines experienced a fitness decline that cannot be accounted for by germline base-substitution mutations alone, suggesting that other genetic or epigenetic factors must be involved. Because selection can only operate to reduce mutation rates based upon the "visible" mutational load, asexual reproduction with a transcriptionally silent germline may allow ciliates to evolve extremely low germline mutation rates.

  4. Evolutionary Stability of Minimal Mutation Rates in an Evo-epidemiological Model.

    PubMed

    Birch, Michael; Bolker, Benjamin M

    2015-11-01

    We consider the evolution of mutation rate in a seasonally forced, deterministic, compartmental epidemiological model with a transmission-virulence trade-off. We model virulence as a quantitative genetic trait in a haploid population and mutation as continuous diffusion in the trait space. There is a mutation rate threshold above which the pathogen cannot invade a wholly susceptible population. The evolutionarily stable (ESS) mutation rate is the one which drives the lowest average density, over the course of one forcing period, of susceptible individuals at steady state. In contrast with earlier eco-evolutionary models in which higher mutation rates allow for better evolutionary tracking of a dynamic environment, numerical calculations suggest that in our model the minimum average susceptible population, and hence the ESS, is achieved by a pathogen strain with zero mutation. We discuss how this result arises within our model and how the model might be modified to obtain a nonzero optimum.

  5. The rate and effects of spontaneous mutation on fitness traits in the social amoeba, Dictyostelium discoideum.

    PubMed

    Hall, David W; Fox, Sara; Kuzdzal-Fick, Jennie J; Strassmann, Joan E; Queller, David C

    2013-07-08

    We performed a mutation accumulation (MA) experiment in the social amoeba Dictyostelium discoideum to estimate the rate and distribution of effects of spontaneous mutations affecting eight putative fitness traits. We found that the per-generation mutation rate for most fitness components is 0.0019 mutations per haploid genome per generation or larger. This rate is an order of magnitude higher than estimates for fitness components in the unicellular eukaryote Saccharomyces cerevisiae, even though the base-pair substitution rate is two orders of magnitude lower. The high rate of fitness-altering mutations observed in this species may be partially explained by a large mutational target relative to S. cerevisiae. Fitness-altering mutations also may occur primarily at simple sequence repeats, which are common throughout the genome, including in coding regions, and may represent a target that is particularly likely to give fitness effects upon mutation. The majority of mutations had deleterious effects on fitness, but there was evidence for a substantial fraction, up to 40%, being beneficial for some of the putative fitness traits. Competitive ability within the multicellular slug appears to be under weak directional selection, perhaps reflecting the fact that slugs are sometimes, but not often, comprised of multiple clones in nature. Evidence for pleiotropy among fitness components across MA lines was absent, suggesting that mutations tend to act on single fitness components.

  6. 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

    2015-01-07

    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.

  7. 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

    2016-05-05

    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.

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

    PubMed Central

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

    2016-01-01

    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

  9. 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).

  10. A Constant Rate of Spontaneous Mutation in DNA-Based Microbes

    NASA Astrophysics Data System (ADS)

    Drake, John W.

    1991-08-01

    In terms of evolution and fitness, the most significant spontaneous mutation rate is likely to be that for the entire genome (or its nonfrivolous fraction). Information is now available to calculate this rate for several DNA-based haploid microbes, including bacteriophages with single- or double-stranded DNA, a bacterium, a yeast, and a filamentous fungus. Their genome sizes vary by ≈6500-fold. Their average mutation rates per base pair vary by ≈16,000-fold, whereas their mutation rates per genome vary by only ≈2.5-fold, apparently randomly, around a mean value of 0.0033 per DNA replication. The average mutation rate per base pair is inversely proportional to genome size. Therefore, a nearly invariant microbial mutation rate appears to have evolved. Because this rate is uniform in such diverse organisms, it is likely to be determined by deep general forces, perhaps by a balance between the usually deleterious effects of mutation and the physiological costs of further reducing mutation rates.

  11. Critical mutation rate has an exponential dependence on population size in haploid and diploid populations.

    PubMed

    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

  12. Efficient Estimation of Mutation Rates during Individual Development by Minimization of Chi-Square.

    PubMed

    Ai, Shi-Meng; Gao, Jian-Jun; Liu, Shu-Qun; Fu, Yun-Xin

    2015-01-01

    Mutation primarily occurs when cells divide and it is highly desirable to have knowledge of the rate of mutations for each of the cell divisions during individual development. Recently, recessive lethal or nearly lethal mutations which were observed in a large mutation accumulation experiment using Drosophila melanogaster suggested that mutation rates vary significantly during the germline development of male Drosophila melanogaster. The analysis of the data was based on a combination of the maximum likelihood framework with numerical assistance from a newly developed coalescent algorithm. Although powerful, the likelihood based framework is computationally highly demanding which limited the scope of the inference. This paper presents a new estimation approach by minimizing chi-square statistics which is asymptotically consistent with the maximum likelihood method. When only at most one mutation in a family is considered the minimization of chi-square is simplified to a constrained weighted minimum least square method which can be solved easily by optimization theory. The new methods effectively eliminates the computational bottleneck of the likelihood. Reanalysis of the published Drosophila melanogaster mutation data results in similar estimates of mutation rates. The new method is also expected to be applicable to the analysis of mutation data generated by next-generation sequencing technology.

  13. The rate and character of spontaneous mutation in an RNA virus.

    PubMed Central

    Malpica, José M; Fraile, Aurora; Moreno, Ignacio; Obies, Clara I; Drake, John W; García-Arenal, Fernando

    2002-01-01

    Estimates of spontaneous mutation rates for RNA viruses are few and uncertain, most notably due to their dependence on tiny mutation reporter sequences that may not well represent the whole genome. We report here an estimate of the spontaneous mutation rate of tobacco mosaic virus using an 804-base cognate mutational target, the viral MP gene that encodes the movement protein (MP). Selection against newly arising mutants was countered by providing MP function from a transgene. The estimated genomic mutation rate was on the lower side of the range previously estimated for lytic animal riboviruses. We also present the first unbiased riboviral mutational spectrum. The proportion of base substitutions is the same as that in a retrovirus but is lower than that in most DNA-based organisms. Although the MP mutant frequency was 0.02-0.05, 35% of the sequenced mutants contained two or more mutations. Therefore, the mutation process in populations of TMV and perhaps of riboviruses generally differs profoundly from that in populations of DNA-based microbes and may be strongly influenced by a subpopulation of mutator polymerases. PMID:12524327

  14. Mutation Rate Variation is a Primary Determinant of the Distribution of Allele Frequencies in Humans

    PubMed Central

    Pritchard, Jonathan K.

    2016-01-01

    The site frequency spectrum (SFS) has long been used to study demographic history and natural selection. Here, we extend this summary by examining the SFS conditional on the alleles found at the same site in other species. We refer to this extension as the “phylogenetically-conditioned SFS” or cSFS. Using recent large-sample data from the Exome Aggregation Consortium (ExAC), combined with primate genome sequences, we find that human variants that occurred independently in closely related primate lineages are at higher frequencies in humans than variants with parallel substitutions in more distant primates. We show that this effect is largely due to sites with elevated mutation rates causing significant departures from the widely-used infinite sites mutation model. Our analysis also suggests substantial variation in mutation rates even among mutations involving the same nucleotide changes. In summary, we show that variable mutation rates are key determinants of the SFS in humans. PMID:27977673

  15. Estimation of the HIV-1 backward mutation rate from transmitted drug-resistant strains.

    PubMed

    Kitayimbwa, J M; Mugisha, J Y T; Saenz, R A

    2016-12-01

    One of the serious threats facing the administration of antiretroviral therapy to human immunodeficiency virus (HIV-1) infected patients is the reported increasing prevalence of transmitted drug resistance. However, given that HIV-1 drug-resistant strains are often less fit than the wild-type strains, it is expected that drug-resistant strains that are present during the primary phase of the HIV-1 infection are replaced by the fitter wild-type strains. This replacement of HIV-1 resistant mutations involves the emergence of wild-type strains by a process of backward mutation. How quickly the replacement happens is dependent on the class of HIV-1 mutation group. We estimate the backward mutation rates and relative fitness of various mutational groups known to confer HIV-1 drug resistance. We do this by fitting a stochastic model to data for individuals who were originally infected by an HIV-1 strain carrying any one of the known drug resistance-conferring mutations and observed over a period of time to see whether the resistant strain is replaced. To do this, we seek a distribution, generated from simulations of the stochastic model, that best describes the observed (clinical data) replacement times of a given mutation. We found that Lamivudine/Emtricitabine-associated mutations have a distinctly higher, backward mutation rate and low relative fitness compared to the other classes (as has been reported before) while protease inhibitors-associated mutations have a slower backward mutation rate and high relative fitness. For the other mutation classes, we found more uncertainty in their estimates.

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

    PubMed Central

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

    2015-01-01

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

  17. Rate of de novo mutations and the importance of father's age to disease risk.

    PubMed

    Kong, Augustine; Frigge, Michael L; Masson, Gisli; Besenbacher, Soren; Sulem, Patrick; Magnusson, Gisli; Gudjonsson, Sigurjon A; Sigurdsson, Asgeir; Jonasdottir, Aslaug; Jonasdottir, Adalbjorg; Wong, Wendy S W; Sigurdsson, Gunnar; Walters, G Bragi; Steinberg, Stacy; Helgason, Hannes; Thorleifsson, Gudmar; Gudbjartsson, Daniel F; Helgason, Agnar; Magnusson, Olafur Th; Thorsteinsdottir, Unnur; Stefansson, Kari

    2012-08-23

    Mutations generate sequence diversity and provide a substrate for selection. The rate of de novo mutations is therefore of major importance to evolution. Here we conduct a study of genome-wide mutation rates by sequencing the entire genomes of 78 Icelandic parent-offspring trios at high coverage. We show that in our samples, with an average father's age of 29.7, the average de novo mutation rate is 1.20 × 10(-8) per nucleotide per generation. Most notably, the diversity in mutation rate of single nucleotide polymorphisms is dominated by the age of the father at conception of the child. The effect is an increase of about two mutations per year. An exponential model estimates paternal mutations doubling every 16.5 years. After accounting for random Poisson variation, father's age is estimated to explain nearly all of the remaining variation in the de novo mutation counts. These observations shed light on the importance of the father's age on the risk of diseases such as schizophrenia and autism.

  18. 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.

  19. 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.

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

    PubMed Central

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

    2016-01-01

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

  1. 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

  2. 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

  3. The mutation rate of the human mtDNA deletion mtDNA4977.

    PubMed

    Shenkar, R; Navidi, W; Tavaré, S; Dang, M H; Chomyn, A; Attardi, G; Cortopassi, G; Arnheim, N

    1996-10-01

    The human mitochondrial mutation mtDNA4977 is a 4,977-bp deletion that originates between two 13-bp direct repeats. We grew 220 colonies of cells, each from a single human cell. For each colony, we counted the number of cells and amplified the DNA by PCR to test for the presence of a deletion. To estimate the mutation fate, we used a model that describes the relationship between the mutation rate and the probability that a colony of a given size will contain no mutants, taking into account such factors as possible mitochondrial turnover and mistyping due to PCR error. We estimate that the mutation rate for mtDNA4977 in cultured human cells is 5.95 x 10(-8) per mitochondrial genome replication. This method can be applied to specific chromosomal, as well as mitochondrial, mutations.

  4. The rate of beneficial mutations surfing on the wave of a range expansion.

    PubMed

    Lehe, Rémi; Hallatschek, Oskar; Peliti, Luca

    2012-01-01

    Many theoretical and experimental studies suggest that range expansions can have severe consequences for the gene pool of the expanding population. Due to strongly enhanced genetic drift at the advancing frontier, neutral and weakly deleterious mutations can reach large frequencies in the newly colonized regions, as if they were surfing the front of the range expansion. These findings raise the question of how frequently beneficial mutations successfully surf at shifting range margins, thereby promoting adaptation towards a range-expansion phenotype. Here, we use individual-based simulations to study the surfing statistics of recurrent beneficial mutations on wave-like range expansions in linear habitats. We show that the rate of surfing depends on two strongly antagonistic factors, the probability of surfing given the spatial location of a novel mutation and the rate of occurrence of mutations at that location. The surfing probability strongly increases towards the tip of the wave. Novel mutations are unlikely to surf unless they enjoy a spatial head start compared to the bulk of the population. The needed head start is shown to be proportional to the inverse fitness of the mutant type, and only weakly dependent on the carrying capacity. The precise location dependence of surfing probabilities is derived from the non-extinction probability of a branching process within a moving field of growth rates. The second factor is the mutation occurrence which strongly decreases towards the tip of the wave. Thus, most successful mutations arise at an intermediate position in the front of the wave. We present an analytic theory for the tradeoff between these factors that allows to predict how frequently substitutions by beneficial mutations occur at invasion fronts. We find that small amounts of genetic drift increase the fixation rate of beneficial mutations at the advancing front, and thus could be important for adaptation during species invasions.

  5. Substantial molecular evolution and mutation rates in prolonged latent Mycobacterium tuberculosis infection in humans.

    PubMed

    Lillebaek, Troels; Norman, Anders; Rasmussen, Erik Michael; Marvig, Rasmus L; Folkvardsen, Dorte Bek; Andersen, Åse Bengård; Jelsbak, Lars

    2016-11-01

    The genome of Mycobacterium tuberculosis (Mtb) of latently infected individuals may hold the key to understanding the processes that lead to reactivation and progression to clinical disease. We report here analysis of pairs of Mtb isolates from putative prolonged latent TB cases. We identified two confirmed cases, and used whole genome sequencing to investigate the mutational processes that occur over decades in latent Mtb. We found an estimated mutation rate between 0.2 and 0.3 over 33 years, suggesting that latent Mtb accumulates mutations at rates similar to observations from cases of active disease.

  6. Germline mutation rates at tandem repeat loci in DNA-repair deficient mice.

    PubMed

    Barber, Ruth C; Miccoli, Laurent; van Buul, Paul P W; Burr, Karen L-A; van Duyn-Goedhart, Annemarie; Angulo, Jaime F; Dubrova, Yuri E

    2004-10-04

    Mutation rates at two expanded simple tandem repeat (ESTR) loci were studied in the germline of non-exposed and irradiated severe combined immunodeficient (scid) and poly(ADP-ribose) polymerase (PARP-1-/-) deficient male mice. Non-exposed scid and PARP-/- male mice showed considerably elevated ESTR mutation rates, far higher than those in wild-type isogenic mice and other inbred strains. The irradiated scid and PARP-1-/- male mice did not show any detectable increases in their mutation rate, whereas significant ESTR mutation induction was observed in the irradiated wild-type isogenic males. ESTR mutation spectra in the scid and PARP-1-/- strains did not differ from those in the isogenic wild-type strains. Considering these data and the results of previous studies, we propose that a delay in repair of DNA damage in scid and PARP-1-/- mice could result in replication fork pausing which, in turn, may affect ESTR mutation rate in the non-irradiated males. The lack of mutation induction in irradiated scid and PARP-1-/- can be explained by the high cell killing effects of irradiation on the germline of deficient mice.

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

    PubMed

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

    2014-11-20

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

  8. 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

  9. 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

  10. 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.

  11. The effect of sexual harassment on lethal mutation rate in female Drosophila melanogaster.

    PubMed

    Maklakov, Alexei A; Immler, Simone; Løvlie, Hanne; Flis, Ilona; Friberg, Urban

    2013-01-07

    The rate by which new mutations are introduced into a population may have far-reaching implications for processes at the population level. Theory assumes that all individuals within a population have the same mutation rate, but this assumption may not be true. Compared with individuals in high condition, those in poor condition may have fewer resources available to invest in DNA repair, resulting in elevated mutation rates. Alternatively, environmentally induced stress can result in increased investment in DNA repair at the expense of reproduction. Here, we directly test whether sexual harassment by males, known to reduce female condition, affects female capacity to alleviate DNA damage in Drosophila melanogaster fruitflies. Female gametes can repair double-strand DNA breaks in sperm, which allows manipulating mutation rate independently from female condition. We show that male harassment strongly not only reduces female fecundity, but also reduces the yield of dominant lethal mutations, supporting the hypothesis that stressed organisms invest relatively more in repair mechanisms. We discuss our results in the light of previous research and suggest that social effects such as density and courtship can play an important and underappreciated role in mediating condition-dependent mutation rate.

  12. 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

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

    PubMed

    Behringer, Megan G; Hall, David W

    2016-08-01

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

  14. Mutation Rates and Discriminating Power for 13 Rapidly-Mutating Y-STRs between Related and Unrelated Individuals

    PubMed Central

    Bini, Carla; Pesci, Valeria; Barbieri, Chiara; De Fanti, Sara; Quagliariello, Andrea; Pagani, Luca; Ayub, Qasim; Ferri, Gianmarco; Pettener, Davide; Luiselli, Donata; Pelotti, Susi

    2016-01-01

    Rapidly Mutating Y-STRs (RM Y-STRs) were recently introduced in forensics in order to increase the differentiation of Y-chromosomal profiles even in case of close relatives. We estimate RM Y-STRs mutation rates and their power to discriminate between related individuals by using samples extracted from a wide set of paternal pedigrees and by comparing RM Y-STRs results with those obtained from the Y-filer set. In addition, we tested the ability of RM Y-STRs to discriminate between unrelated individuals carrying the same Y-filer haplotype, using the haplogroup R-M269 (reportedly characterised by a strong resemblance in Y-STR profiles) as a case study. Our results, despite confirming the high mutability of RM Y-STRs, show significantly lower mutation rates than reference germline ones. Consequently, their power to discriminate between related individuals, despite being higher than the one of Y-filer, does not seem to improve significantly the performance of the latter. On the contrary, when considering R-M269 unrelated individuals, RM Y-STRs reveal significant discriminatory power and retain some phylogenetic signal, allowing the correct classification of individuals for some R-M269-derived sub-lineages. These results have important implications not only for forensics, but also for molecular anthropology, suggesting that RM Y-STRs are useful tools for exploring subtle genetic variability within Y-chromosomal haplogroups. PMID:27802306

  15. Mutation Rates and Discriminating Power for 13 Rapidly-Mutating Y-STRs between Related and Unrelated Individuals.

    PubMed

    Boattini, Alessio; Sarno, Stefania; Bini, Carla; Pesci, Valeria; Barbieri, Chiara; De Fanti, Sara; Quagliariello, Andrea; Pagani, Luca; Ayub, Qasim; Ferri, Gianmarco; Pettener, Davide; Luiselli, Donata; Pelotti, Susi

    2016-01-01

    Rapidly Mutating Y-STRs (RM Y-STRs) were recently introduced in forensics in order to increase the differentiation of Y-chromosomal profiles even in case of close relatives. We estimate RM Y-STRs mutation rates and their power to discriminate between related individuals by using samples extracted from a wide set of paternal pedigrees and by comparing RM Y-STRs results with those obtained from the Y-filer set. In addition, we tested the ability of RM Y-STRs to discriminate between unrelated individuals carrying the same Y-filer haplotype, using the haplogroup R-M269 (reportedly characterised by a strong resemblance in Y-STR profiles) as a case study. Our results, despite confirming the high mutability of RM Y-STRs, show significantly lower mutation rates than reference germline ones. Consequently, their power to discriminate between related individuals, despite being higher than the one of Y-filer, does not seem to improve significantly the performance of the latter. On the contrary, when considering R-M269 unrelated individuals, RM Y-STRs reveal significant discriminatory power and retain some phylogenetic signal, allowing the correct classification of individuals for some R-M269-derived sub-lineages. These results have important implications not only for forensics, but also for molecular anthropology, suggesting that RM Y-STRs are useful tools for exploring subtle genetic variability within Y-chromosomal haplogroups.

  16. 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

  17. Polychlorinated biphenyl contamination and minisatellite DNA mutation rates of tree swallows.

    PubMed

    Stapleton, M; Dunn, P O; McCarty, J; Secord, A; Whittingham, L A

    2001-10-01

    The evidence that exposure to polychlorinated biphenyls (PCBs) leads to mutations is equivocal and controversial. Using multilocus DNA fingerprinting, we compared the mutation rate of tree swallows (Tachycineta bicolor) nesting at sites with high and low levels of contamination with PCBs. The upper Hudson River, USA, is highly contaminated with PCBs as a result of releases from two capacitor manufacturing plants in Hudson Falls and Fort Edward, New York, USA. Tree swallows nesting nearby have some of the highest known concentrations of PCBs in their tissues of any contemporary bird population (up to 114,000 ng PCB/g tissue). We found no difference in mutation rates between sites in New York with high PCB contamination and reference sites in Wisconsin, USA, and Ontario and Alberta, Canada, with known or presumably low levels of contamination. Thus, the mechanism behind altered reproductive behavior of tree swallows along the upper Hudson River is most likely physiological impairment, such as endocrine disruption, rather than mutation.

  18. 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

  19. Plankton predation rates in turbulence: a study of the limitations imposed on a predator with a non-spherical field of sensory perception.

    PubMed

    Lewis, D M; Bala, S I

    2006-09-07

    This paper presents an extension to previously published work which studied encounter rates of planktonic predators with restricted perception fields, to examine the related problems of prey capture and predation rates. Small-scale turbulence influences planktonic predation in two ways: the extra energy of the flow enhances the number of encounter events between individual predator and prey meso/micro-zooplankton, but it lowers the capture probability (because the time spent by the predator and prey in close proximity is reduced). Typically, an 'encounter' has usually been defined as an event when a potential prey swims (or is advected) to within a distance R of the predator in any direction. However, there is a considerable body of experimental evidence showing that predators perception fields are far from spherical; often they are wedge shaped (e.g. fish larvae), or strongly aligned with the directions of sensory antennae (e.g. copepods); and this is certain to influence optimal predation strategies. This paper presents a theoretical model which for the first time examines the combined problems of both encounter and capture for a predator with a restricted perception field swimming in a turbulent flow. If such a predator adopts a cruising strategy (continuous swimming, possibly with direction changes) the model predictions suggest that predation rates actually vary little with swimming speed, in contrast to predictions made for spherical perception fields. Consequently, cruising predators are predicted to swim at relatively low speeds whilst foraging. However, application of the model to examine the net energy gain of a typical pause-travel predator (the Atlantic cod larva), does predict the existence of an optimal ratio of the length of pauses to time spent swimming (specifically one pause phase to every two travel phases), in line with experimental observations. Kinematic simulations are presented which support these findings.

  20. Luria-delbruck estimation of turnip mosaic virus mutation rate in vivo.

    PubMed

    de la Iglesia, Francisca; Martínez, Fernando; Hillung, Julia; Cuevas, José M; Gerrish, Philip J; Daròs, José-Antonio; Elena, Santiago F

    2012-03-01

    A potential drawback of recent antiviral therapies based on the transgenic expression of artificial microRNAs is the ease with which viruses may generate escape mutations. Using a variation of the classic Luria-Delbrück fluctuation assay, we estimated that the spontaneous mutation rate in the artificial microRNA (amiR) target of a plant virus was ca. 6 × 10(-5) per replication event.

  1. 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

    2016-04-22

    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.

  2. Estimates of the genomic mutation rate for detrimental alleles in Drosophila melanogaster.

    PubMed

    Charlesworth, Brian; Borthwick, Helen; Bartolomé, Carolina; Pignatelli, Patricia

    2004-06-01

    The net rate of mutation to deleterious but nonlethal alleles and the sizes of effects of these mutations are of great significance for many evolutionary questions. Here we describe three replicate experiments in which mutations have been accumulated on chromosome 3 of Drosophila melanogaster by means of single-male backcrosses of heterozygotes for a wild-type third chromosome. Egg-to-adult viability was assayed for nonlethal homozygous chromosomes. The rates of decline in mean and increase in variance (DM and DV, respectively) were estimated. Scaled up to the diploid whole genome, the mean DM for homozygous detrimental mutations over the three experiments was between 0.8 and 1.8%. The corresponding DV estimate was approximately 0.11%. Overall, the results suggest a lower bound estimate of at least 12% for the diploid per genome mutation rate for detrimentals. The upper bound estimates for the mean selection coefficient were between 2 and 10%, depending on the method used. Mutations with selection coefficients of at least a few percent must be the major contributors to the effects detected here and are likely to be caused mostly by transposable element insertions or indels.

  3. 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.

  4. Joint Prediction of the Effective Population Size and the Rate of Fixation of Deleterious Mutations.

    PubMed

    Santiago, Enrique; Caballero, Armando

    2016-11-01

    Mutation, genetic drift, and selection are considered the main factors shaping genetic variation in nature. There is a lack, however, of general predictions accounting for the mutual interrelation between these factors. In the context of the background selection model, we provide a set of equations for the joint prediction of the effective population size and the rate of fixation of deleterious mutations, which are applicable both to sexual and asexual species. For a population of N haploid individuals and a model of deleterious mutations with effect s appearing with rate U in a genome L Morgans long, the asymptotic effective population size (Ne) and the average number of generations (T) between consecutive fixations can be approximated by [Formula: see text] and [Formula: see text] The solution is applicable to Muller's ratchet, providing satisfactory approximations to the rate of accumulation of mutations for a wide range of parameters. We also obtain predictions of the effective size accounting for the expected nucleotide diversity. Predictions for sexual populations allow for outlining the general conditions where mutational meltdown occurs. The equations can be extended to any distribution of mutational effects and the consideration of hotspots of recombination, showing that Ne is rather insensitive and not proportional to changes in N for many combinations of parameters. This could contribute to explain the observed small differences in levels of polymorphism between species with very different census sizes.

  5. 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

  6. 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

  7. 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

  8. 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.

  9. The antiretrovirus drug 3'-azido-3'-deoxythymidine increases the retrovirus mutation rate.

    PubMed Central

    Julias, J G; Kim, T; Arnold, G; Pathak, V K

    1997-01-01

    It was previously observed that the nucleoside analog 5-azacytidine increased the spleen necrosis virus (SNV) mutation rate 13-fold in one cycle of retrovirus replication (V. K. Pathak and H. M. Temin, J. Virol. 66:3093-3100, 1992). Based on this observation, we hypothesized that nucleoside analogs used as antiviral drugs may also increase retrovirus mutation rates. We sought to determine if 3'-azido-3'-deoxythymidine (AZT), the primary treatment for human immunodeficiency virus type 1 (HIV-1) infection, increases the retrovirus mutation rate. Two assays were used to determine the effects of AZT on retrovirus mutation rates. The strategy of the first assay involved measuring the in vivo rate of inactivation of the lacZ gene in one replication cycle of SNV- and murine leukemia virus-based retroviral vectors. We observed 7- and 10-fold increases in the SNV mutant frequency following treatment of target cells with 0.1 and 0.5 microM AZT, respectively. The murine leukemia virus mutant frequency increased two- and threefold following treatment of target cells with 0.5 and 1.0 microM AZT, respectively. The second assay used an SNV-based shuttle vector containing the lacZ alpha gene. Proviruses were recovered as plasmids in Escherichia coli, and the rate of inactivation of lacZ alpha was measured. The results indicated that treatment of target cells increased the overall mutation rate two- to threefold. DNA sequence analysis of mutant proviruses indicated that AZT increased both the deletion and substitution rates. These results suggest that AZT treatment of HIV-1 infection may increase the degree of viral variation and alter virus evolution or pathogenesis. PMID:9151812

  10. Antibiotic treatment enhances the genome-wide mutation rate of target cells.

    PubMed

    Long, Hongan; Miller, Samuel F; Strauss, Chloe; Zhao, Chaoxian; Cheng, Lei; Ye, Zhiqiang; Griffin, Katherine; Te, Ronald; Lee, Heewook; Chen, Chi-Chun; Lynch, Michael

    2016-05-03

    Although it is well known that microbial populations can respond adaptively to challenges from antibiotics, empirical difficulties in distinguishing the roles of de novo mutation and natural selection have left several issues unresolved. Here, we explore the mutational properties of Escherichia coli exposed to long-term sublethal levels of the antibiotic norfloxacin, using a mutation accumulation design combined with whole-genome sequencing of replicate lines. The genome-wide mutation rate significantly increases with norfloxacin concentration. This response is associated with enhanced expression of error-prone DNA polymerases and may also involve indirect effects of norfloxacin on DNA mismatch and oxidative-damage repair. Moreover, we find that acquisition of antibiotic resistance can be enhanced solely by accelerated mutagenesis, i.e., without direct involvement of selection. Our results suggest that antibiotics may generally enhance the mutation rates of target cells, thereby accelerating the rate of adaptation not only to the antibiotic itself but to additional challenges faced by invasive pathogens.

  11. Antibiotic treatment enhances the genome-wide mutation rate of target cells

    PubMed Central

    Long, Hongan; Miller, Samuel F.; Strauss, Chloe; Zhao, Chaoxian; Cheng, Lei; Ye, Zhiqiang; Griffin, Katherine; Te, Ronald; Lee, Heewook; Chen, Chi-Chun; Lynch, Michael

    2016-01-01

    Although it is well known that microbial populations can respond adaptively to challenges from antibiotics, empirical difficulties in distinguishing the roles of de novo mutation and natural selection have left several issues unresolved. Here, we explore the mutational properties of Escherichia coli exposed to long-term sublethal levels of the antibiotic norfloxacin, using a mutation accumulation design combined with whole-genome sequencing of replicate lines. The genome-wide mutation rate significantly increases with norfloxacin concentration. This response is associated with enhanced expression of error-prone DNA polymerases and may also involve indirect effects of norfloxacin on DNA mismatch and oxidative-damage repair. Moreover, we find that acquisition of antibiotic resistance can be enhanced solely by accelerated mutagenesis, i.e., without direct involvement of selection. Our results suggest that antibiotics may generally enhance the mutation rates of target cells, thereby accelerating the rate of adaptation not only to the antibiotic itself but to additional challenges faced by invasive pathogens. PMID:27091991

  12. 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.

  13. Mutation rate and novel tt mutants of Arabidopsis thaliana induced by carbon ions.

    PubMed Central

    Shikazono, Naoya; Yokota, Yukihiko; Kitamura, Satoshi; Suzuki, Chihiro; Watanabe, Hiroshi; Tano, Shigemitsu; Tanaka, Atsushi

    2003-01-01

    Irradiation of Arabidopsis thaliana by carbon ions was carried out to investigate the mutational effect of ion particles in higher plants. Frequencies of embryonic lethals and chlorophyll-deficient mutants were found to be significantly higher after carbon-ion irradiation than after electron irradiation (11-fold and 7.8-fold per unit dose, respectively). To estimate the mutation rate of carbon ions, mutants with no pigments on leaves and stems (tt) and no trichomes on leaves (gl) were isolated at the M2 generation and subjected to analysis. Averaged segregation rate of the backcrossed mutants was 0.25, which suggested that large deletions reducing the viability of the gametophytes were not transmitted, if generated, in most cases. During the isolation of mutants, two new classes of flavonoid mutants (tt18, tt19) were isolated from carbon-ion-mutagenized M2 plants. From PCR and sequence analysis, two of the three tt18 mutant alleles were found to have a small deletion within the LDOX gene and the other was revealed to contain a rearrangement. Using the segregation rates, the mutation rate of carbon ions was estimated to be 17-fold higher than that of electrons. The isolation of novel mutants and the high mutation rate suggest that ion particles can be used as a valuable mutagen for plant genetics. PMID:12702688

  14. Indel-associated mutation rate varies with mating system in flowering plants.

    PubMed

    Hollister, Jesse D; Ross-Ibarra, Jeffrey; Gaut, Brandon S

    2010-02-01

    A recently proposed mutational mechanism, indel-associated mutation (IDAM), posits that heterozygous insertions/deletions (indels) increase the point mutation rate at nearby nucleotides due to errors during meiosis. This mechanism could have especially dynamic consequences for the evolution of plant genomes, because the high degree of variation in the rate of self-fertilization among plant species causes differences in the heterozygosity of alleles, including indel alleles, segregating in plant species. In this study, we investigated the consequences of IDAM for species differing in mating system using both forward population genetic simulations and genomewide DNA resequencing data from Arabidopsis thaliana, Oryza sativa, and Oryza rufipogon. Simulations of different levels of selfing suggest that the effect of IDAM on surrounding nucleotide diversity should decrease with increasing selfing rate. Further simulations incorporating selfing rates and the time of onset of selfing suggest that the time since the switch to selfing also affects patterns of nucleotide diversity due to IDAM. Population genetic analyses of A. thaliana and Oryza DNA sequence data sets empirically confirmed our simulation results, revealing the strongest effect of IDAM in the outcrossing O. rufipogon, a weaker effect in the recently evolved selfer O. sativa, and the weakest effect in the relatively ancient selfer A. thaliana. These results support the novel idea that differences in life history, such as the level of selfing, can affect the per-individual mutation rate among species.

  15. Age-Of Dependent Mutation Rate and Weak Children in the Penna Model in Biological Ageing

    NASA Astrophysics Data System (ADS)

    Berntsen, K. Nikolaj

    We investigate the effect of an age-dependent mutation rate in the Penna model of ageing and then we observe that the high mortality for human babies can be reproduced by the model if one assumes babies to be weaker than adults.

  16. Estimation of DNA sequence context-dependent mutation rates using primate genomic sequences.

    PubMed

    Zhang, Wei; Bouffard, Gerard G; Wallace, Susan S; Bond, Jeffrey P

    2007-09-01

    It is understood that DNA and amino acid substitution rates are highly sequence context-dependent, e.g., C --> T substitutions in vertebrates may occur much more frequently at CpG sites and that cysteine substitution rates may depend on support of the context for participation in a disulfide bond. Furthermore, many applications rely on quantitative models of nucleotide or amino acid substitution, including phylogenetic inference and identification of amino acid sequence positions involved in functional specificity. We describe quantification of the context dependence of nucleotide substitution rates using baboon, chimpanzee, and human genomic sequence data generated by the NISC Comparative Sequencing Program. Relative mutation rates are reported for the 96 classes of mutations of the form 5' alphabetagamma 3' --> 5' alphadeltagamma 3', where alpha, beta, gamma, and delta are nucleotides and beta not equal delta, based on maximum likelihood calculations. Our results confirm that C --> T substitutions are enhanced at CpG sites compared with other transitions, relatively independent of the identity of the preceding nucleotide. While, as expected, transitions generally occur more frequently than transversions, we find that the most frequent transversions involve the C at CpG sites (CpG transversions) and that their rate is comparable to the rate of transitions at non-CpG sites. A four-class model of the rates of context-dependent evolution of primate DNA sequences, CpG transitions > non-CpG transitions approximately CpG transversions > non-CpG transversions, captures qualitative features of the mutation spectrum. We find that despite qualitative similarity of mutation rates among different genomic regions, there are statistically significant differences.

  17. 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.

  18. 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

    2016-09-07

    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.

  19. 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

  20. Experimental estimation of mutation rates in a wheat population with a gene genealogy approach.

    PubMed

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

    2008-08-01

    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 x 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.

  1. 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.

  2. 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.

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

    PubMed

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

    2016-02-22

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

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

    PubMed Central

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

    2016-01-01

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

  5. 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.

  6. 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

  7. 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

  8. 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.

  9. Effects of Sublethal Fungicides on Mutation Rates and Genomic Variation in Fungal Plant Pathogen, Sclerotinia sclerotiorum

    PubMed Central

    Amaradasa, B. Sajeewa

    2016-01-01

    Pathogen exposure to sublethal doses of fungicides may result in mutations that may represent an important and largely overlooked mechanism of introducing new genetic variation into strictly clonal populations, including acquisition of fungicide resistance. We tested this hypothesis using the clonal plant pathogen, Sclerotinia sclerotiorum. Nine susceptible isolates were exposed independently to five commercial fungicides with different modes of action: boscalid (respiration inhibitor), iprodione (unclear mode of action), thiophanate methyl (inhibition of microtubulin synthesis) and azoxystrobin and pyraclostrobin (quinone outside inhibitors). Mycelium of each isolate was inoculated onto a fungicide gradient and sub-cultured from the 50–100% inhibition zone for 12 generations and experiment repeated. Mutational changes were assessed for all isolates at six neutral microsatellite (SSR) loci and for a subset of isolates using amplified fragment length polymorphisms (AFLPs). SSR analysis showed 12 of 85 fungicide-exposed isolates had a total of 127 stepwise mutations with 42 insertions and 85 deletions. Most stepwise deletions were in iprodione- and azoxystrobin-exposed isolates (n = 40/85 each). Estimated mutation rates were 1.7 to 60-fold higher for mutated loci compared to that expected under neutral conditions. AFLP genotyping of 33 isolates (16 non-exposed control and 17 fungicide exposed) generated 602 polymorphic alleles. Cluster analysis with principal coordinate analysis (PCoA) and discriminant analysis of principal components (DAPC) identified fungicide-exposed isolates as a distinct group from non-exposed control isolates (PhiPT = 0.15, P = 0.001). Dendrograms based on neighbor-joining also supported allelic variation associated with fungicide-exposure. Fungicide sensitivity of isolates measured throughout both experiments did not show consistent trends. For example, eight isolates exposed to boscalid had higher EC50 values at the end of the experiment

  10. 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.

  11. An alternative derivation of the stationary distribution of the multivariate neutral Wright-Fisher model for low mutation rates with a view to mutation rate estimation from site frequency data.

    PubMed

    Schrempf, Dominik; Hobolth, Asger

    2017-04-01

    Recently, Burden and Tang (2016) provided an analytical expression for the stationary distribution of the multivariate neutral Wright-Fisher model with low mutation rates. In this paper we present a simple, alternative derivation that illustrates the approximation. Our proof is based on the discrete multivariate boundary mutation model which has three key ingredients. First, the decoupled Moran model is used to describe genetic drift. Second, low mutation rates are assumed by limiting mutations to monomorphic states. Third, the mutation rate matrix is separated into a time-reversible part and a flux part, as suggested by Burden and Tang (2016). An application of our result to data from several great apes reveals that the assumption of stationarity may be inadequate or that other evolutionary forces like selection or biased gene conversion are acting. Furthermore we find that the model with a reversible mutation rate matrix provides a reasonably good fit to the data compared to the one with a non-reversible mutation rate matrix.

  12. 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

  13. Highly variable recessive lethal or nearly lethal mutation rates during germ-line development of male Drosophila melanogaster.

    PubMed

    Gao, Jian-Jun; Pan, Xue-Rong; Hu, Jing; Ma, Li; Wu, Jian-Min; Shao, Ye-Lin; Barton, Sara A; Woodruff, Ronny C; Zhang, Ya-Ping; Fu, Yun-Xin

    2011-09-20

    Each cell of higher organism adults is derived from a fertilized egg through a series of divisions, during which mutations can occur. Both the rate and timing of mutations can have profound impacts on both the individual and the population, because mutations that occur at early cell divisions will affect more tissues and are more likely to be transferred to the next generation. Using large-scale multigeneration screening experiments for recessive lethal or nearly lethal mutations of Drosophila melanogaster and recently developed statistical analysis, we show for male D. melanogaster that (i) mutation rates (for recessive lethal or nearly lethal) are highly variable during germ cell development; (ii) first cell cleavage has the highest mutation rate, which drops substantially in the second cleavage or the next few cleavages; (iii) the intermediate stages, after a few cleavages to right before spermatogenesis, have at least an order of magnitude smaller mutation rate; and (iv) spermatogenesis also harbors a fairly high mutation rate. Because germ-line lineage shares some (early) cell divisions with somatic cell lineage, the first conclusion is readily extended to a somatic cell lineage. It is conceivable that the first conclusion is true for most (if not all) higher organisms, whereas the other three conclusions are widely applicable, although the extent may differ from species to species. Therefore, conclusions or analyses that are based on equal mutation rates during development should be taken with caution. Furthermore, the statistical approach developed can be adopted for studying other organisms, including the human germ-line or somatic mutational patterns.

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

    PubMed

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

    2016-03-01

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

  15. Multiplex assay development and mutation rate analysis for 13 RM Y-STRs in Chinese Han population.

    PubMed

    Zhang, Wenqiong; Xiao, Chao; Yu, Jin; Wei, Tian; Liao, Fei; Wei, Wei; Huang, Daixin

    2017-03-01

    In this study, a novel multiplex polymerase chain reaction (PCR) assay was developed for amplifying the newly introduced 13 rapidly mutating Y-STR markers (RM Y-STRs) including DYF387S1, DYF399S1, DYF403S1a/b, DYF404S1, DYS449, DYS518, DYS526b, DYS547, DYS570, DYS576, DYS612, DYS626, and DYS627. In addition, a survey for mutation rates of the 13 RM Y-STRs in Chinese Han population was performed to make sure of the mutation characteristic and application in Chinese group. With 14,476 allele transfers in 1034 father-son pairs, 221 mutation events occurred, of which 215 were one-step mutations and 6 were two-step mutations. Nineteen father-son pairs were found to have mutations at two loci and one pair at three loci. Based upon our research data, 18.96 % of all 1034 father-son pairs were successfully differentiated, and the estimated locus-specific mutation rates varied from 4.84 × 10(-3) to 6.29 × 10(-2), with an average estimated mutation rate 1.53 × 10(-2) (95 % CI 1.33 × 10(-2) to 1.74 × 10(-2)). Among the 13 Y-STR markers, eight loci (DYF399S1, DYF403S1a, DYF404S1, DYS449, DYS518, DYS547, DYS576, and DYS612) had mutation rates higher than 1.00 × 10(-2), and the rest loci lower than 1.00 × 10(-2) in Chinese samples.

  16. Mutation rate estimates for 110 Y-chromosome STRs combining population and father–son pair data

    PubMed Central

    Burgarella, Concetta; Navascués, Miguel

    2011-01-01

    Y-chromosome microsatellites (Y-STRs) are typically used for kinship analysis and forensic identification, as well as for inferences on population history and evolution. All applications would greatly benefit from reliable locus-specific mutation rates, to improve forensic probability calculations and interpretations of diversity data. However, estimates of mutation rate from father–son transmissions are available for few loci and have large confidence intervals, because of the small number of meiosis usually observed. By contrast, population data exist for many more Y-STRs, holding unused information about their mutation rates. To incorporate single locus diversity information into Y-STR mutation rate estimation, we performed a meta-analysis using pedigree data for 80 loci and individual haplotypes for 110 loci, from 29 and 93 published studies, respectively. By means of logistic regression we found that relative genetic diversity, motif size and repeat structure explain the variance of observed rates of mutations from meiosis. This model allowed us to predict locus-specific mutation rates (mean predicted mutation rate 2.12 × 10−3, SD=1.58 × 10−3), including estimates for 30 loci lacking meiosis observations and 41 with a previous estimate of zero. These estimates are more accurate than meiosis-based estimates when a small number of meiosis is available. We argue that our methodological approach, by taking into account locus diversity, could be also adapted to estimate population or lineage-specific mutation rates. Such adjusted estimates would represent valuable information for selecting the most reliable markers for a wide range of applications. PMID:20823913

  17. Mutation rate estimates for 110 Y-chromosome STRs combining population and father-son pair data.

    PubMed

    Burgarella, Concetta; Navascués, Miguel

    2011-01-01

    Y-chromosome microsatellites (Y-STRs) are typically used for kinship analysis and forensic identification, as well as for inferences on population history and evolution. All applications would greatly benefit from reliable locus-specific mutation rates, to improve forensic probability calculations and interpretations of diversity data. However, estimates of mutation rate from father-son transmissions are available for few loci and have large confidence intervals, because of the small number of meiosis usually observed. By contrast, population data exist for many more Y-STRs, holding unused information about their mutation rates. To incorporate single locus diversity information into Y-STR mutation rate estimation, we performed a meta-analysis using pedigree data for 80 loci and individual haplotypes for 110 loci, from 29 and 93 published studies, respectively. By means of logistic regression we found that relative genetic diversity, motif size and repeat structure explain the variance of observed rates of mutations from meiosis. This model allowed us to predict locus-specific mutation rates (mean predicted mutation rate 2.12 × 10(-3), SD=1.58 × 10(-3)), including estimates for 30 loci lacking meiosis observations and 41 with a previous estimate of zero. These estimates are more accurate than meiosis-based estimates when a small number of meiosis is available. We argue that our methodological approach, by taking into account locus diversity, could be also adapted to estimate population or lineage-specific mutation rates. Such adjusted estimates would represent valuable information for selecting the most reliable markers for a wide range of applications.

  18. 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.

  19. Exploring the Relationships between Mutation Rates, Life History, Genome Size, Environment, and Species Richness in Flowering Plants.

    PubMed

    Bromham, Lindell; Hua, Xia; Lanfear, Robert; Cowman, Peter F

    2015-04-01

    A new view is emerging of the interplay between mutation at the genomic level, substitution at the population level, and diversification at the lineage level. Many studies have suggested that rate of molecular evolution is linked to rate of diversification, but few have evaluated competing hypotheses. By analyzing sequences from 130 families of angiosperms, we show that variation in the synonymous substitution rate is correlated among genes from the mitochondrial, chloroplast, and nuclear genomes and linked to differences in traits among families (average height and genome size). Within each genome, synonymous rates are correlated to nonsynonymous substitution rates, suggesting that increasing the mutation rate results in a faster rate of genome evolution. Substitution rates are correlated with species richness in protein-coding sequences from the chloroplast and nuclear genomes. These data suggest that species traits contribute to lineage-specific differences in the mutation rate that drive both synonymous and nonsynonymous rates of change across all three genomes, which in turn contribute to greater rates of divergence between populations, generating higher rates of diversification. These observations link mutation in individuals to population-level processes and to patterns of lineage divergence.

  20. 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.

  1. Impact of Loci Nature on Estimating Recombination and Mutation Rates in Chlamydia trachomatis

    PubMed Central

    Ferreira, Rita; Borges, Vítor; Nunes, Alexandra; Nogueira, Paulo Jorge; Borrego, Maria José; Gomes, João Paulo

    2012-01-01

    The knowledge of the frequency and relative weight of mutation and recombination events in evolution is essential for understanding how microorganisms reach fitted phenotypes. Traditionally, these evolutionary parameters have been inferred by using data from multilocus sequence typing (MLST), which is known to have yielded conflicting results. In the near future, these estimations will certainly be performed by computational analyses of full-genome sequences. However, it is not known whether this approach will yield accurate results as bacterial genomes exhibit heterogeneous representation of loci categories, and it is not clear how loci nature impacts such estimations. Therefore, we assessed how mutation and recombination inferences are shaped by loci with different genetic features, using the bacterium Chlamydia trachomatis as the study model. We found that loci assigning a high number of alleles and positively selected genes yielded nonconvergent estimates and incongruent phylogenies and thus are more prone to confound algorithms. Unexpectedly, for the model under evaluation, housekeeping genes and noncoding regions shaped estimations in a similar manner, which points to a nonrandom role of the latter in C. trachomatis evolution. Although the present results relate to a specific bacterium, we speculate that microbe-specific genomic architectures (such as coding capacity, polymorphism dispersion, and fraction of positively selected loci) may differentially buffer the effect of the confounding factors when estimating recombination and mutation rates and, thus, influence the accuracy of using full-genome sequences for such purpose. This putative bias associated with in silico inferences should be taken into account when discussing the results obtained by the analyses of full-genome sequences, in which the “one size fits all” approach may not be applicable. PMID:22870399

  2. Microsatellite mutation rates in the eastern tiger salamander (Ambystoma tigrinum tigrinum) differ 10-fold across loci.

    PubMed

    Bulut, Zafer; McCormick, Cory R; Gopurenko, David; Williams, Rod N; Bos, David H; DeWoody, J Andrew

    2009-07-01

    Microsatellites are commonly used for mapping and population genetics because of their high heterozygosities and allelic variability (i.e., polymorphism). Microsatellite markers are generally more polymorphic than other types of molecular markers such as allozymes or SNPs because the insertions/deletions that give rise to microsatellite variability are relatively common compared to nucleotide substitutions. Nevertheless, direct evidence of microsatellite mutation rates (MMRs) is lacking in most vertebrate groups despite the importance of such estimates to key population parameters (e.g., genetic differentiation or theta = 4N (e)micro). Herein, we present empirical data on MMRs in eastern tiger salamanders (Ambystoma tigrinum tigrinum). We conducted captive breeding trials and genotyped over 1,000 offspring at a suite of microsatellite loci. These data on 7,906 allele transfers provide the first direct estimates of MMRs in amphibians, and they illustrate that MMRs can vary by more than an order of magnitude across loci within a given species (one locus had ten mutations whereas the others had none).

  3. 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.

  4. Effects of interface mutations on association modes and electron-transfer rates between proteins

    PubMed Central

    Kang, Seong A.; Crane, Brian R.

    2005-01-01

    Although bonding networks determine electron-transfer (ET) rates within proteins, the mechanism by which structure and dynamics influence ET across protein interfaces is not well understood. Measurements of photochemically induced ET and subsequent charge recombination between Zn-porphyrin-substituted cytochrome c peroxidase and cytochrome c in single crystals correlate reactivity with defined structures for different association modes of the redox partners. Structures and ET rates in crystals are consistent with tryptophan oxidation mediating charge recombination reactions. Conservative mutations at the interface can drastically affect how the proteins orient and dispose redox centers. Whereas some configurations are ET inactive, the wild-type complex exhibits the fastest recombination rate. Other association modes generate ET rates that do not correlate with predictions based on cofactor separations or simple bonding pathways. Inhibition of photoinduced ET at <273 K indicates gating by small-amplitude dynamics, even within the crystal. Thus, different associations achieve states of similar reactivity, and within those states conformational fluctuations enable interprotein ET. PMID:16227441

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

    PubMed Central

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

    2015-01-01

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

  6. Male and female differential reproductive rate could explain parental transmission asymmetry of mutation origin in Hirschsprung disease.

    PubMed

    Jannot, Anne-Sophie; Amiel, Jeanne; Pelet, Anna; Lantieri, Francesca; Fernandez, Raquel M; Verheij, Joke B G M; Garcia-Barcelo, Merce; Arnold, Stacey; Ceccherini, Isabella; Borrego, Salud; Hofstra, Robert M W; Tam, Paul K H; Munnich, Arnold; Chakravarti, Aravinda; Clerget-Darpoux, Françoise; Lyonnet, Stanislas

    2012-09-01

    Hirschsprung disease (HSCR, aganglionic megacolon) is a complex and heterogeneous disease with an incidence of 1 in 5000 live births. Despite the multifactorial determination of HSCR in the vast majority of cases, there is a monogenic subgroup for which private rare RET coding sequence mutations with high penetrance are found (45% of HSCR familial cases). An asymmetrical parental origin is observed for RET coding sequence mutations with a higher maternal inheritance. A parent-of-origin effect is usually assumed. Here we show that a differential reproductive rate for males and females also leads to an asymmetrical parental origin, which was never considered as a possible explanation till now. In the case of HSCR, we show a positive association between penetrance of the mutation and parental transmission asymmetry: no parental transmission asymmetry is observed in sporadic RET CDS mutation carrier cases for which penetrance of the mutation is low, whereas a parental transmission asymmetry is observed in affected sib-pairs for which penetrance of the mutation is higher. This allows us to conclude that the explanation for this parental asymmetry is that more severe mutations have resulted in a differential reproductive rate between male and female carriers.

  7. 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

  8. 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.

  9. Exceptionally high and diverse mutation rates in insects small rRNA.

    PubMed

    Feng, Y X; Krupp, G; Gross, J H

    1985-10-01

    The nucleotide sequence of 5S rRNA from the posterior silk gland of the silk worm Philosamia cynthia ricini has been determined. The comparison with other insect 5S rRNAs revealed an exceptionally conserved secondary structure, in spite of an extremely high mutation rate: Thirteen nucleotides are different in Philosamia and Drosophila 5S rRNA, but all substitutions are either compensatory or occur in loops or introduce G:U base pairs. The rates of base substitution per site per year of several insect species (diptera and lepidoptera) 5S and 5.8S rRNAs are compared with those occurring in vertebrate rRNAs. In the latter cases the rates are remarkably constant, whereas their value is not only about twofold higher in insect rRNAs, but is found to be extremely large in the 5S rRNA of the silkworm Bombyx mori. These data demonstrate that phylogenetic conclusions derived from small rRNA sequence comparisons are only of limited value.

  10. 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.

  11. High rate of mutation K103N causing resistance to nevirapine in Indian children with acquired immunodeficiency syndrome.

    PubMed

    Sehgal, S; Pasricha, N; Singh, S

    2008-01-01

    In north India the number of paediatric cases with acquired immunodeficiency syndrome (AIDS) is on the rise. Most drug combinations used for treatment of AIDS incorporate nevirapine, resistance to which develops very fast if given singly or because of unplanned interruptions. This paper investigates presence of mutations at codon 103 and codon 215 of the HIV pol gene causing resistance to nevirapine and zidovudine (AZT) respectively in 25 children with AIDS. Mutations T215Y and K103N were detected by a nested cum amplification refractory mutation system polymerase chain reaction (ARMS PCR) and the results were confirmed by direct sequencing in five randomly selected cases. Nineteen patients had received nevirapine containing regimen and six were drug naive. Mutation K103N was observed in 56% (14/25) of the children while mutation T215Y was found in none. Two of the six drug naïve children also showed K103N mutation. Thus, Indian children drug naïve or treated with nevirapine containing regimens show a high rate of mutation conferring resistance to nevirapine which calls for a judicious use of nevirapine both in antenatal and postnatal setting.

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

    PubMed

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

    2007-10-01

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

  13. 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

  14. 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

  15. 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

  16. piRNA-mediated transposon regulation and the germ-line mutation rate in Drosophila melanogaster males.

    PubMed

    Simmons, Michael J; Peterson, Mark P; Thorp, Michael W; Buschette, Jared T; DiPrima, Stephanie N; Harter, Christine L; Skolnick, Matthew J

    2015-03-01

    Transposons, especially retrotransposons, are abundant in the genome of Drosophila melanogaster. These mobile elements are regulated by small RNAs that interact with the Piwi family of proteins-the piwi-interacting or piRNAs. The Piwi proteins are encoded by the genes argonaute3 (ago3), aubergine (aub), and piwi. Heterochromatin Protein 1 (HP1), a chromatin-organizing protein encoded by the Suppressor of variegation 205 [Su(var)205] gene, also plays a role in this regulation. To assess the mutational impact of weakening the system for transposon regulation, we measured the frequency of recessive X-linked lethal mutations occurring in the germ lines of males from stocks that were heterozygous for mutant alleles of the ago3, aub, piwi, or Su(var)205 genes. These mutant alleles are expected to deplete the wild-type proteins encoded by these genes by as much as 50%. The mutant alleles of piwi and Su(var)205 significantly increased the X-linked lethal mutation frequency, whereas the mutant alleles of ago3 did not. An increased mutation frequency was also observed in males from one of two mutant aub stocks, but this increase may not have been due to the aub mutant. The increased mutation frequency caused by depleting Piwi or HP1suggests that chromatin-organizing proteins play important roles in minimizing the germ-line mutation rate, possibly by stabilizing the structure of the heterochromatin in which many transposons are situated.

  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. The B chromosome polymorphism of the grasshopper Eyprepocnemis plorans in North Africa: III. mutation rate of B chromosomes.

    PubMed

    Bakkali, M; Camacho, J P M

    2004-05-01

    B chromosome variation in nine Moroccan populations of the grasshopper Eyprepocnemis plorans was analysed for 3 consecutive years. In addition to B1, which was the predominant B chromosome in all nine populations, we found 15 other B variants, albeit at very low frequency. Eight variants were found in adults caught in the wild, four appeared in adults reared in the laboratory and seven were found in embryo progeny of controlled crosses between a 0B male and a B-carrying female. Some variants were found in more than one kind of material. At least the seven B variants that appeared in embryo progeny of females carrying a different B type arose de novo through mutation of the maternal B chromosome. The mutation rate of B chromosomes was 0.73%, on average, which explains the high variety of morphs and banding patterns found. The most frequent de novo mutations observed in these chromosomes were centromere misdivision with or without chromatid nondisjunction, which generates iso-B-chromosomes or telocentric Bs, respectively, as well as translocations with A and B chromosomes and deletions. But the whole variation observed, including that found in adult individuals, suggests that other mutations such as duplications, inversions and centric fusions do usually affect B chromosomes. Finally, B chromosome mutation rate was remarkably similar in both Moroccan and Spanish populations, which suggests that it might be dependent on B chromosome intrinsic factors.

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

    PubMed

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

    2002-05-14

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

  20. Simpler way of imposing simplicity constraints

    NASA Astrophysics Data System (ADS)

    Banburski, Andrzej; Chen, Lin-Qing

    2016-11-01

    We investigate a way of imposing simplicity constraints in a holomorphic spin foam model that we recently introduced. Rather than imposing the constraints on the boundary spin network, as is usually done, one can impose the constraints directly on the spin foam propagator. We find that the two approaches have the same leading asymptotic behavior, with differences appearing at higher order. This allows us to obtain a model that greatly simplifies calculations, but still has Regge calculus as its semiclassical limit.

  1. Microsatellite and trinucleotide-repeat evolution: evidence for mutational bias and different rates of evolution in different lineages.

    PubMed Central

    Rubinsztein, D C; Amos, B; Cooper, G

    1999-01-01

    Microsatellites are stretches of repetitive DNA, where individual repeat units comprise one to six bases. These sequences are often highly polymorphic with respect to repeat number and include trinucleotide repeats, which are abnormally expanded in a number of diseases. It has been widely assumed that microsatellite loci are as likely to gain and lose repeats when they mutate. In this review, we present population genetic and empirical data arguing that microsatellites, including normal alleles at trinucleotide-repeat disease loci, are more likely to expand in length when they mutate. In addition, our experiments suggest that the rates of expansion of such sequences differ in related species. PMID:10434312

  2. 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.

  3. Estimation of mutation induction rates in AT-rich sequences using a genome scanning approach after X irradiation of mouse spermatogonia.

    PubMed

    Asakawa, Jun-ichi; Nakamura, Nori; Katayama, Hiroaki; Cullings, Harry M

    2007-08-01

    We have previously used NotI as the marker enzyme (recognizing GCGGCCGC) in a genome scanning approach for detection of mutations induced in mouse spermatogonia and estimated the mutation induction rate as about 0.7 x 10(-5) per locus per Gy. To see whether different parts of the genome have different sensitivities for mutation induction, we used AflII (recognizing CTTAAG) as the marker enzyme in the present study. After the screening of 1,120 spots in each mouse offspring, we found five mutations among 92,655 spots from the unirradiated paternal genome, five mutations among 218,411 spots from the unirradiated maternal genome, and 13 mutations among 92,789 spots from 5 Gy-exposed paternal genome. Among the 23 mutations, 11 involved mouse satellite DNA sequences (AT-rich), and the remaining 12 mutations also involved AT-rich but non-satellite sequences. Both types of sequences were found as multiple, similar-sequence blocks in the genome. Counting each member of cluster mutations separately and excluding results on one hypermutable spot, the spontaneous mutation rates were estimated as 3.2 (+/- 1.9) x 10(-5) and 2.3 (+/- 1.0) x 10(-5) per locus per generation in the male and female genomes, respectively, and the mutation induction rate as 1.1 (+/- 1.2) x 10(-5) per locus per Gy. The induction rate would be reduced to 0.9 x 10(-5) per locus per Gy if satellite sequence mutations were excluded from this analysis. The results indicate that mutation induction rates do not largely differ between GC-rich and AT-rich regions: 1 x 10(-5) per locus per Gy or less, which is close to 1.08 x 10(-5) per locus per Gy, the current estimate for the mean mutation induction rate in mice.

  4. High mutation rate of TPE repeats: a microsatellite in the putative transposase of the hobo element in Drosophila melanogaster.

    PubMed

    Souames, Sémi; Bonnivard, Eric; Bazin, Claude; Higuet, Dominique

    2003-11-01

    The hobo transposable element contains a polymorphic microsatellite sequence located in its coding region, the TPE repeats. Previous surveys of natural populations of Drosophila melanogaster have detected at least seven different hobo transposons. These natural populations are geographically structured with regard to TPE polymorphism, and a scenario has been proposed for the invasion process. Natural populations have recently been completely invaded by hobo elements with three TPE repeats. New elements then appeared by mutation, triggering a new stage of invasion by other elements. Since TPE polymorphism appeared over a short period of time, we focused on estimating the mutation rate of these TPE repeats. We used transgenic lines harboring three TPE and/or five TPE hobo elements that had been evolving for at least 16 generations to search for a new TPE repeat polymorphism. We detected three mutants, with four, seven, and eight TPE repeats, respectively. The estimated mutation rate of the TPE repeats is therefore higher than that of neutral microsatellites in D. melanogaster (4.2 x 10-4 versus 6.5 x 10-6). The role of the transposition mechanism and the particular structure of the TPE repeats of the hobo element in this increase in the mutation rate are discussed.

  5. The effects of Atm haploinsufficiency on mutation rate in the mouse germ line and somatic tissue.

    PubMed

    Ahuja, Akshay K; Barber, Ruth C; Hardwick, Robert J; Weil, Michael M; Genik, Paula C; Brenner, David J; Dubrova, Yuri E

    2008-09-01

    Using single-molecule polymerase chain reaction, the frequency of spontaneous and radiation-induced mutation at an expanded simple tandem repeat (ESTR) locus was studied in DNA samples extracted from sperm and bone marrow of Atm knockout (Atm(+/-)) heterozygous male mice. The frequency of spontaneous mutation in sperm and bone marrow in Atm(+/-) males did not significantly differ from that in wild-type BALB/c mice. Acute exposure to 1 Gy of gamma-rays did not affect ESTR mutation frequency in bone marrow and resulted in similar increases in sperm samples taken from Atm(+/-) and BALB/c males. Taken together, these results suggest that the Atm haploinsufficiency analysed in our study does not affect spontaneous and radiation-induced ESTR mutation frequency in mice.

  6. 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

  7. Evolution of Pseudomonas aeruginosa Antimicrobial Resistance and Fitness under Low and High Mutation Rates

    PubMed Central

    Cabot, Gabriel; Zamorano, Laura; Moyà, Bartolomé; Juan, Carlos; Navas, Alfonso; Blázquez, Jesús

    2015-01-01

    Pseudomonas aeruginosa, a major cause of nosocomial and chronic infections, is considered a paradigm of antimicrobial resistance development. However, the evolutionary trajectories of antimicrobial resistance and the impact of mutator phenotypes remain mostly unexplored. Therefore, whole-genome sequencing (WGS) was performed in lineages of wild-type and mutator (ΔmutS) strains exposed to increasing concentrations of relevant antipseudomonal agents. WGS provided a privileged perspective of the dramatic effect of mutator phenotypes on the accumulation of random mutations, most of which were transitions, as expected. Moreover, a frameshift mutagenic signature, consistent with error-prone DNA polymerase activity as a consequence of SOS system induction, was also seen. This effect was evidenced for all antibiotics tested, but it was higher for fluoroquinolones than for cephalosporins or carbapenems. Analysis of genotype versus phenotype confirmed expected resistance evolution trajectories but also revealed new pathways. Classical mechanisms included multiple mutations leading to AmpC overexpression (ceftazidime), quinolone resistance-determining region (QRDR) mutations (ciprofloxacin), oprD inactivation (meropenem), and efflux pump overexpression (ciprofloxacin and meropenem). Groundbreaking findings included gain-of-function mutations leading to the structural modification of AmpC (ceftazidime), novel DNA gyrase (GyrA) modification (ciprofloxacin), and the alteration of the β-lactam binding site of penicillin-binding protein 3 (PBP3) (meropenem). A further striking finding was seen in the evolution of meropenem resistance, selecting for specific extremely large (>250 kb) genomic deletions providing a growth advantage in the presence of the antibiotic. Finally, fitness and virulence varied within and across evolved antibiotic-resistant populations, but mutator lineages showed a lower biological cost for some antibiotics. PMID:26729493

  8. Evolution of Pseudomonas aeruginosa Antimicrobial Resistance and Fitness under Low and High Mutation Rates.

    PubMed

    Cabot, Gabriel; Zamorano, Laura; Moyà, Bartolomé; Juan, Carlos; Navas, Alfonso; Blázquez, Jesús; Oliver, Antonio

    2016-01-04

    Pseudomonas aeruginosa, a major cause of nosocomial and chronic infections, is considered a paradigm of antimicrobial resistance development. However, the evolutionary trajectories of antimicrobial resistance and the impact of mutator phenotypes remain mostly unexplored. Therefore, whole-genome sequencing (WGS) was performed in lineages of wild-type and mutator (ΔmutS) strains exposed to increasing concentrations of relevant antipseudomonal agents. WGS provided a privileged perspective of the dramatic effect of mutator phenotypes on the accumulation of random mutations, most of which were transitions, as expected. Moreover, a frameshift mutagenic signature, consistent with error-prone DNA polymerase activity as a consequence of SOS system induction, was also seen. This effect was evidenced for all antibiotics tested, but it was higher for fluoroquinolones than for cephalosporins or carbapenems. Analysis of genotype versus phenotype confirmed expected resistance evolution trajectories but also revealed new pathways. Classical mechanisms included multiple mutations leading to AmpC overexpression (ceftazidime), quinolone resistance-determining region (QRDR) mutations (ciprofloxacin), oprD inactivation (meropenem), and efflux pump overexpression (ciprofloxacin and meropenem). Groundbreaking findings included gain-of-function mutations leading to the structural modification of AmpC (ceftazidime), novel DNA gyrase (GyrA) modification (ciprofloxacin), and the alteration of the β-lactam binding site of penicillin-binding protein 3 (PBP3) (meropenem). A further striking finding was seen in the evolution of meropenem resistance, selecting for specific extremely large (>250 kb) genomic deletions providing a growth advantage in the presence of the antibiotic. Finally, fitness and virulence varied within and across evolved antibiotic-resistant populations, but mutator lineages showed a lower biological cost for some antibiotics.

  9. mirDNMR: a gene-centered database of background de novo mutation rates in human

    PubMed Central

    Jiang, Yi; Li, Zhongshan; Liu, Zhenwei; Chen, Denghui; Wu, Wanying; Du, Yaoqiang; Ji, Liying; Jin, Zi-Bing; Li, Wei; Wu, Jinyu

    2017-01-01

    De novo germline mutations (DNMs) are the rarest genetic variants proven to cause a considerable number of sporadic genetic diseases, such as autism spectrum disorders, epileptic encephalopathy, schizophrenia, congenital heart disease, type 1 diabetes, and hearing loss. However, it is difficult to accurately assess the cause of DNMs and identify disease-causing genes from the considerable number of DNMs in probands. A common method to this problem is to identify genes that harbor significantly more DNMs than expected by chance, with accurate background DNM rate (DNMR) required. Therefore, in this study, we developed a novel database named mirDNMR for the collection of gene-centered background DNMRs obtained from different methods and population variation data. The database has the following functions: (i) browse and search the background DNMRs of each gene predicted by four different methods, including GC content (DNMR-GC), sequence context (DNMR-SC), multiple factors (DNMR-MF) and local DNA methylation level (DNMR-DM); (ii) search variant frequencies in publicly available databases, including ExAC, ESP6500, UK10K, 1000G and dbSNP and (iii) investigate the DNM burden to prioritize candidate genes based on the four background DNMRs using three statistical methods (TADA, Binomial and Poisson test). As a case study, we successfully employed our database in candidate gene prioritization for a sporadic complex disease: intellectual disability. In conclusion, mirDNMR (https://www.wzgenomics.cn/mirdnmr/) can be widely used to identify the genetic basis of sporadic genetic diseases. PMID:27799474

  10. 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.

  11. 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.

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

    PubMed

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

    2015-05-01

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

  13. Error-prone DnaE2 Balances the Genome Mutation Rates in Myxococcus xanthus DK1622.

    PubMed

    Peng, Ran; Chen, Jiang-He; Feng, Wan-Wan; Zhang, Zheng; Yin, Jun; Li, Ze-Shuo; Li, Yue-Zhong

    2017-01-01

    dnaE is an alpha subunit of the tripartite protein complex of DNA polymerase III that is responsible for the replication of bacterial genome. The dnaE gene is often duplicated in many bacteria, and the duplicated dnaE gene was reported dispensable for cell survivals and error-prone in DNA replication in a mystery. In this study, we found that all sequenced myxobacterial genomes possessed two dnaE genes. The duplicate dnaE genes were both highly conserved but evolved divergently, suggesting their importance in myxobacteria. Using Myxococcus xanthus DK1622 as a model, we confirmed that dnaE1 (MXAN_5844) was essential for cell survival, while dnaE2 (MXAN_3982) was dispensable and encoded an error-prone enzyme for replication. The deletion of dnaE2 had small effects on cellular growth and social motility, but significantly decreased the development and sporulation abilities, which could be recovered by the complementation of dnaE2. The expression of dnaE1 was always greatly higher than that of dnaE2 in either the growth or developmental stage. However, overexpression of dnaE2 could not make dnaE1 deletable, probably due to their protein structural and functional divergences. The dnaE2 overexpression not only improved the growth, development and sporulation abilities, but also raised the genome mutation rate of M. xanthus. We argued that the low-expressed error-prone DnaE2 played as a balancer for the genome mutation rates, ensuring low mutation rates for cell adaptation in new environments but avoiding damages from high mutation rates to cells.

  14. Error-prone DnaE2 Balances the Genome Mutation Rates in Myxococcus xanthus DK1622

    PubMed Central

    Peng, Ran; Chen, Jiang-he; Feng, Wan-wan; Zhang, Zheng; Yin, Jun; Li, Ze-shuo; Li, Yue-zhong

    2017-01-01

    dnaE is an alpha subunit of the tripartite protein complex of DNA polymerase III that is responsible for the replication of bacterial genome. The dnaE gene is often duplicated in many bacteria, and the duplicated dnaE gene was reported dispensable for cell survivals and error-prone in DNA replication in a mystery. In this study, we found that all sequenced myxobacterial genomes possessed two dnaE genes. The duplicate dnaE genes were both highly conserved but evolved divergently, suggesting their importance in myxobacteria. Using Myxococcus xanthus DK1622 as a model, we confirmed that dnaE1 (MXAN_5844) was essential for cell survival, while dnaE2 (MXAN_3982) was dispensable and encoded an error-prone enzyme for replication. The deletion of dnaE2 had small effects on cellular growth and social motility, but significantly decreased the development and sporulation abilities, which could be recovered by the complementation of dnaE2. The expression of dnaE1 was always greatly higher than that of dnaE2 in either the growth or developmental stage. However, overexpression of dnaE2 could not make dnaE1 deletable, probably due to their protein structural and functional divergences. The dnaE2 overexpression not only improved the growth, development and sporulation abilities, but also raised the genome mutation rate of M. xanthus. We argued that the low-expressed error-prone DnaE2 played as a balancer for the genome mutation rates, ensuring low mutation rates for cell adaptation in new environments but avoiding damages from high mutation rates to cells. PMID:28203231

  15. 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

    2009-04-22

    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.

  16. Studies of human mutation rates. Progress report, November 1992--October 1993

    SciTech Connect

    Neel, J.V.; Hanash, S.M.

    1993-10-27

    The progress during 1992--1993 with respect to ER 60533 is summarized in this report under three headings: The development of two-dimensional DNA gels for the detection of mutation, the mitochondrial DNA of American Indians, and molecular verification of a suggested polyogeny for the eight most common phospheglucomutose-1 (POM1)alleles.

  17. The Roles of Mutation, Selection, and Expression in Determining Relative Rates of Evolution in Mitochondrial versus Nuclear Genomes.

    PubMed

    Havird, Justin C; Sloan, Daniel B

    2016-12-01

    Eukaryotes rely on proteins encoded by the nuclear and mitochondrial (mt) genomes, which interact within multisubunit complexes such as oxidative-phosphorylation enzymes. Although selection is thought to be less efficient on the asexual mt genome, in bilaterian animals the ratio of nonsynonymous to synonymous substitutions (ω) is lower in mt- compared with nuclear-encoded OXPHOS subunits, suggesting stronger effects of purifying selection in the mt genome. Because high levels of gene expression constrain protein sequence evolution, one proposed resolution to this paradox is that mt genes are expressed more highly than nuclear genes. To test this hypothesis, we investigated expression and sequence evolution of mt and nuclear genes from 84 diverse eukaryotes that vary in mt gene content and mutation rate. We found that the relationship between mt and nuclear ω values varied dramatically across eukaryotes. In contrast, transcript abundance is consistently higher for mt genes than nuclear genes, regardless of which genes happen to be in the mt genome. Consequently, expression levels cannot be responsible for the differences in ω Rather, 84% of the variance in the ratio of ω values between mt and nuclear genes could be explained by differences in mutation rate between the two genomes. We relate these findings to the hypothesis that high rates of mt mutation select for compensatory changes in the nuclear genome. We also propose an explanation for why mt transcripts consistently outnumber their nuclear counterparts, with implications for mitonuclear protein imbalance and aging.

  18. 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

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

    PubMed Central

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

    2013-01-01

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

  20. Mutations Affecting Starch Synthase III in Arabidopsis Alter Leaf Starch Structure and Increase the Rate of Starch Synthesis1

    PubMed Central

    Zhang, Xiaoli; Myers, Alan M.; James, Martha G.

    2005-01-01

    The role of starch synthase (SS) III (SSIII) in the synthesis of transient starch in Arabidopsis (Arabidopsis thaliana) was investigated by characterizing the effects of two insertion mutations at the AtSS3 gene locus. Both mutations, termed Atss3-1 and Atss3-2, condition complete loss of SSIII activity and prevent normal gene expression at both the mRNA and protein levels. The mutations cause a starch excess phenotype in leaves during the light period of the growth cycle due to an apparent increase in the rate of starch synthesis. In addition, both mutations alter the physical structure of leaf starch. Significant increases were noted in the mutants in the frequency of linear chains in amylopectin with a degree of polymerization greater than approximately 60, and relatively small changes were observed in chains of degree of polymerization 4 to 50. Furthermore, starch in the Atss3-1 and Atss3-2 mutants has a higher phosphate content, approximately two times that of wild-type leaf starch. Total SS activity is increased in both Atss3 mutants and a specific SS activity appears to be up-regulated. The data indicate that, in addition to its expected direct role in starch assembly, SSIII also has a negative regulatory function in the biosynthesis of transient starch in Arabidopsis. PMID:15908598

  1. Functionally important regions of the factor IX gene have a low rate of polymorphism and a high rate of mutation in the dinucleotide CpG.

    PubMed Central

    Koeberl, D D; Bottema, C D; Buerstedde, J M; Sommer, S S

    1989-01-01

    We have recently described genomic amplification with transcript sequencing (GAWTS), a three-step procedure that allows direct genomic sequencing. By GAWTS more than 100,000 bp of sequence have been generated from eight regions of the factor IX gene, which include the putative promoter region, the coding region, and the splice junctions. All eight regions were examined in 20 unrelated normal individuals of defined ethnicity and subsequently in 22 hemophiliacs in different families. The following three major conclusions emerge: (1) The rate of polymorphism in these eight regions of functional significance has been measured in an X-linked gene, and it is about one-third of the average rate observed for intronic and intergenic sequences on the X chromosome. The rate is low enough that the causative mutation should be the only sequence change seen in the overwhelming majority of hemophiliacs. (2) Transitions of CpG account for 31% (5/16) of the distinct mutations and for 38% (5/13) of the single-base changes. The rate of transitions at CpG is elevated by an estimated 77-fold, presumably owing to lack of repair of thymidine generated by the spontaneous deamination of 5-methylcytidine. (3) High-quality, reproducible sequence data can be obtained on a time scale that makes direct carrier testing and prenatal diagnosis feasible. Images Figure 3 PMID:2773937

  2. Quantification of in vivo progenitor mutation accrual with ultra-low error rate and minimal input DNA using SIP-HAVA-seq.

    PubMed

    Taylor, Pete H; Cinquin, Amanda; Cinquin, Olivier

    2016-11-01

    Assaying in vivo accrual of DNA damage and DNA mutations by stem cells and pinpointing sources of damage and mutations would further our understanding of aging and carcinogenesis. Two main hurdles must be overcome. First, in vivo mutation rates are orders of magnitude lower than raw sequencing error rates. Second, stem cells are vastly outnumbered by differentiated cells, which have a higher mutation rate-quantification of stem cell DNA damage and DNA mutations is thus best performed from small, well-defined cell populations. Here we report a mutation detection technique, based on the "duplex sequencing" principle, with an error rate below ∼10(-10) and that can start from as little as 50 pg DNA. We validate this technique, which we call SIP-HAVA-seq, by characterizing Caenorhabditis elegans germline stem cell mutation accrual and asking how mating affects that accrual. We find that a moderate mating-induced increase in cell cycling correlates with a dramatic increase in accrual of mutations. Intriguingly, these mutations consist chiefly of deletions in nonexpressed genes. This contrasts with results derived from mutation accumulation lines and suggests that mutation spectrum and genome distribution change with replicative age, chronological age, cell differentiation state, and/or overall worm physiological state. We also identify single-stranded gaps as plausible deletion precursors, providing a starting point to identify the molecular mechanisms of mutagenesis that are most active. SIP-HAVA-seq provides the first direct, genome-wide measurements of in vivo mutation accrual in stem cells and will enable further characterization of underlying mechanisms and their dependence on age and cell state.

  3. High mutation rates explain low population genetic divergence at copy-number-variable loci in Homo sapiens

    PubMed Central

    Hu, Xin-Sheng; Yeh, Francis C.; Hu, Yang; Deng, Li-Ting; Ennos, Richard A.; Chen, Xiaoyang

    2017-01-01

    Copy-number-variable (CNV) loci differ from single nucleotide polymorphic (SNP) sites in size, mutation rate, and mechanisms of maintenance in natural populations. It is therefore hypothesized that population genetic divergence at CNV loci will differ from that found at SNP sites. Here, we test this hypothesis by analysing 856 CNV loci from the genomes of 1184 healthy individuals from 11 HapMap populations with a wide range of ancestry. The results show that population genetic divergence at the CNV loci is generally more than three times lower than at genome-wide SNP sites. Populations generally exhibit very small genetic divergence (Gst = 0.05 ± 0.049). The smallest divergence is among African populations (Gst = 0.0081 ± 0.0025), with increased divergence among non-African populations (Gst = 0.0217 ± 0.0109) and then among African and non-African populations (Gst = 0.0324 ± 0.0064). Genetic diversity is high in African populations (~0.13), low in Asian populations (~0.11), and intermediate in the remaining 11 populations. Few significant linkage disequilibria (LDs) occur between the genome-wide CNV loci. Patterns of gametic and zygotic LDs indicate the absence of epistasis among CNV loci. Mutation rate is about twice as large as the migration rate in the non-African populations, suggesting that the high mutation rates play dominant roles in producing the low population genetic divergence at CNV loci. PMID:28225073

  4. Comparison of Detection Rate and Mutational Pattern of Drug-Resistant Mutations Between a Large Cohort of Genotype B and Genotype C Hepatitis B Virus-Infected Patients in North China.

    PubMed

    Li, Xiaodong; Liu, Yan; Xin, Shaojie; Ji, Dong; You, Shaoli; Hu, Jinhua; Zhao, Jun; Wu, Jingjing; Liao, Hao; Zhang, Xin-Xin; Xu, Dongping

    2016-10-28

    The study aimed to investigate the association of prevalent genotypes in China (HBV/C and HBV/B) with HBV drug-resistant mutations. A total of 13,847 nucleos(t)ide analogue (NA)-treated patients with chronic HBV infection from North China were enrolled. HBV genotypes and resistant mutations were determined by direct sequencing and confirmed by clonal sequencing if necessary. HBV/B, HBV/C, and HBV/D occupied 14.3%, 84.9%, and 0.8% across the study population, respectively. NA usage had no significant difference between HBV/B- and HBV/C-infected patients. Lamivudine-resistant mutations were more frequently detected in HBV/C-infected patients, compared with HBV/B-infected patients (31.67% vs. 25.26%, p < 0.01). Adefovir- and entecavir-resistant mutation detection rates were similar, but the mutational pattern was different between the two genotypes. For adefovir-resistant mutations, HBV/C-infected patients had a higher detection rate of rtA181 V (HBV/C 5.29% vs. HBV/B 1.36%, p < 0.01) and a lower detection rate of rtN236T (2.70% vs. 6.54%, p < 0.01). For entecavir-resistant mutations, HBV/C-infected patients had a higher detection rate of rtM204 V/I+T184 substitution or S202G/C (3.66% vs. 2.16%, p < 0.01) and a lower detection rate of rtM204 V/I+M250 V/I/L substitution (0.67% vs. 1.46%, p < 0.01). Multidrug-resistant mutations (defined as coexistence of mutation to nucleoside and nucleotide analogues) were detected in 104 patients. HBV/C-infected patients had a higher detection rate of multidrug-resistant mutation than HBV/B-infected patients (0.83% vs. 0.35%, p < 0.05). The study for the first time clarified that HBV/C-infected patients had a higher risk to develop multidrug-resistant mutations, compared with HBV/B-infected patients; and HBV/C- and HBV/B-infected patients had different inclinations in the ETV-resistant mutational pattern.

  5. Influence of anatomical subsite on the incidence of microsatellite instability, and KRAS and BRAF mutation rates in patients with colon carcinoma.

    PubMed

    Benedix, Frank; Meyer, Frank; Kube, Rainer; Kropf, Siegfried; Kuester, Doerthe; Lippert, Hans; Roessner, Albert; Krüger, Sabine

    2012-10-15

    There is a growing amount of data supporting the concept that cancers originating from the proximal and distal colon are distinct clinicopathological entities. The incidence of MSI and BRAF mutation is strongly associated with right sided tumor location, whereas there are conflicting results for KRAS mutation rates. However, to date, no data exist whether and to what extent defined colonic subsites influence MSI status, KRAS and BRAF mutation rates. We selected primary colon cancer from 171 patients operated on at our institution between 2007 and 2010. BRAF, KRAS mutation rates and microsatellite instability were determined and correlated with clinicopathological features and tumor location. MSI-h cancers were significantly associated with poor histological grade but a lower rate of distant metastases. KRAS-mutated tumors were linked to lower T-stage and better differentiation. Colon carcinomas with BRAF mutation were significantly associated with distant metastatic spread and poor histological grade. Furthermore, we found that MSI-h status, KRAS and BRAF mutation rates varied remarkably among the colonic subsites irrespective of right- and left-sided origin, respectively. The results of the current study provide further evidence that a simple classification into right- and left-sided colon carcinoma does not represent the complexity of this tumor entity.

  6. 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.

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

    PubMed Central

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

    2013-01-01

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

  8. Increased rate of missense/in-frame mutations in individuals with NF1-related pulmonary stenosis: a novel genotype-phenotype correlation.

    PubMed

    Ben-Shachar, Shay; Constantini, Shlomi; Hallevi, Hen; Sach, Emma K; Upadhyaya, Meena; Evans, Gareth D; Huson, Susan M

    2013-05-01

    Neurofibromatosis type 1 (NF1) and its related disorders (NF1-Noonan syndrome (NFNS) and Watson syndrome (WS)) are caused by heterozygous mutations in the NF1 gene. Pulmonary stenosis (PS) occurs more commonly in NF1 and its related disorders than in the general population. This study investigated whether PS is associated with specific types of NF1 gene mutations in NF1, NFNS and WS. The frequency of different NF1 mutation types in a cohort of published and unpublished cases with NF1/NFNS/WS and PS was examined. Compared with NF1 in general, NFNS patients had higher rates of PS (9/35=26% vs 25/2322=1.1%, P value<0.001). Stratification according to mutation type showed that the increased PS rate appears to be driven by the NFNS group with non-truncating mutations. Eight of twelve (66.7%) NFNS cases with non-truncating mutations had PS compared with a 1.1% PS frequency in NF1 in general (P<0.001); there was no increase in the frequency of PS in NFNS patients with truncating mutations. Eight out of eleven (73%) individuals with NF1 and PS, were found to have non-truncating mutations, a much higher frequency than the 19% reported in NF1 cohorts (P<0.015). Only three cases of WS have been published with intragenic mutations, two of three had non-truncating mutations. Therefore, PS in NF1 and its related disorders is clearly associated with non-truncating mutations in the NF1 gene providing a new genotype-phenotype correlation. The data indicate a specific role of non-truncating mutations on the NF1 cardiac phenotype.

  9. Comparison of southern Chinese Han and Brazilian Caucasian mutation rates at autosomal short tandem repeat loci used in human forensic genetics.

    PubMed

    Sun, Hongyu; Liu, Sujuan; Zhang, Yinming; Whittle, Martin R

    2014-01-01

    The short tandem repeat (STR) loci used in human genetic studies are characterized by having relatively high mutation rates. In particular, to ensure an appropriate evaluation of genetic evidence in parentage and forensic analyses, it is essential to have accurate estimates of the mutation rates associated with the commonly used autosomal and sex chromosome STR loci. Differences in STR mutation rates between different ethnic groups should also be determined. Mutation data from two laboratories working with different ethnic groups were extracted from many meiotic transmissions ascertained for 15 autosomal STR loci currently used in forensic routine. Forty-five thousand and eighty-five trios were checked for the biological consistency of maternity and paternity through the analysis of a minimum of 15 loci. Mutations were scored as paternal, maternal, or ambiguous according to the most parsimonious explanation for the inconsistency, using always the least requiring hypothesis in terms of number of repeat differences. The main findings are: (a) the overall mutation rate across the 15 loci was 9.78 × 10(-4) per gamete per generation (95% CI = 9.30 × 10(-4)-1.03 × 10(-3)), and with just 48 (out of 1,587) exceptions, all of the mutations were single-step; (b) repeat gains were more frequent than losses; (c) longer alleles were found to be more mutable; and (d) the mutation rates differ at some loci between the two ethnic groups. Large worldwide meiotic transmission datasets are still needed to measure allele-specific mutation rates at the STR loci consensually used in forensic genetics.

  10. 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

  11. Do variations in substitution rates and male mutation bias correlate with life-history traits? A study of 32 mammalian genomes.

    PubMed

    Wilson Sayres, Melissa A; Venditti, Chris; Pagel, Mark; Makova, Kateryna D

    2011-10-01

    Life-history traits vary substantially across species, and have been demonstrated to affect substitution rates. We compute genome-wide, branch-specific estimates of male mutation bias (the ratio of male-to-female mutation rates) across 32 mammalian genomes and study how these vary with life-history traits (generation time, metabolic rate, and sperm competition). We also investigate the influence of life-history traits on substitution rates at unconstrained sites across a wide phylogenetic range. We observe that increased generation time is the strongest predictor of variation in both substitution rates (for which it is a negative predictor) and male mutation bias (for which it is a positive predictor). Although less significant, we also observe that estimates of metabolic rate, reflecting replication-independent DNA damage and repair mechanisms, correlate negatively with autosomal substitution rates, and positively with male mutation bias. Finally, in contrast to expectations, we find no significant correlation between sperm competition and either autosomal substitution rates or male mutation bias. Our results support the important but frequently opposite effects of some, but not all, life-history traits on substitution rates.

  12. Mutations causing hemophilia B: direct estimate of the underlying rates of spontaneous germ-line transitions, transversions, and deletions in a human gene.

    PubMed Central

    Koeberl, D D; Bottema, C D; Ketterling, R P; Bridge, P J; Lillicrap, D P; Sommer, S S

    1990-01-01

    Spontaneous mutation provides the substrate for evolution on one hand and for genetic susceptibility to disease on the other hand. X-linked diseases such as hemophilia B offer an opportunity to examine recent germ-line mutations in humans. By utilizing the direct sequencing method of genomic amplification with transcript sequencing, eight regions (2.46 kb) of likely functional significance in the factor IX gene have been sequenced in a total of 60 consecutive, unrelated hemophiliacs. The high frequency of patient ascertainment from three regions in the midwestern United States and Canada suggests that the sample is representative of hemophiliacs of northern European descent. Twenty-six of the delineated mutations are reported herein, and the group of 60 is analyzed as a whole. From the pattern of mutations causing disease and from a knowledge of evolutionarily conserved amino acids, it is possible to reconstruct the underlying pattern of mutation and to calculate the mutation rates per base pair per generation for transitions (27 x 10(-10)), transversions (4.1 x 10(-10), and deletions (0.9 x 10(-10)) for a total mutation rate of 32 x 10(-10). The proportion of transitions at non-CpG nucleotides is elevated sevenfold over that expected if one base substitution were as likely as another. At the dinucleotide CpG, transitions are elevated 24-fold relative to transitions at other sites. The pattern of spontaneous mutations in factor IX resembles that observed in Escherichia coli when the data are corrected for ascertainment bias. The aggregate data hint that most mutations may be due to endogenous processes. The following additional conclusions emerge from the data: (1) Although in recent decades reproductive fitness in individuals with mild and moderate hemophilia has been approximately normal, the large number of different mutations found strongly suggest that these levels of disease substantially compromised reproduction in previous centuries. (2) Mutations which

  13. The frequency and mutation rate of balanced autosomal rearrangements in man estimated from prenatal genetic studies for advanced maternal age.

    PubMed Central

    Van Dyke, D L; Weiss, L; Roberson, J R; Babu, V R

    1983-01-01

    The frequencies of balanced chromosome rearrangements were estimated from three series of advanced maternal-age prenatal genetic studies, and were compared to the frequencies that had been estimated from consecutive newborn surveys. In the maternal-age prenatal studies, the frequencies were: Robertsonian translocations, 0.11%; reciprocal translocations, 0.17%; and inversions, 0.12%. The total frequency of balanced rearrangements in the prenatal genetic studies performed with banding (0.40%, or 1 in 250) was twice that in the consecutive newborn surveys performed without banding (0.19%, or 1 in 526). The difference was limited to inversions and reciprocal translocations; the frequency of Robertsonian translocations was similar in the prenatal series and the newborn surveys. Both familial and de novo rearrangements were more common than anticipated. The de novo cases provided a mutation rate estimate of 4.3 per 10,000 gametes per generation (compared with 1.78 to 2.2 per 10,000 gametes in other surveys). These higher estimates may more reliably approximate the true mutation rate and frequencies of balanced rearrangements in the newborn population than do the newborn surveys. PMID:6837576

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

    NASA Astrophysics Data System (ADS)

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

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

  15. Using molecular markers with high mutation rates to obtain estimates of relative population size and to distinguish the effects of gene flow and mutation: a demonstration using data from endemic Mauritian skinks.

    PubMed

    Nichols, R A; Freeman, K L M

    2004-04-01

    We propose a method of analysing genetic data to obtain separate estimates of the size (N(p)) and migration rate (m(p)) for the sampled populations, without precise prior knowledge of mutation rates at each locus ( micro(L)). The effects of migration and mutation can be distinguished because high migration has the effect of reducing genetic differentiation across all loci, whereas a high mutation rate will only affect the locus in question. The method also takes account of any differences between the spectra of immigrant alleles and of new mutant alleles. If the genetic data come from a range of population sizes, and the loci have a range of mutation rates, it is possible to estimate the relative sizes of the different N(p) values, and likewise the m(p) and the micro(L). Microsatellite loci may also be particularly appropriate because loci with a high mutation rate can reach mutation-drift-migration equilibrium more quickly, and because the spectra of mutants arriving in a population can be particularly distinct from the immigrants. We demonstrate this principle using a microsatellite data set from Mauritian skinks. The method identifies low gene flow between a putative new species and populations of its sister species, whereas the differentiation of two other populations is attributed to small population size. These distinct interpretations were not readily apparent from conventional measures of genetic differentiation and gene diversity. When the method is evaluated using simulated data sets, it correctly distinguishes low gene flow from small population size. Loci that are not at mutation-migration-drift equilibrium can distort the parameter estimates slightly. We discuss strategies for detecting and overcoming this effect.

  16. Running on empty: does mitochondrial DNA mutation limit replicative lifespan in yeast?: Mutations that increase the division rate of cells lacking mitochondrial DNA also extend replicative lifespan in Saccharomyces cerevisiae.

    PubMed

    Dunn, Cory D

    2011-10-01

    Mitochondrial DNA (mtDNA) mutations escalate with increasing age in higher organisms. However, it has so far been difficult to experimentally determine whether mtDNA mutation merely correlates with age or directly limits lifespan. A recent study shows that budding yeast can also lose functional mtDNA late in life. Interestingly, independent studies of replicative lifespan (RLS) and of mtDNA-deficient cells show that the same mutations can increase both RLS and the division rate of yeast lacking the mitochondrial genome. These exciting, parallel findings imply a potential causal relationship between mtDNA mutation and replicative senescence. Furthermore, these results suggest more efficient methods for discovering genes that determine lifespan.

  17. Genome-Wide Single-Cell Analysis of Recombination Activity and de novo Mutation Rates in Human Sperm

    PubMed Central

    Wang, Jianbin; Fan, H. Christina; Behr, Barry; Quake, Stephen R.

    2012-01-01

    SUMMARY Meiotic recombination and de novo mutation are the two main contributions towards gamete genome diversity, and many questions remain about how an individual human’s genome is edited by these two processes. Here, we describe a high-throughput method for single-cell whole-genome analysis which was used to measure the genomic diversity in one individual’s gamete genomes. A microfluidic system was used for highly parallel sample processing and to minimize non-specific amplification. High-density genotyping results from 91 single cells were used to create a personal recombination map, which was consistent with population-wide data at low resolution but revealed significant differences from pedigree data at higher resolution. We used the data to test for meiotic drive and found evidence for gene conversion. High throughput sequencing on 31 single cells was used to measure the frequency of large-scale genome instability, and deeper sequencing of eight single cells revealed de novo mutation rates with distinct characteristics. PMID:22817899

  18. Mutation and the environment

    SciTech Connect

    Mendelsohn, M.L. ); Albertini, R.J. )

    1990-01-01

    This book is covered under the following topics: Somatic Mutation: Animal Model; Somatic Mutation: Human; Heritable Mutation: Animal Model; Heritable Mutation: Approaches to Human Induction Rates; Heritable Mutation: Human Risk; Epidemiology: Population Studies on Genotoxicity; and Epidemiology: Workplace Studies of Genotoxicity.

  19. 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

  20. 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

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

    PubMed

    Paz-Y-Miño C, Guillermo; Espinosa, Avelina; Bai, Chunyan Y

    2011-09-01

    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 "edition" and gene duplications to generate the 6

  2. TP53 mutations are associated with higher rates of pathologic complete response to anthracycline/cyclophosphamide-based neoadjuvant chemotherapy in operable primary breast cancer.

    PubMed

    Wang, Yuxia; Xu, Ye; Chen, Jiuan; Ouyang, Tao; Li, Jinfeng; Wang, Tianfeng; Fan, Zhaoqing; Fan, Tie; Lin, Benyao; Xie, Yuntao

    2016-01-15

    The role of TP53 mutations in predicting response to neoadjuvant chemotherapy in breast cancer remains controversial. The aims of this study were to investigate whether TP53 mutations were associated with response and survival in breast cancer patients who received neoadjuvant chemotherapy. Therefore, we identified TP53 mutations in the core-needle biopsy tumor samples obtained before the neoadjuvant chemotherapy from 351 operable primary breast cancer patients who either received anthracycline/cyclophosphamide-based (n = 252) or paclitaxel (n = 99) neoadjuvant chemotherapy. We found that 41.0% (144 of 351) of patients harbored TP53 mutations, and 14.8% of patients achieved a pCR (pathologic complete response) after neoadjuvant chemotherapy. Among patients treated with anthracycline/cyclophosphamide (n = 252), patients with TP53 mutations had a significantly higher pCR rate than those with wild-type (28.6 vs.7.1%; p < 0.001), and TP53 mutation was an independent favorable predictor of pCR [odds ratio (OR) = 3.41; 95% confidence interval (CI) 1.50-7.77; p = 0.003] in this group; moreover, patients with TP53 mutation had a better distant recurrence-free survival (DRFS) than those with wild-type [unadjusted hazard ratio (HR) = 0.43; 95% CI 0.20-0.94; p = 0.030] in this group. Among patients treated with paclitaxel (n = 99), no significant difference in pCR rates was observed between patients with or without TP53 mutations (15.2 vs. 11.3%; p = 0.57). Our results suggested that patients with TP53 mutations are more likely to respond to anthracycline/ cyclophosphamide-based neoadjuvant chemotherapy and have a favorable survival.

  3. Essentiality Is a Strong Determinant of Protein Rates of Evolution during Mutation Accumulation Experiments in Escherichia coli.

    PubMed

    Alvarez-Ponce, David; Sabater-Muñoz, Beatriz; Toft, Christina; Ruiz-González, Mario X; Fares, Mario A

    2016-09-26

    The Neutral Theory of Molecular Evolution is considered the most powerful theory to understand the evolutionary behavior of proteins. One of the main predictions of this theory is that essential proteins should evolve slower than dispensable ones owing to increased selective constraints. Comparison of genomes of different species, however, has revealed only small differences between the rates of evolution of essential and nonessential proteins. In some analyses, these differences vanish once confounding factors are controlled for, whereas in other cases essentiality seems to have an independent, albeit small, effect. It has been argued that comparing relatively distant genomes may entail a number of limitations. For instance, many of the genes that are dispensable in controlled lab conditions may be essential in some of the conditions faced in nature. Moreover, essentiality can change during evolution, and rates of protein evolution are simultaneously shaped by a variety of factors, whose individual effects are difficult to isolate. Here, we conducted two parallel mutation accumulation experiments in Escherichia coli, during 5,500-5,750 generations, and compared the genomes at different points of the experiments. Our approach (a short-term experiment, under highly controlled conditions) enabled us to overcome many of the limitations of previous studies. We observed that essential proteins evolved substantially slower than nonessential ones during our experiments. Strikingly, rates of protein evolution were only moderately affected by expression level and protein length.

  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.

    PubMed

    Russell, Liane B; Hunsicker, Patricia R

    2012-05-01

    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. 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.

  6. TERT PROMOTER MUTATIONS OCCUR FREQUENTLY IN GLIOMAS AND A SUBSET OF TUMORS DERIVED FROM CELLS WITH LOW RATES OF SELF-RENEWAL

    PubMed Central

    Yan, Hai; Killela, P.J.; Reitman, Z.J.; Jiao, Y.; Bettegowda, C.; Agrawal, N.; Diaz, L.A.; Friedman, A.H.; Friedman, H.; Gallia, G.L.; Giovanella, B.C.; Grollman, A.P.; He, T.C.; He, Y.; Hruban, R.H.; Jallo, G.I.; Mandahl, N.; Meeker, A.K.; Mertens, F.; Netto, G.J.; Rasheed, B.A.; Riggins, G.J.; Rosenquist, T.A.; Schiffman, M.; Shih, IeM; Theodorescu, D.; Torbenson, M.S.; Velculescu, V.E.; Wang, T.L.; Wentzensen, N.; Wood, L.D.; Zhang, M.; Healy, P.; Yang, R.; Diplas, B.; Wang, Z.H.; Greer, P.; Zhu, H.S.; Wang, C.; Carpenter, A.; Herndon, J.E.; McLendon, R.E.; Kinzler, K.W.; Vogelstein, B.; Papadopoulos, N.; Bigner, D.D.

    2014-01-01

    BACKGROUND: Malignant cells must maintain their telomeres, but genetic mechanisms responsible for telomere maintenance in tumors have only recently been discovered. In particular, mutations of the telomere binding proteins alpha thalassemia/mental retardation syndrome X-linked (ATRX) or death-domain associated protein (DAXX) have been shown to underlie a telomere maintenance mechanism not involving telomerase (alternative lengthening of telomeres), and point mutations in the promoter of the telomerase reverse transcriptase (TERT) gene increase telomerase expression and have been shown to occur in melanomas. METHODS: To further define the tumor types in which TERT plays a role, we surveyed 1,230 tumors of 60 different types. We also analyzed the relationship between median overall survival (OS) of patients with IDH1/2 and TERT promoter mutations in a panel of 473 adult gliomas with the hypothesis that genetic signatures capable of distinguishing among several types of gliomas could be established providing clinically relevant information that can serve as an adjunct to histopathological diagnosis. RESULTS: We found that tumors could be divided into types with low and high frequencies of TERT promoter mutations. The nine TERT-high tumor types almost always originated in tissues with relatively low rates of self renewal, including melanomas, liposarcomas, hepatocellular carcinomas, urothelial carcinomas, squamous cell carcinomas of the tongue, medulloblastomas, and subtypes of gliomas. TERT and ATRX mutations were mutually exclusive, suggesting that these two genetic mechanisms confer equivalent selective growth advantages. We found that mutations in the TERT promoter occurred in 74.2% of glioblastomas (GBM), but occurred in a minority of Grade II-III astrocytomas (18.2%). In contrast, IDH1/2 mutations were observed in 78.4% of Grade II-III astrocytomas, but were uncommon in primary GBM. In oligodendrogliomas, TERT promoter and IDH1/2 mutations co-occurred in 79% of

  7. 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.

  8. 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.

  9. 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

  10. Sequential imposed layer epitaxy of cuprate films

    SciTech Connect

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

    1994-02-01

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

  11. Specific-locus mutation rates in the mouse following inhalation of ethylene oxide, and application of the results to estimation of human genetic risk.

    PubMed

    Russell, L B; Cumming, R B; Hunsicker, P R

    1984-12-01

    Male (101 X C3H)F1 mice were exposed in an inhalation chamber to ethylene oxide (EtO) in air at a concentration of (generally) 255 ppm. After accumulating total exposures of 101 000 or 150 000 ppm.h in 16-23 weeks, the males were mated to T-stock females for a standard specific-locus mutation-rate study in which 71387 offspring were observed. The spermatogonial stem-cell mutation rate at each exposure level, as well as the combined result, does not differ significantly from the historical control frequency. At the lower and higher exposure levels, the results rule out (at the 5% significance level) an induced frequency that is, respectively, 0.97 and 6.33 times the spontaneous rate; the combined results rule out a multiple of 1.64. The relationship between mouse spermatogonial stem-cell mutation rates and EtO-induced testis ethylations was compared with the relationship between Drosophila post-stem-cell mutation rates and sperm ethylations (Lee, 1980). The comparison does not rule out equal mutability per ethylation; but it cannot prove parallelism. An assessment of the mouse-Drosophila relationship will require a more efficient alkylator than EtO and the use of comparable germ-cell stages. More meaningful conclusions may be drawn by utilizing the data for direct estimation of human risk by expressing the induced mutation frequency that is ruled out (at the 5% significance level) as a multiple of control rate and extrapolating to human exposure levels. The probable absence of major stem-cell killing (and thus, possibly, cell selection) by EtO indicates that such extrapolation probably does not produce an underestimate. For a human exposure concentration of 0.1 ppm on working days during the reproductive lifespan, the mouse experimental results rule out (at the 5% significance level) an induced spermatogonial stem-cell gene mutation rate greater than 8% of the spontaneous rate; for 1.0 ppm, they rule out an induced rate roughly equal to the spontaneous rate. The

  12. Is imposing risk awareness cultural imperialism?

    PubMed

    Førde, O H

    1998-11-01

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

  13. Phenocopy breast cancer rates in Israeli BRCA1 BRCA2 mutation carrier families: is the risk increased in non-carriers?

    PubMed

    Bernholtz, Shiri; Laitman, Yael; Kaufman, Bella; Shimon-Paluch, Shnai; Friedman, Eitan

    2012-04-01

    BRCA1 and BRCA2 mutation carriers have an increased risk for developing breast (and ovarian) cancer. Non-carriers from within such families (=true negatives) are counseled that their risk for developing breast cancer is similar to that of the average-risk population. Breast cancer diagnosed in a non-carrier from a family with a known mutation is coined phenocopy. The rate of breast cancer phenocopy and the risk for breast cancer in true negatives are unsettled. The rate of phenocopy breast cancer was assessed in non-carriers from Jewish families with a BRCA1 or BRCA2 mutation, identified at the Sheba medical center. Analysis was performed by t test for comparison of mean age at counseling or breast cancer diagnosis, and by calculating a standardized incidence ratio (SIR). Overall, 1318 females from 884 mutation carrying families (620 with BRCA1 264 with BRCA2 mutations) were genotyped, of whom 307 women from 245 families were assigned a true negative status (mean age at counseling 43.01 ± 13.03 years (range 19.7-92.8 years). Of these true negatives, 20 women (6.51-2.26% of families) developed breast cancer at a mean age of 54.1 ± 12.9 years (range 48.1 -60.1 years). The SIR for breast cancer in true negatives was not significantly different than the expected in the average-risk Israeli population [observed 20-expected 23.8 cases SIR = 0.84, 95% CI (0.51, 1.30)]. The rate of phenocopy breast cancer in non-carriers from Israeli BRCA1 BRCA2 mutation carrier families is 2.26% with no increased breast cancer risk over the average-risk population.

  14. Characterization of Imposed Ordered Structures in MDPX

    NASA Astrophysics Data System (ADS)

    Hall, Taylor; Thomas, Edward; Konopka, Uwe; Merlino, Robert; Rosenberg, Marlene

    2016-10-01

    It is well understood that the microparticles in complex, or dusty, plasmas will form self-consistent crystalline patterns at the proper plasma parameters. In the Magnetized Dusty Plasma Experiment (MDPX) device, studies have been made of imposed, ordered structuring of the dust particles to a two dimensional grid. At high magnetic field (B >1 Tesla), the dust particles are shown to become spatially oriented to the structure of a wire mesh embedded in an electrically floating, upper electrode while the particles are suspended in a plasma that is generated by the powered, lower electrode in the experiment. With even higher magnetic field (B >2 Tesla), the particles become strongly confined to the mesh pattern with the particles constrained to a quasi-discreet motion that closely follows the mesh pattern. This presentation characterizes the structure of the potential energy well in which the dust particles are trapped through observation of particle motion and measurement of the thermal properties of the particles. This work is supported by funding from the U. S. Department of Energy Grant Number DE - SC0010485 and the NASA/Jet Propulsion Laboratory, JPL-1543114.

  15. Vacuolar Protein Sorting Genes in Parkinson's Disease: A Re-appraisal of Mutations Detection Rate and Neurobiology of Disease

    PubMed Central

    Gambardella, Stefano; Biagioni, Francesca; Ferese, Rosangela; Busceti, Carla L.; Frati, Alessandro; Novelli, Giuseppe; Ruggieri, Stefano; Fornai, Francesco

    2016-01-01

    Mammalian retromers play a critical role in protein trans-membrane sorting from endosome to the trans-Golgi network (TGN). Recently, retromer alterations have been related to the onset of Parkinson's Disease (PD) since the variant p.Asp620Asn in VPS35 (Vacuolar Protein Sorting 35) was identified as a cause of late onset PD. This variant causes a primary defect in endosomal trafficking and retromers formation. Other mutations in VPS genes have been reported in both sporadic and familial PD. These mutations are less defined. Understanding the specific prevalence of all VPS gene mutations is key to understand the relevance of retromers impairment in the onset of PD. A number of PD-related mutations despite affecting different biochemical systems (autophagy, mitophagy, proteasome, endosomes, protein folding), all converge in producing an impairment in cell clearance. This may explain how genetic predispositions to PD may derive from slightly deleterious VPS mutations when combined with environmental agents overwhelming the clearance of the cell. This manuscript reviews genetic data produced in the last 5 years to re-define the actual prevalence of VPS gene mutations in the onset of PD. The prevalence of p.Asp620Asn mutation in VPS35 is 0.286 of familial PD. This increases up to 0.548 when considering mutations affecting all VPS genes. This configures mutations in VPS genes as the second most frequent autosomal dominant PD genotype. This high prevalence, joined with increased awareness of the role played by retromers in the neurobiology of PD, suggests environmentally-induced VPS alterations as crucial in the genesis of PD. PMID:27932943

  16. Vacuolar Protein Sorting Genes in Parkinson's Disease: A Re-appraisal of Mutations Detection Rate and Neurobiology of Disease.

    PubMed

    Gambardella, Stefano; Biagioni, Francesca; Ferese, Rosangela; Busceti, Carla L; Frati, Alessandro; Novelli, Giuseppe; Ruggieri, Stefano; Fornai, Francesco

    2016-01-01

    Mammalian retromers play a critical role in protein trans-membrane sorting from endosome to the trans-Golgi network (TGN). Recently, retromer alterations have been related to the onset of Parkinson's Disease (PD) since the variant p.Asp620Asn in VPS35 (Vacuolar Protein Sorting 35) was identified as a cause of late onset PD. This variant causes a primary defect in endosomal trafficking and retromers formation. Other mutations in VPS genes have been reported in both sporadic and familial PD. These mutations are less defined. Understanding the specific prevalence of all VPS gene mutations is key to understand the relevance of retromers impairment in the onset of PD. A number of PD-related mutations despite affecting different biochemical systems (autophagy, mitophagy, proteasome, endosomes, protein folding), all converge in producing an impairment in cell clearance. This may explain how genetic predispositions to PD may derive from slightly deleterious VPS mutations when combined with environmental agents overwhelming the clearance of the cell. This manuscript reviews genetic data produced in the last 5 years to re-define the actual prevalence of VPS gene mutations in the onset of PD. The prevalence of p.Asp620Asn mutation in VPS35 is 0.286 of familial PD. This increases up to 0.548 when considering mutations affecting all VPS genes. This configures mutations in VPS genes as the second most frequent autosomal dominant PD genotype. This high prevalence, joined with increased awareness of the role played by retromers in the neurobiology of PD, suggests environmentally-induced VPS alterations as crucial in the genesis of PD.

  17. 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.

  18. The effect of the interval between dose applications on the observed specific-locus mutation rate in the mouse following fractionated treatments of spermatogonia with ethylnitrosourea.

    PubMed

    Favor, J; Neuhäuser-Klaus, A; Ehling, U H; Wulff, A; van Zeeland, A A

    1997-03-21

    Our earlier analyses have suggested an apparent threshold dose-response for ethylnitrosourea-induced specific-locus mutations in treated spermatogonia of the mouse to be due to a saturable repair process. In the current study a series of fractionated-treatment experiments was carried out in which male (102 x C3H)F1 mice were exposed to 4 x 10, 2 x 40. 4 x 20 or 4 x 40 mg ethylnitrosourea per kg body weight with 24 h between applications; 4 x 40 mg ethylnitrosourea per kg body weight with 72 h between dose applications; and 2 x 40, 4 x 20 and 4 x 40 mg ethylnitrosourea per kg body weight with 168 h between dose applications. For all experiments with 24-h intervals between dose applications, there was no effect due to dose fractionation on the observed mutation rates, indicating the time interval between dose applications to be shorter than the recovery time of the repair processes acting on ethylnitrosourea-induced DNA adducts. In contrast, a fractionation interval of 168 h was associated with a significant reduction in the observed mutation rate due to recovery of the repair process. However, although reduced, the observed mutation rates for fractionation intervals of 168 h were higher than the spontaneous specific-locus mutation rate. These observations contradict the expectation for a true threshold dose response. We interpret this discrepancy to be due to the differences in the predictions of a mathematical abstraction of experimental data and the complexities of the biological system being studied. Biologically plausible explanations of the discrepancy are presented.

  19. Identification of G2607A mutation in EGFR gene with a significative rate in Moroccan patients with nasopharyngeal carcinoma.

    PubMed

    Naji, F; Attaleb, M; Laantri, N; Benchakroun, N; El Gueddari, B; Benider, A; Azeddoug, H; Ennaji, M M; El Mzibri, M; Khyatti, M

    2010-12-15

    The epidermal growth factor receptor (EGFR) is involved in the regulation of several cellular processes and in the development of many human cancers. Somatic mutations of EGFR at tyrosine kinase domain have been associated with clinical response to tyrosine kinase inhibitors (TKIs) in lung cancer patients. In this study, we evaluated the frequency of point mutations in EGFR for future use of TKI in clinical treatment of nasopharyngeal carcinoma (NPC). Sixty Moroccan patient specimens of NPC were analysed for EGFR mutations in the region delimiting exons 18 and 21 by direct sequencing. Our results showed the absence of mutations in the EGFR kinase domain in these exons in all 60 analysed specimens. Sequence analysis of the EGFR—TK domain, revealed the presence of (G2607A) polymorphism at exon 20. The genotypes AA and GA were found respectively in 39 (65%) and 16 (26.6%) cases. Statistical analysis showed no difference between the polymorphism and either gender or age of patients. Mutations in EGFR kinase domain are rare events in NPC biopsies, suggesting, that treatment of NPC patients with TKI may not be effective. However, EGFR G2607A polymorphism at exon 20 is frequent in NPC cases and could be associated to clinical response to TKI therapy.

  20. 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

  1. 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

  2. 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.

  3. Prevention of avoidable mutational disease: memorandum from a WHO meeting.

    PubMed

    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.

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

    PubMed

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

    2015-12-28

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

  5. 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.

  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. Mutation rate switch inside Eurasian mitochondrial haplogroups: impact of selection and consequences for dating settlement in Europe.

    PubMed

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

    2011-01-01

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

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

    PubMed Central

    Bauch, Chris T.; McElreath, Richard

    2016-01-01

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

  9. p53 gene mutational rate, Gleason score, and BK virus infection in prostate adenocarcinoma: Is there a correlation?

    PubMed

    Russo, Giuseppe; Anzivino, Elena; Fioriti, Daniela; Mischitelli, Monica; Bellizzi, Anna; Giordano, Antonio; Autran-Gomez, Anamaria; Di Monaco, Franco; Di Silverio, Franco; Sale, Patrizio; Di Prospero, Laura; Pietropaolo, Valeria

    2008-12-01

    Prostate cancer represents the second leading cause of cancer deaths in Western countries. Viral infections could play a role in prostate carcinogenesis. Human polyomavirus BK (BKV) is a possible candidate because of its transforming properties. In this study, BKV sequences in urine, blood, fresh, and paraffin-embedded prostate cancer samples from 26 patients were searched using Q-PCR analysis. T antigen (TAg) and p53 localization in neoplastic cells were evaluated by immunohistochemical analysis. Also, the presence of mutations in 5-9 exons of p53 gene was analyzed. Results showed that BKV-DNA was found in urine (54%), plasma (31%), and in fresh prostate cancer specimens (85%). The analysis of p53 gene evidenced several mutations in high Gleason patients, according to tumor advanced stage. Immunohistochemical analysis results evidenced the localization of p53 and TAg into cytoplasm, whereas in TAg-negative tumors, p53 was nuclear. This study suggests that BKV acts as cofactor in the pathogenesis of prostate cancer. These observations emphasize previous studies regarding the cellular pathways that may be deregulated by BKV.

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

    PubMed Central

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

    2013-01-01

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

  11. 26 CFR 20.2101-1 - Estates of nonresidents not citizens; tax imposed.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... the United States at the time of death. In the case of estates of decedents dying after November 10, 1988, the tax is computed at the same rates as the tax that is imposed on the transfer of the taxable... the payment of the tax, see section 2002. For special rules as to the phaseout of the graduated...

  12. 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.

  13. On the effects of an imposed magnetic field on the elliptical instability in rotating spheroids

    NASA Astrophysics Data System (ADS)

    Herreman, W.; Le Bars, M.; Le Gal, P.

    2009-04-01

    The effects of an imposed magnetic field on the development of the elliptical instability in a rotating spheroid filled with a conducting fluid are considered. Theoretical and experimental studies of the spin-over mode, as well as a more general short-wavelength Lagrangian approach, demonstrate that the linear growth rate of the instability and the square amplitude of the induced magnetic field fall down linearly with the square of the imposed magnetic field. Application of the results to the Galilean moon Io confirms the fundamental role played by the elliptical instability at the planetary scale.

  14. 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.

  15. 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

  16. 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.

  17. Detecting Mutations in the Mycobacterium tuberculosis Pyrazinamidase Gene pncA to Improve Infection Control and Decrease Drug Resistance Rates in Human Immunodeficiency Virus Coinfection

    PubMed Central

    Dudley, Matthew Z.; Sheen, Patricia; Gilman, Robert H.; Ticona, Eduardo; Friedland, Jon S.; Kirwan, Daniela E.; Caviedes, Luz; Rodriguez, Richard; Cabrera, Lilia Z.; Coronel, Jorge; Grandjean, Louis; Moore, David A. J.; Evans, Carlton A.; Huaroto, Luz; Chávez-Pérez, Víctor; Zimic, Mirko

    2016-01-01

    Hospital infection control measures are crucial to tuberculosis (TB) control strategies within settings caring for human immunodeficiency virus (HIV)–positive patients, as these patients are at heightened risk of developing TB. Pyrazinamide (PZA) is a potent drug that effectively sterilizes persistent Mycobacterium tuberculosis bacilli. However, PZA resistance associated with mutations in the nicotinamidase/pyrazinamidase coding gene, pncA, is increasing. A total of 794 patient isolates obtained from four sites in Lima, Peru, underwent spoligotyping and drug resistance testing. In one of these sites, the HIV unit of Hospital Dos de Mayo (HDM), an isolation ward for HIV/TB coinfected patients opened during the study as an infection control intervention: circulating genotypes and drug resistance pre- and postintervention were compared. All other sites cared for HIV-negative outpatients: genotypes and drug resistance rates from these sites were compared with those from HDM. HDM patients showed high concordance between multidrug resistance, PZA resistance according to the Wayne method, the two most common genotypes (spoligotype international type [SIT] 42 of the Latino American-Mediterranean (LAM)-9 clade and SIT 53 of the T1 clade), and the two most common pncA mutations (G145A and A403C). These associations were absent among community isolates. The infection control intervention was associated with 58–92% reductions in TB caused by SIT 42 or SIT 53 genotypes (odds ratio [OR] = 0.420, P = 0.003); multidrug-resistant TB (OR = 0.349, P < 0.001); and PZA-resistant TB (OR = 0.076, P < 0.001). In conclusion, pncA mutation typing, with resistance testing and spoligotyping, was useful in identifying a nosocomial TB outbreak and demonstrating its resolution after implementation of infection control measures. PMID:27928075

  18. Detecting Mutations in the Mycobacterium tuberculosis Pyrazinamidase Gene pncA to Improve Infection Control and Decrease Drug Resistance Rates in Human Immunodeficiency Virus Coinfection.

    PubMed

    Dudley, Matthew Z; Sheen, Patricia; Gilman, Robert H; Ticona, Eduardo; Friedland, Jon S; Kirwan, Daniela E; Caviedes, Luz; Rodriguez, Richard; Cabrera, Lilia Z; Coronel, Jorge; Grandjean, Louis; Moore, David A J; Evans, Carlton A; Huaroto, Luz; Chávez-Pérez, Víctor; Zimic, Mirko

    2016-12-07

    Hospital infection control measures are crucial to tuberculosis (TB) control strategies within settings caring for human immunodeficiency virus (HIV)-positive patients, as these patients are at heightened risk of developing TB. Pyrazinamide (PZA) is a potent drug that effectively sterilizes persistent Mycobacterium tuberculosis bacilli. However, PZA resistance associated with mutations in the nicotinamidase/pyrazinamidase coding gene, pncA, is increasing. A total of 794 patient isolates obtained from four sites in Lima, Peru, underwent spoligotyping and drug resistance testing. In one of these sites, the HIV unit of Hospital Dos de Mayo (HDM), an isolation ward for HIV/TB coinfected patients opened during the study as an infection control intervention: circulating genotypes and drug resistance pre- and postintervention were compared. All other sites cared for HIV-negative outpatients: genotypes and drug resistance rates from these sites were compared with those from HDM. HDM patients showed high concordance between multidrug resistance, PZA resistance according to the Wayne method, the two most common genotypes (spoligotype international type [SIT] 42 of the Latino American-Mediterranean (LAM)-9 clade and SIT 53 of the T1 clade), and the two most common pncA mutations (G145A and A403C). These associations were absent among community isolates. The infection control intervention was associated with 58-92% reductions in TB caused by SIT 42 or SIT 53 genotypes (odds ratio [OR] = 0.420, P = 0.003); multidrug-resistant TB (OR = 0.349, P < 0.001); and PZA-resistant TB (OR = 0.076, P < 0.001). In conclusion, pncA mutation typing, with resistance testing and spoligotyping, was useful in identifying a nosocomial TB outbreak and demonstrating its resolution after implementation of infection control measures.

  19. 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

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

    PubMed

    Khasin, M; Dykman, M I

    2011-03-01

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

  1. Mutations in the genes for oocyte-derived growth factors GDF9 and BMP15 are associated with both increased ovulation rate and sterility in Cambridge and Belclare sheep (Ovis aries).

    PubMed

    Hanrahan, James P; Gregan, Scott M; Mulsant, Philippe; Mullen, Michael; Davis, George H; Powell, Richard; Galloway, Susan M

    2004-04-01

    Belclare and Cambridge are prolific sheep breeds, the origins of which involved selecting ewes with exceptionally high litter size records from commercial flocks. The variation in ovulation rate in both breeds is consistent with segregation of a gene (or genes) with a large effect on this trait. Sterile ewes, due to a failure of normal ovarian follicle development, occur in both breeds. New naturally occurring mutations in genes for the oocyte-derived growth factors growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) are described. These mutations are associated with increased ovulation rate in heterozygous carriers and sterility in homozygous carriers in both breeds. This is the first time that a mutation in the gene for GDF9 has been found that causes increased ovulation rate and infertility in a manner similar to inactivating mutations in BMP15, and shows that GDF9 is essential for normal folliculogenesis in sheep. Furthermore, it is shown, for the first time in any species, that individuals with mutations in both GDF9 and BMP15 have a greater ovulation rate than sheep with either of the mutations separately.

  2. 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.

  3. Alignment to natural and imposed mismatches between the senses.

    PubMed

    van der Kooij, K; Brenner, E; van Beers, R J; Schot, W D; Smeets, J B J

    2013-04-01

    Does the nervous system continuously realign the senses so that objects are seen and felt in the same place? Conflicting answers to this question have been given. Research imposing a sensory mismatch has provided evidence that the nervous system realigns the senses to reduce the mismatch. Other studies have shown that when subjects point with the unseen hand to visual targets, their end points show visual-proprioceptive biases that do not disappear after episodes of visual feedback. These biases are indicative of intersensory mismatches that the nervous system does not align for. Here, we directly compare how the nervous system deals with natural and imposed mismatches. Subjects moved a hand-held cube to virtual cubes appearing at pseudorandom locations in three-dimensional space. We alternated blocks in which subjects moved without visual feedback of the hand with feedback blocks in which we rendered a cube representing the hand-held cube. In feedback blocks, we rotated the visual feedback by 5° relative to the subject's head, creating an imposed mismatch between vision and proprioception on top of any natural mismatches. Realignment occurred quickly but was incomplete. We found more realignment to imposed mismatches than to natural mismatches. We propose that this difference is related to the way in which the visual information changed when subjects entered the experiment: the imposed mismatches were different from the mismatch in daily life, so alignment started from scratch, whereas the natural mismatches were not imposed by the experimenter, so subjects are likely to have entered the experiment partly aligned.

  4. 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.

  5. High rate of somatic point mutation in vitro in and near the variable-region segment of an immunoglobulin heavy chain gene.

    PubMed Central

    Meyer, J; Jäck, H M; Ellis, N; Wabl, M

    1986-01-01

    The "silent" allele at the immunoglobulin heavy-chain locus in the pre-B-lymphocyte line 18-81 contains a correctly assembled gene. However, an amber termination codon within the variable-region gene segment prematurely terminates translation into complete heavy chain. Revertants that do produce heavy chain are generated at a high rate, which is termed hypermutation. By DNA sequencing of subclones, we have confirmed that whenever mu chain is produced by the usually silent allele, a true reversion is found in the DNA. Mutations are not confined to the position of the amber termination codon but are also found at other sites in and near the variable-region gene segment. Images PMID:3092221

  6. 36 CFR 1256.42 - Who imposes general restrictions?

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 36 Parks, Forests, and Public Property 3 2014-07-01 2014-07-01 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...

  7. Coercion or Compromise: How Schools React to Imposed Change.

    ERIC Educational Resources Information Center

    Croll, Paul; Abbott, Dorothy

    This paper examines the responses of English primary schools to the changes imposed on them by the introduction of the National Curriculum. The study first focused on schools' management strategies and their impact on the school's management culture. A second focus was on the relationship of the school and its headteacher with external agencies.…

  8. 50 CFR 270.17 - Authority to impose assessments.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 50 Wildlife and Fisheries 7 2010-10-01 2010-10-01 false Authority to impose assessments. 270.17 Section 270.17 Wildlife and Fisheries NATIONAL MARINE FISHERIES SERVICE, NATIONAL OCEANIC AND ATMOSPHERIC ADMINISTRATION, DEPARTMENT OF COMMERCE FISH AND SEAFOOD PROMOTION SPECIES-SPECIFIC SEAFOOD MARKETING...

  9. 50 CFR 270.18 - Method of imposing assessments.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 50 Wildlife and Fisheries 7 2010-10-01 2010-10-01 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...

  10. 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.

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

    PubMed

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

    2015-01-01

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

  12. Defense Acquistion: Rationale for Imposing Domestic Source Restrictions.

    DTIC Science & Technology

    2007-11-02

    retained the restriction for polyacrylonitrile-based carbon fiber, periscope tube forgings, bull gear ring forgings, and ship propulsion shaft...forgings 1984 Protect sensitive data Ship propulsion shaft forgings 1984 Unsettled conditions among suppliers In its reviews of industrial base... Ship Propulsion Shafts 14 14 15 16 17 Appendix III Rationale for 10 U.S.C. 2534-Imposed Restrictions Buses Chemical Weapons Antidote

  13. Concurrent porcine circovirus type 2a (PCV2a) or PCV2b infection increases the rate of amino acid mutations of porcine reproductive and respiratory syndrome virus (PRRSV) during serial passages in pigs.

    PubMed

    Yin, Shuang-Hui; Xiao, Chao-Ting; Gerber, Priscilla F; Beach, Nathan M; Meng, Xiang-Jin; Halbur, Patrick G; Opriessnig, Tanja

    2013-12-26

    Porcine reproductive and respiratory syndrome virus (PRRSV) has a high degree of genetic and antigenic variability. The purpose of this study was to determine if porcine circovirus type 2 (PCV2) infection increases genetic variability of PRRSV during serial passages in pigs and to determine if there is a difference in the PRRSV mutation rate between pigs concurrently infected with PCV2a or PCV2b. After 8 consecutive passages of PRRSV alone (group 1), PRRSV with PCV2a (group 2), or PCV2b (group 3) in pigs, the sequences of PRRSV structural genes for open reading frame (ORF) 5, ORF6, ORF7 and the partial non-structural protein gene (Nsp) 2 were determined. The total number of identified amino acid mutations in ORF5, ORF6, ORF7 and Nsp2 sequences was 30 for PRRSV infection only, 63 for PRRSV/PCV2a concurrent infection, and 77 for PRRSV/PCV2b concurrent infection when compared with the original VR2385 virus used to infect the passage 1 pigs. Compared to what occurred in pigs infected with PRRSV only, the mutation rates in ORF5 and ORF6 were significantly higher for concurrent PRRSV/PCV2b infected pigs. The PRRSV/PCV2a pigs had a significantly higher mutation rate in ORF7. The results from this study indicated that, besides ORF5 and Nsp2, the PRRSV structural genes ORF6 and ORF7 were shown to mutate at various degrees when the PRRSV was passaged over time in vivo. Furthermore, a significantly higher mutation rate of PRRSV was observed when pigs were co-infected with PCV2 highlighting the importance of concurrent infections on PRRSV evolution and control.

  14. 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

  15. Rate of EGFR mutation testing for patients with nonsquamous non-small-cell lung cancer with implementation of reflex testing by pathologists

    PubMed Central

    Cheema, P.K.; Raphael, S.; El-Maraghi, R.; Li, J.; McClure, R.; Zibdawi, L.; Chan, A.; Victor, J.C.; Dolley, A.; Dziarmaga, A.

    2017-01-01

    Background Testing for mutation of the EGFR (epidermal growth factor receptor) gene is a standard of care for patients with advanced nonsquamous non-small-cell lung cancer (nsclc). To improve timely access to EGFR results, a few centres implemented reflex testing, defined as a request for EGFR testing by the pathologist at the time of a nonsquamous nsclc diagnosis. We evaluated the impact of reflex testing on EGFR testing rates. Methods A retrospective observational review of the Web-based AstraZeneca Canada EGFR Database from 1 April 2010 to 31 March 2014 found centres within Ontario that had requested EGFR testing through the database and that had implemented reflex testing (with at least 2 years’ worth of data, including the pre- and post-implementation period). Results The 7 included centres had requested EGFR tests for 2214 patients. The proportion of pathologists requesting EGFR tests increased after implementation of reflex testing (53% vs. 4%); conversely, the proportion of medical oncologists requesting tests decreased (46% vs. 95%, p < 0.001). After implementation of reflex testing, the mean number of patients having EGFR testing per centre per month increased significantly [12.6 vs. 4.9 (range: 4.5–14.9), p < 0.001]. Before reflex testing, EGFR testing rates showed a significant monthly increase over time (1.37 more tests per month; 95% confidence interval: 1.19 to 1.55 tests; p < 0.001). That trend could not account for the observed increase with reflex testing, because an immediate increase in EGFR test requests was observed with the introduction of reflex testing (p = 0.003), and the overall trend was sustained throughout the post–reflex testing period (p < 0.001). Conclusions Reflex EGFR testing for patients with nonsquamous nsclc was successfully implemented at multiple centres and was associated with an increase in EGFR testing. PMID:28270720

  16. 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.

  17. 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.

  18. 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...

  19. 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...

  20. 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...

  1. 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...

  2. 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

  3. 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.

  4. 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.

  5. 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.

  6. Therapeutic effects of an imposed foraging task in disturbed monkeys.

    PubMed

    Rosenblum, L A; Smiley, J

    1984-07-01

    A group of twelve bonnet macaques (Macaca radiata) raised in partial social isolation from birth to adulthood expressed moderate-to-severe behavioral disturbance as a function of their early rearing environments. The range of these behavioral function of their early rearing environments. The range of these behavioral abnormalities in this species are described for the first time. In order to assess the role of the current environment on their behavior, the animals as a group were required to obtain all of their food from a foraging device presenting two levels of difficulty. The therapeutic effect of the imposed foraging task was dependent upon the individual's status in the dominance hierarchy. Low- and high-ranking animals responded positively and became more social (338% above baseline levels) and showed lower levels of specific abnormal behaviors (nearly 75% lower). Mid-ranking animals responded negatively and became less social (89% lower), while their levels of abnormal behavior dramatically increased (200% higher).

  7. Body iron stores and iron restoration rate in Japanese patients with chronic hepatitis C as measured during therapeutic iron removal revealed neither increased body iron stores nor effects of C282Y and H63D mutations on iron indices.

    PubMed

    Shiono, Y; Hayashi, H; Wakusawa, S; Sanae, F; Takikawa, T; Yano, M; Yoshioka, K; Saito, H

    2001-05-01

    Information on the level of iron stores in chronic hepatitis C is clinically important because its reduction is technically simple and therapeutically effective. This study was performed to measure the levels of iron stores from the total amounts of hemoglobin removed during iron reduction therapy. The C282Y and H63D mutations of HFE gene were analyzed in 94 patients. All of the patients were negative for C282Y mutation. One patient was homozygous, and 4 patients were heterozygous for H63D mutation. The body iron stores and iron restoration rate were measured in 59 patients in serial courses of iron reduction therapy. Mean values of body iron stores in the two groups with and without H63D mutation were 890 and 606 mg, while those of iron restoration rate were 1.85 and 1.52 mg/day, respectively. None of the indices of iron metabolism were different from the reference values measured similarly in healthy subjects, suggesting that the iron deposition in chronic hepatitis C is limited to the liver, probably due to changes in the iron distribution in tissues.

  8. Disease-modifying polymorphisms and C609Y mutation of RET associated with high penetrance of phaeochromocytoma and low rate of MTC in MEN2A

    PubMed Central

    Speak, Rowena; Cook, Jackie; Harrison, Barney

    2016-01-01

    Mutations of the rearranged during transfection (RET) proto-oncogene, located on chromosome 10q11.2, cause multiple endocrine neoplasia type 2A (MEN2A). Patients with mutations at the codon 609 usually exhibit a high penetrance of medullary thyroid cancer (MTC), but a sufficiently low penetrance of phaeochromocytoma that screening for this latter complication has been called to question. Patients with other RET mutations are at higher risk of younger age onset phaeochromocytoma if they also possess other RET polymorphisms (L769L, S836S, G691S and S904S), but there are no similar data for patients with 609 mutations. We investigated the unusual phenotypic presentation in a family with MEN2A due to a C609Y mutation in RET. Sanger sequencing of the entire RET-coding region and exon–intron boundaries was performed. Five family members were C609Y mutation positive: 3/5 initially presented with phaeochromocytoma, but only 1/5 had MTC. The index case aged 73 years had no evidence of MTC, but presented with phaeochromocytoma. Family members also possessed the G691S and S904S RET polymorphisms. We illustrate a high penetrance of phaeochromocytoma and low penetrance of MTC in patients with a RET C609Y mutation and polymorphisms G691S and S904S. These data highlight the need for life-long screening for the complications of MEN2A in these patients and support the role for the screening of RET polymorphisms for the purposes of risk stratification. Learning points: C609Y RET mutations may be associated with a life-long risk of phaeochromocytoma indicating the importance of life-long screening for this condition in patients with MEN2A. C609Y RET mutations may be associated with a lower risk of MTC than often quoted, questioning the need for early prophylactic thyroid surgery discussion at the age of 5 years. There may be a role for the routine screening of RET polymorphisms, and this is greatly facilitated by the increasing ease of access to next-generation sequencing. PMID

  9. 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.

  10. 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

  11. 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

  12. 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.

  13. 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 Central

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

    2012-01-01

    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 G1 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. PMID:22447585

  14. 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.

  15. 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

  16. 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.

  17. 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.

  18. Extra inspiratory work of breathing imposed by cricothyrotomy devices.

    PubMed

    Ooi, R; Fawcett, W J; Soni, N; Riley, B

    1993-01-01

    Using a lung model for spontaneous ventilation, we have assessed the additional work of inspiration imposed by a variety of cannulae ranging from the 12- and 14-gauge intravascular cannulae to the 8.0-mm i.d. adult tracheostomy tube. Work (W) ranged between 9 and 2262 mJ litre-1 and power (W) between 0.2 and 37.7 mW litre-1 min; the smallest values were obtained with the 8.0-mm i.d. adult tracheostomy tube and the 12- and 14-gauge intravascular cannulae gave the largest values. With any given cannula, W and W were influenced by ventilation (tidal volume and frequency) and ventilatory wave pattern of the analogue lung. The results obtained from the 12- and 14-gauge cannulae represent what is probably an excessive inspiratory workload, whereas the other four devices (Portex MiniTrach, 4.0, 6.0 and 8.0 tracheostomy tubes) may be suitable in the short term for relieving airway obstruction and compatible with spontaneous ventilation.

  19. Externally imposed electric field enhances plant root tip regeneration

    PubMed Central

    Kral, Nicolas; Hanna Ougolnikova, Alexandra

    2016-01-01

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

  20. Imposing spatio-temporal support in magnetic resonance angiographic imaging

    NASA Astrophysics Data System (ADS)

    Bones, Philip J.; Vafadar, Bahareh; Watts, Richard; Wu, Bing

    2010-08-01

    A method to improve time resolution in 3D contrast-enhanced magnetic resonance angiography (CE-MRA) is proposed. A temporal basis based on prior knowledge of the contrast flow dynamics is applied to a sequence of image reconstructions. In CE-MRA a contrast agent (gadolinium) is injected into a peripheral vein and MR data is acquired as the agent arrives in the arteries and then the veins of the region of clinical interest. The acquisition extends over several minutes. Information is effectively measured in 3D k-space (spatial frequency space) one line at-atime. That line may be along a Cartesian grid line in k-space, a radial line or a spiral trajectory. A complete acquisition comprises many such lines but in order to improve temporal resolution, reconstructions are made from only partial sets of k-space data. By imposing a basis for the temporal changes, based on prior expectation of the smoothness of the changes in contrast concentration with time, it is demonstrated that a significant reduction in artifacts caused by the under-sampling of k-space can be achieved. The basis is formed from a set of gamma variate functions. Results are presented for a simulated set of 2D spiral-sampled CE-MRA data.

  1. Local similarity in evolutionary rates extends over whole chromosomes in human-rodent and mouse-rat comparisons: implications for understanding the mechanistic basis of the male mutation bias.

    PubMed

    Lercher, M J; Williams, E J; Hurst, L D

    2001-11-01

    The sex chromosomes and autosomes spend different times in the germ line of the two sexes. If cell division is mutagenic and if the sexes differ in number of cell divisions, then we expect that sequences on the X and Y chromosomes and autosomes should mutate at different rates. Tests of this hypothesis for several mammalian species have led to conflicting results. At the same time, recent evidence suggests that the chromosomal location of genes on autosomes affects their rate of evolution at synonymous sites. This suggests a mutagenic source different from germ cell replication. To correctly interpret the previous estimates of male mutation bias, it is crucial to understand the degree and range of this local similarity. With a carefully chosen randomization protocol, local similarity in synonymous rates of evolution can be detected in human-rodent and mouse-rat comparisons. However, the synonymous-site similarity in the mouse-rat comparison remains weak. Simulations suggest that this difference between the mouse-human and the mouse-rat comparisons is not artifactual and that there is therefore a difference between humans and rodents in the local patterns of mutation or selection on synonymous sites (conversely, we show that the previously reported absence of a local similarity in nonsynonymous rates of evolution in the human-rodent comparison was a methodological artifact). We show that linkage effects have a long-range component: not one in a million random genomes shows such levels of autosomal heterogeneity. The heterogeneity is so great that more autosomes than expected by chance have rates of synonymous evolution comparable with that of the X chromosome. As autosomal heterogeneity cannot be owing to different times spent in the germ line, this demonstrates that the dominant determiner of synonymous rates of evolution is not, as has been conjectured, the time spent in the male germ line.

  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. 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...

  4. 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...

  5. 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...

  6. 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...

  7. 42 CFR 460.40 - Violations for which CMS may impose sanctions.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 4 2013-10-01 2013-10-01 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...

  8. 42 CFR 460.40 - Violations for which CMS may impose sanctions.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 4 2014-10-01 2014-10-01 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...

  9. 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...

  10. 42 CFR 460.40 - Violations for which CMS may impose sanctions.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 4 2012-10-01 2012-10-01 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...

  11. 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...

  12. 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

    ... Management Service, is increasing the fees it imposes on and collects from surety companies and reinsuring... Fiscal Service Application and Renewal Fees Imposed on Surety Companies and Reinsuring Companies; Increase in Fees Imposed AGENCY: Financial Management Service, Fiscal Service, Department of the...

  13. 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

    ... Management Service, is increasing the fees it imposes on and collects from surety companies and reinsuring... Fiscal Service Application and Renewal Fees Imposed on Surety Companies and Reinsuring Companies Increase in Fees Imposed AGENCY: Financial Management Service, Fiscal Service, Department of the...

  14. 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 companies. (a) In general. For taxable years beginning after December 31, 1957, section 802(a)(1) imposes...

  15. Lethal Consequences of Overcoming Metabolic Restrictions Imposed on a Cooperative Bacterial Population

    PubMed Central

    Goo, Eunhye; Kang, Yongsung; Lim, Jae Yun; Ham, Hyeonheui

    2017-01-01

    ABSTRACT Quorum sensing (QS) controls cooperative activities in many Proteobacteria. In some species, QS-dependent specific metabolism contributes to the stability of the cooperation. However, the mechanism by which QS and metabolic networks have coevolved to support stable public good cooperation and maintenance of the cooperative group remains unknown. Here we explored the underlying mechanisms of QS-controlled central metabolism in the evolutionary aspects of cooperation. In Burkholderia glumae, the QS-dependent glyoxylate cycle plays an important role in cooperativity. A bifunctional QS-dependent transcriptional regulator, QsmR, rewired central metabolism to utilize the glyoxylate cycle rather than the tricarboxylic acid cycle. Defects in the glyoxylate cycle caused metabolic imbalance and triggered high expression of the stress-responsive chaperonin GroEL. High-level expression of GroEL in glyoxylate cycle mutants interfered with the biosynthesis of a public resource, oxalate, by physically interrupting the oxalate biosynthetic enzyme ObcA. Under such destabilized cooperativity conditions, spontaneous mutations in the qsmR gene in glyoxylate cycle mutants occurred to relieve metabolic stresses, but these mutants lost QsmR-mediated pleiotropy. Overcoming the metabolic restrictions imposed on the population of cooperators among glyoxylate cycle mutants resulted in the occurrence and selection of spontaneous qsmR mutants despite the loss of other important functions. These results provide insight into how QS bacteria have evolved to maintain stable cooperation via QS-mediated metabolic coordination. PMID:28246357

  16. 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.

  17. 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.

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

    PubMed

    Sollom, T

    1996-09-01

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

  19. Propulsion efficiency and imposed flow fields of a copepod jump.

    PubMed

    Jiang, Houshuo; Kiørboe, Thomas

    2011-02-01

    Pelagic copepods jump to relocate, to attack prey and to escape predators. However, there is a price to be paid for these jumps in terms of their energy costs and the hydrodynamic signals they generate to rheotactic predators. Using observed kinematics of various types of jumps, we computed the imposed flow fields and associated energetics of jumps by means of computational fluid dynamics simulations by modeling the copepod as a self-propelled body. The computational fluid dynamics simulation was validated by particle image velocimetry data. The flow field generated by a repositioning jump quickly evolves into two counter-rotating viscous vortex rings that are near mirror image of one another, one in the wake and one around the body of the copepod; this near symmetrical flow may provide hydrodynamic camouflage because it contains no information about the position of the copepod prey within the flow structure. The flow field associated with an escape jump sequence also includes two dominant vortex structures: one leading wake vortex generated as a result of the first jump and one around the body, but between these two vortex structures is an elongated, long-lasting flow trail with flow velocity vectors pointing towards the copepod; such a flow field may inform the predator of the whereabouts of the escaping copepod prey. High Froude propulsion efficiency (0.94-0.98) was obtained for individual power stroke durations of all simulated jumps. This is unusual for small aquatic organisms but is caused by the rapidity and impulsiveness of the jump that allows only a low-cost viscous wake vortex to travel backwards.

  20. Fluconazole and Echinocandin Resistance of Candida glabrata Correlates Better with Antifungal Drug Exposure Rather than with MSH2 Mutator Genotype in a French Cohort of Patients Harboring Low Rates of Resistance

    PubMed Central

    Dellière, Sarah; Healey, Kelley; Gits-Muselli, Maud; Carrara, Bastien; Barbaro, Alessandro; Guigue, Nicolas; Lecefel, Christophe; Touratier, Sophie; Desnos-Ollivier, Marie; Perlin, David S.; Bretagne, Stéphane; Alanio, Alexandre

    2016-01-01

    Candida glabrata is a major pathogenic yeast in humans that is known to rapidly acquire resistance to triazole and echinocandin antifungal drugs. A mutator genotype (MSH2 polymorphism) inducing a mismatch repair defect has been recently proposed to be responsible for resistance acquisition in C. glabrata clinical isolates. Our objectives were to evaluate the prevalence of antifungal resistance in a large cohort of patients in Saint-Louis hospital, Paris, France, some of whom were pre-exposed to antifungal drugs, as well as to determine whether MSH2 polymorphisms are associated with an increased rate of fluconazole or echinocandin resistance. We collected 268 isolates from 147 patients along with clinical data and previous antifungal exposure. Fluconazole and micafungin minimal inhibition concentrations (MICs) were tested, short tandem repeat genotyping was performed, and the MSH2 gene was sequenced. According to the European Committee on Antimicrobial Susceptibility breakpoints, 15.7% of isolates were resistant to fluconazole (MIC > 32 mg/L) and 0.7% were resistant to micafungin (MIC > 0.03 mg/L). A non-synonymous mutation within MSH2 occurred in 44% of the isolates, and 17% were fluconazole resistant. In comparison, fluconazole resistant isolates with no MSH2 mutation represented 15% (P = 0.65). MSH2 polymorphisms were associated with the short tandem repeat genotype. The rate of echinocandin resistance is low and correlates with prior exposure to echinocandin. The mutator genotype was not associated with enrichment in fluconazole resistance but instead corresponded to rare and specific genotypes. PMID:28066361

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. Mutation breeding by ion implantation

    NASA Astrophysics Data System (ADS)

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

    1991-07-01

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

  6. Dynamics of a Recurrent Buchnera Mutation That Affects Thermal Tolerance of Pea Aphid Hosts

    PubMed Central

    Burke, Gaelen R.; McLaughlin, Heather J.; Simon, Jean-Christophe; Moran, Nancy A.

    2010-01-01

    Mutations in maternally transmitted symbionts can affect host fitness. In this study we investigate a mutation in an obligate bacterial symbiont (Buchnera), which has dramatic effects on the heat tolerance of pea aphid hosts (Acyrthosiphon pisum). The heat-sensitive allele arises through a single base deletion in a homopolymer within the promoter of ibpA, which encodes a universal small heat-shock protein. In laboratory cultures reared under cool conditions (20°), the rate of fixation (1.4 × 10−3 substitutions per Buchnera replication) is much higher than the previously estimated mutation rate for single base deletions in homopolymers in the Buchnera genome, implying a strong selective benefit. This mutation recurs in natural populations, but seldom reaches high frequencies, implying that it is only rarely favored by selection. Another potential source of physiological stress in pea aphids is infection by other microorganisms, including facultative bacterial symbionts, which occur in a majority of pea aphids in field populations. Frequency of the heat-sensitive Buchnera allele is negatively correlated with presence of facultative symbionts in both laboratory colonies and field populations, suggesting that these infections impose stress that is ameliorated by ibpA expression. This single base polymorphism in Buchnera has the potential to allow aphid populations to adapt quickly to prevailing conditions. PMID:20610410

  7. Exercise Limitation Imposed by an Approved Air Purifying Respirator (APR)

    DTIC Science & Technology

    2010-05-01

    mentioned that they did not have enough time to inhale, that inspiratory muscles were fatigued, that they got out of rhythm with their breathing and...frequency, tidal volume, respiratory duty cycle, mask pressure, resistive effort (WOB/VT), minute ventilation (VE), peak inspiratory flow (Vi peak), rate...and VO2 at end running endurance decreased 15 to 18%. Because required inspiratory pressures from laminar and turbulent flow were so high at the

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

    PubMed Central

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

    2011-01-01

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

  9. 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

  10. 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.

  11. Radiation-induced mutation at minisatellite loci

    SciTech Connect

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

    1997-10-01

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

  12. 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

  13. 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

  14. 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....

  15. 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...

  16. 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...

  17. 42 CFR 423.758 - Collection of civil money penalties imposed by CMS.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 3 2013-10-01 2013-10-01 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...

  18. 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...

  19. 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...

  20. 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... 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...

  1. 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...

  2. 42 CFR 423.758 - Collection of civil money penalties imposed by CMS.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 3 2012-10-01 2012-10-01 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...

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

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 3 2013-10-01 2013-10-01 false Collection of civil money penalties imposed by CMS... Sanctions § 422.758 Collection of civil money penalties imposed by CMS. (a) When an MA organization does not request a hearing, CMS initiates collection of the civil money penalty following the expiration of...

  4. 42 CFR 422.758 - Collection of civil money penalties imposed by CMS.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 3 2012-10-01 2012-10-01 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...

  5. 26 CFR 1.665(d)-1A - Taxes imposed on the trust.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ...) is used and there are no net short-term gains, an amount equal to such total taxes less the amount of... short-term gains, the amount is the amount of the alternative tax imposed on the trust and attributable... general. (1) For purposes of subpart D, the term taxes imposed on the trust means the amount of...

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

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 8 2013-04-01 2013-04-01 false Tax imposed on life insurance companies. 1.802-3... TAX (CONTINUED) INCOME TAXES (CONTINUED) Life Insurance Companies § 1.802-3 Tax imposed on life insurance companies. (a) In general. For taxable years beginning after December 31, 1957, section...

  7. 26 CFR 1.802-3 - Tax imposed on life insurance companies.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 8 2014-04-01 2014-04-01 false Tax imposed on life insurance companies. 1.802-3... TAX (CONTINUED) INCOME TAXES (CONTINUED) Life Insurance Companies § 1.802-3 Tax imposed on life insurance companies. (a) In general. For taxable years beginning after December 31, 1957, section...

  8. 26 CFR 1.665(d)-1 - Taxes imposed on the trust.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Taxes imposed on the trust. 1.665(d)-1 Section 1... (CONTINUED) INCOME TAXES Treatment of Excess Distributions of Trusts Applicable to Taxable Years Beginning Before January 1, 1969 § 1.665(d)-1 Taxes imposed on the trust. (a) For the purpose of subpart D...

  9. Wnt/β-catenin signaling accelerates mouse lung tumorigenesis by imposing an embryonic distal progenitor phenotype on lung epithelium.

    PubMed

    Pacheco-Pinedo, Eugenia C; Durham, Amy C; Stewart, Kathleen M; Goss, Ashley M; Lu, Min Min; Demayo, Francesco J; Morrisey, Edward E

    2011-05-01

    Although mutations in Kras are present in 21% of lung tumors, there is a high level of heterogeneity in phenotype and outcome among patients with lung cancer bearing similar mutations, suggesting that other pathways are important. Wnt/β-catenin signaling is a known oncogenic pathway that plays a well-defined role in colon and skin cancer; however, its role in lung cancer is unclear. We have shown here that activation of Wnt/β-catenin in the bronchiolar epithelium of the adult mouse lung does not itself promote tumor development. However, concurrent activation of Wnt/β-catenin signaling and expression of a constitutively active Kras mutant (KrasG12D) led to a dramatic increase in both overall tumor number and size compared with KrasG12D alone. Activation of Wnt/β-catenin signaling altered the KrasG12D tumor phenotype, resulting in a phenotypic switch from bronchiolar epithelium to the highly proliferative distal progenitors found in the embryonic lung. This was associated with decreased E-cadherin expression at the cell surface, which may underlie the increased metastasis of tumors with active Wnt/β-catenin signaling. Together, these data suggest that activation of Wnt/β-catenin signaling can combine with other oncogenic pathways in lung epithelium to produce a more aggressive tumor phenotype by imposing an embryonic distal progenitor phenotype and by decreasing E-cadherin expression.

  10. Mutations in the yeast RNA14 and RNA15 genes result in an abnormal mRNA decay rate; sequence analysis reveals an RNA-binding domain in the RNA15 protein.

    PubMed Central

    Minvielle-Sebastia, L; Winsor, B; Bonneaud, N; Lacroute, F

    1991-01-01

    In Saccharomyces cerevisiae, temperature-sensitive mutations in the genes RNA14 and RNA15 correlate with a reduction of mRNA stability and poly(A) tail length. Although mRNA transcription is not abolished in these mutants, the transcripts are rapidly deadenylated as in a strain carrying an RNA polymerase B(II) temperature-sensitive mutation. This suggests that the primary defect could be in the control of the poly(A) status of the mRNAs and that the fast decay rate may be due to the loss of this control. By complementation of their temperature-sensitive phenotype, we have cloned the wild-type genes. They are essential for cell viability and are unique in the haploid genome. The RNA14 gene, located on chromosome H, is transcribed as three mRNAs, one major and two minor, which are 2.2, 1.5, and 1.1 kb in length. The RNA15 gene gives rise to a single 1.2-kb transcript and maps to chromosome XVI. Sequence analysis indicates that RNA14 encodes a 636-amino-acid protein with a calculated molecular weight of 75,295. No homology was found between RNA14 and RNA15 or between RNA14 and other proteins contained in data banks. The RNA15 DNA sequence predicts a protein of 296 amino acids with a molecular weight of 32,770. Sequence comparison reveals an N-terminal putative RNA-binding domain in the RNA15-encoded protein, followed by a glutamine and asparagine stretch similar to the opa sequences. Both RNA14 and RNA15 wild-type genes, when cloned on a multicopy plasmid, are able to suppress the temperature-sensitive phenotype of strains bearing either the rna14 or the rna15 mutation, suggesting that the encoded proteins could interact with each other. Images PMID:1674817

  11. 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...

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

    Code of Federal Regulations, 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...

  13. 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...

  14. 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...

  15. 14 CFR 382.33 - May carriers impose other restrictions on passengers with a disability that they do not impose on...

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 4 2010-01-01 2010-01-01 false May carriers impose other restrictions on... and Space OFFICE OF THE SECRETARY, DEPARTMENT OF TRANSPORTATION (AVIATION PROCEEDINGS) SPECIAL REGULATIONS NONDISCRIMINATION ON THE BASIS OF DISABILITY IN AIR TRAVEL Nondiscrimination and Access...

  16. Comparison of uncommon EGFR exon 21 L858R compound mutations with single mutation.

    PubMed

    Peng, Liang; Song, Zhigang; Jiao, Shunchang

    2015-01-01

    Non-small-cell lung cancer with epidermal growth factor receptor (EGFR) mutation is sensitive to EGFR tyrosine kinase inhibitors (TKIs). But little is known about the response to EGFR TKIs and the prognostic role of compound mutations. This study compared the uncommon EGFR exon 21 L858R compound mutations with single mutation to characterize EGFR compound mutations and investigated their response to EGFR TKI treatment. We retrospectively screened 799 non-small-cell lung cancer patients from August 1, 2009 to June 1, 2012 by EGFR mutation testing. EGFR mutations were detected in 443 patients, with 22 (4.97%) compound mutations. Subsequently, six patients with EGFR exon 21 L858R compound mutations and 18 paired patients with single L858R mutation were well characterized. Finally, we also analyzed the EGFR TKI treatment response and patients' outcomes of compound or single L858R mutations. There was no differential treatment effect on the disease control rate and objective response rate between the L858R compound mutations and single mutation groups. No significant difference in overall survival or progression-free survival of these two groups was found by log-rank test. In conclusion, we demonstrated that no significant difference was detected in the response to EGFR TKIs and patients' outcomes in the compound and single mutation groups.

  17. 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.

  18. 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

  19. Paradoxical Sensitivity to an Integrated Stress Response Blocking Mutation in Vanishing White Matter Cells

    PubMed Central

    2016-01-01

    The eukaryotic translation initiation factor eIF2B promotes mRNA translation as a guanine nucleotide exchange factor (GEF) for translation initiation factor 2 (eIF2). Endoplasmic reticulum (ER) stress-mediated activation of the kinase PERK and the resultant phosphorylation of eIF2’s alpha subunit (eIF2α) attenuates eIF2B GEF activity thereby inducing an integrated stress response (ISR) that defends against protein misfolding in the ER. Mutations in all five subunits of human eIF2B cause an inherited leukoencephalopathy with vanishing white matter (VWM), but the role of the ISR in its pathogenesis remains unclear. Using CRISPR-Cas9 genome editing we introduced the most severe known VWM mutation, EIF2B4A391D, into CHO cells. Compared to isogenic wildtype cells, GEF activity of cells with the VWM mutation was impaired and the mutant cells experienced modest enhancement of the ISR. However, despite their enhanced ISR, imposed by the intrinsic defect in eIF2B, disrupting the inhibitory effect of phosphorylated eIF2α on GEF by a contravening EIF2S1/eIF2αS51A mutation that functions upstream of eIF2B, selectively enfeebled both EIF2B4A391D and the related severe VWM EIF2B4R483W cells. The basis for paradoxical dependence of cells with the VWM mutations on an intact eIF2α genotype remains unclear, as both translation rates and survival from stressors that normally activate the ISR were not reproducibly affected by the VWM mutations. Nonetheless, our findings support an additional layer of complexity in the development of VWM, beyond a hyperactive ISR. PMID:27812215

  20. Paradoxical Sensitivity to an Integrated Stress Response Blocking Mutation in Vanishing White Matter Cells.

    PubMed

    Sekine, Yusuke; Zyryanova, Alisa; Crespillo-Casado, Ana; Amin-Wetzel, Niko; Harding, Heather P; Ron, David

    2016-01-01

    The eukaryotic translation initiation factor eIF2B promotes mRNA translation as a guanine nucleotide exchange factor (GEF) for translation initiation factor 2 (eIF2). Endoplasmic reticulum (ER) stress-mediated activation of the kinase PERK and the resultant phosphorylation of eIF2's alpha subunit (eIF2α) attenuates eIF2B GEF activity thereby inducing an integrated stress response (ISR) that defends against protein misfolding in the ER. Mutations in all five subunits of human eIF2B cause an inherited leukoencephalopathy with vanishing white matter (VWM), but the role of the ISR in its pathogenesis remains unclear. Using CRISPR-Cas9 genome editing we introduced the most severe known VWM mutation, EIF2B4A391D, into CHO cells. Compared to isogenic wildtype cells, GEF activity of cells with the VWM mutation was impaired and the mutant cells experienced modest enhancement of the ISR. However, despite their enhanced ISR, imposed by the intrinsic defect in eIF2B, disrupting the inhibitory effect of phosphorylated eIF2α on GEF by a contravening EIF2S1/eIF2αS51A mutation that functions upstream of eIF2B, selectively enfeebled both EIF2B4A391D and the related severe VWM EIF2B4R483W cells. The basis for paradoxical dependence of cells with the VWM mutations on an intact eIF2α genotype remains unclear, as both translation rates and survival from stressors that normally activate the ISR were not reproducibly affected by the VWM mutations. Nonetheless, our findings support an additional layer of complexity in the development of VWM, beyond a hyperactive ISR.

  1. 77 FR 65220 - Certain Licensees Requesting Unescorted Access to Radioactive Material; Order Imposing...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-10-25

    ... From the Federal Register Online via the Government Publishing Office NUCLEAR REGULATORY COMMISSION Certain Licensees Requesting Unescorted Access to Radioactive Material; Order Imposing Trustworthiness and Reliability Requirements for Unescorted Access to Certain Radioactive Material (Effective Immediately) I The Licensee identified...

  2. 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

  3. Dendritic solidification. III - Some further refinements to the model for dendritic growth under an imposed thermal gradient

    NASA Technical Reports Server (NTRS)

    Laxmanan, V.

    1985-01-01

    Some further refinements to a simple model for dendritic solidification in a binary alloy melt under an imposed positive thermal gradient are presented. Two new expressions for the dendrite tip undercooling have been obtained and shown to yield a limiting value of Delta T sub 0 and very small growth rates. Here Delta T sub 0 is the equilibrium solidification range of the alloy. At very large growth rates, all three tip undercooling expressions reach the same limiting value depending on the value of a dimensionless parameter lambda which is related to the effective diffusion distance ahead of the dendrite tip. The predicted tip undercoolings are, however, somewhat lower at intermediate growth rates. An improved calculation for the solute buildup at the dendrite tip due to curvature effects is also included.

  4. 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.

  5. Mutations of a residue within the polyproline-rich region of Env alter the replication rate and level of cytopathic effects in chimeric avian retroviral vectors.

    PubMed

    Chang, Kevin W; Barsov, Eugene V; Ferris, Andrea L; Hughes, Stephen H

    2005-08-01

    Previous attempts to extend the host range of the avian sarcoma/leukosis virus (ASLV)-based RCASBP vectors produced two viral vectors, RCASBP M2C (4070A) and RCASBP M2C (797-8), which replicate using the amphotropic murine leukemia virus 4070A Env protein (2). Both viruses were adapted to replicate efficiently in the avian cell line DF-1, but RCASBP M2C (4070A) caused extensive cytopathic effects (CPE) in DF-1 cells whereas RCASBP M2C (797-8) induced low levels of CPE. The two viruses differed only at amino acid 242 of the polyproline-rich region in the surface (SU) subunit of the Env protein. In RCASBP M2C (4070A), an isoleucine replaced the wild-type proline residue, whereas a threonine residue was found in RCASBP M2C (797-8). In the present study, we show that other amino acid substitutions at position 242 strongly influence the CPE and replication rate of the chimeric viruses. There was a correlation between the amount of unintegrated linear retroviral DNA present in infected DF-1 cells and the level of CPE. This suggests that there may be a role for superinfection in the CPE. The treatment of RCASBP M2C (4070A)-infected cells with dantrolene, which inhibits the release of calcium from the endoplasmic reticulum (ER), reduced the amount of CPE seen during infection with the highly cytotoxic virus. Dantrolene treatment did not appear to affect virus production, suggesting that Ca2+ release from the ER had a role in the CPE caused by these viruses.

  6. Common Charge-Shift Mutation Glu65Lys in K+ Channel β1-Subunit KCNMB1: Pleiotropic Consequences for Glomerular Filtration Rate and Progressive Renal Disease

    PubMed Central

    Chen, Yuqing; Salem, Rany M.; Rao, Fangwen; Fung, Maple M.; Bhatnagar, Vibha; Pandey, Braj; Mahata, Manjula; Waalen, Jill; Nievergelt, Caroline M.; Lipkowitz, Michael S.; Hamilton, Bruce A.; Mahata, Sushil K.; O'Connor, Daniel T.

    2010-01-01

    Background Glomerular filtration rate (GFR) is a heritable trait, and hyperfiltration (GFR increment in remnant nephrons) may accelerate renal functional decline in chronic kidney disease (CKD). Mesangial and vascular smooth myocytes control GFR by contraction, dependent on voltage-gated Ca2+ influx, which is controlled by the regulatory β1-subunit (KCNMB1) of large-conductance heteromeric K+ (‘BK’) channels. KCNMB1 gain-of-function variant Glu65Lys results in generalized vasorelaxation and thus protection against systemic hypertension. Here we asked whether the Glu65Lys variant influences GFR, in the basal state or during progressive renal decline. Methods We explored Glu65Lys effects on GFR in three populations spanning two ethnicities and two diseases (hypertension and nephrosclerosis). GFR was either estimated (eGFR from serum creatinine) or directly measured (iothalamate clearance). Results The 65Lys variant was relatively common, occurring on ∼5−10% of chromosomes in different biogeographic ancestry groups, and 65Lys carriers exhibited higher eGFR in two primary care populations: extreme BP values in Kaiser clinics (p = 0.029, accounting for ∼0.2% of trait variance), or treated hypertensives in VA clinics (p = 0.017, accounting for ∼0.9% of trait variance). In blacks with progressive renal disease (NIDDK AASK), 65Lys carriers displayed a steeper slope in GFR chronic decline (p = 0.030, accounting for ∼0.4% of trait variance), and Glu65Lys genotype also predicted time of onset of renal failure (log rank p = 0.019). Conclusions Common KCNMB1 gain-of-function variant Glu65Lys influences GFR, and 65Lys carriers exhibit not only elevated baseline GFR, but also more rapid GFR decline (and consequent development of renal failure) in CKD. The results suggest that profiling patients at Glu65Lys can assist in gauging renal prognosis as well as selection of rational therapy in hypertension with progressive renal disease. PMID:20861615

  7. 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

  8. 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

  9. 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

  10. Dendritic solidification. I - Analysis of current theories and models. II - A model for dendritic growth under an imposed thermal gradient

    NASA Technical Reports Server (NTRS)

    Laxmanan, V.

    1985-01-01

    A critical review of the present dendritic growth theories and models is presented. Mathematically rigorous solutions to dendritic growth are found to rely on an ad hoc assumption that dendrites grow at the maximum possible growth rate. This hypothesis is found to be in error and is replaced by stability criteria which consider the conditions under which a dendrite tip advances in a stable fashion in a liquid. The important elements of a satisfactory model for dendritic solidification are summarized and a theoretically consistent model for dendritic growth under an imposed thermal gradient is proposed and described. The model is based on the modification of an analysis due to Burden and Hunt (1974) and predicts correctly in all respects, the transition from a dendritic to a planar interface at both very low and very large growth rates.

  11. 25 CFR 170.916 - May tribes impose taxes or fees on those performing IRR Program services?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 25 Indians 1 2010-04-01 2010-04-01 false May tribes impose taxes or fees on those performing IRR... Indian Preference § 170.916 May tribes impose taxes or fees on those performing IRR Program services? Yes. Tribes, as sovereign nations, may impose taxes and fees for IRR Program activities. When a...

  12. 25 CFR 170.916 - May tribes impose taxes or fees on those performing IRR Program services?

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 25 Indians 1 2011-04-01 2011-04-01 false May tribes impose taxes or fees on those performing IRR... Indian Preference § 170.916 May tribes impose taxes or fees on those performing IRR Program services? Yes. Tribes, as sovereign nations, may impose taxes and fees for IRR Program activities. When a...

  13. 42 CFR 422.760 - Determinations regarding the amount of civil money penalties and assessment imposed by CMS.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... penalties and assessment imposed by CMS. 422.760 Section 422.760 Public Health CENTERS FOR MEDICARE... money penalties and 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)...

  14. 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)...

  15. 42 CFR 422.760 - Determinations regarding the amount of civil money penalties and assessment imposed by CMS.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... penalties and assessment imposed by CMS. 422.760 Section 422.760 Public Health CENTERS FOR MEDICARE... money penalties and 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)...

  16. 42 CFR 423.760 - Determinations regarding the amount of civil money penalties and assessment imposed by CMS.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... penalties and assessment imposed by CMS. 423.760 Section 423.760 Public Health CENTERS FOR MEDICARE... amount of civil money 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...

  17. 42 CFR 422.760 - Determinations regarding the amount of civil money penalties and assessment imposed by CMS.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... penalties and assessment imposed by CMS. 422.760 Section 422.760 Public Health CENTERS FOR MEDICARE... money penalties and 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)...

  18. 42 CFR 423.760 - Determinations regarding the amount of civil money penalties and assessment imposed by CMS.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... penalties and assessment imposed by CMS. 423.760 Section 423.760 Public Health CENTERS FOR MEDICARE... amount of civil money 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 considers...

  19. 42 CFR 423.760 - Determinations regarding the amount of civil money penalties and assessment imposed by CMS.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... penalties and assessment imposed by CMS. 423.760 Section 423.760 Public Health CENTERS FOR MEDICARE... amount of civil money 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...

  20. 42 CFR 423.760 - Determinations regarding the amount of civil money penalties and assessment imposed by CMS.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 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)...

  1. 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...

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

    Code of Federal Regulations, 2010 CFR

    2010-10-01

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

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... a sentence of death imposed by a United States District Court. 1.10 Section 1.10 Judicial... sentence of death imposed by a United States District Court. The following procedures shall apply with respect to any request for clemency by a person under a sentence of death imposed by a United...

  4. 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.

  5. 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

  6. Rare beneficial mutations can halt Muller's ratchet

    NASA Astrophysics Data System (ADS)

    Balick, Daniel; Goyal, Sidhartha; Jerison, Elizabeth; Neher, Richard; Shraiman, Boris; Desai, Michael

    2012-02-01

    In viral, bacterial, and other asexual populations, the vast majority of non-neutral mutations are deleterious. This motivates the application of models without beneficial mutations. Here we show that the presence of surprisingly few compensatory mutations halts fitness decay in these models. Production of deleterious mutations is balanced by purifying selection, stabilizing the fitness distribution. However, stochastic vanishing of fitness classes can lead to slow fitness decay (i.e. Muller's ratchet). For weakly deleterious mutations, production overwhelms purification, rapidly decreasing population fitness. We show that when beneficial mutations are introduced, a stable steady state emerges in the form of a dynamic mutation-selection balance. We argue this state is generic for all mutation rates and population sizes, and is reached as an end state as genomes become saturated by either beneficial or deleterious mutations. Assuming all mutations have the same magnitude selective effect, we calculate the fraction of beneficial mutations necessary to maintain the dynamic balance. This may explain the unexpected maintenance of asexual genomes, as in mitochondria, in the presence of selection. This will affect in the statistics of genetic diversity in these populations.

  7. Dynamics and Fate of Beneficial Mutations Under Lineage Contamination by Linked Deleterious Mutations.

    PubMed

    Pénisson, Sophie; Singh, Tanya; Sniegowski, Paul; Gerrish, Philip

    2017-03-01

    Beneficial mutations drive adaptive evolution, yet their selective advantage does not ensure their fixation. Haldane's application of single-type branching process theory showed that genetic drift alone could cause the extinction of newly arising beneficial mutations with high probability. With linkage, deleterious mutations will affect the dynamics of beneficial mutations and might further increase their extinction probability. Here, we model the lineage dynamics of a newly arising beneficial mutation as a multitype branching process. Our approach accounts for the combined effects of drift and the stochastic accumulation of linked deleterious mutations, which we call lineage contamination We first study the lineage-contamination phenomenon in isolation, deriving dynamics and survival probabilities (the complement of extinction probabilities) of beneficial lineages. We find that survival probability is zero when [Formula: see text] where U is deleterious mutation rate and [Formula: see text] is the selective advantage of the beneficial mutation in question, and is otherwise depressed below classical predictions by a factor bounded from below by [Formula: see text] We then put the lineage contamination phenomenon into the context of an evolving population by incorporating the effects of background selection. We find that, under the combined effects of lineage contamination and background selection, ensemble survival probability is never zero but is depressed below classical predictions by a factor bounded from below by [Formula: see text] where [Formula: see text] is mean selective advantage of beneficial mutations, and [Formula: see text] This factor, and other bounds derived from it, are independent of the fitness effects of deleterious mutations. At high enough mutation rates, lineage contamination can depress fixation probabilities to values that approach zero. This fact suggests that high mutation rates can, perhaps paradoxically, (1) alleviate competition

  8. GENETIC MUTATIONS AFFECTING THE FIRST LINE ERADICATION THERAPY OF Helicobacter pylori-INFECTED EGYPTIAN PATIENTS

    PubMed Central

    RAMZY, Iman; ELGAREM, Hassan; HAMZA, Iman; GHAITH, Doaa; ELBAZ, Tamer; ELHOSARY, Waleed; MOSTAFA, Gehan; ELZAHRY, Mohammad A. Mohey Eldin

    2016-01-01

    SUMMARY Introduction: Several genetic mutations affect the first-line triple therapy for Helicobacter pylori. We aimed to study the most common genetic mutations affecting the metronidazole and clarithromycin therapy for H. pylori-infected Egyptian patients. Patients and Methods: In our study, we included 100 successive dyspeptic patients scheduled for diagnosis through upper gastroscopy at Cairo's University Hospital, Egypt. Gastric biopsies were tested for the presence of H. pylori by detection of the 16S rRNA gene. Positive biopsies were further studied for the presence of the rdxA gene deletion by Polymerase Chain Reaction (PCR), while clarithromycin resistance was investigated by the presence of nucleotide substitutions within H. pylori 23S rRNA V domain using MboII and BsaI to carry out a Restricted Fragment Length Polymorphism (RFLP) assay. Results: Among 70 H. pylori positive biopsies, the rdxA gene deletion was detected in 44/70 (62.9%) samples, while predominance of the A2142G mutations within the H. pylori 23S rRNA V domain was evidenced in 39/70 (55.7%) of the positive H. pylori cases. No statistically significant difference was found between the presence of gene mutations and different factors such as patients 'age, gender, geographic distribution, symptoms and endoscopic findings. Conclusion: Infection with mutated H. pylori strains is considerably high, a finding that imposes care in the use of the triple therapy to treat H. pylori in Egypt, since the guidelines recommend to abandon the standard triple therapy when the primary clarithromycin resistance rate is over 20%1. PMID:27982354

  9. 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...

  10. 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...

  11. 78 FR 56832 - Extension of Import Restrictions Imposed on Archaeological Material From Cambodia From the Bronze...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-09-16

    ... Extension of Import Restrictions Imposed on Archaeological Material From Cambodia From the Bronze Age... material from Cambodia from the Bronze Age through the Khmer era. The restrictions, which were originally... archaeological material from the Bronze Age through the Khmer Era. Import restrictions listed in 19 CFR...

  12. 26 CFR 1.802-3 - Tax imposed on life insurance companies.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... a life insurance business within the United States if with respect to its United States business it... insurance companies. Foreign life insurance companies not carrying on an insurance business within the... 26 Internal Revenue 8 2011-04-01 2011-04-01 false Tax imposed on life insurance companies....

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

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... alternative tax computation under section 1201(b) is used and there are no net short-term gains, the amount is... purposes of subpart D, the term taxes imposed on the trust means the amount of Federal income taxes... distributable net income and gains in excess of losses from the sales or exchanges of capital assets. Except...

  14. 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)

  15. 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... with the organization whose medical condition or history indicates a need for substantial...

  16. 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... BENEFIT Intermediate Sanctions § 423.752 Basis for imposing intermediate sanctions and civil money... permitted by this part) by eligible individuals with the organization whose medical condition or...

  17. Characteristic alterations in responses to imposed wrist displacements in parkinsonian rigidity and dystonia musculorum deformans.

    PubMed

    Tatton, W G; Bedingham, W; Verrier, M C; Blair, R D

    1984-05-01

    The amplitude and temporal modulation of the segmented EMG activity in flexor carpi radialis, evoked by imposed angular wrist extension, was studied with respect to the level of pre-existing background activity in rigid parkinsonian (PK) and dystonia musculorum deformans (DMD) patients. The interdependence of the evoked M1 and M2-3 segments on pre-existing background EMG activity and initial velocity of imposed displacement was established previously for a normal population. Individual responses of 21 parkinsonian and 12 dystonic patients were compared to the established normal "response volume". The augmented magnitude of the M2-3 segment in rigid PK patients, which correlates to the measure of rigidity, could not be accounted for by the low level of pre-existing EMG activity. Therefore, increased descending facilitation does not impinge directly on alpha motoneurons. Paradoxical excitation in the shortened muscle and resetting of tonic tremor of the stretched muscle by the imposed wrist extension are two other demonstrated abnormalities which may also contribute to PK rigidity. In contrast, DMD patients demonstrated normal amplitude modulation of the M1 and M2-3 segments, but exhibited a disturbance of normal temporal mechanisms that result in constant duration of the M1 and M2-3 responses with imposed force step loads.

  18. Identification during imposed change: the roles of personal values, type of change, and anxiety.

    PubMed

    Sverdlik, Noga; Oreg, Shaul

    2015-06-01

    Using a person-situation perspective, we explain what happens to individuals' identification with a collective in the context of a change. We propose that given the anxiety that often emerges during change, individuals' personal values (conservation and openness to change) interact with type of change (imposed vs. voluntary) in predicting identification following change. In a pilot, longitudinal field study (N = 61, 67% female) of an imposed university campus relocation, we measured employees' values and identification with the university before and several months after the relocation. In two lab experiments (Study 1: N = 104, 91.3% female; Study 2: N = 113, 75.2% female), we manipulated a change to be either imposed or voluntary and compared the relationships between values and identification across types of change. In Study 2, we also measured anxiety from the change. When change was imposed (all three studies), but not when voluntary (Studies 1 and 2), individuals' conservation was positively, and openness negatively, related to individuals' post-change identification. The effects emerged only for individuals who experienced change-related anxiety (Study 2). Our findings demonstrate that individuals' identification with a changing collective depends on the amount of anxiety change elicits and on the particular combination of their values and type of change.

  19. Dress-Related Responses to the Columbine Shootings: Other-Imposed and Self-Designed.

    ERIC Educational Resources Information Center

    Ogle, Jennifer Paff; Eckman, Molly

    2002-01-01

    An inductive content analysis approach was used to examine 155 dress-related newspaper articles following the Columbine High School shootings in 1999. Analysis revealed two dress-related responses: (1) other-imposed regulation to protect students and deter them from expressing hatred and (2) self-designed acts of resistance for grieving. (Contains…

  20. 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…

  1. 28 CFR 71.54 - Collection and compromise of liabilities imposed by Agency.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 28 Judicial Administration 2 2010-07-01 2010-07-01 false Collection and compromise of liabilities...) IMPLEMENTATION OF THE PROVISIONS OF THE PROGRAM FRAUD CIVIL REMEDIES ACT OF 1986 Assignment of Responsibilities... and civil penalties imposed under the Program Fraud Civil Remedies Act of 1986, and, subsequent to...

  2. 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...

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

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... tentative tax amount), over (B) The sum of the taxes previously imposed (if any) on the ODC under sections... consumption, use, or warehousing—(i) In general. Except as otherwise provided in this paragraph (c)(4), the term “entered into the United States for consumption, use, or warehousing” when used with respect...

  4. 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...

  5. 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...

  6. 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...

  7. A new method of imposing boundary conditions in pseudospectral approximations of hyperbolic equations

    NASA Technical Reports Server (NTRS)

    Funaro, D.; Gottlieb, D.

    1988-01-01

    A new method to impose boundary conditions for pseudospectral approximations to hyperbolic equations is suggested. This method involves the collocation of the equation at the boundary nodes as well as satisfying boundary conditions. Stability and convergence results are proven for the Chebyshev approximation of linear scalar hyperbolic equations. The eigenvalues of this method applied to parabolic equations are shown to be real and negative.

  8. 13 CFR 127.700 - What penalties may be imposed under this part?

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 13 Business Credit and Assistance 1 2012-01-01 2012-01-01 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 PROGRAM Penalties § 127.700 What penalties may be...

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

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 13 Business Credit and Assistance 1 2010-01-01 2010-01-01 false What penalties may be imposed under this part? 125.29 Section 125.29 Business Credit and Assistance SMALL BUSINESS ADMINISTRATION... penalties under the False Claims Act, 31 U.S.C. 3729-3733, and under the Program Fraud Civil Remedies...

  10. 13 CFR 126.900 - What penalties may be imposed under this part?

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 13 Business Credit and Assistance 1 2010-01-01 2010-01-01 false What penalties may be imposed under this part? 126.900 Section 126.900 Business Credit and Assistance SMALL BUSINESS ADMINISTRATION...-3733, and under the Program Fraud Civil Remedies Act, 31 U.S.C. 3801-3812, and any other...

  11. 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...

  12. 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...

  13. 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...

  14. 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...

  15. 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...

  16. Mutational profiles in triple-negative breast cancer defined by ultradeep multigene sequencing show high rates of PI3K pathway alterations and clinically relevant entity subgroup specific differences.

    PubMed

    Kriegsmann, Mark; Endris, Volker; Wolf, Thomas; Pfarr, Nicole; Stenzinger, Albrecht; Loibl, Sibylle; Denkert, Carsten; Schneeweiss, Andreas; Budczies, Jan; Sinn, Peter; Weichert, Wilko

    2014-10-30

    Mutational profiling of triple-negative breast cancer (TNBC) by whole exome sequencing (WES) yielded a landscape of genomic alterations in this tumor entity. However, the clinical significance of these findings remains enigmatic. Further, integration of WES in routine diagnostics using formalin-fixed paraffin-embedded (FFPE) material is currently not feasible. Therefore, we designed and validated a breast cancer specific gene panel for semiconductor-based sequencing comprising 137 amplicons covering mutational hotspots in 44 genes and applied this panel on a cohort of 104 well-characterized FFPE TNBC with complete clinical follow-up. TP53 mutations were present in more than 80% of cases. PI3K pathway alterations (29.8%) comprising mainly PIK3CA mutations (22.1%) but also mutations and/or amplifications/deletions in other PI3K-associated genes (7.7%) were far more frequently observed, when compared to WES data. Alterations in MAPK signaling genes (8.7%) and cell-cycle regulators (14.4%) were also frequent. Mutational profiles were linked to TNBC subgroups defined by morphology and immunohistochemistry. Alterations in cell-cycle pathway regulators were linked with better overall (p=0.053) but not disease free survival. Taken together, we could demonstrate that breast cancer targeted hotspot sequencing is feasible in a routine setting and yields reliable and clinically meaningful results. Mutational spectra were linked to clinical and immunohistochemically defined parameters.

  17. Clock-like mutational processes in human somatic cells

    DOE PAGES

    Alexandrov, Ludmil B.; Jones, Philip H.; Wedge, David C.; ...

    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

  18. Molecular Analysis of Hereditary Nonpolyposis Colorectal Cancer in the United States: High Mutation Detection Rate among Clinically Selected Families and Characterization of an American Founder Genomic Deletion of the MSH2 Gene

    PubMed Central

    Wagner, Anja; Barrows, Alicia; Wijnen, Juul Th.; van der Klift, Heleen; Franken, Patrick F.; Verkuijlen, Paul; Nakagawa, Hidewaki; Geugien, Marjan; Jaghmohan-Changur, Shantie; Breukel, Cor; Meijers-Heijboer, Hanne; Morreau, Hans; van Puijenbroek, Marjo; Burn, John; Coronel, Stephany; Kinarski, Yulia; Okimoto, Ross; Watson, Patrice; Lynch, Jane F.; de la Chapelle, Albert; Lynch, Henry T.; Fodde, Riccardo

    2003-01-01

    The identification of germline mutations in families with HNPCC is hampered by genetic heterogeneity and clinical variability. In previous studies, MSH2 and MLH1 mutations were found in approximately two-thirds of the Amsterdam-criteria–positive families and in much lower percentages of the Amsterdam-criteria–negative families. Therefore, a considerable proportion of HNPCC seems not to be accounted for by the major mismatch repair (MMR) genes. Does the latter result from a lack of sensitivity of mutation detection techniques, or do additional genes underlie the remaining cases? In this study we address these questions by thoroughly investigating a cohort of clinically selected North American families with HNPCC. We analyzed 59 clinically well-defined U.S. families with HNPCC for MSH2, MLH1, and MSH6 mutations. To maximize mutation detection, different techniques were employed, including denaturing gradient gel electrophoresis, Southern analysis, microsatellite instability, immunohistochemistry, and monoallelic expression analysis. In 45 (92%) of the 49 Amsterdam-criteria–positive families and in 7 (70%) of the 10 Amsterdam-criteria–negative families, a mutation was detected in one of the three analyzed MMR genes. Forty-nine mutations were in MSH2 or MLH1, and only three were in MSH6. A considerable proportion (27%) of the mutations were genomic rearrangements (12 in MSH2 and 2 in MLH1). Notably, a deletion encompassing exons 1–6 of MSH2 was detected in seven apparently unrelated families (12% of the total cohort) and was subsequently proven to be a founder. Screening of a second U.S. cohort with HNPCC from Ohio allowed the identification of two additional kindreds with the identical founder deletion. In the present study, we show that optimal mutation detection in HNPCC is achieved by combining accurate and expert clinical selection with an extensive mutation detection strategy. Notably, we identified a common North American deletion in MSH2, accounting

  19. Imposing periodic suction to stabilise thin-film flow down an inclined plane

    NASA Astrophysics Data System (ADS)

    Thompson, Alice; Papageorgiou, Demetrios; Tseluiko, Dmitri; Imperial Collaboration; Loughborough Collaboration

    2014-11-01

    Flow of a thin film down an inclined plane becomes unstable when the slope angle or Reynolds number are sufficiently large; enhancement or suppression of these instabilities is relevant to a range of industrial applications. Here we study the effect of introducing spatially periodic blowing and sucking through the rigid planar boundary. We derive two long-wave, thin-film models to describe the system, including the imposed suction as well as inertia, surface tension, gravity and viscosity. We explore the bifurcation structure in each model, and perform linear stability and time-dependent simulations for both small and large forcing amplitude. Both models predict that forcing via imposed suction can be chosen to either destabilize or stabilize the flow, and we show that forcing at very long wavelengths always has a stabilizing effect on the flow. Support provided by the EPSRC Grant Number EP/K041134/1.

  20. 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.

  1. Slow-Wave Sleep-Imposed Replay Modulates Both Strength and Precision of Memory

    PubMed Central

    2014-01-01

    Odor perception is hypothesized to be an experience-dependent process involving the encoding of odor objects by distributed olfactory cortical ensembles. Olfactory cortical neurons coactivated by a specific pattern of odorant evoked input become linked through association fiber synaptic plasticity, creating a template of the familiar odor. In this way, experience and memory play an important role in odor perception and discrimination. In other systems, memory consolidation occurs partially via slow-wave sleep (SWS)-dependent replay of activity patterns originally evoked during waking. SWS is ideal for replay given hyporesponsive sensory systems, and thus reduced interference. Here, using artificial patterns of olfactory bulb stimulation in a fear conditioning procedure in the rat, we tested the effects of imposed post-training replay during SWS and waking on strength and precision of pattern memory. The results show that imposed replay during post-training SWS enhanced the subsequent strength of memory, whereas the identical replay during waking induced extinction. The magnitude of this enhancement was dependent on the timing of imposed replay relative to cortical sharp-waves. Imposed SWS replay of stimuli, which differed from the conditioned stimulus, did not affect conditioned stimulus memory strength but induced generalization of the fear memory to novel artificial patterns. Finally, post-training disruption of piriform cortex intracortical association fiber synapses, hypothesized to be critical for experience-dependent odor coding, also impaired subsequent memory precision but not strength. These results suggest that SWS replay in the olfactory cortex enhances memory consolidation, and that memory precision is dependent on the fidelity of that replay. PMID:24719093

  2. Slow-wave sleep-imposed replay modulates both strength and precision of memory.

    PubMed

    Barnes, Dylan C; Wilson, Donald A

    2014-04-09

    Odor perception is hypothesized to be an experience-dependent process involving the encoding of odor objects by distributed olfactory cortical ensembles. Olfactory cortical neurons coactivated by a specific pattern of odorant evoked input become linked through association fiber synaptic plasticity, creating a template of the familiar odor. In this way, experience and memory play an important role in odor perception and discrimination. In other systems, memory consolidation occurs partially via slow-wave sleep (SWS)-dependent replay of activity patterns originally evoked during waking. SWS is ideal for replay given hyporesponsive sensory systems, and thus reduced interference. Here, using artificial patterns of olfactory bulb stimulation in a fear conditioning procedure in the rat, we tested the effects of imposed post-training replay during SWS and waking on strength and precision of pattern memory. The results show that imposed replay during post-training SWS enhanced the subsequent strength of memory, whereas the identical replay during waking induced extinction. The magnitude of this enhancement was dependent on the timing of imposed replay relative to cortical sharp-waves. Imposed SWS replay of stimuli, which differed from the conditioned stimulus, did not affect conditioned stimulus memory strength but induced generalization of the fear memory to novel artificial patterns. Finally, post-training disruption of piriform cortex intracortical association fiber synapses, hypothesized to be critical for experience-dependent odor coding, also impaired subsequent memory precision but not strength. These results suggest that SWS replay in the olfactory cortex enhances memory consolidation, and that memory precision is dependent on the fidelity of that replay.

  3. Imposed Power of Breathing Associated With Use of an Impedance Threshold Device

    DTIC Science & Technology

    2007-02-01

    per min is the power of breathing ( POB ). The objectives of this study were to measure and compare the inspiratory imposed POB (POBI) and other...testing. During an orientation period that preceded each experiment, all subjects were made familiar with the lab - oratory, the protocol, and the...through the impedance threshold de- vice (–7 cm H2O), the total POB [physiologic POB plus POBI]) is expected to be approximately 12–16 J/min. All the

  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. 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.

    PubMed

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

    2007-03-01

    Mutagenic, 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 spermatogonia (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 spermatogonia (DG) and preleptotene spermatocytes are exposed. The mutation frequency induced by 75mgMNU/kg during this peak interval is, to date, the highest induced by any single-exposure 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 spermatogonia 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

  6. Cancer-associated TERT promoter mutations abrogate telomerase silencing

    PubMed Central

    Chiba, Kunitoshi; Johnson, Joshua Z; Vogan, Jacob M; Wagner, Tina; Boyle, John M; Hockemeyer, Dirk

    2015-01-01

    Mutations in the human telomerase reverse transcriptase (TERT) promoter are the most frequent non-coding mutations in cancer, but their molecular mechanism in tumorigenesis has not been established. We used genome editing of human pluripotent stem cells with physiological telomerase expression to elucidate the mechanism by which these mutations contribute to human disease. Surprisingly, telomerase-expressing embryonic stem cells engineered to carry any of the three most frequent TERT promoter mutations showed only a modest increase in TERT transcription with no impact on telomerase activity. However, upon differentiation into somatic cells, which normally silence telomerase, cells with TERT promoter mutations failed to silence TERT expression, resulting in increased telomerase activity and aberrantly long telomeres. Thus, TERT promoter mutations are sufficient to overcome the proliferative barrier imposed by telomere shortening without additional tumor-selected mutations. These data establish that TERT promoter mutations can promote immortalization and tumorigenesis of incipient cancer cells. DOI: http://dx.doi.org/10.7554/eLife.07918.001 PMID:26194807

  7. 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.

  8. 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...

  9. 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...

  10. 42 CFR 488.433 - Civil money penalties: Uses and approval of civil money penalties imposed by CMS.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 5 2012-10-01 2012-10-01 false Civil money penalties: Uses and approval of civil money penalties imposed by CMS. 488.433 Section 488.433 Public Health CENTERS FOR MEDICARE & MEDICAID... Deficiencies § 488.433 Civil money penalties: Uses and approval of civil money penalties imposed by CMS....

  11. 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....

  12. 42 CFR 488.433 - Civil money penalties: Uses and approval of civil money penalties imposed by CMS.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 5 2014-10-01 2014-10-01 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....

  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 488.431 - 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... imposed by CMS and independent informal dispute resolution: for SNFS, dually-participating SNF/NFs, and NF-only facilities. (a) Opportunity for independent review. CMS retains ultimate authority for the...

  15. 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... imposed by CMS and independent informal dispute resolution: for SNFS, dually-participating SNF/NFs, and NF-only facilities. (a) Opportunity for independent review. CMS retains ultimate authority for the...

  16. 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... imposed by CMS and independent informal dispute resolution: for SNFS, dually-participating SNF/NFs, and NF-only facilities. (a) Opportunity for independent review. CMS retains ultimate authority for the...

  17. 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... imposed by CMS and independent informal dispute resolution: for SNFS, dually-participating SNF/NFs, and NF-only facilities. (a) Opportunity for independent review. CMS retains ultimate authority for the...

  18. 26 CFR 301.7422-1 - Special rules for certain excise taxes imposed by chapter 42 or 43.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 18 2010-04-01 2010-04-01 false Special rules for certain excise taxes imposed... Proceedings Civil Actions by the United States § 301.7422-1 Special rules for certain excise taxes imposed by... in subparagraphs (1) through (4). (b) Right to bring action. With respect to any taxable...

  19. 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

  20. Mutation tendency of mutator Plasmodium berghei with proofreading-deficient DNA polymerase δ

    PubMed Central

    Honma, Hajime; Niikura, Mamoru; Kobayashi, Fumie; Horii, Toshihiro; Mita, Toshihiro; Endo, Hiroyoshi; Hirai, Makoto

    2016-01-01

    In this study, we investigated the mutation tendency of a mutator rodent malaria parasite, Plasmodium berghei, with proofreading-deficient DNA polymerase δ. Wild-type and mutator parasites were maintained in mice for over 24 weeks, and the genome-wide accumulated mutations were determined by high-throughput sequencing. The mutator P. berghei had a significant preference for C/G to A/T substitutions; thus, its genome had a trend towards a higher AT content. The mutation rate was influenced by the sequence context, and mutations were markedly elevated at TCT. Some genes mutated repeatedly in replicate passage lines. In particular, knockout mutations of the AP2-G gene were frequent, which conferred strong growth advantages on parasites during the blood stage but at the cost of losing the ability to form gametocytes. This is the first report to demonstrate a biased mutation tendency in malaria parasites, and its results help to promote our basic understanding of Plasmodium genetics. PMID:27845384

  1. 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

  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. 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.

  4. System for imposing directional stability on a rocket-propelled vehicle

    NASA Technical Reports Server (NTRS)

    Perkins, H. (Inventor)

    1976-01-01

    An improved system for use in imposing directional stability on a rocket-propelled vehicle is described. The system includes a pivotally supported engine-mounting platform, a gimbal ring mounted on the platform and adapted to pivotally support a rocket engine and an hydraulic actuator connected to the platform for imparting selected pivotal motion. An accelerometer and a signal comparator circuit for providing error intelligence indicative of aberration in vehicle acceleration is included along with an actuator control circuit connected with the actuator and responsive to error intelligence for imparting pivotal motion to the platform. Relocation of the engine's thrust vector is thus achieved for imparting directional stability to the vehicle.

  5. 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

  6. Increased transversions in a novel mutator colon cancer cell line.

    PubMed

    Eshleman, J R; Donover, P S; Littman, S J; Swinler, S E; Li, G M; Lutterbaugh, J D; Willson, J K; Modrich, P; Sedwick, W D; Markowitz, S D; Veigl, M L

    1998-03-05

    We describe a novel mutator phenotype in the Vaco411 colon cancer cell line which increases the spontaneous mutation rate 10-100-fold over background. This mutator results primarily in transversion base substitutions which are found infrequently in repair competent cells. Of the four possible types of transversions, only three were principally recovered. Spontaneous mutations recovered also included transitions and large deletions, but very few frameshifts were recovered. When compared to known mismatch repair defective colon cancer mutators, the distribution of mutations in Vaco411 is significantly different. Consistent with this difference, Vaco411 extracts are proficient in assays of mismatch repair. The Vaco411 mutator appears to be novel, and is not an obvious human homologue of any of the previously characterized bacterial or yeast transversion phenotypes. Several hypotheses by which this mutator may produce transversions are presented.

  7. New mutation to Huntington's disease.

    PubMed

    Wolff, G; Deuschl, G; Wienker, T F; Hummel, K; Bender, K; Lücking, C H; Schumacher, M; Hammer, J; Oepen, G

    1989-01-01

    We report a large family with an isolated case of Huntington's disease (HD), which is probably the result of a new mutation. The patient developed clinical signs typical of HD at the age of 36. The clinical course of the patient's disease is documented by several clinical admissions over a period of 14 years at present. The family history is strikingly negative with the parents having been clearly unaffected into their 80s and with 13 older and two younger, living, healthy sibs. Extensive testing of polymorphic markers (blood groups, red cell and serum proteins, HLA antigens) showed no indication of non-paternity, but rather gave strong support to the hypothesis that the proband is a full sib. In addition, DNA typing for several RFLPs known to be closely linked to the HD gene locus indicated that several clearly unaffected sibs share one or the other or both of the patient's haplotypes. This is further evidence in favour of the hypothesis of a new mutation at the HD locus. The posterior probability of a new mutation to HD in the patient exceeds 99%, even if an a priori probability of non-paternity of 10% and a mutation rate of HD of 10(-7) is assumed.

  8. Nucleosomes suppress spontaneous mutations base-specifically in eukaryotes.

    PubMed

    Chen, Xiaoshu; Chen, Zhidong; Chen, Han; Su, Zhijian; Yang, Jianfeng; Lin, Fangqin; Shi, Suhua; He, Xionglei

    2012-03-09

    It is unknown how the composition and structure of DNA within the cell affect spontaneous mutations. Theory suggests that in eukaryotic genomes, nucleosomal DNA undergoes fewer C→T mutations because of suppressed cytosine hydrolytic deamination relative to nucleosome-depleted DNA. Comparative genomic analyses and a mutation accumulation experiment showed that nucleosome occupancy nearly eliminated cytosine deamination, resulting in an ~50% decrease of the C→T mutation rate in nucleosomal DNA. Furthermore, the rates of G→T and A→T mutations were also about twofold suppressed by nucleosomes. On the basis of these results, we conclude that nucleosome-dependent mutation spectra affect eukaryotic genome structure and evolution and may have implications for understanding the origin of mutations in cancers and in induced pluripotent stem cells.

  9. Early mutation bursts in colorectal tumors

    PubMed Central

    Salomon, Matthew P.; Shibata, Darryl; Curtis, Christina; Siegmund, Kimberly; Marjoram, Paul

    2017-01-01

    Tumor growth is an evolutionary process involving accumulation of mutations, copy number alterations, and cancer stem cell (CSC) division and differentiation. As direct observation of this process is impossible, inference regarding when mutations occur and how stem cells divide is difficult. However, this ancestral information is encoded within the tumor itself, in the form of intratumoral heterogeneity of the tumor cell genomes. Here we present a framework that allows simulation of these processes and estimation of mutation rates at the various stages of tumor development and CSC division patterns for single-gland sequencing data from colorectal tumors. We parameterize the mutation rate and the CSC division pattern, and successfully retrieve their posterior distributions based on DNA sequence level data. Our approach exploits Approximate Bayesian Computation (ABC), a method that is becoming widely-used for problems of ancestral inference. PMID:28257429

  10. Transmission of mitochondrial mutations and action of purifying selection in Drosophila melanogaster.

    PubMed

    Ma, Hansong; Xu, Hong; O'Farrell, Patrick H

    2014-04-01

    It is not known how selection affects mutations in the multiple copies of the mitochondrial genome. We transferred cytoplasm between D. melanogaster embryos carrying mitochondrial mutations to create heteroplasmic lines transmitting two mitochondrial genotypes. Increased temperature imposed selection against a temperature-sensitive mutation affecting cytochrome oxidase, driving decreases in the abundance of the mutant genome over successive generations. Selection did not influence the health or fertility of the flies but acted during midoogenesis to influence competition between the genomes. Mitochondria might incur an advantage through selective localization, survival or proliferation, yet timing and insensitivity to park mutation suggest that preferential proliferation underlies selection. Selection drove complete replacement of the temperature-sensitive mitochondrial genome by a wild-type genome but also stabilized the multigenerational transmission of two genomes carrying complementing detrimental mutations. While they are so balanced, these stably transmitted mutations have no detrimental phenotype, but their segregation could contribute to disease phenotypes and somatic aging.

  11. Respiratory muscle dynamics and control during exercise with externally imposed expiratory flow limitation.

    PubMed

    Aliverti, Andrea; Iandelli, Iacopo; Duranti, Roberto; Cala, Stephen J; Kayser, Bengt; Kelly, Susan; Misuri, Gianni; Pedotti, Antonio; Scano, Giorgio; Sliwinski, Pawel; Yan, Sheng; Macklem, Peter T

    2002-05-01

    To determine how decreasing velocity of shortening (U) of expiratory muscles affects breathing during exercise, six normal men performed incremental exercise with externally imposed expiratory flow limitation (EFLe) at approximately 1 l/s. We measured volumes of chest wall, lung- and diaphragm-apposed rib cage (Vrc,p and Vrc,a, respectively), and abdomen (Vab) by optoelectronic plethysmography; esophageal, gastric, and transdiaphragmatic pressures (Pdi); and end-tidal CO2 concentration. From these, we calculated velocity of shortening and power (W) of diaphragm, rib cage, and abdominal muscles (di, rcm, ab, respectively). EFLe forced a decrease in Uab, which increased Pab and which lasted well into inspiration. This imposed a load, overcome by preinspiratory diaphragm contraction. Udi and inspiratory Urcm increased, reducing their ability to generate pressure. Pdi, Prcm, and Wab increased, indicating an increased central drive to all muscle groups secondary to hypercapnia, which developed in all subjects. These results suggest a vicious cycle in which EFLe decreases Uab, increasing Pab and exacerbating the hypercapnia, which increases central drive increasing Pab even more, leading to further CO2 retention, and so forth.

  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. 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.

  14. Interaction between murine spf-ash mutation and genetic background yields different metabolic phenotypes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The spf-ash mutation in mice results in reduced hepatic and intestinal ornithine transcarbamylase. However, a reduction in enzyme activity only translates in reduced ureagenesis and hyperammonemia when an unbalanced nitrogen load is imposed. Six-week-old wild-type control and spf-ash mutant male mic...

  15. Prediction of the micro-fluid dynamic environment imposed to three-dimensional engineered cell systems in bioreactors.

    PubMed

    Boschetti, Federica; Raimondi, Manuela Teresa; Migliavacca, Francesco; Dubini, Gabriele

    2006-01-01

    Bioreactors allowing culture medium perfusion overcome diffusion limitations associated with static culturing and provide flow-mediated mechanical stimuli. The hydrodynamic stress imposed to cells will depend not only on the culture medium flow rate, but also on the scaffold three-dimensional (3D) micro-architecture. We developed a CFD model of the flow of culture medium through a 3D scaffold of homogeneous geometry, with the aim of predicting the shear stress acting on cells as a function of parameters that can be controlled during the scaffold fabrication process, such as the scaffold porosity and the pore size, and during the cell culture, such as the medium flow rate and the diameter of the perfused scaffold section. We built three groups of models corresponding to three pore sizes: 50, 100 and 150 microm. Each group was made of four models corresponding to 59%, 65%, 77%, and 89% porosity. A commercial finite-element code was used to set up and solve the problem and to analyze the results. The mode value of shear stress varied between 2 and 5 mPa, and was obtained for a circular scaffold of 15.5 mm diameter, perfused by a flow rate of 0.5 ml/min. The simulations showed that the pore size is a variable strongly influencing the predicted shear stress level, whereas the porosity is a variable strongly affecting the statistical distribution of the shear stresses, but not their magnitude. Our results provide a basis for the completion of more exhaustive quantitative studies to further assess the relationship between perfusion, at known micro-fluid dynamic conditions, and tissue growth in vitro.

  16. 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.

  17. Effective Temperature of Mutations

    NASA Astrophysics Data System (ADS)

    Derényi, Imre; Szöllősi, Gergely J.

    2015-02-01

    Biological macromolecules experience two seemingly very different types of noise acting on different time scales: (i) point mutations corresponding to changes in molecular sequence and (ii) thermal fluctuations. Examining the secondary structures of a large number of microRNA precursor sequences and model lattice proteins, we show that the effects of single point mutations are statistically indistinguishable from those of an increase in temperature by a few tens of kelvins. The existence of such an effective mutational temperature establishes a quantitative connection between robustness to genetic (mutational) and environmental (thermal) perturbations.

  18. Conformational SERS Classification of K-Ras Point Mutations for Cancer Diagnostics.

    PubMed

    Morla-Folch, Judit; Gisbert-Quilis, Patricia; Masetti, Matteo; Garcia-Rico, Eduardo; Alvarez-Puebla, Ramon A; Guerrini, Luca

    2017-02-20

    Point mutations in Ras oncogenes are routinely screened for diagnostics and treatment of tumors (especially in colorectal cancer). Here, we develop an optical approach based on direct SERS coupled with chemometrics for the study of the specific conformations that single-point mutations impose on a relatively large fragment of the K-Ras gene (141 nucleobases). Results obtained offer the unambiguous classification of different mutations providing a potentially useful insight for diagnostics and treatment of cancer in a sensitive, fast, direct and inexpensive manner.

  19. 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

  20. 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

  1. 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.

  2. Modeling the phase separation in binary lipid membrane under externally imposed oscillatory shear flow.

    PubMed

    Chen, Xiao-Bo; Niu, Li-Sha; Shi, Hui-Ji

    2008-09-01

    By adding external velocity terms, the two-dimensional time-dependent Ginzburg-Landau (TDGL) equations are modified. Based on this, the phase separation in binary lipid membrane under externally imposed oscillatory shear flow is numerically modeled employing the Cell Dynamical System (CDS) approach. Considering shear flows with different frequencies and amplitudes, several aspects of such a phase evolving process are studied. Firstly, visualized results are shown via snapshot figures of the membrane shape. And then, the simulated scattering patterns at typical moments are presented. Furthermore, in order to more quantitatively discuss this phase-separation process, the time growth laws of the characteristic domain sizes in both directions parallel and perpendicular to the flow are investigated for each case. Finally, the peculiar rheological properties of such binary lipid membrane system have been discussed, mainly the normal stress difference and the viscoelastic complex shear moduli.

  3. 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.

  4. 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.

  5. 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.

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

    DOE PAGES

    Strozzi, David J.; Perkins, L. J.; Marinak, M. M.; ...

    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

  7. Spectrum of small mutations in the dystrophin coding region.

    PubMed Central

    Prior, T W; Bartolo, C; Pearl, D K; Papp, A C; Snyder, P J; Sedra, M S; Burghes, A H; Mendell, J R

    1995-01-01

    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. Images Figure 2 PMID:7611292

  8. Spectrum of small mutations in the dystrophin coding region.

    PubMed

    Prior, T W; Bartolo, C; Pearl, D K; Papp, A C; Snyder, P J; Sedra, M S; Burghes, A H; Mendell, J R

    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.

  9. 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

  10. Fitness effects of mutations in bacteria.

    PubMed

    Gordo, Isabel; Perfeito, Lilia; Sousa, Ana

    2011-01-01

    Mutation is the primary source of variation in any organism. Without it, natural selection cannot operate and organisms cannot adapt to novel environments. Mutation is also generally a source of defect: many mutations are not neutral but cause fitness decreases in the organisms where they arise. In bacteria, another important source of variation is horizontal gene transfer. This source of variation can also cause beneficial or deleterious effects. Determining the distribution of fitness effects of mutations in different environments and genetic backgrounds is an active research field. In bacteria, knowledge of these distributions is key for understanding important traits. For example, for determining the dynamics of microorganisms with a high genomic mutation rate (mutators), and for understanding the evolution of antibiotic resistance, and the emergence of pathogenic traits. All of these characteristics are extremely relevant for human health both at the individual and population levels. Experimental evolution has been a valuable tool to address these questions. Here, we review some of the important findings of mutation effects in bacteria revealed through laboratory experiments.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. Mutations responsible for 3-phosphoserine phosphatase deficiency.

    PubMed

    Veiga-da-Cunha, Maria; Collet, Jean-François; Prieur, Benoît; Jaeken, Jaak; Peeraer, Yves; Rabbijns, Anja; Van Schaftingen, Emile

    2004-02-01

    We report the identification of the mutations in the only known case of L-3-phosphoserine phosphatase deficiency, a recessively inherited condition. The two mutations correspond to the replacement of the semiconserved Asp32 residue by an asparagine and of the extremely conserved Met52 by a threonine. The effects of both mutations were studied on the human recombinant enzyme, expressed in Escherichia coli. Met52Thr almost abolished the enzymatic activity, whereas the Asp32Asn mutation caused a 50% decrease in Vmax. In addition, L-serine, which inhibits the conversion of [(14)C] phosphoserine to serine when catalysed by the wild-type enzyme, had a lesser inhibitory effect on the Asp32Asn mutant, indicating a reduction in the rate of phosphoenzyme hydrolysis. These modifications in the properties of the enzyme are consistent with the modification in the kinetic properties observed in fibroblasts from the patient.

  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. 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

  18. Risk estimation based on germ-cell mutations in animals.

    PubMed

    Favor, J

    1989-01-01

    The set of mouse germ cell mutation rate results following spermatogonial exposure to high dose rate irradiation have been presented as the most relevant experimental results upon which to extrapolate the expected genetic risk of offspring of the survivors of the Hiroshima and Nagasaki atomic bombings. Results include mutation rates to recessive specific-locus, dominant cataract, protein-charge, and enzyme-activity alleles. The mutability as determined by the various genetic end points differed: the mutation rates to recessive specific-locus alleles and enzyme-activity alleles were similar and greater than the mutation rates to dominant cataract and protein-charge alleles. It is argued that the type of mutation event scored by a particular test will determine the mutability of the genetic end point screened. When the loss of functional gene product can be scored in a particular mutation test, as in the recessive specific-locus and enzyme-activity tests, a wide spectrum of DNA alterations may result in a loss of and a higher mutation rate is observed. When an altered gene product is scored, as in the dominant cataract and protein-charge tests, a narrower spectrum of DNA alterations is screened and a lower mutation rate is observed. The radiation doubling dose, defined as the dose that induces as many mutations as occur spontaneously per generation, was shown to be four times higher in the dominant cataract test than the specific-locus test. These results indicate that to extrapolate to genetic risks in humans using the doubling-dose method, the extrapolation must be based on experimental mutation rate results for the same genetic end point.(ABSTRACT TRUNCATED AT 250 WORDS)

  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. The rich phase structure of a mutator model

    NASA Astrophysics Data System (ADS)

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

    2016-10-01

    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.

  1. Wind tunnel validation of AeroDyn within LIFES50+ project: imposed Surge and Pitch tests

    NASA Astrophysics Data System (ADS)

    Bayati, I.; Belloli, M.; Bernini, L.; Zasso, A.

    2016-09-01

    This paper presents the first set of results of the steady and unsteady wind tunnel tests, performed at Politecnico di Milano wind tunnel, on a 1/75 rigid scale model of the DTU 10 MW wind turbine, within the LIFES50+ project. The aim of these tests is the validation of the open source code AeroDyn developed at NREL. Numerical and experimental steady results are compared in terms of thrust and torque coefficients, showing good agreement, as well as for unsteady measurements gathered with a 2 degree-of-freedom test rig, capable of imposing the displacements at the base of the model, and providing the surge and pitch motion of the floating offshore wind turbine (FOWT) scale model. The measurements of the unsteady test configuration are compared with AeroDyn/Dynin module results, implementing the generalized dynamic wake (GDW) model. Numerical and experimental comparison showed similar behaviours in terms of non linear hysteresis, however some discrepancies are herein reported and need further data analysis and interpretations about the aerodynamic integral quantities, with a special attention to the physics of the unsteady phenomenon.

  2. 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.

  3. 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

  4. Life history trade-offs imposed by dragline use in two money spiders.

    PubMed

    Bonte, Dries; Verduyn, Lieselot; Braeckman, Bart P

    2016-01-01

    Trade-offs among life history traits are central to understanding the limits of adaptations to stress. In animals, virtually all decisions taken during life are expected to have downstream consequences. To what degree rare, but energy-demanding, decisions carry over to individual performance is rarely studied in arthropods. We used spiders as a model system to test how single investments in silk use - for dispersal or predator escape - affect individual performance. Silk produced for safe lines and as threads for ballooning is of the strongest kind and is energetically costly, especially when resources are limited. We induced dragline spinning in two species of money spider at similar quantities to that under natural conditions and tested trade-offs with lifespan and egg sac production under unlimited prey availability and a dietary restriction treatment. We demonstrate strong trade-offs between dragline spinning and survival and fecundity. Survival trade-offs were additive to those imposed by the dietary treatment, but a reduction in eggs produced after silk use was only prevalent under conditions where food was restricted during the spider's life. Because draglines are not recycled after their use for dispersal or predator escape, their spinning incurs substantial fitness costs in dispersal, especially in environments with prey limitation. Rare but energetically costly decisions related to dispersal or predator escape may thus carry over to adult performance and explain phenotypic heterogeneity in natural populations.

  5. Damage Characterization of EBC-SiCSiC Ceramic Matrix Composites Under Imposed Thermal Gradient Testing

    NASA Technical Reports Server (NTRS)

    Appleby, Matthew P.; Morscher, Gregory N.; Zhu, Dongming

    2014-01-01

    Due to their high temperature capabilities, Ceramic Matrix Composite (CMC) components are being developed for use in hot-section aerospace engine applications. Harsh engine environments have led to the development of Environmental Barrier Coatings (EBCs) for silicon-based CMCs to further increase thermal and environmental capabilities. This study aims at understanding the damage mechanisms associated with these materials under simulated operating conditions. A high heat-flux laser testing rig capable of imposing large through-thickness thermal gradients by means of controlled laser beam heating and back-side air cooling is used. Tests are performed on uncoated composites, as well as CMC substrates that have been coated with state-of-the-art ceramic EBC systems. Results show that the use of the EBCs may help increase temperature capability and creep resistance by reducing the effects of stressed oxidation and environmental degradation. Also, the ability of electrical resistance (ER) and acoustic emission (AE) measurements to monitor material condition and damage state during high temperature testing is shown; suggesting their usefulness as a valuable health monitoring technique. Micromechanics models are used to describe the localized stress state of the composite system, which is utilized along with ER modeling concepts to develop an electromechanical model capable of characterizing material behavior.

  6. 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.

  7. 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

  8. Conceptualization and nursing implications of self-imposed activity limitation among community-dwelling elders.

    PubMed

    Guo, Guifang; Phillips, Linda R

    2010-01-01

    The purposes of this paper are to explore, from a theoretical perspective, explanations for why some community-dwelling elders self-impose activity limitations (SIALs); to develop an integrated explanation for SIAL from a nursing perspective; and to identify some clinical implications of relevance to public health nursing practice. Activity limitation is an important risk factor for functional decline, morbidity, and mortality among community-dwelling elders. Many studies have focused on disease and environmental influences on activity limitations. The intrinsic processes associated with voluntary or SIAL in old age among otherwise physically and mentally capable elders are poorly understood and little studied. The conceptualization of SIAL provides nurses with an understanding of an understudied aging phenomenon and helps nurses understand how elders see activities related to their life priorities. The conceptual framework will facilitate future qualitative and quantitative study of SIAL, assist nurses in the development of a new gerontological nursing theory, and design of interventions for elders with activity limitations. Public health nurses with a better understanding of SIAL may be able to help elders improve or maintain their independence.

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

    NASA Astrophysics Data System (ADS)

    Strozzi, David J.; Perkins, L. J.; Marinak, M. M.; Larson, D. J.; Koning, J. M.; Logan, B. G.

    2015-12-01

    > . 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. 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.

  10. Metabolic constraint imposes tradeoff between body size and number of brain neurons in human evolution

    PubMed Central

    Fonseca-Azevedo, Karina; Herculano-Houzel, Suzana

    2012-01-01

    Despite a general trend for larger mammals to have larger brains, humans are the primates with the largest brain and number of neurons, but not the largest body mass. Why are great apes, the largest primates, not also those endowed with the largest brains? Recently, we showed that the energetic cost of the brain is a linear function of its numbers of neurons. Here we show that metabolic limitations that result from the number of hours available for feeding and the low caloric yield of raw foods impose a tradeoff between body size and number of brain neurons, which explains the small brain size of great apes compared with their large body size. This limitation was probably overcome in Homo erectus with the shift to a cooked diet. Absent the requirement to spend most available hours of the day feeding, the combination of newly freed time and a large number of brain neurons affordable on a cooked diet may thus have been a major positive driving force to the rapid increased in brain size in human evolution. PMID:23090991

  11. The Potential Landscape of Genetic Circuits Imposes the Arrow of Time in Stem Cell Differentiation

    PubMed Central

    Wang, Jin; Xu, Li; Wang, Erkang; Huang, Sui

    2010-01-01

    Abstract Differentiation from a multipotent stem or progenitor state to a mature cell is an essentially irreversible process. The associated changes in gene expression patterns exhibit time-directionality. This “arrow of time” in the collective change of gene expression across multiple stable gene expression patterns (attractors) is not explained by the regulated activation, the suppression of individual genes which are bidirectional molecular processes, or by the standard dynamical models of the underlying gene circuit which only account for local stability of attractors. To capture the global dynamics of this nonequilibrium system and gain insight in the time-asymmetry of state transitions, we computed the quasipotential landscape of the stochastic dynamics of a canonical gene circuit that governs branching cell fate commitment. The potential landscape reveals the global dynamics and permits the calculation of potential barriers between cell phenotypes imposed by the circuit architecture. The generic asymmetry of barrier heights indicates that the transition from the uncommitted multipotent state to differentiated states is inherently unidirectional. The model agrees with observations and predicts the extreme conditions for reprogramming cells back to the undifferentiated state. PMID:20655830

  12. Metastability in pixelation patterns of coexisting fluid lipid bilayer phases imposed by e-beam patterned substrates.

    PubMed

    Ogunyankin, Maria O; Longo, Marjorie L

    2013-02-14

    We study the dynamic evolution of pixilation patterns of the liquid-ordered (Lo) phase in coexistence with the liquid-disordered phase in lipid multibilayers. The pixilation patterns were formed by imposing lattice patterns of localized high curvature on phase-separating multibilayers using curvature-patterned regions of an underlying support. The projected radius of underlying hemisphere-like features, that provided the local curvature, was varied from 60 nm to 100 nm and the square lattice spacing between the features was varied between 200 nm and 400 nm using standard electron (e) -beam lithography. Over time, the area fraction of the Lo phase on the patterned regions of the substrate decreased toward zero at room temperature. This apparent metastability of the pattern derives from the high line energy of a pixelation pattern where a Boltzmann distribution shows near zero equilibrium partitioning of the Lo phase in the patterned regions. Kinetic rate analysis identifies two pattern-dependent mechanisms that dominate the transition to zero Lo area fraction; diffusion limited dissolution of the Lo phase driven by an Ostwald ripening-type process or the cooperative formation of vesicles containing Lo phase lipids. Interestingly, we observed the spontaneous formation of tubules in the corners of the array due to the high local curvature applied to the membrane. Furthermore we show that it is possible to regenerate pixilation patterns on the curvature-patterned regions by cooling below room temperature. Regenerated area fractions are in agreement with a room-temperature composition of primarily Ld phase and the high degree of overlap with the original patterns is suggestive of fixed nucleation sites.

  13. 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.

  14. Mutational spectrum of adult T-ALL

    PubMed Central

    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.

    2015-01-01

    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

  15. Germline Stem Cell Competition, Mutation Hot Spots, Genetic Disorders, and Older Fathers.

    PubMed

    Arnheim, Norman; Calabrese, Peter

    2016-08-31

    Some de novo human mutations arise at frequencies far exceeding the genome average mutation rate. Examples include the common mutations at one or a few sites in the genes that cause achondroplasia, Apert syndrome, multiple endocrine neoplasia type 2B, and Noonan syndrome. These mutations are recurrent, provide a gain of function, are paternally derived, and are more likely to be transmitted as the father ages. Recent experiments have tested whether the high mutation frequencies are due to an elevated mutation rate per cell division, as expected, or to an advantage of the mutant spermatogonial stem cells over wild-type stem cells. The evidence, which includes the surprising discovery of testis mutation clusters, rules out the former model but not the latter. We propose how the mutations might alter spermatogonial stem cell function and discuss how germline selection contributes to the paternal age effect, the human mutational load, and adaptive evolution.

  16. 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

  17. Landscape of somatic mutations in 560 breast cancer whole-genome sequences

    SciTech Connect

    Nik-Zainal, Serena; Davies, Helen; Staaf, Johan; Ramakrishna, Manasa; Glodzik, Dominik; Zou, Xueqing; Martincorena, Inigo; Alexandrov, Ludmil B.; Martin, Sancha; Wedge, David C.; Van Loo, Peter; Ju, Young Seok; Smid, Marcel; Brinkman, Arie B.; Morganella, Sandro; Aure, Miriam R.; Lingjærde, Ole Christian; Langerod, Anita; Ringner, Markus; Ahn, Sung -Min; Boyault, Sandrine; Brock, Jane E.; Broeks, Annegien; Butler, Adam; Desmedt, Christine; Dirix, Luc; Dronov, Serge; Fatima, Aquila; Foekens, John A.; Gerstung, Moritz; Hooijer, Gerrit K. J.; Jang, Se Jin; Jones, David R.; Kim, Hyung -Yong; King, Tari A.; Krishnamurthy, Savitri; Lee, Hee Jin; Lee, Jeong -Yeon; Li, Yilong; McLaren, Stuart; Menzies, Andrew; Mustonen, Ville; O’Meara, Sarah; Pauporte, Iris; Pivot, Xavier; Purdie, Colin A.; Raine, Keiran; Ramakrishnan, Kamna; Rodríguez-Gonzalez, F. German; Romieu, Gilles; Sieuwerts, Anieta M.; Simpson, Peter T.; Shepherd, Rebecca; Stebbings, Lucy; Stefansson, Olafur A.; Teague, Jon; Tommasi, Stefania; Treilleux, Isabelle; Van den Eynden, Gert G.; Vermeulen, Peter; Vincent-Salomon, Anne; Yates, Lucy; Caldas, Carlos; Veer, Laura van’t; Tutt, Andrew; Knappskog, Stian; Tan, Benita Kiat Tee; Jonkers, Jos; Borg, Ake; Ueno, Naoto T.; Sotiriou, Christos; Viari, Alain; Futreal, P. Andrew; Campbell, Peter J.; Span, Paul N.; Van Laere, Steven; Lakhani, Sunil R.; Eyfjord, Jorunn E.; Thompson, Alastair M.; Birney, Ewan; Stunnenberg, Hendrik G.; van de Vijver, Marc J.; Martens, John W. M.; Borresen-Dale, Anne -Lise; Richardson, Andrea L.; Kong, Gu; Thomas, Gilles; Stratton, Michael R.

    2016-05-02

    Here, we analysed whole-genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. We found that 93 protein-coding cancer genes carried probable driver mutations. Some non-coding regions exhibited high mutation frequencies, but most have distinctive structural features probably causing elevated mutation rates and do not contain driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed twelve base substitution and six rearrangement signatures. Three rearrangement signatures, characterized by tandem duplications or deletions, appear associated with defective homologous-recombination-based DNA repair: one with deficient BRCA1 function, another with deficient BRCA1 or BRCA2 function, the cause of the third is unknown. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operating, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer.

  18. Landscape of somatic mutations in 560 breast cancer whole genome sequences

    PubMed Central

    Nik-Zainal, Serena; Davies, Helen; Staaf, Johan; Ramakrishna, Manasa; Glodzik, Dominik; Zou, Xueqing; Martincorena, Inigo; Alexandrov, Ludmil B.; Martin, Sancha; Wedge, David C.; Van Loo, Peter; Ju, Young Seok; Smid, Marcel; Brinkman, Arie B; Morganella, Sandro; Aure, Miriam R.; Lingjærde, Ole Christian; Langerød, Anita; Ringnér, Markus; Ahn, Sung-Min; Boyault, Sandrine; Brock, Jane E.; Broeks, Annegien; Butler, Adam; Desmedt, Christine; Dirix, Luc; Dronov, Serge; Fatima, Aquila; Foekens, John A.; Gerstung, Moritz; Hooijer, Gerrit KJ; Jang, Se Jin; Jones, David R.; Kim, Hyung-Yong; King, Tari A.; Krishnamurthy, Savitri; Lee, Hee Jin; Lee, Jeong-Yeon; Li, Yilong; McLaren, Stuart; Menzies, Andrew; Mustonen, Ville; O’Meara, Sarah; Pauporté, Iris; Pivot, Xavier; Purdie, Colin A.; Raine, Keiran; Ramakrishnan, Kamna; Rodríguez-González, F. Germán; Romieu, Gilles; Sieuwerts, Anieta M.; Simpson, Peter T; Shepherd, Rebecca; Stebbings, Lucy; Stefansson, Olafur A; Teague, Jon; Tommasi, Stefania; Treilleux, Isabelle; Van den Eynden, Gert G.; Vermeulen, Peter; Vincent-Salomon, Anne; Yates, Lucy; Caldas, Carlos; van’t Veer, Laura; Tutt, Andrew; Knappskog, Stian; Tan, Benita Kiat Tee; Jonkers, Jos; Borg, Åke; Ueno, Naoto T; Sotiriou, Christos; Viari, Alain; Futreal, P. Andrew; Campbell, Peter J; Span, Paul N.; Van Laere, Steven; Lakhani, Sunil R; Eyfjord, Jorunn E.; Thompson, Alastair M.; Birney, Ewan; Stunnenberg, Hendrik G; van de Vijver, Marc J; Martens, John W.M.; Børresen-Dale, Anne-Lise; Richardson, Andrea L.; Kong, Gu; Thomas, Gilles; Stratton, Michael R.

    2016-01-01

    We analysed whole genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. 93 protein-coding cancer genes carried likely driver mutations. Some non-coding regions exhibited high mutation frequencies but most have distinctive structural features probably causing elevated mutation rates and do not harbour driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed 12 base substitution and six rearrangement signatures. Three rearrangement signatures, characterised by tandem duplications or deletions, appear associated with defective homologous recombination based DNA repair: one with deficient BRCA1 function; another with deficient BRCA1 or BRCA2 function; the cause of the third is unknown. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operative, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer. PMID:27135926

  19. A critical role of lateral hypothalamus in context-induced relapse to alcohol seeking after punishment-imposed abstinence.

    PubMed

    Marchant, Nathan J; Rabei, Rana; Kaganovsky, Konstantin; Caprioli, Daniele; Bossert, Jennifer M; Bonci, Antonello; Shaham, Yavin

    2014-05-28

    In human alcoholics, abstinence is often self-imposed, despite alcohol availability, because of the negative consequences of excessive use. During abstinence, relapse is often triggered by exposure to contexts associated with alcohol use. We recently developed a rat model that captures some features of this human condition: exposure to the alcohol self-administration environment (context A), after punishment-imposed suppression of alcohol self-administration in a different environment (context B), provoked renewal of alcohol seeking in alcohol-preferring P rats. The mechanisms underlying context-induced renewal of alcohol seeking after punishment-imposed abstinence are unknown. Here, we studied the role of the lateral hypothalamus (LH) and its forebrain projections in this effect. We first determined the effect of context-induced renewal of alcohol seeking on Fos (a neuronal activity marker) expression in LH. We next determined the effect of LH reversible inactivation by GABAA + GABAB receptor agonists (muscimol + baclofen) on this effect. Finally, we determined neuronal activation in brain areas projecting to LH during context-induced renewal tests by measuring double labeling of the retrograde tracer cholera toxin subunit B (CTb; injected in LH) with Fos. Context-induced renewal of alcohol seeking after punishment-imposed abstinence was associated with increased Fos expression in LH. Additionally, renewal was blocked by muscimol + baclofen injections into LH. Finally, double-labeling analysis of CTb + Fos showed that context-induced renewal of alcohol seeking after punishment-imposed abstinence was associated with selective activation of accumbens shell neurons projecting to LH. The results demonstrate an important role of LH in renewal of alcohol seeking after punishment-imposed abstinence and suggest a role of accumbens shell projections to LH in this form of relapse.

  20. Microbial communities imposed by different geochemical contexts in Sicilian mud volcanoes

    NASA Astrophysics Data System (ADS)

    Wang, Pei-Ling; Chiu, Yi-Ping; Lin, Li-Hung; Italiano, Francesco

    2016-04-01

    Mud volcanoes and seeps are prominent surface manifestation of fluid channels connected to fluid/gas reservoirs in deep subsurface environments. While methane and carbon dioxide constitute the main components of exsolved gases, the discharge of these gases into the atmosphere have been estimated to exert profound effects on greenhouse over contemporary and geological time scales. How microbial processes and what community compositions imposed by different geochemical contexts near surface regulate the exact quantity of gas emission remain poorly constrained. In this study, porewater, gas and sediment geochemistry, and 16S rRNA genes for samples collected from mud volcanoes in Sicily of Italy were analyzed to investigate the changes of methane cycling and compositions of methanotrophic populations in response to different methane/CO2 ratios and other geochemical characteristics in gas bubbling environments. The analyses yielded contrast patterns of solute and gas geochemistry, and gene assemblages and abundances between sites related to different tectonic regimes. For sites located at the southern flank of Mt. Etna, methane and other hydrocarbons were low (less than tens of μM) in concentrations, whereas fluids were more saline than seawater and enriched with various solutes. No apparent methane consumption could be identified from geochemical profiles. Cell abundances were low, varying between 104 - 106 cells g-1 with anaerobic methanotrophs being generally less than 104 cells g-1. Communities were primarily composed of Halobacteriales, Gamma-Proteobacteria, Defferibacteres, Chloroflexi, and Delta-Proteobacteria. The dominant OTUs were related to heterotrophic halophiles, and sulfide oxidizers. While a fraction of sequences related to aerobic methanotrophs were detected, anaerobic methanotrophs and methanogens were rarely present. In contrast, methane and other hydrocarbons were high (generally more than 0.4 mM) at sites located within accretionary wedge. Fluids

  1. Multi-nucleotide de novo Mutations in Humans

    PubMed Central

    Sulem, Patrick; Helgason, Agnar; Helgason, Hannes; Kristjansson, Helgi; Jonasdottir, Aslaug; Jonasdottir, Adalbjorg; Magnusson, Olafur Th.; Thorsteinsdottir, Unnur; Masson, Gisli; Kong, Augustine; Gudbjartsson, Daniel F.; Stefansson, Kari

    2016-01-01

    Mutation of the DNA molecule is one of the most fundamental processes in biology. In this study, we use 283 parent-offspring trios to estimate the rate of mutation for both single nucleotide variants (SNVs) and short length variants (indels) in humans and examine the mutation process. We found 17812 SNVs, corresponding to a mutation rate of 1.29 × 10−8 per position per generation (PPPG) and 1282 indels corresponding to a rate of 9.29 × 10−10 PPPG. We estimate that around 3% of human de novo SNVs are part of a multi-nucleotide mutation (MNM), with 558 (3.1%) of mutations positioned less than 20kb from another mutation in the same individual (median distance of 525bp). The rate of de novo mutations is greater in late replicating regions (p = 8.29 × 10−19) and nearer recombination events (p = 0.0038) than elsewhere in the genome. PMID:27846220

  2. Variability in Floral Scent in Rewarding and Deceptive Orchids: The Signature of Pollinator-imposed Selection?

    PubMed Central

    Salzmann, Charlotte C.; Nardella, Antonio M.; Cozzolino, Salvatore; Schiestl, Florian P.

    2007-01-01

    Background and Aims A comparative investigation was made of floral scent variation in the closely related, food-rewarding Anacamptis coriophora and the food-deceptive Anacamptis morio in order to identify patterns of variability of odour compounds in the two species and their role in pollinator attraction/avoidance learning. Methods Scent was collected from plants in natural populations and samples were analysed via quantitative gas chromatography and mass spectrometry. Combined gas chromatography and electroantennographic detection was used to identify compounds that are detected by the pollinators. Experimental reduction of scent variability was performed in the field with plots of A. morio plants supplemented with a uniform amount of anisaldehyde. Key Results Both orchid species emitted complex odour bouquets. In A. coriophora the two main benzenoid compounds, hydroquinone dimethyl ether (1,4-dimethoxybenzene) and anisaldehyde (methoxybenzaldehyde), triggered electrophysiological responses in olfactory neurons of honey-bee and bumble-bee workers. The scent of A. morio, however, was too weak to elicit any electrophysiological responses. The overall variation in scent was significantly lower in the rewarding A. coriophora than in the deceptive A. morio, suggesting pollinator avoidance-learning selecting for high variation in the deceptive species. A. morio flowers supplemented with non-variable scent in plot experiments, however, did not show significantly reduced pollination success. Conclusions Whereas in the rewarding A. coriophora stabilizing selection imposed by floral constancy of the pollinators may reduce scent variability, in the deceptive A. morio the emitted scent seems to be too weak to be detected by pollinators and thus its high variability may result from relaxed selection on this floral trait. PMID:17684024

  3. Cellular crowding imposes global constraints on the chemistry and evolution of proteomes.

    PubMed

    Levy, Emmanuel D; De, Subhajyoti; Teichmann, Sarah A

    2012-12-11

    In living cells, functional protein-protein interactions compete with a much larger number of nonfunctional, or promiscuous, interactions. Several cellular properties contribute to avoiding unwanted protein interactions, including regulation of gene expression, cellular compartmentalization, and high specificity and affinity of functional interactions. Here we investigate whether other mechanisms exist that shape the sequence and structure of proteins to favor their correct assembly into functional protein complexes. To examine this question, we project evolutionary and cellular abundance information onto 397, 196, and 631 proteins of known 3D structure from Escherichia coli, Saccharomyces cerevisiae, and Homo sapiens, respectively. On the basis of amino acid frequencies in interface patches versus the solvent-accessible protein surface, we define a propensity or "stickiness" scale for each of the 20 amino acids. We find that the propensity to interact in a nonspecific manner is inversely correlated with abundance. In other words, high abundance proteins have less sticky surfaces. We also find that stickiness constrains protein evolution, whereby residues in sticky surface patches are more conserved than those found in nonsticky patches. Finally, we find that the constraint imposed by stickiness on protein divergence is proportional to protein abundance, which provides mechanistic insights into the correlation between protein conservation and protein abundance. Overall, the avoidance of nonfunctional interactions significantly influences the physico-chemical and evolutionary properties of proteins. Remarkably, the effects observed are consistently larger in E. coli and S. cerevisiae than in H. sapiens, suggesting that promiscuous protein-protein interactions may be freer to accumulate in the human lineage.

  4. Granular avalanches in a two-dimensional rotating drum with imposed vertical vibration

    NASA Astrophysics Data System (ADS)

    Amon, Daniel L.; Niculescu, Tatiana; Utter, Brian C.

    2013-07-01

    We present statistics on granular avalanches in a rotating drum with and without imposed vertical vibration. The experiment consists of a quasi-two-dimensional, vertical drum containing pentagonal particles and rotated at a constant angular velocity. The drum rests on an electromagnetic shaker to allow vibration of the assembly as it rotates. We measure time series of the slope of the interface and find that the critical angle for slope failure θc and the resulting angle of repose θr are broadly distributed with an approximate power-law distribution of avalanches θc-θr for large avalanches. The faceted pentagonal grains used lead to significant interlocking with critical and repose angles (θc≈45∘ and θr≈39∘) larger than experiments using spherical grains, even with vibration, and avalanche magnitudes correlated with the prior build-up and anti-correlated with the prior avalanche. We find that the stability of the assembly increases with small vibrations and is destabilized at vibration amplitudes above a dimensionless acceleration (peak acceleration divided by acceleration due to gravity) of Γ=0.2. We also study history dependence of the avalanches by periodically oscillating the drum to compare the initial avalanche upon reversal of shear to steady-state distributions for avalanches during continuous rotation. We observe history dependence as an initial decrease in critical angle upon reversal of the drum rotation direction, indicating that a texture is induced to resist continued shear such that the surface is weaker to reversals in shear direction. Memory of this history is removed by sufficient external vibration (Γ≥0.8), which leads to compaction and relaxation of the surface layer grains responsible for avalanching dynamics, as initial and steady-state avalanche distributions become indistinguishable.

  5. Force produced by isolated sarcomeres and half-sarcomeres after an imposed stretch.

    PubMed

    Rassier, Dilson E; Pavlov, Ivan

    2012-01-01

    When a stretch is imposed to activated muscles, there is a residual force enhancement that persists after the stretch; the force is higher than that produced during an isometric contraction in the corresponding length. The mechanisms behind the force enhancement remain elusive, and there is disagreement if it represents a sarcomeric property, or if it is associated with length nonuniformities among sarcomeres and half-sarcomeres. The purpose of this study was to investigate the effects of stretch on single sarcomeres and myofibrils with predetermined numbers of sarcomeres (n = 2, 3. . . , 8) isolated from the rabbit psoas muscle. Sarcomeres were attached between two precalibrated microneedles for force measurements, and images of the preparations were projected onto a linear photodiode array for measurements of half-sarcomere length (SL). Fully activated sarcomeres were subjected to a stretch (5-10% of initial SL, at a speed of 0.3 μm·s(-1)·SL(-1)) after which they were maintained isometric for at least 5 s before deactivation. Single sarcomeres showed two patterns: 31 sarcomeres showed a small level of force enhancement after stretch (10.46 ± 0.78%), and 28 sarcomeres did not show force enhancement (-0.54 ± 0.17%). In these preparations, there was not a strong correlation between the force enhancement and half-sarcomere length nonuniformities. When three or more sarcomeres arranged in series were stretched, force enhancement was always observed, and it increased linearly with the degree of half-sarcomere length nonuniformities. The results show that the residual force enhancement has two mechanisms: 1) stretch-induced changes in sarcomeric structure(s); we suggest that titin is responsible for this component, and 2) stretch-induced nonuniformities of half-sarcomere lengths, which significantly increases the level of force enhancement.

  6. Lower-limb amputee recovery response to an imposed error in mediolateral foot placement.

    PubMed

    Segal, Ava D; Klute, Glenn K

    2014-09-22

    Despite walking with a wider step width, amputees remain 20% more likely to fall than non-amputees. Since mediolateral (ML) balance is critical for ambulation and contingent on ML foot placement, we used a ML disturbance to perturb walking balance and explore the influence of prosthetic foot stiffness on balance recovery. Ten transtibial amputees were fit with two commonly prescribed prosthetic feet with differing stiffness characteristics; 12 non-amputees also participated. A perturbation device that released an air burst just before heel strike imposed a repeatable medial or lateral disturbance in foot placement. After a medial disturbance, the first recovery step width was narrowed (p<0.0001) for the prosthetic limb (-103%), the sound limb (-51%) and non-amputees (-41%) and more than twice as variable. The ML inclination angle remained reduced (-109%) for the prosthetic limb, while the sound limb and non-amputees approached undisturbed levels (p<0.0004). Amputees required five steps to return to undisturbed step width after a prosthetic medial disturbance versus two steps for the sound limb and for non-amputees. After a lateral disturbance, the first recovery step was widened for the prosthetic limb (+82%), sound limb (+75%), and wider than non-amputees (+51%; p<0.0001), with all participants requiring three steps to return to undisturbed step width. Amputees also exhibited a similar upper torso response compared to the non-amputees for both disturbances. Prosthetic feet with different stiffness properties did not have a significant effect. In conclusion, amputee balance was particularly challenged by medial disturbances to the prosthetic limb implying a need for improved interventions that address these balance deficits.

  7. Human health safety evaluation of cosmetics in the EU: a legally imposed challenge to science.

    PubMed

    Pauwels, M; Rogiers, V

    2010-03-01

    As stated in the European legislation, cosmetic products present on the European market must be safe for the consumer. Safety evaluation of the products is carried out by a qualified safety assessor who needs to consider potential exposure scenarios next to the physicochemical and toxicological profiles of all composing ingredients. Whereas, until recently, the tools to determine the toxicological profile of cosmetic ingredients mainly consisted of animal experiments, they have now been narrowed down substantially by the legally imposed animal testing ban on cosmetic ingredients, taken up in the Cosmetic Products Directive (76/768/EEC). This Directive, however, is not a stand-alone piece of European legislation, since as well directly as indirectly it is influenced by a complex web of related legislations. Vertical legislations deal with different categories of chemicals, including dangerous substances, biocides, plant protection products, food additives, medicinal products, and of course also cosmetics. Horizontal legislative texts, on the contrary, cover more general fields such as protection of experimental animals, consumer product safety, misleading of consumers, specific provisions for aerosols, and others. Experience has learnt that having a general overview of these related legislations is necessary to understand their impact on the cosmetic world in general terms and on cosmetic safety evaluation in particular. This goes for a variety of concerned parties, including national and European regulators/agencies, contract laboratories, raw material suppliers, cosmetic companies, research and educational centers. They all deal with a number of aspects important for the quality and toxicity of cosmetics and their ingredients. This review summarises the most relevant points of the legislative texts of different types of product categories and emphasises their impact on the safety evaluation of cosmetics.

  8. Granular avalanches in a two-dimensional rotating drum with imposed vertical vibration.

    PubMed

    Amon, Daniel L; Niculescu, Tatiana; Utter, Brian C

    2013-07-01

    We present statistics on granular avalanches in a rotating drum with and without imposed vertical vibration. The experiment consists of a quasi-two-dimensional, vertical drum containing pentagonal particles and rotated at a constant angular velocity. The drum rests on an electromagnetic shaker to allow vibration of the assembly as it rotates. We measure time series of the slope of the interface and find that the critical angle for slope failure θ(c) and the resulting angle of repose θ(r) are broadly distributed with an approximate power-law distribution of avalanches θ(c)-θ(r) for large avalanches. The faceted pentagonal grains used lead to significant interlocking with critical and repose angles (θ(c)≈45° and θ(r)≈39°) larger than experiments using spherical grains, even with vibration, and avalanche magnitudes correlated with the prior build-up and anti-correlated with the prior avalanche. We find that the stability of the assembly increases with small vibrations and is destabilized at vibration amplitudes above a dimensionless acceleration (peak acceleration divided by acceleration due to gravity) of Γ=0.2. We also study history dependence of the avalanches by periodically oscillating the drum to compare the initial avalanche upon reversal of shear to steady-state distributions for avalanches during continuous rotation. We observe history dependence as an initial decrease in critical angle upon reversal of the drum rotation direction, indicating that a texture is induced to resist continued shear such that the surface is weaker to reversals in shear direction. Memory of this history is removed by sufficient external vibration (Γ≥0.8), which leads to compaction and relaxation of the surface layer grains responsible for avalanching dynamics, as initial and steady-state avalanche distributions become indistinguishable.

  9. RBP-J imposes a requirement for ITAM-mediated costimulation of osteoclastogenesis.

    PubMed

    Li, Susan; Miller, Christine H; Giannopoulou, Eugenia; Hu, Xiaoyu; Ivashkiv, Lionel B; Zhao, Baohong

    2014-11-01

    Osteoclastogenesis requires activation of RANK signaling as well as costimulatory signals from immunoreceptor tyrosine-based activation motif-containing (ITAM-containing) receptors/adaptors, predominantly tyrosine kinase-binding proteins DAP12 and FcRγ, in osteoclast precursors. It is not well understood how costimulatory signals are regulated and integrated with RANK signaling. Here, we found that osteopetrotic bone phenotypes in mice lacking DAP12 or DAP12 and FcRγ are mediated by the transcription factor RBP-J, as deletion of Rbpj in these mice substantially rescued the defects of bone remodeling. Using a TNF-α-induced model of inflammatory bone resorption, we determined that RBP-J deficiency enables TNF-α to induce osteoclast formation and bone resorption in DAP12-deficient animals. Thus, RBP-J imposes a requirement for ITAM-mediated costimulation of RANKL or TNF-α-induced osteoclastogenesis. Mechanistically, RBP-J suppressed induction of key osteoclastogenic factors NFATc1, BLIMP1, and c-FOS by inhibiting ITAM-mediated expression and function of PLCγ2 and activation of downstream calcium-CaMKK/PYK2 signaling. Moreover, RBP-J suppressed Plcg2 expression and downstream calcium oscillations indirectly by a TGF-β/PLCγ2/calcium axis. Together, our findings indicate that RBP-J suppresses ITAM-mediated costimulation, thereby limiting crosstalk between ITAM and RANK/TNFR signaling and allowing fine tuning of osteoclastogenesis during bone homeostasis and under inflammatory conditions. Furthermore, these data suggest that environmental cues that regulate RBP-J expression/function potentially modulate the requirement for costimulatory signaling for osteoclast differentiation and bone remodeling.

  10. Pleistocene corals of the Florida keys: Architects of imposing reefs - Why?

    USGS Publications Warehouse

    Lidz, B.H.

    2006-01-01

    Five asymmetrical, discontinuous, stratigraphically successive Pleistocene reef tracts rim the windward platform margin off the Florida Keys. Built of large head corals, the reefs are imposing in relief (???30 m high by 1 km wide), as measured from seismic profiles. Well dated to marine oxygen isotope substages 5c, 5b, and 5a, corals at depth are inferred to date to the Stage 6/5 transition. The size of these reefs attests to late Pleistocene conditions that repeatedly induced vigorous and sustained coral growth. In contrast, the setting today, linked to Florida Bay and the Gulf of Mexico, is generally deemed marginal for reef accretion. Incursion onto the reef tract of waters that contain seasonally inconsistent temperature, salinity, turbidity, and nutrient content impedes coral growth. Fluctuating sea level and consequent settings controlled deposition. The primary dynamic was position of eustatic zeniths relative to regional topographic elevations. Sea level during the past 150 ka reached a maximum of ???10.6 m higher than at present ???125 ka, which gave rise to an inland coral reef (Key Largo Limestone) and ooid complex (Miami Limestone) during isotope substage 5e. These formations now form the Florida Keys and a bedrock ridge beneath The Quicksands (Gulf of Mexico). High-precision radiometric ages and depths of dated corals indicate subsequent apices remained ???15 to 9 m, respectively, below present sea level. Those peaks provided accommodation space sufficient for vertical reef growth yet exposed a broad landmass landward of the reefs for >100 ka. With time, space, lack of bay waters, and protection from the Gulf of Mexico, corals thrived in clear oceanic waters of the Gulf Stream, the only waters to reach them.

  11. Response of Stem Respiration of Two Tropical Species to an Imposed Drought

    NASA Astrophysics Data System (ADS)

    Brigham, L.; Van Haren, J. L. M.

    2015-12-01

    Increased instances of drought are predicted for tropical forests; therefore, it is important to better understand how drought will affect individual aspects of the forest carbon cycle. Through photosynthesis, CO2 is assimilated into sugars, a dominant portion of which goes to the stems where it is used for growth and cell maintenance. Both processes produce CO2 through respiration, which leaves the stem through the bark. This investigation focused on how stem CO2 efflux differs between two tree species in the tropical rainforest biome of Biosphere 2 in Oracle, Arizona—a species of legume (Clitoria racemosa) and a species of non-legume (Phytolacca dioica). A flexible chamber was strapped to each tree and the CO2 that diffused across the bark was measured with a LI-7000. A 4-week long drought was imposed in an effort to simulate future conditions resulting from climate change. It was found that C. racemosa had an overall higher CO2 efflux than P. dioica. C. racemosa has thinner bark than P. dioica, which displays a secondary thickening of its stem as a result of successive cambia; therefore, CO2 could mo