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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. Mutation rates and mutational loads in man

    SciTech Connect

    Cavalli-Sforza, L.L.

    1984-01-01

    The following areas of research are discussed: (1) the study of human mutation rates; (2) geography of human genes and its relevance to mutation; (3) sociocultural studies correlated with population genetics; (4) consanguineous marriages; and (5) surnames. (ACR)

  3. Mutation Rates among RNA Viruses

    NASA Astrophysics Data System (ADS)

    Drake, John W.; Holland, John J.

    1999-11-01

    The rate of spontaneous mutation is a key parameter in modeling the genetic structure and evolution of populations. The impact of the accumulated load of mutations and the consequences of increasing the mutation rate are important in assessing the genetic health of populations. Mutation frequencies are among the more directly measurable population parameters, although the information needed to convert them into mutation rates is often lacking. A previous analysis of mutation rates in RNA viruses (specifically in riboviruses rather than retroviruses) was constrained by the quality and quantity of available measurements and by the lack of a specific theoretical framework for converting mutation frequencies into mutation rates in this group of organisms. Here, we describe a simple relation between ribovirus mutation frequencies and mutation rates, apply it to the best (albeit far from satisfactory) available data, and observe a central value for the mutation rate per genome per replication of μ g≈ 0.76. (The rate per round of cell infection is twice this value or about 1.5.) This value is so large, and ribovirus genomes are so informationally dense, that even a modest increase extinguishes the population.

  4. 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.

  5. 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

  6. Biological evolution model with conditional mutation rates

    NASA Astrophysics Data System (ADS)

    Saakian, David B.; Ghazaryan, Makar; Bratus, Alexander; Hu, Chin-Kun

    2017-05-01

    We consider an evolution model, in which the mutation rates depend on the structure of population: the mutation rates from lower populated sequences to higher populated sequences are reduced. We have applied the Hamilton-Jacobi equation method to solve the model and calculate the mean fitness. We have found that the modulated mutation rates, directed to increase the mean fitness.

  7. 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

  8. Studies of human mutation rates: Progress report

    SciTech Connect

    Neel, J.V.

    1988-07-01

    Progress was recorded between January 1 and July 1, 1987 on a project entitled ''Studies of Human Mutation Rates''. Studies underway include methodology for studying mutation at the DNA level, algorithms for automated analyses of two-dimensional polyacrylamide DNA gels, theoretical and applied population genetics, and studies of mutation frequency in A-bomb survivors.

  9. Estimating mutation rates from paternity casework.

    PubMed

    Vicard, P; Dawid, A P; Mortera, J; Lauritzen, S L

    2008-01-01

    We present a statistical methodology for making inferences about mutation rates from paternity casework. This takes account of a number of sources of potential bias, including hidden mutation, incomplete family triplets, uncertain paternity status and differing maternal and paternal mutation rates, while allowing a wide variety of mutation models. An object-oriented Bayesian network is used to facilitate computation of the likelihood function for the mutation parameters. This can process either full or summary genotypic information, both from complete putative father-mother-child triplets and from defective cases where only the child and one of its parents are observed. We use a dataset from paternity casework to illustrate the effects on inferences about mutation parameters of various types of biases and the mutation model assumed. In particular, we show that there can be relevant information in cases of unconfirmed paternity, and that excluding these, as has generally been done, can lead to biased conclusions.

  10. 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.

  11. 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'.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. The adaptation rate of asexuals: deleterious mutations, clonal interference and population bottlenecks.

    PubMed

    Campos, Paulo R A; Wahl, Lindi M

    2010-07-01

    The rate at which a population adapts to its environment is a cornerstone of evolutionary theory, and recent experimental advances in microbial populations have renewed interest in predicting and testing this rate. Efforts to understand the adaptation rate theoretically are complicated by high mutation rates, to both beneficial and deleterious mutations, and by the fact that beneficial mutations compete with each other in asexual populations (clonal interference). Testable predictions must also include the effects of population bottlenecks, repeated reductions in population size imposed by the experimental protocol. In this contribution, we integrate previous work that addresses each of these issues, developing an overall prediction for the adaptation rate that includes: beneficial mutations with probabilistically distributed effects, deleterious mutations of arbitrary effect, population bottlenecks, and clonal interference.

  17. 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

  18. Integrating the Imposed Query into the Evaluation of Reference Service: A Dichotomous Analysis of User Ratings.

    ERIC Educational Resources Information Center

    Gross, Melissa; Saxton, Matthew L.

    2002-01-01

    Discusses a secondary analysis of a user survey from 13 public libraries to isolate factors that contribute to high levels of performance by reference librarians and to identify reliable indicators that can be used to measure and evaluate reference services. Examined user ratings of reference services by transaction type, either self-generated or…

  19. On the mutation rate of herpes simplex virus type 1.

    PubMed

    Drake, John W; Hwang, Charles B C

    2005-06-01

    All seven DNA-based microbes for which carefully established mutation rates and mutational spectra were previously available displayed a genomic mutation rate in the neighborhood of 0.003 per chromosome replication. The pathogenic mammalian DNA virus herpes simplex type 1 has an estimated genomic mutation rate compatible with that value.

  20. 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

  1. 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

  2. Ratings of Perceived Exertion During Acute Resistance Exercise Performed at Imposed and Self-Selected Loads in Recreationally Trained Women.

    PubMed

    Cotter, Joshua A; Garver, Matthew J; Dinyer, Taylor K; Fairman, Ciaran M; Focht, Brian C

    2017-08-01

    Cotter, JA, Garver, MJ, Dinyer, TK, Fairman, CM, and Focht, BC. Ratings of perceived exertion during acute resistance exercise performed at imposed and self-selected loads in recreationally trained women. J Strength Cond Res 31(8): 2313-2318, 2017-Resistance exercise (RE) is commonly used to elicit skeletal muscle adaptation. Relative intensity of a training load links closely with the outcomes of regular RE. This study examined the rating of perceived exertion (RPE) responses to acute bouts of RE using imposed (40% and 70% of 1 repetition maximum [1RM]) and self-selected (SS) loads in recreationally trained women. Twenty physically active women (23.15 ± 2.92 years), who reported regular RE training of at least 3 weekly sessions for the past year, volunteered to participate. During the initial visit, participants completed 1RM testing on 4 exercises in the following order: leg extension, chest press, leg curl, and lat pull-down. On subsequent visits, the same exercises were completed at the SS or imposed loads. The RPE was assessed after the completion of each set of exercises during the 3 RE conditions using the Borg-15 category scale. Self-selected loads corresponded to an average of approximately 57%1RM (±7.62). Overall, RPE increased with load (40%1RM = 11.26 [±1.95]; SS 57%1RM = 13.94 [±1.58]; and, 70%1RM = 15.52 [±2.05]). Reflecting the linear pattern found between load and perceived effort, the present data provide evidence that RPE levels less than 15 likely equate to loads which are not consistent with contemporary American College of Sports Medicine (ACSM) guidelines for enhancing musculoskeletal health which includes strength and hypertrophy. Women desiring increases in strength and lean mass likely need to train at an exertion level at or surpassing a rating of 15 on the Borg-15 category. This article examined the modification of training load on perceived exertion, but other variables, such as the number of repetitions completed, may also be

  3. 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.

  4. 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

  5. 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.

  6. 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

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

    PubMed

    Sanjuán, Rafael

    2012-01-01

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

  8. From Molecular Genetics to Phylodynamics: Evolutionary Relevance of Mutation Rates Across Viruses

    PubMed Central

    Sanjuán, Rafael

    2012-01-01

    Although evolution is a multifactorial process, theory posits that the speed of molecular evolution should be directly determined by the rate at which spontaneous mutations appear. To what extent these two biochemical and population-scale processes are related in nature, however, is largely unknown. Viruses are an ideal system for addressing this question because their evolution is fast enough to be observed in real time, and experimentally-determined mutation rates are abundant. This article provides statistically supported evidence that the mutation rate determines molecular evolution across all types of viruses. Properties of the viral genome such as its size and chemical composition are identified as major determinants of these rates. Furthermore, a quantitative analysis reveals that, as expected, evolution rates increase linearly with mutation rates for slowly mutating viruses. However, this relationship plateaus for fast mutating viruses. A model is proposed in which deleterious mutations impose an evolutionary speed limit and set an extinction threshold in nature. The model is consistent with data from replication kinetics, selection strength and chemical mutagenesis studies. PMID:22570614

  9. Impacts of mutation effects and population size on mutation rate in asexual populations: a simulation study

    PubMed Central

    2010-01-01

    Background In any natural population, mutation is the primary source of genetic variation required for evolutionary novelty and adaptation. Nevertheless, most mutations, especially those with phenotypic effects, are harmful and are consequently removed by natural selection. For this reason, under natural selection, an organism will evolve to a lower mutation rate. Overall, the action of natural selection on mutation rate is related to population size and mutation effects. Although theoretical work has intensively investigated the relationship between natural selection and mutation rate, most of these studies have focused on individual competition within a population, rather than on competition among populations. The aim of the present study was to use computer simulations to investigate how natural selection adjusts mutation rate among asexually reproducing subpopulations with different mutation rates. Results The competition results for the different subpopulations showed that a population could evolve to an "optimum" mutation rate during long-term evolution, and that this rate was modulated by both population size and mutation effects. A larger population could evolve to a higher optimum mutation rate than could a smaller population. The optimum mutation rate depended on both the fraction and the effects of beneficial mutations, rather than on the effects of deleterious ones. The optimum mutation rate increased with either the fraction or the effects of beneficial mutations. When strongly favored mutations appeared, the optimum mutation rate was elevated to a much higher level. The competition time among the subpopulations also substantially shortened. Conclusions Competition at the population level revealed that the evolution of the mutation rate in asexual populations was determined by both population size and mutation effects. The most striking finding was that beneficial mutations, rather than deleterious mutations, were the leading force that modulated the

  10. 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

  11. 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.

  12. Spontaneous Mutation Rate in the Smallest Photosynthetic Eukaryotes

    PubMed Central

    Krasovec, Marc; Eyre-Walker, Adam; Sanchez-Ferandin, Sophie

    2017-01-01

    Abstract Mutation is the ultimate source of genetic variation, and knowledge of mutation rates is fundamental for our understanding of all evolutionary processes. High throughput sequencing of mutation accumulation lines has provided genome wide spontaneous mutation rates in a dozen model species, but estimates from nonmodel organisms from much of the diversity of life are very limited. Here, we report mutation rates in four haploid marine bacterial-sized photosynthetic eukaryotic algae; Bathycoccus prasinos, Ostreococcus tauri, Ostreococcus mediterraneus, and Micromonas pusilla. The spontaneous mutation rate between species varies from μ = 4.4 × 10−10 to 9.8 × 10−10 mutations per nucleotide per generation. Within genomes, there is a two-fold increase of the mutation rate in intergenic regions, consistent with an optimization of mismatch and transcription-coupled DNA repair in coding sequences. Additionally, we show that deviation from the equilibrium GC content increases the mutation rate by ∼2% to ∼12% because of a GC bias in coding sequences. More generally, the difference between the observed and equilibrium GC content of genomes explains some of the inter-specific variation in mutation rates. PMID:28379581

  13. Normal Mutation Rate Variants Arise in a Mutator (Mut S) Escherichia coli Population

    PubMed Central

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

    2013-01-01

    The rate at which mutations are generated is central to the pace of evolution. Although this rate is remarkably similar amongst all cellular organisms, bacterial strains with mutation rates 100 fold greater than the modal rates of their species are commonly isolated from natural sources and emerge in experimental populations. Theoretical studies postulate and empirical studies teort the hypotheses that these “mutator” strains evolved in response to selection for elevated rates of generation of inherited variation that enable bacteria to adapt to novel and/or rapidly changing environments. Less clear are the conditions under which selection will favor reductions in mutation rates. Declines in rates of mutation for established populations of mutator bacteria are not anticipated if such changes are attributed to the costs of augmented rates of generation of deleterious mutations. Here we report experimental evidence of evolution towards reduced mutation rates in a clinical isolate of Escherichia coli with an hyper-mutable phenotype due a deletion in a mismatch repair gene, (ΔmutS). The emergence in a ΔmutS background of variants with mutation rates approaching those of the normal rates of strains carrying wild-type MutS was associated with increase in fitness with respect to ancestral strain. We postulate that such an increase in fitness could be attributed to the emergence of mechanisms driving a permanent “aerobic style of life”, the negative consequence of this behavior being regulated by the evolution of mechanisms protecting the cell against increased endogenous oxidative radicals involved in DNA damage, and thus reducing mutation rate. Gene expression assays and full sequencing of evolved mutator and normo-mutable variants supports the hypothesis. In conclusion, we postulate that the observed reductions in mutation rate are coincidental to, rather than, the selective force responsible for this evolution. PMID:24069167

  14. Single genome retrieval of context-dependent variability in mutation rates for human germline.

    PubMed

    Sahakyan, Aleksandr B; Balasubramanian, Shankar

    2017-01-13

    Accurate knowledge of the core components of substitution rates is of vital importance to understand genome evolution and dynamics. By performing a single-genome and direct analysis of 39,894 retrotransposon remnants, we reveal sequence context-dependent germline nucleotide substitution rates for the human genome. The rates are characterised through rate constants in a time-domain, and are made available through a dedicated program (Trek) and a stand-alone database. Due to the nature of the method design and the imposed stringency criteria, we expect our rate constants to be good estimates for the rates of spontaneous mutations. Benefiting from such data, we study the short-range nucleotide (up to 7-mer) organisation and the germline basal substitution propensity (BSP) profile of the human genome; characterise novel, CpG-independent, substitution prone and resistant motifs; confirm a decreased tendency of moieties with low BSP to undergo somatic mutations in a number of cancer types; and, produce a Trek-based estimate of the overall mutation rate in human. The extended set of rate constants we report may enrich our resources and help advance our understanding of genome dynamics and evolution, with possible implications for the role of spontaneous mutations in the emergence of pathological genotypes and neutral evolution of proteomes.

  15. 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.

  16. Microsatellite Mutation Rate in Atlantic Sturgeon (Acipenser oxyrinchus).

    PubMed

    Panagiotopoulou, Hanna; Austin, James D; Zalewska, Katarzyna; Gonciarz, Magdalena; Czarnogórska, Kinga; Gawor, Jan; Weglenski, Piotr; Popovic, Danijela

    2017-09-01

    Understanding mutation rates can greatly extend the utility of population and conservation genetic analyses. Herein, we present an estimate of genome-wide microsatellite mutation rate in Atlantic sturgeon (Acipenser oxyrinchus) based on parent-offspring transmission patterns. We screened 307 individuals for parentage and mutation-rate analysis applying 43 variable markers. Out of 13228 allele transfers, 11 mutations were detected, producing a mutation rate of 8.3 × 10-4 per locus per generation (95% confidence interval: 1.48 × 10-3, 4.15 × 10-4). Single-step mutations predominated and there were trends toward mutations in loci with greater polymorphism and allele length. Two of the detected mutations were most probably cluster mutations, being identified in 12 and 28 sibs, respectively. Finally, we observed evidences of polyploidy based on the sporadic presence of 3 or 4 alleles per locus in the genotyped individuals, supporting previous reports of incomplete diploidization in Atlantic sturgeon. © The American Genetic Association 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  17. 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.

  18. 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.

  19. 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.

  20. 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.

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

    PubMed

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

    2015-10-01

    The rate at which new mutations arise in the genome is a key factor in the evolution and adaptation of species. Here we describe the rate and spectrum of spontaneous mutations for the fission yeast Schizosaccharomyces pombe, a key model organism with many similarities to higher eukaryotes. We undertook an ∼1700-generation mutation accumulation (MA) experiment with a haploid S. pombe, generating 422 single-base substitutions and 119 insertion-deletion mutations (indels) across the 96 replicates. This equates to a base-substitution mutation rate of 2.00 × 10(-10) mutations per site per generation, similar to that reported for the distantly related budding yeast Saccharomyces cerevisiae. However, these two yeast species differ dramatically in their spectrum of base substitutions, the types of indels (S. pombe is more prone to insertions), and the pattern of selection required to counteract a strong AT-biased mutation rate. Overall, our results indicate that GC-biased gene conversion does not play a major role in shaping the nucleotide composition of the S. pombe genome and suggest that the mechanisms of DNA maintenance may have diverged significantly between fission and budding yeasts. Unexpectedly, CpG sites appear to be excessively liable to mutation in both species despite the likely absence of DNA methylation. Copyright © 2015 by the Genetics Society of America.

  2. 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

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

    SciTech Connect

    Crow, J.F. )

    1993-01-01

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

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

    NASA Astrophysics Data System (ADS)

    Redfield, Rosemary J.

    1994-05-01

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

  5. 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

  6. 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.

  7. 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.

  8. De novo mutational profile in RB1 clarified using a mutation rate modeling algorithm.

    PubMed

    Aggarwala, Varun; Ganguly, Arupa; Voight, Benjamin F

    2017-02-14

    Studies of de novo mutations offer great promise to improve our understanding of human disease. After a causal gene has been identified, it is natural to hypothesize that disease relevant mutations accumulate within a sub-sequence of the gene - for example, an exon, a protein domain, or at CpG sites. These assessments are typically qualitative, because we lack methodology to assess the statistical significance of sub-gene mutational burden ultimately to infer disease-relevant biology. To address this issue, we present a generalized algorithm to grade the significance of de novo mutational burden within a gene ascertained from affected probands, based on our model for mutation rate informed by local sequence context. We applied our approach to 268 newly identified de novo germline mutations by re-sequencing the coding exons and flanking intronic regions of RB1 in 642 sporadic, bilateral probands affected with retinoblastoma (RB). We confirm enrichment of loss-of-function mutations, but demonstrate that previously noted 'hotspots' of nonsense mutations in RB1 are compatible with the elevated mutation rates expected at CpG sites, refuting a RB specific pathogenic mechanism. Our approach demonstrates an enrichment of splice-site donor mutations of exon 6 and 12 but depletion at exon 5, indicative of previously unappreciated heterogeneity in penetrance within this class of substitution. We demonstrate the enrichment of missense mutations to the pocket domain of RB1, which contains the known Arg661Trp low-penetrance mutation. Our approach is generalizable to any phenotype, and affirms the importance of statistical interpretation of de novo mutations found in human genomes.

  9. 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.

  10. 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.

  11. 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

  12. 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.

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

    PubMed Central

    Blumenstiel, Justin P.

    2007-01-01

    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. PMID:17919661

  14. 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

  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. 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.

  17. Mutation rate is linked to diversification in birds

    PubMed Central

    Lanfear, Robert; Ho, Simon Y. W.; Love, Dominic; Bromham, Lindell

    2010-01-01

    How does genome evolution affect the rate of diversification of biological lineages? Recent studies have suggested that the overall rate of genome evolution is correlated with the rate of diversification. If true, this claim has important consequences for understanding the process of diversification, and implications for the use of DNA sequence data to reconstruct evolutionary history. However, the generality and cause of this relationship have not been established. Here, we test the relationship between the rate of molecular evolution and net diversification with a 19-gene, 17-kb DNA sequence dataset from 64 families of birds. We show that rates of molecular evolution are positively correlated to net diversification in birds. Using a 7.6-kb dataset of protein-coding DNA, we show that the synonymous substitution rate, and therefore the mutation rate, is correlated to net diversification. Further analysis shows that the link between mutation rates and net diversification is unlikely to be the indirect result of correlations with life-history variables that may influence both quantities, suggesting that there might be a causal link between mutation rates and net diversification. PMID:21059910

  18. Imposed rate and extent of weight loss in obese men and adaptive changes in resting and total energy expenditure.

    PubMed

    Siervo, Mario; Faber, Peter; Lara, Jose; Gibney, Eileen R; Milne, Eric; Ritz, Patrick; Lobley, Gerald E; Elia, Marinos; Stubbs, R James; Johnstone, Alexandra M

    2015-08-01

    Weight loss (WL) is associated with a decrease in total and resting energy expenditure (EE). We aimed to investigate whether (1) diets with different rate and extent of WL determined different changes in total and resting EE and if (2) they influenced the level of adaptive thermogenesis, defined as the decline in total or resting EE not accounted by changes in body composition. Three groups of six, obese men participated in a total fast for 6 days to achieve a 5% WL and a very low calorie (VLCD, 2.5 MJ/day) for 3 weeks or a low calorie (LCD, 5.2 MJ/day) diet for 6 weeks to achieve a 10% WL. A four-component model was used to measure body composition. Indirect calorimetry was used to measure resting EE. Total EE was measured by doubly labelled water (VLCD, LCD) and 24-hour whole-body calorimetry (fasting). VLCD and LCD showed a similar degree of metabolic adaptation for total EE (VLCD = -6.2%; LCD = -6.8%). Metabolic adaptation for resting EE was greater in the LCD (-0.4 MJ/day, -5.3%) compared to the VLCD (-0.1 MJ/day, -1.4%) group. Resting EE did not decrease after short-term fasting and no evidence of adaptive thermogenesis (+0.4 MJ/day) was found after 5% WL. The rate of WL was inversely associated with changes in resting EE (n = 30, r = 0.-42, p=0.01). The rate of WL did not appear to influence the decline in total EE in obese men after 10% WL. Approximately 6% of this decline in total EE was explained by mechanisms of adaptive thermogenesis. Copyright © 2015. Published by Elsevier Inc.

  19. 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.

  20. 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.

  1. 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

  2. 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.

  3. 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.

  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. 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

  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. 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

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

    PubMed

    Møller, Anders Pape; Mousseau, Timothy A

    2015-02-10

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

  9. Evolutionarily Stable Mutation Rate in a Periodically Changing Environment

    PubMed Central

    Ishii, K.; Matsuda, H.; Iwasa, Y.; Sasaki, A.

    1989-01-01

    Evolution of mutation rate controlled by a neutral modifier is studied for a locus with two alleles under temporally fluctuating selection pressure. A general formula is derived to calculate the evolutionarily stable mutation rate μ(ess) in an infinitely large haploid population, and following results are obtained. (I) For any fluctuation, periodic or random: (1) if the recombination rate r per generation between the modifier and the main locus is 0, μ(ess) is the same as the optimal mutation rate μ(op) which maximizes the long-term geometric average of population fitness; and (2) for any r, if the strength s of selection per generation is very large, μ(ess) is equal to the reciprocal of the average number T of generations (duration time) during which one allele is persistently favored than the other. (II) For a periodic fluctuation in the limit of small s and r, μ(ess)T is a function of sT and rT with properties: (1) for a given sT, μ(ess)T decreases with increasing rT; (2) for sT > 1; and (3) for sT >/= 1, and for a given rT, μ(ess)T decreases with increasing sT to a certain minimum less than 1, and then increases to 1 asymptotically in the limit of large sT. (III) For a fluctuation consisting of multiple Fourier components (i.e., sine wave components), the component with the longest period is the most effective in determining μ(ess) (low pass filter effect). (IV) When the cost c of preventing mutation is positive, the modifier is nonneutral, and μ(ess) becomes larger than in the case of neutral modifier under the same selection pressure acting at the main locus. The value of c which makes μ(ess) equal to μ(op) of the neutral modifier case is calculated. It is argued that this value gives a critical cost such that, so long as the actual cost exceeds this value, the evolution rate at the main locus must be smaller than its mutation

  10. 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.

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

    PubMed

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

    2010-10-01

    Extreme environmental perturbations are rare, but may have important evolutionary consequences. Responses to current perturbations may provide important information about the ability of living organisms to cope with similar conditions in the evolutionary past. Radioactive contamination from Chernobyl constitutes one such extreme perturbation, with significant but highly variable impact on local population density and mutation rates of different species of animals and plants. We explicitly tested the hypothesis that species with strong impacts of radiation on abundance were those with high rates of historical mutation accumulation as reflected by cytochrome b mitochondrial DNA base-pair substitution rates during past environmental perturbations. Using a dataset of 32 species of birds, we show higher historical mitochondrial substitution rates in species with the strongest negative impact of local levels of radiation on local population density. These effects were robust to different estimates of impact of radiation on abundance, weighting of estimates of abundance by sample size, statistical control for similarity in the response among species because of common phylogenetic descent, and effects of population size and longevity. Therefore, species that respond strongly to the impact of radiation from Chernobyl are also the species that in the past have been most susceptible to factors that have caused high substitution rates in mitochondrial DNA. © 2010 The Authors. Journal Compilation © 2010 European Society For Evolutionary Biology.

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

    PubMed Central

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

    2015-01-01

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

  13. 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.

  14. 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.

  15. 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.

  16. 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”.

  17. 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.

  18. 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.

  19. Whole Genome Sequencing of Mutation Accumulation Lines Reveals a Low Mutation Rate in the Social Amoeba Dictyostelium discoideum

    PubMed Central

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

    2012-01-01

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

  20. 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

  1. 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.

  2. 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)

  3. 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.

  4. 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.

  5. A simple model of asymmetric quasi-species: network sustained by emergent high mutation rates

    NASA Astrophysics Data System (ADS)

    Iwasaki, Yuishi; Yonezawa, Fumiko

    1999-02-01

    A simple model of adaptive mutation rates is studied to understand asymmetric adaptive systems. In the model, two sources of asymmetries are introduced. One is a spin-glass-type energy function and gives an asymmetry of the fitness landscape. The other is the variable mutation rate associated with each gene and gives an asymmetry of the transition probabilities. A control parameter is a selection pressure rather than a mutation rate. We find that the model shows three results: (i) High mutation rates emerge in the iterative Darwinian selection process. (ii) Detailed balance is satisfied in the diverse system sustained by the emergent high mutation rates. (iii) A transition from the positive Darwinian selection (ordered state) to the nearly neutral selection (disordered state) takes place as the selection pressure decreases. Based on these results, we study the asymmetric network sustained by emergent high mutation rates.

  6. 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

  7. 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.

  8. The Genetic Equidistance Result of Molecular Evolution is Independent of Mutation Rates.

    PubMed

    Huang, Shi

    2008-12-26

    The well-established genetic equidistance result shows that sister species are approximately equidistant to a simpler outgroup as measured by DNA or protein dissimilarity. The equidistance result is the most direct evidence, and remains the only evidence, for the constant mutation rate interpretation of this result, known as the molecular clock. However, data independent of the equidistance result have steadily accumulated in recent years that often violate a constant mutation rate. Many have automatically inferred non-equidistance whenever a non-constant mutation rate was observed, based on the unproven assumption that the equidistance result is an outcome of constant mutation rate. Here it is shown that the equidistance result remains valid even when different species can be independently shown to have different mutation rates. A random sampling of 50 proteins shows that nearly all proteins display the equidistance result despite the fact that many proteins have non-constant mutation rates. Therefore, the genetic equidistance result does not necessarily mean a constant mutation rate. Observations of different mutation rates do not invalidate the genetic equidistance result. New ideas are needed to explain the genetic equidistance result that must grant different mutation rates to different species and must be independently testable.

  9. 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.

  10. 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. Copyright 1999 Academic Press.

  11. Spontaneous mutation rate is a plastic trait associated with population density across domains of life

    PubMed Central

    Gifford, Danna R.; Hatcher, Charlie; Faulkner, Katy J.; Belavkin, Roman V.; Channon, Alastair; Aston, Elizabeth; McBain, Andrew J.

    2017-01-01

    Rates of random, spontaneous mutation can vary plastically, dependent upon the environment. Such plasticity affects evolutionary trajectories and may be adaptive. We recently identified an inverse plastic association between mutation rate and population density at 1 locus in 1 species of bacterium. It is unknown how widespread this association is, whether it varies among organisms, and what molecular mechanisms of mutagenesis or repair are required for this mutation-rate plasticity. Here, we address all 3 questions. We identify a strong negative association between mutation rate and population density across 70 years of published literature, comprising hundreds of mutation rates estimated using phenotypic markers of mutation (fluctuation tests) from all domains of life and viruses. We test this relationship experimentally, determining that there is indeed density-associated mutation-rate plasticity (DAMP) at multiple loci in both eukaryotes and bacteria, with up to 23-fold lower mutation rates at higher population densities. We find that the degree of plasticity varies, even among closely related organisms. Nonetheless, in each domain tested, DAMP requires proteins scavenging the mutagenic oxidised nucleotide 8-oxo-dGTP. This implies that phenotypic markers give a more precise view of mutation rate than previously believed: having accounted for other known factors affecting mutation rate, controlling for population density can reduce variation in mutation-rate estimates by 93%. Widespread DAMP, which we manipulate genetically in disparate organisms, also provides a novel trait to use in the fight against the evolution of antimicrobial resistance. Such a prevalent environmental association and conserved mechanism suggest that mutation has varied plastically with population density since the early origins of life. PMID:28837573

  12. Hybridization alters spontaneous mutation rates in a parent-of-origin-dependent fashion in Arabidopsis.

    PubMed

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

    2014-05-01

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

  13. Spontaneous mutation rate is a plastic trait associated with population density across domains of life.

    PubMed

    Krašovec, Rok; Richards, Huw; Gifford, Danna R; Hatcher, Charlie; Faulkner, Katy J; Belavkin, Roman V; Channon, Alastair; Aston, Elizabeth; McBain, Andrew J; Knight, Christopher G

    2017-08-01

    Rates of random, spontaneous mutation can vary plastically, dependent upon the environment. Such plasticity affects evolutionary trajectories and may be adaptive. We recently identified an inverse plastic association between mutation rate and population density at 1 locus in 1 species of bacterium. It is unknown how widespread this association is, whether it varies among organisms, and what molecular mechanisms of mutagenesis or repair are required for this mutation-rate plasticity. Here, we address all 3 questions. We identify a strong negative association between mutation rate and population density across 70 years of published literature, comprising hundreds of mutation rates estimated using phenotypic markers of mutation (fluctuation tests) from all domains of life and viruses. We test this relationship experimentally, determining that there is indeed density-associated mutation-rate plasticity (DAMP) at multiple loci in both eukaryotes and bacteria, with up to 23-fold lower mutation rates at higher population densities. We find that the degree of plasticity varies, even among closely related organisms. Nonetheless, in each domain tested, DAMP requires proteins scavenging the mutagenic oxidised nucleotide 8-oxo-dGTP. This implies that phenotypic markers give a more precise view of mutation rate than previously believed: having accounted for other known factors affecting mutation rate, controlling for population density can reduce variation in mutation-rate estimates by 93%. Widespread DAMP, which we manipulate genetically in disparate organisms, also provides a novel trait to use in the fight against the evolution of antimicrobial resistance. Such a prevalent environmental association and conserved mechanism suggest that mutation has varied plastically with population density since the early origins of life.

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

    PubMed Central

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

    2016-01-01

    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. PMID:27635054

  15. 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.

  16. Rates of Spontaneous Mutation in Bacteriophage T4 Are Independent of Host Fidelity Determinants

    PubMed Central

    Santos, M. E.; Drake, J. W.

    1994-01-01

    Bacteriophage T4 encodes most of the genes whose products are required for its DNA metabolism, and host (Escherichia coli) genes can only infrequently complement mutationally inactivated T4 genes. We screened the following host mutator mutations for effects on spontaneous mutation rates in T4: mutT (destruction of aberrant dGTPs), polA, polB and polC (DNA polymerases), dnaQ (exonucleolytic proofreading), mutH, mutS, mutL and uvrD (methyl-directed DNA mismatch repair), mutM and mutY (excision repair of oxygen-damaged DNA), mutA (function unknown), and topB and osmZ (affecting DNA topology). None increased T4 spontaneous mutation rates within a resolving power of about twofold (nor did optA, which is not a mutator but overexpresses a host dGTPase). Previous screens in T4 have revealed strong mutator mutations only in the gene encoding the viral DNA polymerase and proofreading 3'-exonuclease, plus weak mutators in several polymerase accessory proteins or determinants of dNTP pool sizes. T4 maintains a spontaneous mutation rate per base pair about 30-fold greater than that of its host. Thus, the joint high fidelity of insertion by T4 DNA polymerase and proofreading by its associated 3'-exonuclease appear to determine the T4 spontaneous mutation rate, whereas the host requires numerous additional systems to achieve high replication fidelity. PMID:7851754

  17. 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.

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

    PubMed

    Supek, Fran; Lehner, Ben

    2015-05-07

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

  19. 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.

  20. Rates and genomic consequences of spontaneous mutational events in Drosophila melanogaster.

    PubMed

    Schrider, Daniel R; Houle, David; Lynch, Michael; Hahn, Matthew W

    2013-08-01

    Because spontaneous mutation is the source of all genetic diversity, measuring mutation rates can reveal how natural selection drives patterns of variation within and between species. We sequenced eight genomes produced by a mutation-accumulation experiment in Drosophila melanogaster. Our analysis reveals that point mutation and small indel rates vary significantly between the two different genetic backgrounds examined. We also find evidence that ∼2% of mutational events affect multiple closely spaced nucleotides. Unlike previous similar experiments, we were able to estimate genome-wide rates of large deletions and tandem duplications. These results suggest that, at least in inbred lines like those examined here, mutational pressures may result in net growth rather than contraction of the Drosophila genome. By comparing our mutation rate estimates to polymorphism data, we are able to estimate the fraction of new mutations that are eliminated by purifying selection. These results suggest that ∼99% of duplications and deletions are deleterious--making them 10 times more likely to be removed by selection than nonsynonymous mutations. Our results illuminate not only the rates of new small- and large-scale mutations, but also the selective forces that they encounter once they arise.

  1. The allele-frequency spectrum in a decoupled Moran model with mutation, drift, and directional selection, assuming small mutation rates

    PubMed Central

    Vogl, Claus; Clemente, Florian

    2012-01-01

    We analyze a decoupled Moran model with haploid population size N, a biallelic locus under mutation and drift with scaled forward and backward mutation rates θ1=μ1N and θ0=μ0N, and directional selection with scaled strength γ=sN. With small scaled mutation rates θ0 and θ1, which is appropriate for single nucleotide polymorphism data in highly recombining regions, we derive a simple approximate equilibrium distribution for polymorphic alleles with a constant of proportionality. We also put forth an even simpler model, where all mutations originate from monomorphic states. Using this model we derive the sojourn times, conditional on the ancestral and fixed allele, and under equilibrium the distributions of fixed and polymorphic alleles and fixation rates. Furthermore, we also derive the distribution of small samples in the diffusion limit and provide convenient recurrence relations for calculating this distribution. This enables us to give formulas analogous to the Ewens–Watterson estimator of θ for biased mutation rates and selection. We apply this theory to a polymorphism dataset of fourfold degenerate sites in Drosophila melanogaster. PMID:22269092

  2. 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.

  3. 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. Copyright © 2016 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  4. 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

  5. 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).

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

    PubMed

    Zeyl, C; DeVisser, J A

    2001-01-01

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

  7. An ABC Method for Estimating the Rate and Distribution of Effects of Beneficial Mutations

    PubMed Central

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

    2013-01-01

    Determining the distribution of adaptive mutations available to natural selection is a difficult task. These are rare events and most of them are lost by chance. Some theoretical works propose that the distribution of newly arising beneficial mutations should be close to exponential. Empirical data are scarce and do not always support an exponential distribution. Analysis of the dynamics of adaptation in asexual populations of microorganisms has revealed that these can be summarized by two effective parameters, the effective mutation rate, Ue, and the effective selection coefficient of a beneficial mutation, Se. Here, we show that these effective parameters will not always reflect the rate and mean effect of beneficial mutations, especially when the distribution of arising mutations has high variance, and the mutation rate is high. We propose a method to estimate the distribution of arising beneficial mutations, which is motivated by a common experimental setup. The method, which we call One Biallelic Marker Approximate Bayesian Computation, makes use of experimental data consisting of periodic measures of neutral marker frequencies and mean population fitness. Using simulations, we find that this method allows the discrimination of the shape of the distribution of arising mutations and that it provides reasonable estimates of their rates and mean effects in ranges of the parameter space that may be of biological relevance. PMID:23542207

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

    PubMed Central

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

    2009-01-01

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

  9. 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.

  10. 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

  11. 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.

  12. 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

  13. Elevated Minisatellite Mutation Rate in the Post-Chernobyl Families from Ukraine

    PubMed Central

    Dubrova, Yuri E.; Grant, Gemma; Chumak, Anatoliy A.; Stezhka, Vasyl A.; Karakasian, Angela N.

    2002-01-01

    Germline mutation at eight human minisatellite loci has been studied among families from rural areas of the Kiev and Zhitomir regions of Ukraine, which were heavily contaminated by radionuclides after the Chernobyl accident. The control and exposed groups were composed of families containing children conceived before and after the Chernobyl accident, respectively. The groups were matched by ethnicity, maternal age, parental occupation, and smoking habits, and they differed only slightly by paternal age. A statistically significant 1.6-fold increase in mutation rate was found in the germline of exposed fathers, whereas the maternal germline mutation rate in the exposed families was not elevated. These data, together with the results of our previous analysis of the exposed families from Belarus, suggest that the elevated minisatellite mutation rate can be attributed to post-Chernobyl radioactive exposure. The mechanisms of mutation induction at human minisatellite loci are discussed. PMID:12226793

  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. Mutation Rates across Budding Yeast Chromosome VI Are Correlated with Replication Timing

    PubMed Central

    Lang, Gregory I.; Murray, Andrew W.

    2011-01-01

    Previous experimental studies suggest that the mutation rate is nonuniform across the yeast genome. To characterize this variation across the genome more precisely, we measured the mutation rate of the URA3 gene integrated at 43 different locations tiled across Chromosome VI. We show that mutation rate varies 6-fold across a single chromosome, that this variation is correlated with replication timing, and we propose a model to explain this variation that relies on the temporal separation of two processes for replicating past damaged DNA: error-free DNA damage tolerance and translesion synthesis. This model is supported by the observation that eliminating translesion synthesis decreases this variation. PMID:21666225

  17. 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

  18. 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.

  19. 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.

  20. Effect of Translesion DNA Polymerases, Endonucleases and RpoS on Mutation Rates in Salmonella typhimurium

    PubMed Central

    Koskiniemi, Sanna; Hughes, Diarmaid; Andersson, Dan I.

    2010-01-01

    It has been suggested that bacteria have evolved mechanisms to increase their mutation rate in response to various stresses and that the translesion DNA polymerase Pol IV under control of the LexA regulon and the alternative sigma factor RpoS are involved in regulating this mutagenesis. Here we examined in Salmonella enterica serovar Typhimurium LT2 the rates for four different types of mutations (rifampicin, nalidixic acid, and chlorate resistance and Lac+ reversion) during various growth conditions and with different levels of four translesion DNA polymerases (Pol II, Pol IV, Pol V, and SamAB) and RpoS. Constitutive derepression of the LexA regulon by a lexA(def) mutation had no effect on Lac+ reversion rates but increased the other three mutation rates up to 11-fold, and the contribution of the translesion DNA polymerases to this mutagenesis varied with the type of mutation examined. The increase in mutation rates in the lexA(def) mutant required the presence of the LexA-controlled UvrB protein and endonucleases UvrC and Cho. With regard to the potential involvement of RpoS in mutagenesis, neither an increase in RpoS levels conferred by artificial overexpression from a plasmid nor long-term stationary phase incubation or slow growth caused an increase in any of the four mutation rates measured, alone or in combination with overexpression of the translesion DNA polymerases. In conclusion, mutation rates are remarkably robust and no combination of growth conditions, induction of translesion DNA polymerases by inactivation of LexA, or increased RpoS expression could confer an increase in mutation rates higher than the moderate increase caused by derepression of the LexA regulon alone. PMID:20421601

  1. 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.

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

    PubMed Central

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

    2013-01-01

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

  3. 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

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

    PubMed Central

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

    2016-01-01

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

  5. 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

  6. A novel twelve class fluctuation test reveals higher than expected mutation rates for influenza A viruses

    PubMed Central

    Pauly, Matthew D; Procario, Megan C; Lauring, Adam S

    2017-01-01

    Influenza virus’ low replicative fidelity contributes to its capacity for rapid evolution. Clonal sequencing and fluctuation tests have suggested that the influenza virus mutation rate is 2.7 × 10–6 - 3.0 × 10–5 substitutions per nucleotide per strand copied (s/n/r). However, sequencing assays are biased toward mutations with minimal fitness impacts and fluctuation tests typically investigate only a subset of all possible single nucleotide mutations. We developed a fluctuation test based on reversion to fluorescence in a set of virally encoded mutant green fluorescent proteins, which allowed us to measure the rates of selectively neutral mutations representative of the twelve different mutation types. We measured an overall mutation rate of 1.8 × 10–4 s/n/r for PR8 (H1N1) and 2.5 × 10–4 s/n/r for Hong Kong 2014 (H3N2) and a transitional bias of 2.7–3.6. Our data suggest that each replicated genome will have an average of 2–3 mutations and highlight the importance of mutational load in influenza virus evolution. DOI: http://dx.doi.org/10.7554/eLife.26437.001 PMID:28598328

  7. 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.

  8. Strong heterogeneity in mutation rate causes misleading hallmarks of natural selection on indel mutations in the human genome.

    PubMed

    Kvikstad, Erika M; Duret, Laurent

    2014-01-01

    Elucidating the mechanisms of mutation accumulation and fixation is critical to understand the nature of genetic variation and its contribution to genome evolution. Of particular interest is the effect of insertions and deletions (indels) on the evolution of genome landscapes. Recent population-scaled sequencing efforts provide unprecedented data for analyzing the relative impact of selection versus nonadaptive forces operating on indels. Here, we combined McDonald-Kreitman tests with the analysis of derived allele frequency spectra to investigate the dynamics of allele fixation of short (1-50 bp) indels in the human genome. Our analyses revealed apparently higher fixation probabilities for insertions than deletions. However, this fixation bias is not consistent with either selection or biased gene conversion and varies with local mutation rate, being particularly pronounced at indel hotspots. Furthermore, we identified an unprecedented number of loci with evidence for multiple indel events in the primate phylogeny. Even in nonrepetitive sequence contexts (a priori not prone to indel mutations), such loci are 60-fold more frequent than expected according to a model of uniform indel mutation rate. This provides evidence of as yet unidentified cryptic indel hotspots. We propose that indel homoplasy, at known and cryptic hotspots, produces systematic errors in determination of ancestral alleles via parsimony and advise caution interpreting classic selection tests given the strong heterogeneity in indel rates across the genome. These results will have great impact on studies seeking to infer evolutionary forces operating on indels observed in closely related species, because such mutations are traditionally presumed homoplasy-free.

  9. 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.

  10. 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.

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

    PubMed Central

    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.; 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.

    2014-01-01

    Summary 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 novel relationship between transcription, chromatin state and DNA repair, revealing a new, personalized determinant of cancer risk. PMID:25456125

  12. 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.

  13. 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.

  14. 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

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

    PubMed

    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

    2015-10-13

    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. 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. 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. 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.

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

    PubMed Central

    Semple, Colin A.

    2016-01-01

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

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

    PubMed

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

    2011-06-12

    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.

  18. 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.

  19. Adaptive tuning of mutation rates allows fast response to lethal stress in Escherichia coli

    PubMed Central

    Swings, Toon; Van den Bergh, Bram; Wuyts, Sander; Oeyen, Eline; Voordeckers, Karin; Verstrepen, Kevin J; Fauvart, Maarten; Verstraeten, Natalie; Michiels, Jan

    2017-01-01

    While specific mutations allow organisms to adapt to stressful environments, most changes in an organism's DNA negatively impact fitness. The mutation rate is therefore strictly regulated and often considered a slowly-evolving parameter. In contrast, we demonstrate an unexpected flexibility in cellular mutation rates as a response to changes in selective pressure. We show that hypermutation independently evolves when different Escherichia coli cultures adapt to high ethanol stress. Furthermore, hypermutator states are transitory and repeatedly alternate with decreases in mutation rate. Specifically, population mutation rates rise when cells experience higher stress and decline again once cells are adapted. Interestingly, we identified cellular mortality as the major force driving the quick evolution of mutation rates. Together, these findings show how organisms balance robustness and evolvability and help explain the prevalence of hypermutation in various settings, ranging from emergence of antibiotic resistance in microbes to cancer relapses upon chemotherapy. DOI: http://dx.doi.org/10.7554/eLife.22939.001 PMID:28460660

  20. 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.

  1. 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

  2. Use of whole genome sequencing to estimate the mutation rate of Mycobacterium tuberculosis during latent infection

    PubMed Central

    Ford, Christopher B.; Lin, Philana Ling; Chase, Michael; Shah, Rupal R.; Iartchouk, Oleg; Galagan, James; Mohaideen, Nilofar; Ioerger, Thomas R.; Sacchettini, James C.; Lipsitch, Marc; Flynn, JoAnne L.; Fortune, Sarah M.

    2011-01-01

    Mycobacterium tuberculosis (Mtb) has generated a global health catastrophe that has been compounded by the emergence of drug resistant Mtb strains. We used whole genome sequencing to compare the accumulation of mutations in Mtb isolated from cynomolgus macaques with active, latent and reactivated disease. Based on the distribution of SNPs observed, we calculated the mutation rates for these disease states. Our data suggest that Mtb acquires a similar number of chromosomal mutations during latency as occurs during active disease or in a logarithmically growing culture over the same period of time despite reduced bacterial replication during latent infection. The pattern of polymorphisms suggests that the mutational burden in vivo is due to oxidative DNA damage. Thus, we demonstrate that Mtb continues to acquire mutations during latency and provide a novel explanation for the observation that isoniazid monotherapy for latent tuberculosis is a risk factor for the emergence of INH resistance1,2. PMID:21516081

  3. 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.

  4. 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.

  5. 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

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

    PubMed

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

    2013-10-01

    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.

  7. 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

  8. 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.

  9. 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

  10. Mutation and evolutionary rates in adélie penguins from the antarctic.

    PubMed

    Millar, Craig D; Dodd, Andrew; Anderson, Jennifer; Gibb, Gillian C; Ritchie, Peter A; Baroni, Carlo; Woodhams, Michael D; Hendy, Michael D; Lambert, David M

    2008-10-03

    Precise estimations of molecular rates are fundamental to our understanding of the processes of evolution. In principle, mutation and evolutionary rates for neutral regions of the same species are expected to be equal. However, a number of recent studies have shown that mutation rates estimated from pedigree material are much faster than evolutionary rates measured over longer time periods. To resolve this apparent contradiction, we have examined the hypervariable region (HVR I) of the mitochondrial genome using families of Adélie penguins (Pygoscelis adeliae) from the Antarctic. We sequenced 344 bps of the HVR I from penguins comprising 508 families with 915 chicks, together with both their parents. All of the 62 germline heteroplasmies that we detected in mothers were also detected in their offspring, consistent with maternal inheritance. These data give an estimated mutation rate (micro) of 0.55 mutations/site/Myrs (HPD 95% confidence interval of 0.29-0.88 mutations/site/Myrs) after accounting for the persistence of these heteroplasmies and the sensitivity of current detection methods. In comparison, the rate of evolution (k) of the same HVR I region, determined using DNA sequences from 162 known age sub-fossil bones spanning a 37,000-year period, was 0.86 substitutions/site/Myrs (HPD 95% confidence interval of 0.53 and 1.17). Importantly, the latter rate is not statistically different from our estimate of the mutation rate. These results are in contrast to the view that molecular rates are time dependent.

  11. 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.

  12. Luria-Delbrück Estimation of Turnip Mosaic Virus Mutation Rate In Vivo

    PubMed Central

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

    2012-01-01

    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. PMID:22238294

  13. 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.

  14. 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.

  15. 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.

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

    PubMed Central

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

    2004-01-01

    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. PMID:15238530

  17. 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.

  18. 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

  19. 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

  20. 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

  1. 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.

  2. Is there a proportionality between the spontaneous and the X-ray-induction rates of mutations? Experiments with mutations at 13 X-chromosome loci in Drosophila melanogaster.

    PubMed

    Shukla, P T; Sankaranarayanan, K; Sobels, F H

    1979-07-01

    The X-ray induction of recessive visible specific locus mutations at 14 X-chromsome loci was studied in Drosophila melanogaster using the "Maxy" technique. The X-ray exposure was 3000 R to 5-day-old males and the sampling of germ cells was restricted to mature spermatozoa. Presumptive mutant females recovered in the F1 generation were tested for transmission, allelism, fertility and viability in males. A total of 128 mutations (115 completes and 13 mosaics including those that were male viable as well as male-lethal) recovered among 38 898 female progeny were found to be transmitted. On the basis of the above frequency, the average mutation rate can be estimated as 7.8 X 10(-8)/locus/R; for mutations that were viable and fertile in males, the rate is 3.0 X 10(-5)/locus/R (49 mutations among 38 898 progeny). The frequency of mutations at the different loci encompassed a wide range: while no mutations were recovered at the raspberry and carnation loci, at others, the numbers ranged from 1 at echinus to 31 at garnet; in addition, the proportion of mutations that was male-viable was also different, depending on the locus. Schalet's extensive data on spontaneous mutations at 13 (of the 14 loci employed in the present study) loci permit an estimate of the spontaneous rate which is 6.1 X 10(-6)/locus (a total of39 mutations among 490 000 progeny); for mutations that were viable and fertile in males, the rate is 3.0 X 10(-6)/locus (19 mutations among 490 000 progeny). The mutability of the different loci varied over a 9-fold range. When the different loci are ranked depending on their relative mutability (for spontaneous and induced mutations) it is found that in general, loci that mutate spontaneously relatively more frequently are also those at which more mutations have been recovered in the radiation experiments and likewise, those that are less mutable spontaneously are also those that mutate less after irradiation. Since the data are limited, it is concluded that the

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

    PubMed

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

    2010-02-01

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

  4. Toward a consensus on SNP and STR mutation rates on the human Y-chromosome.

    PubMed

    Balanovsky, O

    2017-05-01

    The mutation rate on the Y-chromosome matters for estimating the time-to-the-most-recent-common-ancestor (TMRCA, i.e. haplogroup age) in population genetics, as well as for forensic, medical, and genealogical studies. Large-scale sequencing efforts have produced several independent estimates of Y-SNP mutation rates. Genealogical, or pedigree, rates tend to be slightly faster than evolutionary rates obtained from ancient DNA or calibrations using dated (pre)historical events. It is, therefore, suggested to report TMRCAs using an envelope defined by the average aDNA-based rate and the average pedigree-based rate. The current estimate of the "envelope rate" is 0.75-0.89 substitutions per billion base pairs per year. The available Y-SNP mutation rates can be applied to high-coverage data from the entire X-degenerate region, but other datasets may demand recalibrated rates. While a consensus on Y-SNP rates is approaching, the debate on Y-STR rates has continued for two decades, because multiple genealogical rates were consistent with each other but three times faster than the single evolutionary estimate. Applying Y-SNP and Y-STR rates to the same haplogroups recently helped to clarify the issue. Genealogical and evolutionary STR rates typically provide lower and upper bounds of the "true" (SNP-based) age. The genealogical rate often-but not always-works well for haplogroups less than 7000 years old. The evolutionary rate, although calibrated using recent events, inflates ages of young haplogroups and deflates the age of the entire Y-chromosomal tree, but often provides reasonable estimates for intermediate ages (old haplogroups). Future rate estimates and accumulating case studies should further clarify the Y-SNP rates.

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

    PubMed Central

    Smith, N G; Hurst, L D

    1999-01-01

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

  6. 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

  7. 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.

  8. 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

  9. 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.

  10. 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.

  11. 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

  12. 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.

  13. 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.

  14. 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.

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

    PubMed

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

    2016-09-01

    Studies on protein unfolding rates are limited and challenging due to the complexity of unfolding mechanism and the larger dynamic range of the experimental data. Though attempts have been made to predict unfolding rates using protein sequence-structure information there is no available method for predicting the unfolding rates of proteins upon specific point mutations. In this work, we have systematically analyzed a set of 790 single mutants and developed a robust method for predicting protein unfolding rates upon mutations (Δlnku) in two-state proteins by combining amino acid properties and knowledge-based classification of mutants with multiple linear regression technique. We obtain a mean absolute error (MAE) of 0.79/s and a Pearson correlation coefficient (PCC) of 0.71 between predicted unfolding rates and experimental observations using jack-knife test. We have developed a web server for predicting protein unfolding rates upon mutation and it is freely available at https://www.iitm.ac.in/bioinfo/proteinunfolding/unfoldingrace.html. Prominent features that determine unfolding kinetics as well as plausible reasons for the observed outliers are also discussed. Copyright © 2016 Elsevier B.V. All rights reserved.

  16. 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.

  17. 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

  18. 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.

  19. 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.

  20. The osmotic resistance, and zeta potential responses of human erythrocytes to transmembrane modification of Ca2+ fluxes in the presence of the imposed low rate radiation field of 90Sr.

    PubMed

    Zhirnov, Victor V; Iakovenko, Igor N

    2015-01-01

    To investigate the effects of the imposed low dose rate ionizing field on membrane stability of human erythrocytes under modulation of transmembrane exchange of Ca(2+). Osmotic resistance of human erythrocytes was determined by a measure of haemoglobin released from erythrocytes when placed in a medium containing serial dilutions of Krebs isotonic buffer. The zeta potential as indicator of surface membrane potential was calculated from value of the cellular electrophoretic mobility. The irradiation of erythrocyte suspensions carried out by applying suitable aliquots of (90)Sr in incubation media. Irradiation of human erythrocytes by (90)Sr (1.5-15.0 μGy·h(-1)) induced a reversible increase of hyposmotic hemolysis and negative charge value on the outer membrane surface as well as changed responses these parameters to modification of Ca(2+) fluxes with calcimycin and nitrendipine. Findings indicate that the low dose rate radionuclides ((90)Sr) field modifies both Ca(2+)-mediated, and Ca(2+)-independent cellular signalling regulating mechanical stability of erythrocyte membrane. A direction of that modification presumably depends on the initial structure of membranes, and it is determined by the quality and quantitative parameters of changes in membrane structure caused by concrete operable factors.

  1. 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.

  2. Real value prediction of protein folding rate change upon point mutation

    NASA Astrophysics Data System (ADS)

    Huang, Liang-Tsung; Gromiha, M. Michael

    2012-03-01

    Prediction of protein folding rate change upon amino acid substitution is an important and challenging problem in protein folding kinetics and design. In this work, we have analyzed the relationship between amino acid properties and folding rate change upon mutation. Our analysis showed that the correlation is not significant with any of the studied properties in a dataset of 476 mutants. Further, we have classified the mutants based on their locations in different secondary structures and solvent accessibility. For each category, we have selected a specific combination of amino acid properties using genetic algorithm and developed a prediction scheme based on quadratic regression models for predicting the folding rate change upon mutation. Our results showed a 10-fold cross validation correlation of 0.72 between experimental and predicted change in protein folding rates. The correlation is 0.73, 0.65 and 0.79, respectively in strand, helix and coil segments. The method has been further tested with an extended dataset of 621 mutants and a blind dataset of 62 mutants, and we observed a good agreement with experiments. We have developed a web server for predicting the folding rate change upon mutation and it is available at http://bioinformatics.myweb.hinet.net/fora.htm.

  3. A genome-wide view of mutation rate co-variation using multivariate analyses

    PubMed Central

    2011-01-01

    Background While the abundance of available sequenced genomes has led to many studies of regional heterogeneity in mutation rates, the co-variation among rates of different mutation types remains largely unexplored, hindering a deeper understanding of mutagenesis and genome dynamics. Here, utilizing primate and rodent genomic alignments, we apply two multivariate analysis techniques (principal components and canonical correlations) to investigate the structure of rate co-variation for four mutation types and simultaneously explore the associations with multiple genomic features at different genomic scales and phylogenetic distances. Results We observe a consistent, largely linear co-variation among rates of nucleotide substitutions, small insertions and small deletions, with some non-linear associations detected among these rates on chromosome X and near autosomal telomeres. This co-variation appears to be shaped by a common set of genomic features, some previously investigated and some novel to this study (nuclear lamina binding sites, methylated non-CpG sites and nucleosome-free regions). Strong non-linear relationships are also detected among genomic features near the centromeres of large chromosomes. Microsatellite mutability co-varies with other mutation rates at finer scales, but not at 1 Mb, and shows varying degrees of association with genomic features at different scales. Conclusions Our results allow us to speculate about the role of different molecular mechanisms, such as replication, recombination, repair and local chromatin environment, in mutagenesis. The software tools developed for our analyses are available through Galaxy, an open-source genomics portal, to facilitate the use of multivariate techniques in future large-scale genomics studies. PMID:21426544

  4. 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.

  5. 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

  6. A marked decrease in heart rate variability in Marfan syndrome patients with confirmed FBN1 mutations.

    PubMed

    Cherkas, Andriy; Zhuraev, Rustam

    2016-01-01

    The studies on heart rate variability (HRV), a key predictor of all-cause mortality, in Marfan syndrome (MS), up to now have not been reported, especially in patients with FBN1 mutations. Among 18 MS patients with the phenotype of MS meeting inclusion criteria 15 have had a FBN1 gene mutation. Short electrocardiography records were taken in the supine position and during orthostatic tests. The control group consisted of 30 apparently healthy nonathletes matched by age and gender. Heart rates in MS patients with the FBN1 mutation were increased in both the supine position and orthostatic test (p < 0.001). Most of the time-domain (standard deviation, pNN50) and frequency-domain (total power, very low, low, and high frequency) parameters of HRV were significantly reduced in the MS patients (p < 0.001). A marked decrease in HRV, documented in the study, may be an important clinical feature in MS patients with confirmed FBN1 gene mutations.

  7. 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.

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

    PubMed Central

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

    2013-01-01

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

  9. 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

  10. 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

  11. Density behavior of spatial birth-and-death stochastic evolution of mutating genotypes under selection rates

    NASA Astrophysics Data System (ADS)

    Finkelshtein, D.; Kondratiev, Yu.; Kutoviy, O.; Molchanov, S.; Zhizhina, E.

    2014-10-01

    We consider birth-and-death stochastic evolution of genotypes with different lengths. The genotypes might mutate, which provides a stochastic changing of lengths by a free diffusion law. The birth and death rates are length dependent, which corresponds to a selection effect. We study an asymptotic behavior of a density for an infinite collection of genotypes. The cases of space homogeneous and space heterogeneous densities are considered.

  12. Effect of the mutation rate and background size on the quality of pathogen identification.

    PubMed

    Reed, Chris; Fofanov, Viacheslav; Putonti, Catherine; Chumakov, Sergei; Slezak, Tom; Fofanov, Yuriy

    2007-10-15

    Genomic-based methods have significant potential for fast and accurate identification of organisms or even genes of interest in complex environmental samples (air, water, soil, food, etc.), especially when isolation of the target organism cannot be performed by a variety of reasons. Despite this potential, the presence of the unknown, variable and usually large quantities of background DNA can cause interference resulting in false positive outcomes. In order to estimate how the genomic diversity of the background (total length of all of the different genomes present in the background), target length and target mutation rate affect the probability of misidentifications, we introduce a mathematical definition for the quality of an individual signature in the presence of a background based on its length and number of mismatches needed to transform the signature into the closest subsequence present in the background. This definition, in conjunction with a probabilistic framework, allows one to predict the minimal signature length required to identify the target in the presence of different sizes of backgrounds and the effect of the target's mutation rate on the quality of its identification. The model assumptions and predictions were validated using both Monte Carlo simulations and real genomic data examples. The proposed model can be used to determine appropriate signature lengths for various combinations of target and background genome sizes. It also predicted that any genomic signatures will be unable to identify target if its mutation rate is >5%. Supplementary data are available at Bioinformatics online.

  13. Selection Constrains High Rates of Tandem Repetitive DNA Mutation in Daphnia pulex.

    PubMed

    Flynn, Jullien M; Caldas, Ian; Cristescu, Melania E; Clark, Andrew G

    2017-10-01

    A long-standing evolutionary puzzle is that all eukaryotic genomes contain large amounts of tandemly-repeated DNA whose sequence motifs and abundance vary greatly among even closely related species. To elucidate the evolutionary forces governing tandem repeat dynamics, quantification of the rates and patterns of mutations in repeat copy number and tests of its selective neutrality are necessary. Here, we used whole-genome sequences of 28 mutation accumulation (MA) lines of Daphnia pulex, in addition to six isolates from a non-MA population originating from the same progenitor, to both estimate mutation rates of abundances of repeat sequences and evaluate the selective regime acting upon them. We found that mutation rates of individual repeats were both high and highly variable, ranging from additions/deletions of 0.29-105 copies per generation (reflecting changes of 0.12-0.80% per generation). Our results also provide evidence that new repeat sequences are often formed from existing ones. The non-MA population isolates showed a signal of either purifying or stabilizing selection, with 33% lower variation in repeat copy number on average than the MA lines, although the level of selective constraint was not evenly distributed across all repeats. The changes between many pairs of repeats were correlated, and the pattern of correlations was significantly different between the MA lines and the non-MA population. Our study demonstrates that tandem repeats can experience extremely rapid evolution in copy number, which can lead to high levels of divergence in genome-wide repeat composition between closely related species. Copyright © 2017 by the Genetics Society of America.

  14. Different rates of spontaneous mutation of chloroplastic and nuclear viroids as determined by high-fidelity ultra-deep sequencing.

    PubMed

    López-Carrasco, Amparo; Ballesteros, Cristina; Sentandreu, Vicente; Delgado, Sonia; Gago-Zachert, Selma; Flores, Ricardo; Sanjuán, Rafael

    2017-09-01

    Mutation rates vary by orders of magnitude across biological systems, being higher for simpler genomes. The simplest known genomes correspond to viroids, subviral plant replicons constituted by circular non-coding RNAs of few hundred bases. Previous work has revealed an extremely high mutation rate for chrysanthemum chlorotic mottle viroid, a chloroplast-replicating viroid. However, whether this is a general feature of viroids remains unclear. Here, we have used high-fidelity ultra-deep sequencing to determine the mutation rate in a common host (eggplant) of two viroids, each representative of one family: the chloroplastic eggplant latent viroid (ELVd, Avsunviroidae) and the nuclear potato spindle tuber viroid (PSTVd, Pospiviroidae). This revealed higher mutation frequencies in ELVd than in PSTVd, as well as marked differences in the types of mutations produced. Rates of spontaneous mutation, quantified in vivo using the lethal mutation method, ranged from 1/1000 to 1/800 for ELVd and from 1/7000 to 1/3800 for PSTVd depending on sequencing run. These results suggest that extremely high mutability is a common feature of chloroplastic viroids, whereas the mutation rates of PSTVd and potentially other nuclear viroids appear significantly lower and closer to those of some RNA viruses.

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

    PubMed

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

    2015-07-01

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

  16. 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.

  17. 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

  18. Characterizing Changes in the Rate of Protein-Protein Dissociation upon Interface Mutation Using Hotspot Energy and Organization

    PubMed Central

    Agius, Rudi; Torchala, Mieczyslaw; Moal, Iain H.; Fernández-Recio, Juan; Bates, Paul A.

    2013-01-01

    Predicting the effects of mutations on the kinetic rate constants of protein-protein interactions is central to both the modeling of complex diseases and the design of effective peptide drug inhibitors. However, while most studies have concentrated on the determination of association rate constants, dissociation rates have received less attention. In this work we take a novel approach by relating the changes in dissociation rates upon mutation to the energetics and architecture of hotspots and hotregions, by performing alanine scans pre- and post-mutation. From these scans, we design a set of descriptors that capture the change in hotspot energy and distribution. The method is benchmarked on 713 kinetically characterized mutations from the SKEMPI database. Our investigations show that, with the use of hotspot descriptors, energies from single-point alanine mutations may be used for the estimation of off-rate mutations to any residue type and also multi-point mutations. A number of machine learning models are built from a combination of molecular and hotspot descriptors, with the best models achieving a Pearson's Correlation Coefficient of 0.79 with experimental off-rates and a Matthew's Correlation Coefficient of 0.6 in the detection of rare stabilizing mutations. Using specialized feature selection models we identify descriptors that are highly specific and, conversely, broadly important to predicting the effects of different classes of mutations, interface regions and complexes. Our results also indicate that the distribution of the critical stability regions across protein-protein interfaces is a function of complex size more strongly than interface area. In addition, mutations at the rim are critical for the stability of small complexes, but consistently harder to characterize. The relationship between hotregion size and the dissociation rate is also investigated and, using hotspot descriptors which model cooperative effects within hotregions, we show how the

  19. Characterizing changes in the rate of protein-protein dissociation upon interface mutation using hotspot energy and organization.

    PubMed

    Agius, Rudi; Torchala, Mieczyslaw; Moal, Iain H; Fernández-Recio, Juan; Bates, Paul A

    2013-01-01

    Predicting the effects of mutations on the kinetic rate constants of protein-protein interactions is central to both the modeling of complex diseases and the design of effective peptide drug inhibitors. However, while most studies have concentrated on the determination of association rate constants, dissociation rates have received less attention. In this work we take a novel approach by relating the changes in dissociation rates upon mutation to the energetics and architecture of hotspots and hotregions, by performing alanine scans pre- and post-mutation. From these scans, we design a set of descriptors that capture the change in hotspot energy and distribution. The method is benchmarked on 713 kinetically characterized mutations from the SKEMPI database. Our investigations show that, with the use of hotspot descriptors, energies from single-point alanine mutations may be used for the estimation of off-rate mutations to any residue type and also multi-point mutations. A number of machine learning models are built from a combination of molecular and hotspot descriptors, with the best models achieving a Pearson's Correlation Coefficient of 0.79 with experimental off-rates and a Matthew's Correlation Coefficient of 0.6 in the detection of rare stabilizing mutations. Using specialized feature selection models we identify descriptors that are highly specific and, conversely, broadly important to predicting the effects of different classes of mutations, interface regions and complexes. Our results also indicate that the distribution of the critical stability regions across protein-protein interfaces is a function of complex size more strongly than interface area. In addition, mutations at the rim are critical for the stability of small complexes, but consistently harder to characterize. The relationship between hotregion size and the dissociation rate is also investigated and, using hotspot descriptors which model cooperative effects within hotregions, we show how the

  20. Genome-Wide Mutation Rate Response to pH Change in the Coral Reef Pathogen Vibrio shilonii AK1.

    PubMed

    Strauss, Chloe; Long, Hongan; Patterson, Caitlyn E; Te, Ronald; Lynch, Michael

    2017-08-22

    Recent application of mutation accumulation techniques combined with whole-genome sequencing (MA/WGS) has greatly promoted studies of spontaneous mutation. However, such explorations have rarely been conducted on marine organisms, and it is unclear how marine habitats have influenced genome stability. This report resolves the mutation rate and spectrum of the coral reef pathogen Vibrio shilonii, which causes coral bleaching and endangers the biodiversity maintained by coral reefs. We found that its mutation rate and spectrum are highly similar to those of other studied bacteria from various habitats, despite the saline environment. The mutational properties of this marine bacterium are thus controlled by other general evolutionary forces such as natural selection and genetic drift. We also found that as pH drops, the mutation rate decreases and the mutation spectrum is biased in the direction of generating G/C nucleotides. This implies that evolutionary features of this organism and perhaps other marine microbes might be altered by the increasingly acidic ocean water caused by excess CO2 emission. Nonetheless, further exploration is needed as the pH range tested in this study was rather narrow and many other possible mutation determinants, such as carbonate increase, are associated with ocean acidification.IMPORTANCE This study explored the pH dependence of a bacterial genome-wide mutation rate. We discovered that the genome-wide rates of appearance of most mutation types decrease linearly and that the mutation spectrum is biased in generating more G/C nucleotides with pH drop in the coral reef pathogen V. shilonii. Copyright © 2017 Strauss et al.

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

    PubMed Central

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

    2011-01-01

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

  2. 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.

  3. Fossil calibration of molecular divergence infers a moderate mutation rate and recent radiations for pinus.

    PubMed

    Willyard, Ann; Ann, Willyard; Syring, John; Gernandt, David S; Liston, Aaron; Cronn, Richard

    2007-01-01

    Silent mutation rate estimates for Pinus vary 50-fold, ranging from angiosperm-like to among the slowest reported for plants. These differences either reflect extraordinary genomic processes or inconsistent fossil calibration, and they have important consequences for population and biogeographical inferences. Here we estimate mutation rates from 4 Pinus species that represent the major lineages using 11 nuclear and 4 chloroplast loci. Calibration was tested at the divergence of Pinus subgenera with the oldest leaf fossil from subg. Strobus (Eocene; 45 MYA) or a recently published subg. Strobus wood fossil (Cretaceous; 85 MYA). These calibrations place the origin of Pinus 190-102 MYA and give absolute silent rate estimates of 0.70-1.31x10(-9) and 0.22-0.42x10(-9).site-1.year-1 for the nuclear and chloroplast genomes, respectively. These rates are approximately 4- to 20-fold slower than angiosperms, but unlike many previous estimates, they are more consistent with the high per-generation deleterious mutation rates observed in pines. Chronograms from nuclear and chloroplast genomes show that the divergence of subgenera accounts for about half of the time since Pinus diverged from Picea, with subsequent radiations occurring more recently. By extending the sampling to encompass the phylogenetic diversity of Pinus, we predict that most extant subsections diverged during the Miocene. Moreover, subsect. Australes, Ponderosae, and Contortae, containing over 50 extant species, radiated within a 5 Myr time span starting as recently as 18 MYA. An Eocene divergence of pine subgenera (using leaf fossils) does not conflict with fossil-based estimates of the Pinus-Picea split, but a Cretaceous divergence using wood fossils accommodates Oligocene fossils that may represent modern subsections. Because homoplasy and polarity of character states have not been tested for fossil pine assignments, the choice of fossil and calibration node represents a significant source of uncertainty

  4. 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.

  5. 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.

  6. 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

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

    PubMed

    Amos, William; Filipe, Laura N S

    2014-01-01

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

  8. Non-coding cancer driver candidates identified with a sample- and position-specific model of the somatic mutation rate

    PubMed Central

    Juul, Malene; Bertl, Johanna; Guo, Qianyun; Nielsen, Morten Muhlig; Świtnicki, Michał; Hornshøj, Henrik; Madsen, Tobias; Hobolth, Asger; Pedersen, Jakob Skou

    2017-01-01

    Non-coding mutations may drive cancer development. Statistical detection of non-coding driver regions is challenged by a varying mutation rate and uncertainty of functional impact. Here, we develop a statistically founded non-coding driver-detection method, ncdDetect, which includes sample-specific mutational signatures, long-range mutation rate variation, and position-specific impact measures. Using ncdDetect, we screened non-coding regulatory regions of protein-coding genes across a pan-cancer set of whole-genomes (n = 505), which top-ranked known drivers and identified new candidates. For individual candidates, presence of non-coding mutations associates with altered expression or decreased patient survival across an independent pan-cancer sample set (n = 5454). This includes an antigen-presenting gene (CD1A), where 5’UTR mutations correlate significantly with decreased survival in melanoma. Additionally, mutations in a base-excision-repair gene (SMUG1) correlate with a C-to-T mutational-signature. Overall, we find that a rich model of mutational heterogeneity facilitates non-coding driver identification and integrative analysis points to candidates of potential clinical relevance. DOI: http://dx.doi.org/10.7554/eLife.21778.001 PMID:28362259

  9. Adrenoleukodystrophy in Norway: high rate of de novo mutations and age-dependent penetrance.

    PubMed

    Horn, Morten A; Retterstøl, Lars; Abdelnoor, Michael; Skjeldal, Ola H; Tallaksen, Chantal M E

    2013-03-01

    To investigate X-linked adrenoleukodystrophy in an unselected population, we performed a population based, cross-sectional prevalence study, supplemented by a retrospective study of deceased subjects. Sixty-three subjects (34 males, 29 females) belonging to 22 kindreds were included. Thirty-nine subjects (13 males, 26 females) were alive, and 24 (21 males, 3 females) were deceased on the prevalence day. The point prevalence of X-linked adrenoleukodystrophy in Norway on July 1, 2011, was 0.8 per 100,000 inhabitants. The incidence at birth in the period 1956-1995 was 1.6 per 100,000 inhabitants. An age-dependent penetrance was observed among males and females, with more severe phenotypes appearing with rising age. Only 5% of deceased males had not developed cerebral leukodystrophy. No female older than 50 years was neurologically intact. Sixteen mutations in the ABCD1 gene were identified. De novo mutations were found in 19% of probands. The frequency of X-linked adrenoleukodystrophy was lower in Norway than reported in the literature. A more severe natural course than previously reported was observed, indicating a need for better follow-up of both male and female patients. Given the high rate of de novo mutations, identification programs such as newborn screening may be required to offer timely treatment to all patients. Copyright © 2013 Elsevier Inc. All rights reserved.

  10. Mutation rates for 20 STR loci in a population from São Paulo state, Southeast, Brazil.

    PubMed

    Martinez, Juliana; Braganholi, Danilo Faustino; Ambrósio, Isabela Brunelli; Polverari, Fernanda Silva; Cicarelli, Regina Maria Barretto

    2017-09-11

    Short tandem repeats (STRs) are genetic markers largely employed in forensic analysis and paternity investigation cases. When an inconsistency between the parent and child is considered as a possible mutation, the mutation rate should be incorporated into paternity index calculations to give a robust result and to reduce the chance of misinterpretation. The aim of this study was to estimate the mutation rates of 20 autosomal STRs loci used for paternity tests. In these loci we analysed 29,831 parent-child allelic transfers from 929 duo or trio paternity tests carried out during 2012?2016 from São Paulo State, Brazil. We identified 35 mutations in 16 loci, and they were more frequent in the paternal germline compared to the maternal germline. The loci with the highest rate were vWA and FGA and the ones with the lowest rate were PENTA E, PENTA D, D21S11, D7S820 and D6S1043. We did not identified any mutation in D2S1338, TH01, TPOX and D16S539 loci. All mutations consisted of losses or gains of one repeat unit. Mutation rates found in the São Paulo population have peculiarities, which justifies the use of regional databases in laboratories.

  11. The Role of Mutation Rates of GNAQ or GNA11 in Cases of Uveal Melanoma in Japan.

    PubMed

    Ominato, Jun; Fukuchi, Takeo; Sato, Ayako; Yamaguchi, Naoyuki; Kobayashi, Kazue; Cho, Hiroyuki; Oyama, Tokuhide; Ajioka, Yoichi

    2017-02-28

    GNAQ and GNA11 mutations are thought to be important for the tumorigenesis of uveal melanoma. Although previous studies have reported on mutation rates in cases of uveal melanoma, presently, no such report for the Japanese population exists. In this study, we examined the frequency of GNAQ and GNA11 somatic mutations in cases of uveal melanoma in Japan and their relationship with clinicopathologic features or Ki-67-positive cell rates (Ki-67 labeling index: Ki-67 LI) using immunofluorescence methods. The study involved 19 cases of uveal melanoma. We extracted the template DNA from formalin-fixed, paraffin-embedded specimens using a DNA extraction kit. We amplified the DNA sequences of GNAQ and GNA11 using polymerase chain reaction and analyzed mutations by direct sequencing. We evaluated Ki-67 LI using immunofluorescence methods. The frequencies of GNAQ and GNA11 somatic mutations were 26.3% (5/19) and 31.6% (6/19), respectively. The GNAQ and GNA11 mutations were mutually exclusive, as indicated in previous reports. The frequency of GNA11 mutations was significantly higher in epithelioid cells; however, no significant association between GNAQ mutations and cell type was evident, and there was no significant difference in Ki-67 LI between the mutation-positive and mutation-negative tumors. GNAQ and GNA11 mutations were identified in cases of uveal melanoma in Japan, although at lower frequencies than in white counterparts. The mutation frequency of GNA11 was significantly higher in epithelioid cells.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/.

  12. Characterization of a mutated Geobacillus stearothermophilus L-arabinose isomerase that increases the production rate of D-tagatose.

    PubMed

    Kim, H-J; Kim, J-H; Oh, H-J; Oh, D-K

    2006-07-01

    Characterization of a mutated Geobacillus stearothermophilus L-arabinose isomerase used to increase the production rate of D-tagatose. A mutated gene was obtained by an error-prone polymerase chain reaction using L-arabinose isomerase gene from G. stearothermophilus as a template and the gene was expressed in Escherichia coli. The expressed mutated L-arabinose isomerase exhibited the change of three amino acids (Met322-->Val, Ser393-->Thr, and Val408-->Ala), compared with the wild-type enzyme and was then purified to homogeneity. The mutated enzyme had a maximum galactose isomerization activity at pH 8.0, 65 degrees C, and 1.0 mM Co2+, while the wild-type enzyme had a maximum activity at pH 8.0, 60 degrees C, and 1.0-mM Mn2+. The mutated L-arabinose isomerase exhibited increases in D-galactose isomerization activity, optimum temperature, catalytic efficiency (kcat/Km) for D-galactose, and the production rate of D-tagatose from D-galactose. The mutated L-arabinose isomerase from G. stearothermophilus is valuable for the commercial production of D-tagatose. This work contributes knowledge on the characterization of a mutated L-arabinose isomerase, and allows an increased production rate for D-tagatose from D-galactose using the mutated enzyme.

  13. 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.

  14. 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.

  15. 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

  16. Cortical volumes and atrophy rates in FTD-3 CHMP2B mutation carriers and related non-carriers.

    PubMed

    Eskildsen, Simon F; Østergaard, Lasse R; Rodell, Anders B; Østergaard, Leif; Nielsen, Jørgen E; Isaacs, Adrian M; Johannsen, Peter

    2009-04-15

    Frontotemporal dementia constitutes the third most prevalent neurodegenerative disease with dementia. We compared cortical structural changes in nine presymptomatic CHMP2B frontotemporal dementia mutation positive individuals with seven mutation negative family members. Using serial MRI scans with a mean interval of 16 months and surface based cortical segmentation we measured cortical thickness and volume, and quantified atrophy rates. Cortical thickness and atrophy rates were averaged within major lobes and focal effects were determined by parametric statistical maps. The volumetric atrophy rates in the presymptomatic CHMP2B mutation carriers were statistically significant, though of a lower magnitude than those previously reported in patients of other types of frontotemporal dementia. Cortical thickness measurements revealed cortical thinning in mutation carriers bilaterally in the frontal and occipital lobes, and in the left temporal lobe. Results indicated that cortical thickness has a higher sensitivity for detecting small changes than whole-brain volumetric measures. Comparing mutation carriers with non-carriers revealed increased atrophy rates in mutation carriers bilaterally in the inferio-temporal cortex, the superior frontal cortex, and the insular cortex. These findings indicated impairment of regions involved in both behaviour and language. The symptoms previously reported in clinical CHMP2B frontotemporal dementia patients are associated with the anatomically affected regions here found in the presymptomatic mutation carriers.

  17. 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.

  18. 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.

  19. 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.

  20. 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

  1. Genome-Wide Biases in the Rate and Molecular Spectrum of Spontaneous Mutations in Vibrio cholerae and Vibrio fischeri.

    PubMed

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

    2017-01-01

    The vast diversity in nucleotide composition and architecture among bacterial genomes may be partly explained by inherent biases in the rates and spectra of spontaneous mutations. Bacterial genomes with multiple chromosomes are relatively unusual but some are relevant to human health, none more so than the causative agent of cholera, Vibrio cholerae Here, we present the genome-wide mutation spectra in wild-type and mismatch repair (MMR) defective backgrounds of two Vibrio species, the low-%GC squid symbiont V. fischeri and the pathogen V. cholerae, collected under conditions that greatly minimize the efficiency of natural selection. In apparent contrast to their high diversity in nature, both wild-type V. fischeri and V. cholerae have among the lowest rates for base-substitution mutations (bpsms) and insertion-deletion mutations (indels) that have been measured, below 10(-)(3)/genome/generation. Vibrio fischeri and V. cholerae have distinct mutation spectra, but both are AT-biased and produce a surprising number of multi-nucleotide indels. Furthermore, the loss of a functional MMR system caused the mutation spectra of these species to converge, implying that the MMR system itself contributes to species-specific mutation patterns. Bpsm and indel rates varied among genome regions, but do not explain the more rapid evolutionary rates of genes on chromosome 2, which likely result from weaker purifying selection. More generally, the very low mutation rates of Vibrio species correlate inversely with their immense population sizes and suggest that selection may not only have maximized replication fidelity but also optimized other polygenic traits relative to the constraints of genetic drift. © The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

  2. Achondroplasia and hypochondroplasia. Comments on frequency, mutation rate, and radiological features in skull and spine.

    PubMed Central

    Oberklaid, F; Danks, D M; Jensen, F; Stace, L; Rosshandler, S

    1979-01-01

    An attempt was made to ascertain all the dwarfs in the State of Victoria. The incidence of achondroplasia proved to be approximately 1 in 26,000 live births in the period 1969 to 1975 when ascertainment was nearly complete. This indicates a mutation rate of 1.93 X 10(-5) per generation in this locus. Paternal age was shown to influence mutation. Ascertainment in earlier years of the study was low despite the very great effort made to find all cases. Patients with hypochondroplasia were particularly difficult to find. However, 25 cases were found for study. Overlap between hypochondroplasia and achondroplasia was found in all features except the facial appearance (which was the basis of definition). Achondroplasia was more severe in all regards, but some individuals with hypochondroplasia were very short and some had extreme degrees of spinal canal stenosis. The classical measurements used to describe the skull changes in acondroplasia failed to distinguish this condition from hypochondroplasia. More efficient indices were devised, but visual assessment of the size of the facial region compared to that of the cranial valult proved more reliable than any index. The clinical distinction based upon facial appearance remains the arbitrary basis of definition. Images PMID:458831

  3. Evolution Models with Conditional Mutation Rates: Strange Plateaus in Population Distribution

    NASA Astrophysics Data System (ADS)

    Saakian, David B.

    2017-08-01

    Cancer is related to clonal evolution with a strongly nonlinear, collective behavior. Here we investigate a slightly advanced version of the popular Crow-Kimura evolution model, suggested recently, by simply assuming a conditional mutation rate. We investigated the steady-state solution and found a highly intriguing plateau in the distribution. There are selective and nonselective phases, with a rather narrow plateau in the distribution at the peak in the first phase, and a wide plateau for many Hamming classes (a collection of genomes with the same number of mutations from the reference genome) in the second phase. We analytically solved the steady state distribution in the selective and nonselective phases, calculating the widths of the plateaus. Numerically, we also found an intermediate phase with several plateaus in the steady-state distribution, related to large finite-genome-length corrections. We assume that the newly observed phenomena should exist in other versions of evolution dynamics when the parameters of the model are conditioned to the population distribution.

  4. 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).

  5. 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. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  6. 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

  7. High concordance rate of KRAS/BRAF mutations and MSI-H between primary colorectal cancer and corresponding metastases.

    PubMed

    Fujiyoshi, Kenji; Yamamoto, Gou; Takahashi, Akemi; Arai, Yoshiko; Yamada, Mina; Kakuta, Miho; Yamaguchi, Kensei; Akagi, Yoshito; Nishimura, Yoji; Sakamoto, Hirohiko; Akagi, Kiwamu

    2017-02-01

    Genetic testing is needed for the treatment of colorectal cancer (CRC), especially molecular-targeted therapy. The effects of anti-EGFR therapy and prognosis are affected by the presence of KRAS mutations. However, whether primary CRC or metastatic tissues are appropriate in the analysis is still unclear. In the present study, we assessed the concordance of KRAS/BRAF mutation status and microsatellite instability (MSI) in primary CRC and corresponding metastases. This study enrolled 457 patients with surgically resected primary and corresponding metastatic CRC (499 synchronous metastases and 57 metachronous metastases) and seven local recurrences, and KRAS/BRAF mutation and MSI status were analysed for these tumours. The concordance rates of KRAS mutation, BRAF mutation, wild-type, MSI-H and MSS between primary CRC and corresponding metastases were 93.9% (214/228), 100% (30/30), 99.3% (304/306), 87.5% (21/24) and 100% (137/137), respectively. These high concordance rates were not different between synchronous and metachronous metastases. In conclusion, a high concordance of KRAS/BRAF mutation status and MSI status was observed between primary CRC and corresponding metastases in this study. Either primary CRC or metastatic tissues can be used for testing KRAS/BRAF mutation status and MSI status.

  8. 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

  9. 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.

  10. 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

  11. 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

  12. 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.

  13. 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.

  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. © The Author 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  15. 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.

  16. 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.

  17. 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.

  18. 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.

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

    PubMed Central

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

    2013-01-01

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

  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. 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

  2. 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

  3. 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.

  4. K-core decomposition of a protein domain co-occurrence network reveals lower cancer mutation rates for interior cores.

    PubMed

    Emerson, Arnold I; Andrews, Simeon; Ahmed, Ikhlak; Azis, Thasni Ka; Malek, Joel A

    2015-01-01

    Network biology currently focuses primarily on metabolic pathways, gene regulatory, and protein-protein interaction networks. While these approaches have yielded critical information, alternative methods to network analysis will offer new perspectives on biological information. A little explored area is the interactions between domains that can be captured using domain co-occurrence networks (DCN). A DCN can be used to study the function and interaction of proteins by representing protein domains and their co-existence in genes and by mapping cancer mutations to the individual protein domains to identify signals. The domain co-occurrence network was constructed for the human proteome based on PFAM domains in proteins. Highly connected domains in the central cores were identified using the k-core decomposition technique. Here we show that these domains were found to be more evolutionarily conserved than the peripheral domains. The somatic mutations for ovarian, breast and prostate cancer diseases were obtained from the TCGA database. We mapped the somatic mutations to the individual protein domains and the local false discovery rate was used to identify significantly mutated domains in each cancer type. Significantly mutated domains were found to be enriched in cancer disease pathways. However, we found that the inner cores of the DCN did not contain any of the significantly mutated domains. We observed that the inner core protein domains are highly conserved and these domains co-exist in large numbers with other protein domains. Mutations and domain co-occurrence networks provide a framework for understanding hierarchal designs in protein function from a network perspective. This study provides evidence that a majority of protein domains in the inner core of the DCN have a lower mutation frequency and that protein domains present in the peripheral regions of the k-core contribute more heavily to the disease. These findings may contribute further to drug development.

  5. 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.

  6. 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.

  7. 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.

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

    PubMed Central

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

    2015-01-01

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

  9. 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

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

    PubMed Central

    Behringer, Megan G.; Hall, David W.

    2015-01-01

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

  11. 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.

  12. 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.

  13. Implications of High Rates of Metastatic Prostate Cancer in BRCA2 Mutation Carriers.

    PubMed

    Gleicher, Stephanie; Kauffman, Eric C; Kotula, Leszek; Bratslavsky, Gennady; Vourganti, Srinivas

    2016-09-01

    Patients with germline BRCA2 gene mutations (BRCA2mut) have more aggressive prostate cancer. Analysis of all reported germline BRCA2mut prostate cancer cases allows better understanding of the clinicopathologic features and survival outcomes of these men. A systematic review was performed with the MEDLINE database to capture articles evaluating clinicopathologic characteristics of men with BRCA2mut associated prostate cancer. Inclusion criteria were at least five subjects, confirmation of BRCA2mut status, and data for at least 2 clinical parameters of disease. Meta-analysis was performed on outcomes data. Chi-squared tests were used to compare disease features among men undergoing formal versus ad hoc screening, as well as an age of diagnosis less than versus greater than 65 years. Rates of metastatic disease among BRCA2mut cases were compared to rates among non-carrier control subjects and the general population using the SEER database. Twelve out of 289 studies met our inclusion criteria, representing 261 BRCA2mut men. Among carriers, the median age at diagnosis was 62 years and median PSA was 15 ng/dl with 95% of men having a PSA>3. Over 40% of BRCA2mut patients had T3/T4 disease and over 25% were metastatic at presentation. Survival was worse in BRCA2mut men with prostate cancer when compared to non-BRCA2mut subjects. BRCA2mut carriers had significantly higher rates of metastatic disease (18%) versus non-carrier controls (8%) and the SEER population (4%). BRCA2mut carriers are more likely to have poor risk of prostate cancer at presentation and exhibit worse oncologic outcomes relative to non-carriers, including a fourfold increase in metastatic disease. Younger men and those undergoing formal screening present with less advanced disease which supports a need for earlier identification and screening protocols. Additionally, this population may benefit from alternative therapeutic paradigms. Prostate 76:1135-1145, 2016. © 2016 Wiley Periodicals, Inc. © 2016

  14. 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.

  15. 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

  16. Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder.

    PubMed

    Lim, Elaine T; Uddin, Mohammed; De Rubeis, Silvia; Chan, Yingleong; Kamumbu, Anne S; Zhang, Xiaochang; D'Gama, Alissa M; Kim, Sonia N; Hill, Robert Sean; Goldberg, Arthur P; Poultney, Christopher; Minshew, Nancy J; Kushima, Itaru; Aleksic, Branko; Ozaki, Norio; Parellada, Mara; Arango, Celso; Penzol, Maria J; Carracedo, Angel; Kolevzon, Alexander; Hultman, Christina M; Weiss, Lauren A; Fromer, Menachem; Chiocchetti, Andreas G; Freitag, Christine M; Church, George M; Scherer, Stephen W; Buxbaum, Joseph D; Walsh, Christopher A

    2017-09-01

    We systematically analyzed postzygotic mutations (PZMs) in whole-exome sequences from the largest collection of trios (5,947) with autism spectrum disorder (ASD) available, including 282 unpublished trios, and performed resequencing using multiple independent technologies. We identified 7.5% of de novo mutations as PZMs, 83.3% of which were not described in previous studies. Damaging, nonsynonymous PZMs within critical exons of prenatally expressed genes were more common in ASD probands than controls (P < 1 × 10(-6)), and genes carrying these PZMs were enriched for expression in the amygdala (P = 5.4 × 10(-3)). Two genes (KLF16 and MSANTD2) were significantly enriched for PZMs genome-wide, and other PZMs involved genes (SCN2A, HNRNPU and SMARCA4) whose mutation is known to cause ASD or other neurodevelopmental disorders. PZMs constitute a significant proportion of de novo mutations and contribute importantly to ASD risk.

  17. 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.

  18. 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

  19. 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.

  20. 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

  1. 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.

  2. Low rates of synonymous mutations in sequences of Mycobacterium tuberculosis GyrA and KatG genes.

    PubMed

    Khrustalev, Vladislav Victorovich; Arjomandzadegan, Mohammad; Barkovsky, Eugene Victorovich; Titov, Leonid Petrovich

    2012-07-01

    Partial sequences of KatG and GyrA genes have been obtained from multi and extensively drug-resistant (MDR and XDR) clinical isolates of Mycobacterium tuberculosis. Nonsynonymous (DN) and synonymous (DS) distances between those sequences have been calculated by Kumar method. Results revealed that DN is significantly higher than DS between some pairs of partial GyrA sequences. We found out that DN is higher than DS in many other partial and complete sequences of KatG and GyrA coding regions deposited in GenBank. The cause of the DN > DS situation is in several nonsynonymous substitutions occurrence (which may be associated with drug-resistance or not) in the absence of synonymous substitutions. Low rates of synonymous mutations occurrence is a consequence of the strong mutational GC-pressure. Due to the high saturation of third codon positions by guanine and cytosine (78.81 ± 0.17% for all the genes from M. tuberculosis H37Rv genome), the probability to be synonymous for the nucleotide mutation of preferable (AT to GC) direction is low. Fixation of a single nonsynonymous mutation leading to drug-resistance is a consequence of Darwinian selection. This clear example of Darwinian selection on the molecular level can be confirmed by selection test (DN > DS) only in case of DN and DS calculation in pairs of sequences possessing at least two additional nonsynonymous mutations which may be neutral or excessive. Copyright © 2012 Elsevier Ltd. All rights reserved.

  3. Mutations in the human immunodeficiency virus type 1 polypurine tract (PPT) reduce the rate of PPT cleavage and plus-strand DNA synthesis.

    PubMed

    McWilliams, M J; Julias, J G; Hughes, S H

    2008-05-01

    Previously, we analyzed the effects of point mutations in the human immunodeficiency virus type 1 (HIV-1) polypurine tract (PPT) and found that some mutations affected both titer and cleavage specificity. We used HIV-1 vectors containing two PPTs and the D116N integrase active-site mutation in a cell-based assay to measure differences in the relative rates of PPT processing and utilization. The relative rates were measured by determining which of the two PPTs in the vector is used to synthesize viral DNA. The results indicate that mutations that have subtle effects on titer and cleavage specificity can have dramatic effects on rates of PPT generation and utilization.

  4. High Rate of Large Deletions in Caenorhabditis briggsae Mitochondrial Genome Mutation Processes

    PubMed Central

    Howe, Dana K.; Baer, Charles F.; Denver, Dee R.

    2010-01-01

    Mitochondrial DNA (mtDNA) mutations underlie a variety of human genetic disorders and are associated with the aging process. mtDNA polymorphisms are widely used in a variety of evolutionary applications. Although mtDNA mutation spectra are known to differ between distantly related model organisms, the extent to which mtDNA mutation processes vary between more closely related species and within species remains enigmatic. We analyzed mtDNA divergence in two sets of 250-generation Caenorhabditis briggsae mutation-accumulation (MA) lines, each derived from a different natural isolate progenitor: strain HK104 from Okayama, Japan, and strain PB800 from Ohio, United States. Both sets of C. briggsae MA lines accumulated numerous large heteroplasmic mtDNA deletions, whereas only one similar event was observed in a previous analysis of Caenorhabditis elegans MA line mtDNA. Homopolymer length change mutations were frequent in both sets of C. briggsae MA lines and occurred in both intergenic and protein-coding gene regions. The spectrum of C. briggsae mtDNA base substitution mutations differed from the spectrum previously observed in C. elegans. In C. briggsae, the HK104 MA lines experienced many different base substitution types, whereas the PB800 lines displayed only C:G → T:A transitions, although the difference was not significant. Over half of the mtDNA base substitutions detected in the C. briggsae MA lines were in a heteroplasmic state, whereas all those previously characterized in C. elegans MA line mtDNA were fixed changes, indicating a narrower mtDNA bottleneck in C. elegans as compared with C. briggsae. Our results show that C. briggsae mtDNA is highly susceptible to large deletions and that the mitochondrial mutation process varies between Caenorhabditis nematode species. PMID:20333220

  5. The erratic mitochondrial clock: variations of mutation rate, not population size, affect mtDNA diversity across birds and mammals.

    PubMed

    Nabholz, Benoit; Glémin, Sylvain; Galtier, Nicolas

    2009-03-10

    During the last ten years, major advances have been made in characterizing and understanding the evolution of mitochondrial DNA, the most popular marker of molecular biodiversity. Several important results were recently reported using mammals as model organisms, including (i) the absence of relationship between mitochondrial DNA diversity and life-history or ecological variables, (ii) the absence of prominent adaptive selection, contrary to what was found in invertebrates, and (iii) the unexpectedly large variation in neutral substitution rate among lineages, revealing a possible link with species maximal longevity. We propose to challenge these results thanks to the bird/mammal comparison. Direct estimates of population size are available in birds, and this group presents striking life-history trait differences with mammals (higher mass-specific metabolic rate and longevity). These properties make birds the ideal model to directly test for population size effects, and to discriminate between competing hypotheses about the causes of substitution rate variation. A phylogenetic analysis of cytochrome b third-codon position confirms that the mitochondrial DNA mutation rate is quite variable in birds, passerines being the fastest evolving order. On average, mitochondrial DNA evolves slower in birds than in mammals of similar body size. This result is in agreement with the longevity hypothesis, and contradicts the hypothesis of a metabolic rate-dependent mutation rate. Birds show no footprint of adaptive selection on cytochrome b evolutionary patterns, but no link between direct estimates of population size and cytochrome b diversity. The mutation rate is the best predictor we have of within-species mitochondrial diversity in birds. It partly explains the differences in mitochondrial DNA diversity patterns observed between mammals and birds, previously interpreted as reflecting Hill-Robertson interferences with the W chromosome. Mitochondrial DNA diversity patterns in

  6. Flanking sequence specificity determines coding microsatellite heteroduplex and mutation rates with defective DNA mismatch repair (MMR).

    PubMed

    Chung, H; Lopez, C G; Young, D J; Lai, J F; Holmstrom, J; Ream-Robinson, D; Cabrera, B L; Carethers, J M

    2010-04-15

    The activin type II receptor (ACVR2) contains two identical microsatellites in exons 3 and 10, but only the exon 10 microsatellite is frameshifted in mismatch repair (MMR)-defective colonic tumors. The reason for this selectivity is not known. We hypothesized that ACVR2 frameshifts were influenced by DNA sequences surrounding the microsatellite. We constructed plasmids in which exons 3 or 10 of ACVR2 were cloned +1 bp out of frame of enhanced green fluorescent protein (EGFP), allowing -1 bp frameshift to express EGFP. Plasmids were stably transfected into MMR-deficient cells, and subsequent non-fluorescent cells were sorted, cultured and harvested for mutation analysis. We swapped DNA sequences flanking the exon 3 and 10 microsatellites to test our hypothesis. Native ACVR2 exon 3 and 10 microsatellites underwent heteroduplex formation (A(7)/T(8)) in hMLH1(-/-) cells, but only exon 10 microsatellites fully mutated (A(7)/T(7)) in both hMLH1(-/-) and hMSH6(-/-) backgrounds, showing selectivity for exon 10 frameshifts and inability of exon 3 heteroduplexes to fully mutate. Substituting nucleotides flanking the exon 3 microsatellite for nucleotides flanking the exon 10 microsatellite significantly reduced heteroduplex and full mutation in hMLH1(-/-) cells. When the exon 3 microsatellite was flanked by nucleotides normally surrounding the exon 10 microsatellite, fully mutant exon 3 frameshifts appeared. Mutation selectivity for ACVR2 lies partly with flanking nucleotides surrounding each microsatellite.

  7. 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.

  8. Mutation of Spirulina sp. by nuclear irradiation to improve growth rate under 15% carbon dioxide in flue gas.

    PubMed

    Cheng, Jun; Lu, Hongxiang; He, Xin; Yang, Weijuan; Zhou, Junhu; Cen, Kefa

    2017-08-01

    Spirulina sp. was mutated by γ-rays from (60)Co nuclear irradiation to improve growth and CO2 fixation rate under 15vol.% CO2 (in flue gas from a power plant). Mutants with enhanced growth phenotype were obtained, with the best strain exhibiting 310% increment in biomass yield on day 4. The mutant was then domesticated with elevated CO2 concentration, and the biomass yield increased by 500% after domestication under 15vol.% CO2, with stable inheritance. Ultrastructure of Spirulina sp. shows that the fractal dimension of Spirulina cells decreased by 23% after mutation. Pore size in the cell wall of Spirulina mutant increased by 33% after 15vol.% CO2 domestication. This characteristic facilitated the direct penetration of CO2 into cells, thus improving CO2 biofixation rate. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. 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.

  10. Folding RaCe: a robust method for predicting changes in protein folding rates upon point mutations.

    PubMed

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

    2015-07-01

    Protein engineering methods are commonly employed to decipher the folding mechanism of proteins and enzymes. However, such experiments are exceedingly time and resource intensive. It would therefore be advantageous to develop a simple computational tool to predict changes in folding rates upon mutations. Such a method should be able to rapidly provide the sequence position and chemical nature to modulate through mutation, to effect a particular change in rate. This can be of importance in protein folding, function or mechanistic studies. We have developed a robust knowledge-based methodology to predict the changes in folding rates upon mutations formulated from amino and acid properties using multiple linear regression approach. We benchmarked this method against an experimental database of 790 point mutations from 26 two-state proteins. Mutants were first classified according to secondary structure, accessible surface area and position along the primary sequence. Three prime amino acid features eliciting the best relationship with folding rates change were then shortlisted for each class along with an optimized window length. We obtained a self-consistent mean absolute error of 0.36 s(-1) and a mean Pearson correlation coefficient (PCC) of 0.81. Jack-knife test resulted in a MAE of 0.42 s(-1) and a PCC of 0.73. Moreover, our method highlights the importance of outlier(s) detection and studying their implications in the folding mechanism. A web server 'Folding RaCe' has been developed and is available at http://www.iitm.ac.in/bioinfo/proteinfolding/foldingrace.html. gromiha@iitm.ac.in Supplementary data are available at Bioinformatics online. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  11. 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

  12. 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.

  13. 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.

  14. 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.

  15. 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

  16. 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

  17. 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

  18. The role of weak selection and high mutation rates in nearly neutral evolution.

    PubMed

    Lawson, Daniel John; Jensen, Henrik Jeldtoft

    2009-04-21

    Neutral dynamics occur in evolution if all types are 'effectively equal' in their reproductive success, where the definition of 'effectively equal' depends on the population size and the details of mutations. Empirically observed neutral genetic evolution in extremely large clonal populations can only be explained under current models if selection is completely absent. Such models typically consider the case where population dynamics occurs on a different timescale to evolution. However, this assumption is invalid when mutations are not rare in a whole population. We show that this has important consequences for the occurrence of neutral evolution in clonal populations. In highly connected type spaces, neutral dynamics can occur for all population sizes despite significant selective differences, via the forming of effectively neutral networks connecting rare neutral types. Biological implications include an explanation for the high diversity of rare types that survive in large clonal populations, and a theoretical justification for the use of neutral null models.

  19. 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

  20. 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.

  1. Renditions: Constraints Imposed by Laws on Torture

    DTIC Science & Technology

    2006-04-05

    level of torture. Besides CAT, additional obligations may be imposed upon U.S. rendition practice via the Geneva Conventions, the War Crimes Act, the...13 Other Statutes and Treaties Relevant to the Issue of Renditions . . . . . . . . . 17 War Crimes Act...surrender of persons from one treaty party to another, facilitating treaty parties’ shared interest in punishing certain crimes while providing persons

  2. 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

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

    NASA Technical Reports Server (NTRS)

    Jukes, T. H.; Kimura, M.

    1984-01-01

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

  4. 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.

  5. 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

    2017-06-01

    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.

  6. The rate and significance of Mediterranean fever gene mutations in patients with ankylosing spondylitis: a three-month, longitudinal clinical study.

    PubMed

    Cinar, Muhammet; Dinc, Ayhan; Simsek, Ismail; Erdem, Hakan; Koc, Bayram; Pay, Salih; Tunca, Yusuf; Kilic, Selim; Gul, Davud

    2008-11-01

    In this study, our aim was to investigate the prevalence of Mediterranean fever (MEFV) gene mutations in patients with ankylosing spondylitis (AS) and assessing their clinical significance. Ninety-five consecutive patients (12 women, 83 men) with active AS were included to the study. All patient's relevant clinical data were recorded at the beginning and patient assessment measures were performed. The frequency of the eight most common MEFV mutations: M694V, V726A, E148Q, M680I, M694I, P369S, F479L, and the R761H were determined. Genetic analysis was carried out by the NanoChip Molecular Genetics Workstation. NSAIDs were given to patients for treatment. The rate of MEFV mutations and their clinical significance were assessed. With regard to the MEFV mutation analysis, 30.5% of AS patients were found to have at least one mutation. The response rate to the NSAIDs (P=0.825) or frequency of patients having active disease (P=0.066) after the treatment, were not found different between the patients those have MEFV mutations and the patients those were non-carriers. Furthermore, no clinical and laboratory difference between MEFV mutation carriers and non-carriers were found. We think that although prevalence of MEFV mutations is significantly high in AS patients without clinical features of familial Mediterranean fever, its influence to the prognosis is less likely. Further investigations are needed to define the impact of MEFV mutations on the disease course of ankylosing spondylitis.

  7. 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. © The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  8. 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.

  9. 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.

  10. 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

  11. 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

  12. 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.

  13. Evidence That Replication-Associated Mutation Alone Does Not Explain Between-Chromosome Differences In Substitution Rates

    PubMed Central

    Pink, Catherine J.; Swaminathan, Siva K.; Dunham, Ian; Rogers, Jane; Ward, Andrew

    2009-01-01

    Since Haldane first noticed an excess of paternally derived mutations, it has been considered that most mutations derive from errors during germ line replication. Miyata et al. (1987) proposed that differences in the rate of neutral evolution on X, Y, and autosome can be employed to measure the extent of this male bias. This commonly applied method assumes replication to be the sole source of between-chromosome variation in substitution rates. We propose a simple test of this assumption: If true, estimates of the male bias should be independent of which two chromosomal classes are compared. Prior evidence from rodents suggested that this might not be true, but conclusions were limited by a lack of rat Y-linked sequence. We therefore sequenced two rat Y-linked bacterial artificial chromosomes and determined evolutionary rate by comparison with mouse. For estimation of rates we consider both introns and synonymous rates. Surprisingly, for both data sets the prediction of congruent estimates of α is strongly rejected. Indeed, some comparisons suggest a female bias with autosomes evolving faster than Y-linked sequence. We conclude that the method of Miyata et al. (1987) has the potential to provide incorrect estimates. Correcting the method requires understanding of the other causes of substitution that might differ between chromosomal classes. One possible cause is recombination-associated substitution bias for which we find some evidence. We note that if, as some suggest, this association is dominantly owing to male recombination, the high estimates of α seen in birds is to be expected as Z chromosomes recombine in males. PMID:20333173

  14. 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

  15. 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.

  16. Site-Directed Chemical Mutations on Abzymes: Large Rate Accelerations in the Catalysis by Exchanging the Functionalized Small Nonprotein Components.

    PubMed

    Ishikawa, Fumihiro; Shirahashi, Masato; Hayakawa, Hiroshi; Yamaguchi, Asako; Hirokawa, Takatsugu; Tsumuraya, Takeshi; Fujii, Ikuo

    2016-10-21

    Taking advantage of antibody molecules to generate tailor-made binding sites, we propose a new class of protein modifications, termed as "site-directed chemical mutation." In this modification, chemically synthesized catalytic components with a variety of steric and electronic properties can be noncovalently and nongenetically incorporated into specific sites in antibody molecules to induce enzymatic activity. Two catalytic antibodies, 25E2 and 27C1, possess antigen-combining sites which bind catalytic components and act as apoproteins in catalytic reactions. By simply exchanging these components, antibodies 25E2 and 27C1 can catalyze a wide range of chemical transformations including acyl-transfer, β-elimination, aldol, and decarboxylation reactions. Although both antibodies were generated with the same hapten, phosphonate diester 1, they showed different catalytic activity. When phenylacetic acid 4 was used as the catalytic component, 25E2 efficiently catalyzed the elimination reaction of β-haloketone 2, whereas 27C1 showed no catalytic activity. In this work, we focused on the β-elimination reaction and examined the site-directed chemical mutation of 27C1 to induce activity and elucidate the catalytic mechanism. Molecular models showed that the cationic guanidyl group of Arg(H52) in 27C1 makes a hydrogen bond with the P═O oxygen in the hapten. This suggested that during β-elimination, Arg(H52) of 27C1 would form a salt bridge with the carboxylate of 4, thus destroying reactivity. Therefore, we utilized site-directed chemical mutation to change the charge properties of the catalytic components. When amine components 7-10 were used, 27C1 efficiently catalyzed the β-elimination reaction. It is noteworthy that chemical mutation with secondary amine 8 provided extremely high activity, with a rate acceleration [(kcat/Km 2)/kuncat] of 1 000 000. This catalytic activity likely arises from the proximity effect, plus general-base catalysis associated the

  17. 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

  18. Mutations in the Human Immunodeficiency Virus Type 1 Polypurine Tract (PPT) Reduce the Rate of PPT Cleavage and Plus-Strand DNA Synthesis▿ †

    PubMed Central

    McWilliams, M. J.; Julias, J. G.; Hughes, S. H.

    2008-01-01

    Previously, we analyzed the effects of point mutations in the human immunodeficiency virus type 1 (HIV-1) polypurine tract (PPT) and found that some mutations affected both titer and cleavage specificity. We used HIV-1 vectors containing two PPTs and the D116N integrase active-site mutation in a cell-based assay to measure differences in the relative rates of PPT processing and utilization. The relative rates were measured by determining which of the two PPTs in the vector is used to synthesize viral DNA. The results indicate that mutations that have subtle effects on titer and cleavage specificity can have dramatic effects on rates of PPT generation and utilization. PMID:18321979

  19. 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.

  20. 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.

  1. 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.

  2. 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

  3. 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.

  4. 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

  5. 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

  6. 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

  7. 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.

  8. Misfolded proteins impose a dosage-dependent fitness cost and trigger a cytosolic unfolded protein response in yeast

    PubMed Central

    Dion, Michael F.; Budnik, Bogdan A.; Wang, Stephanie M.; Hartl, Daniel L.; Drummond, D. Allan

    2011-01-01

    Evolving lineages face a constant intracellular threat: most new coding sequence mutations destabilize the folding of the encoded protein. Misfolded proteins form insoluble aggregates and are hypothesized to be intrinsically cytotoxic. Here, we experimentally isolate a fitness cost caused by toxicity of misfolded proteins. We exclude other costs of protein misfolding, such as loss of functional protein or attenuation of growth-limiting protein synthesis resources, by comparing growth rates of budding yeast expressing folded or misfolded variants of a gratuitous protein, YFP, at equal levels. We quantify a fitness cost that increases with misfolded protein abundance, up to as much as a 3.2% growth rate reduction when misfolded YFP represents less than 0.1% of total cellular protein. Comparable experiments on variants of the yeast gene orotidine-5′-phosphate decarboxylase (URA3) produce similar results. Quantitative proteomic measurements reveal that, within the cell, misfolded YFP induces coordinated synthesis of interacting cytosolic chaperone proteins in the absence of a wider stress response, providing evidence for an evolved modular response to misfolded proteins in the cytosol. These results underscore the distinct and evolutionarily relevant molecular threat of protein misfolding, independent of protein function. Assuming that most misfolded proteins impose similar costs, yeast cells express almost all proteins at steady-state levels sufficient to expose their encoding genes to selection against misfolding, lending credibility to the recent suggestion that such selection imposes a global constraint on molecular evolution. PMID:21187411

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

    PubMed Central

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

    2014-01-01

    Decitabine (5-aza-2′-deoxycytidine) is a DNA methyltransferase inhibitor and an archetypal epigenetic drug for the therapy of myeloid leukemias. The mode of action of decitabine strictly depends on the incorporation of the drug into DNA. However, DNA incorporation and ensuing genotoxic effects of decitabine have not yet been investigated in human cancer cell lines or in models related to the approved indication of the drug. Here we describe a robust assay for the quantitative determination of decitabine incorporation rates into DNA from human cancer cells. Using a panel of human myeloid leukemia cell lines we show appreciable amounts of decitabine incorporation that closely correlated with cellular drug uptake. Decitabine incorporation was also detectable in primary cells from myeloid leukemia patients, indicating that the assay is suitable for biomarker analyses to predict drug responses in patients. Finally, we also used next-generation sequencing to comprehensively analyze the effects of decitabine incorporation on the DNA sequence level. Interestingly, this approach failed to reveal significant changes in the rates of point mutations and genome rearrangements in myeloid leukemia cell lines. These results indicate that standard rates of decitabine incorporation are not genotoxic in myeloid leukemia cells. PMID:25159616

  11. 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. © The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

  12. 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.

  13. The effect of dose rate on the frequency of specific-locus mutations induced in mouse spermatogonia is restricted to larger lesions; a retrospective analysis of historical data.

    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.

  14. 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.

  15. Brief temperature stress during reproductive stages alters meiotic recombination and somatic mutation rates in the progeny of Arabidopsis.

    PubMed

    Saini, Ramswaroop; Singh, Amit Kumar; Dhanapal, Shanmuhapreya; Saeed, Thoufeequl Hakeem; Hyde, Geoffrey J; Baskar, Ramamurthy

    2017-06-14

    Plants exposed to environmental stresses draw upon many genetic and epigenetic strategies, with the former sometimes modulated by the latter. This can help the plant, and its immediate progeny, at least, to better endure the stress. Some evidence has led to proposals that (epi) genetic changes can be both selective and sustainably heritable, while other evidence suggests that changes are effectively stochastic, and important only because they induce genetic variation. One type of stress with an arguably high level of stochasticity in its effects is temperature stress. Studies of how heat and cold affect the rates of meiotic recombination (MR) and somatic mutations (SMs, which are potentially heritable in plants) report increases, decreases, or no effect. Collectively, they do not point to any consistent patterns. Some of this variability, however, might arise from the stress being applied for such an extended time, typically days or weeks. Here, we adopted a targeted approach by (1) limiting exposure to one hour; and (2) timing it to coincide with (a) gamete, and early gametophyte, development, a period of high stress sensitivity; and (b) a late stage of vegetative development. For plants (Arabidopsis thaliana) otherwise grown at 22 °C, we measured the effects of a 1 h exposure to cold (12 °C) or heat (32 °C) on the rates of MR, and four types of SMs (frameshift mutations; intrachromosomal recombination; base substitutions; transpositions) in the F1 progeny. One parent (wild type) was stressed, the other (unstressed) carried a genetic event detector. When rates were compared to those in progeny of control (both parents unstressed) two patterns emerged. In the progeny of younger plants (stressed at 36 days; pollinated at 40 days) heat and cold either had no effect (on MR) or (for SMs) had effects that were rare and stochastic. In the progeny of older plants (stressed at 41 days; pollinated at 45 days), while effects were also infrequent, those that were

  16. MutS and MutL are dispensable for maintenance of the genomic mutation rate in the halophilic archaeon Halobacterium salinarum NRC-1.

    PubMed

    Busch, Courtney R; DiRuggiero, Jocelyne

    2010-02-04

    The genome of the halophilic archaeon Halobacterium salinarum NRC-1 encodes for homologs of MutS and MutL, which are key proteins of a DNA mismatch repair pathway conserved in Bacteria and Eukarya. Mismatch repair is essential for retaining the fidelity of genetic information and defects in this pathway result in the deleterious accumulation of mutations and in hereditary diseases in humans. We calculated the spontaneous genomic mutation rate of H. salinarum NRC-1 using fluctuation tests targeting genes of the uracil monophosphate biosynthesis pathway. We found that H. salinarum NRC-1 has a low incidence of mutation suggesting the presence of active mechanisms to control spontaneous mutations during replication. The spectrum of mutational changes found in H. salinarum NRC-1, and in other archaea, appears to be unique to this domain of life and might be a consequence of their adaption to extreme environmental conditions. In-frame targeted gene deletions of H. salinarum NRC-1 mismatch repair genes and phenotypic characterization of the mutants demonstrated that the mutS and mutL genes are not required for maintenance of the observed mutation rate. We established that H. salinarum NRC-1 mutS and mutL genes are redundant to an alternative system that limits spontaneous mutation in this organism. This finding leads to the puzzling question of what mechanism is responsible for maintenance of the low genomic mutation rates observed in the Archaea, which for the most part do not have MutS and MutL homologs.

  17. MutS and MutL Are Dispensable for Maintenance of the Genomic Mutation Rate in the Halophilic Archaeon Halobacterium salinarum NRC-1

    PubMed Central

    2010-01-01

    Background The genome of the halophilic archaeon Halobacterium salinarum NRC-1 encodes for homologs of MutS and MutL, which are key proteins of a DNA mismatch repair pathway conserved in Bacteria and Eukarya. Mismatch repair is essential for retaining the fidelity of genetic information and defects in this pathway result in the deleterious accumulation of mutations and in hereditary diseases in humans. Methodology/Principal Findings We calculated the spontaneous genomic mutation rate of H. salinarum NRC-1 using fluctuation tests targeting genes of the uracil monophosphate biosynthesis pathway. We found that H. salinarum NRC-1 has a low incidence of mutation suggesting the presence of active mechanisms to control spontaneous mutations during replication. The spectrum of mutational changes found in H. salinarum NRC-1, and in other archaea, appears to be unique to this domain of life and might be a consequence of their adaption to extreme environmental conditions. In-frame targeted gene deletions of H. salinarum NRC-1 mismatch repair genes and phenotypic characterization of the mutants demonstrated that the mutS and mutL genes are not required for maintenance of the observed mutation rate. Conclusions/Significance We established that H. salinarum NRC-1 mutS and mutL genes are redundant to an alternative system that limits spontaneous mutation in this organism. This finding leads to the puzzling question of what mechanism is responsible for maintenance of the low genomic mutation rates observed in the Archaea, which for the most part do not have MutS and MutL homologs. PMID:20140215

  18. 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

  19. 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.

  20. The "fossilized" mitochondrial genome of Liriodendron tulipifera: ancestral gene content and order, ancestral editing sites, and extraordinarily low mutation rate.

    PubMed

    Richardson, Aaron O; Rice, Danny W; Young, Gregory J; Alverson, Andrew J; Palmer, Jeffrey D

    2013-04-15

    The mitochondrial genomes of flowering plants vary greatly in size, gene content, gene order, mutation rate and level of RNA editing. However, the narrow phylogenetic breadth of available genomic data has limited our ability to reconstruct these traits in the ancestral flowering plant and, therefore, to infer subsequent patterns of evolution across angiosperms. We sequenced the mitochondrial genome of Liriodendron tulipifera, the first from outside the monocots or eudicots. This 553,721 bp mitochondrial genome has evolved remarkably slowly in virtually all respects, with an extraordinarily low genome-wide silent substitution rate, retention of genes frequently lost in other angiosperm lineages, and conservation of ancestral gene clusters. The mitochondrial protein genes in Liriodendron are the most heavily edited of any angiosperm characterized to date. Most of these sites are also edited in various other lineages, which allowed us to polarize losses of editing sites in other parts of the angiosperm phylogeny. Finally, we added comprehensive gene sequence data for two other magnoliids, Magnolia stellata and the more distantly related Calycanthus floridus, to measure rates of sequence evolution in Liriodendron with greater accuracy. The Magnolia genome has evolved at an even lower rate, revealing a roughly 5,000-fold range of synonymous-site divergence among angiosperms whose mitochondrial gene space has been comprehensively sequenced. Using Liriodendron as a guide, we estimate that the ancestral flowering plant mitochondrial genome contained 41 protein genes, 14 tRNA genes of mitochondrial origin, as many as 7 tRNA genes of chloroplast origin, >700 sites of RNA editing, and some 14 colinear gene clusters. Many of these gene clusters, genes and RNA editing sites have been variously lost in different lineages over the course of the ensuing ∽200 million years of angiosperm evolution.

  1. 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

  2. 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.

  3. 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.

  4. Explaining the high mutation rates of cancer cells to drug and multidrug resistance by chromosome reassortments that are catalyzed by aneuploidy.

    PubMed

    Duesberg, P; Stindl, R; Hehlmann, R

    2000-12-19

    The mutation rates of cancer cells to drug and multidrug resistance are paradoxically high, i.e., 10(-3) to 10(-6), compared with those altering phenotypes of recessive genes in normal diploid cells of about 10(-12). Here the hypothesis was investigated that these mutations are due to chromosome reassortments that are catalyzed by aneuploidy. Aneuploidy, an abnormal number of chromosomes, is the most common genetic abnormality of cancer cells and is known to change phenotypes (e.g., Down's syndrome). Moreover, we have shown recently that aneuploidy autocatalyzes reassortments of up to 2% per chromosome per mitosis because it unbalances spindle proteins, even centrosome numbers, via gene dosage. The hypothesis predicts that a selected phenotype is associated with multiple unselected ones, because chromosome reassortments unbalance simultaneously thousands of regulatory and structural genes. It also predicts variants of a selected phenotype based on variant reassortments. To test our hypothesis we have investigated in parallel the mutation rates of highly aneuploid and of normal diploid Chinese hamster cells to resistance against puromycin, cytosine arabinoside, colcemid, and methotrexate. The mutation rates of aneuploid cells ranged from 10(-4) to 10(-6), but no drug-resistant mutants were obtained from diploid cells in our conditions. Further selection increased drug resistance at similar mutation rates. Mutants selected from cloned cells for resistance against one drug displayed different unselected phenotypes, e.g., polygonal or fusiform cellular morphology, flat or three-dimensional colonies, and resistances against other unrelated drugs. Thus our hypothesis offers a unifying explanation for the high mutation rates of aneuploid cancer cells and for the association of selected with unselected phenotypes, e.g., multidrug resistance. It also predicts drug-specific chromosome combinations that could become a basis for selecting alternative chemotherapy against drug

  5. Terrestrial locomotion imposes high metabolic requirements on bats.

    PubMed

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

    2012-12-15

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

  6. 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

  7. 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.

  8. 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

  9. 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.

  10. A novel 'splice site' HCN4 Gene mutation, c.1737+1 G>T, causes familial bradycardia, reduced heart rate response, impaired chronotropic competence and increased short-term heart rate variability.

    PubMed

    Hategan, Lidia; Csányi, Beáta; Ördög, Balázs; Kákonyi, Kornél; Tringer, Annamária; Kiss, Orsolya; Orosz, Andrea; Sághy, László; Nagy, István; Hegedűs, Zoltán; Rudas, László; Széll, Márta; Varró, András; Forster, Tamás; Sepp, Róbert

    2017-08-15

    The most important molecular determinant of heart rate regulation in sino-atrial pacemaker cells includes hyperpolarization-activated, cyclic nucleotide-gated ion channels, the major isoform of which is encoded by the HCN4 gene. Mutations affecting the HCN4 gene are associated primarily with sick sinus syndrome. A novel c.1737+1 G>T 'splice-site' HCN4 mutation was identified in a large family with familial bradycardia which co-segregated with the disease providing a two-point LOD score of 4.87. Twelve out of the 22 investigated family members [4 males, 8 females average age 36 (SD 6) years] were considered as clinically affected (heart rate<60/min on resting ECG). Minimum [36 (SD 7) vs. 47 (SD 5) bpm, p=0.0087) and average heart rates [62 (SD 8) vs. 73 (SD 8) bpm, p=0.0168) were significantly lower in carriers on 24-hour Holter recordings. Under maximum exercise test carriers achieved significantly lower heart rates than non-carrier family members, and percent heart rate reserve and percent corrected heart rate reserve were significantly lower in carriers. Applying rigorous criteria for chronotropic incompetence a higher number of carriers exhibited chronotropic incompetence. Parameters, characterizing short-term variability of heart rate (i.e. rMSSD and pNN50%) were increased in carrier family members, even after normalization for heart rate, in the 24-hour ECG recordings with the same relative increase in 5-minute recordings. The identified novel 'splice site' HCN4 gene mutation, c.1737+1 G>T, causes familial bradycardia and leads to reduced heart rate response, impaired chronotropic competence and increased short-term heart rate variability in the mutation carriers. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. 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.

  12. 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.

  13. Mechanisms of viral mutation.

    PubMed

    Sanjuán, Rafael; Domingo-Calap, Pilar

    2016-12-01

    The remarkable capacity of some viruses to adapt to new hosts and environments is highly dependent on their ability to generate de novo diversity in a short period of time. Rates of spontaneous mutation vary amply among viruses. RNA viruses mutate faster than DNA viruses, single-stranded viruses mutate faster than double-strand virus, and genome size appears to correlate negatively with mutation rate. Viral mutation rates are modulated at different levels, including polymerase fidelity, sequence context, template secondary structure, cellular microenvironment, replication mechanisms, proofreading, and access to post-replicative repair. Additionally, massive numbers of mutations can be introduced by some virus-encoded diversity-generating elements, as well as by host-encoded cytidine/adenine deaminases. Our current knowledge of viral mutation rates indicates that viral genetic diversity is determined by multiple virus- and host-dependent processes, and that viral mutation rates can evolve in response to specific selective pressures.

  14. 49 CFR 199.209 - Other requirements imposed by operators.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... HAZARDOUS MATERIALS SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) PIPELINE SAFETY DRUG AND ALCOHOL TESTING Alcohol Misuse Prevention Program § 199.209 Other requirements imposed by operators. (a...

  15. 49 CFR 199.209 - Other requirements imposed by operators.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... HAZARDOUS MATERIALS SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) PIPELINE SAFETY DRUG AND ALCOHOL TESTING Alcohol Misuse Prevention Program § 199.209 Other requirements imposed by operators. (a...

  16. 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.

  17. 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.

  18. 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.

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

    PubMed Central

    1986-01-01

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

  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. 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

    ABSTRACT

    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 1012individuals 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 thatNeis<107. An argument for highNevalues 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 estimateNecorrectly. Given an estimate ofNe, standard population genetics models imply that selection should be sufficient to drive evolution ifNe×sis >1, wheresis 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 ifsis above 10-7or so.

    IMPORTANCEBecause 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 10-9per generation. In other words, virtually every nucleotide would be at the local

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

    DOE PAGES

    Price, Morgan N.; Arkin, Adam P.

    2015-12-15

    Free-living bacteria are usually thought to have large effective population sizes, and so tiny selective differences can drive their evolution. However, because recombination is infrequent, “background selection” against slightly deleterious alleles should reduce the effective population size (Ne) by orders of magnitude. For example, for a well-mixed population with 1012individuals 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 thatNeis<107. An argument for highNevalues for bacteria has been the high genetic diversity within many bacterial “species,” but this diversity may be duemore » to population structure: diversity across subpopulations can be far higher than diversity within a subpopulation, which makes it difficult to estimateNecorrectly. Given an estimate ofNe, standard population genetics models imply that selection should be sufficient to drive evolution ifNe×sis >1, wheresis 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 ifsis above 10-7or so. IMPORTANCEBecause 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 10-9per 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 the

  4. Decreasing institutionally imposed regulatory burden for animal research.

    PubMed

    Pritt, Stacy; McNulty, Justin A; Greene, Molly; Light, Sally; Brown, Marcy

    2016-07-20

    With the ever-increasing call to reduce self-imposed regulatory and administrative burden in the animal research oversight process, knowledge of the regulations and a desire to streamline policies and procedures are needed to affect a change in culture. In this opinion piece, we provide details on why institutionally imposed regulatory burden can arise.

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

    ERIC Educational Resources Information Center

    Gross, Melissa

    1998-01-01

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

  6. 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.

  7. 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

  8. 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.

  9. Human mismatch repair system balances mutation rates between strands by removing more mismatches from the lagging strand.

    PubMed

    Andrianova, Maria A; Bazykin, Georgii A; Nikolaev, Sergey I; Seplyarskiy, Vladimir B

    2017-08-01

    Mismatch repair (MMR) is one of the main systems maintaining fidelity of replication. Differences in correction of errors produced during replication of the leading and the lagging DNA strands were reported in yeast and in human cancers, but the causes of these differences remain unclear. Here, we analyze data on human cancers with somatic mutations in two of the major DNA polymerases, delta and epsilon, that replicate the genome. We show that these cancers demonstrate a substantial asymmetry of the mutations between the leading and the lagging strands. The direction of this asymmetry is the opposite between cancers with mutated polymerases delta and epsilon, consistent with the role of these polymerases in replication of the lagging and the leading strands in human cells, respectively. Moreover, the direction of strand asymmetry observed in cancers with mutated polymerase delta is similar to that observed in MMR-deficient cancers. Together, these data indicate that polymerase delta (possibly together with polymerase alpha) contributes more mismatches during replication than its leading-strand counterpart, polymerase epsilon; that most of these mismatches are repaired by the MMR system; and that MMR repairs about three times more mismatches produced in cells during lagging strand replication compared with the leading strand. © 2017 Andrianova et al.; Published by Cold Spring Harbor Laboratory Press.

  10. Elevated rates of force development and MgATP binding in F764L and S532P myosin mutations causing dilated cardiomyopathy.

    PubMed

    Palmer, Bradley M; Schmitt, Joachim P; Seidman, Christine E; Seidman, J G; Wang, Yuan; Bell, Stephen P; Lewinter, Martin M; Maughan, David W

    2013-04-01

    Dilated cardiomyopathy (DCM) is a disease characterized by dilation of the ventricular chambers and reduced contractile function. We examined the contractile performance of chemically-skinned ventricular strips from two heterozygous murine models of DCM-causing missense mutations of myosin, F764L/+ and S532P/+, in an α-myosin heavy chain (MyHC) background. In Ca(2+)-activated skinned myocardial strips, the maximum developed tension in F764L/+ was only ~50% that of litter-mate controls (+/+). The F764L/+ also exhibited significantly reduced rigor stiffness, loaded shortening velocity and power output. Corresponding indices for S532P/+ strips were not different from controls. Manipulation of MgATP concentration in conjunction with measures of viscoelasticity, which provides estimates of myosin detachment rate 2πc, allowed us to probe the molecular basis of changes in crossbridge kinetics that occur with the myosin mutations. By examining the response of detachment rate to varying MgATP we found the rate of MgADP release was unaffected by the myosin mutations. However, MgATP binding rate was higher in the DCM groups compared to controls (422±109mM(-1)·s(-1) in F764L/+, 483±74mM(-1)·s(-1) in S532P/+ and 303±18mM(-1)·s(-1) in +/+). In addition, the rate constant of force development, 2πb, was significantly higher in DCM groups compared to controls (at 5mM MgATP: 36.9±4.9s(-1) in F764L/+, 32.9±4.5s(-1) in S532P/+ and 18.2±1.7s(-1) in +/+). These results suggest that elevated rates of force development and MgATP binding are features of cardiac myofilament function that underlie the development of DCM.

  11. 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.

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

    PubMed

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

    2016-03-10

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

  13. 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.

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

    PubMed Central

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

    2011-01-01

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

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

    PubMed Central

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

    2015-01-01

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

  16. Deep phylogenetic analysis of haplogroup G1 provides estimates of SNP and STR mutation rates on the human Y-chromosome and reveals migrations of Iranic speakers.

    PubMed

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

    2015-01-01

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

  17. 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...

  18. En bloc duplications, mutation rates, and densities of amino acid changes clarify the evolution of vertebrate alpha-1,3/4-fucosyltransferases.

    PubMed

    Petit, Daniel; Maftah, Abderrahman; Julien, Raymond; Petit, Jean-Michel

    2006-09-01

    Numerous vertebrates have four alpha-1,3/4-fucosyltransferase genes (FUT9, FUT7, FUT4, and FUT Lewis) belonging to the same family. Until now, studies on the evolution of this family have mainly focused on Lewis genes but how the other alpha-1,3/4-fucosyltransferases have emerged from a common ancestor is not well known. In order to define the respective roles of duplications and mutations, we have compared amino acid sequences representative of bony fish (Takifugu rubripes), amphibians (Xenopus laevis), birds (Gallus gallus), and mammals (Bos taurus). The FUT tree has two fundamental branches, each split into two subfamilies. We found evidence for two duplication events, dated around 710-760 Myr and 590-640 Myr, respectively, compatible with the hypothesis of two rounds of whole genome duplications in chordate genomes, before the emergence of bony vertebrates. Based on the Homo sapiens (human) physical map, we identified blocks of paralogues belonging to regions of FUT9 (6q16), FUT4 (11q21), FUT7 (9q34), and FUT Lewis (19p13) and to a region on HSA1p that is devoid of any FUT. In zebrafish (Danio rerio), an orthologue region of HSA1 harbors an FUT9 specific to bony fish, showing that duplications are not restricted to a single FUT gene but involve blocks of paralogues. In addition, sets of genes within each block clarify the order of duplication events and, as a result, the order of alpha-1,3/4-fucosyltransferase gene emergence. We have also determined the mutation rates and the density of amino acid changes along protein sequences in each alpha-1,3/4-fucosyltransferase subfamily during the main vertebrate transitions. After the emergence of tetrapods, the mutation rate of FUT9 decreased dramatically, suggesting the early acquisition of a crucial fucosyltransferase activity in the first stages of development. The FUT7 mutation rate, which in tetrapod ancestors is about half that in amniote ancestors, may be related to the role of this gene in immune systems. In

  19. 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.

  20. 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.

  1. The functional transfer of genes from the mitochondria to the nucleus: the effects of selection, mutation, population size and rate of self-fertilization.

    PubMed

    Brandvain, Yaniv; Wade, Michael J

    2009-08-01

    The transfer of mitochondrial genes to the nucleus is a recurrent and consistent feature of eukaryotic genome evolution. Although many theories have been proposed to explain such transfers, little relevant data exist. The observation that clonal and self-fertilizing plants transfer more mitochondrial genes to their nuclei than do outcrossing plants contradicts predictions of major theories based on nuclear recombination and leaves a gap in our conceptual understanding how the observed pattern of gene transfer could arise. Here, with a series of deterministic and stochastic simulations, we show how epistatic selection and relative mutation rates of mitochondrial and nuclear genes influence mitochondrial-to-nuclear gene transfer. Specifically, we show that when there is a benefit to having a mitochondrial gene present in the nucleus, but absent in the mitochondria, self-fertilization dramatically increases both the rate and the probability of gene transfer. However, absent such a benefit, when mitochondrial mutation rates exceed those of the nucleus, self-fertilization decreases the rate and probability of transfer. This latter effect, however, is much weaker than the former. Our results are relevant to understanding the probabilities of fixation when loci in different genomes interact.

  2. Context-dependent mutation rates may cause spurious signatures of a fixation bias favoring higher GC-content in humans.

    PubMed

    Hernandez, Ryan D; Williamson, Scott H; Zhu, Lan; Bustamante, Carlos D

    2007-10-01

    Understanding the proximate and ultimate causes underlying the evolution of nucleotide composition in mammalian genomes is of fundamental interest to the study of molecular evolution. Comparative genomics studies have revealed that many more substitutions occur from G and C nucleotides to A and T nucleotides than the reverse, suggesting that mammalian genomes are not at equilibrium for base composition. Analysis of human polymorphism data suggests that mutations that increase GC-content tend to be at much higher frequencies than those that decrease or preserve GC-content when the ancestral allele is inferred via parsimony using the chimpanzee genome. These observations have been interpreted as evidence for a fixation bias in favor of G and C alleles due to either positive natural selection or biased gene conversion. Here, we test the robustness of this interpretation to violations of the parsimony assumption using a data set of 21,488 noncoding single nucleotide polymorphisms (SNPs) discovered by the National Institute of Environmental Health Sciences (NIEHS) SNPs project via direct resequencing of n = 95 individuals. Applying standard nonparametric and parametric population genetic approaches, we replicate the signatures of a fixation bias in favor of G and C alleles when the ancestral base is assumed to be the base found in the chimpanzee outgroup. However, upon taking into account the probability of misidentifying the ancestral state of each SNP using a context-dependent mutation model, the corrected distribution of SNP frequencies for GC-content increasing SNPs are nearly indistinguishable from the patterns observed for other types of mutations, suggesting that the signature of fixation bias is a spurious artifact of the parsimony assumption.

  3. Circumsporozoite protein rates, blood-feeding pattern and frequency of knockdown resistance mutations in Anopheles spp. in two ecological zones of Mauritania.

    PubMed

    Lekweiry, Khadijetou Mint; Salem, Mohamed Salem Ould Ahmedou; Cotteaux-Lautard, Christelle; Jarjaval, Fanny; Marin-Jauffre, Adeline; Bogreau, Hervé; Basco, Leonardo; Briolant, Sébastien; Boukhary, Ali Ould Mohamed Salem; Brahim, Khyarhoum Ould; Pagès, Frédéric

    2016-05-05

    Mosquitoes belonging to Anopheles gambiae species complex are the main malaria vector in Mauritania but data on their vector capacities, feeding habits and insecticide susceptibility are still scanty. The objectives of this study were to fill this gap. Adult Anopheles spp. mosquitoes were collected using pyrethrum spray catch method from two ecological zones of Mauritania: Nouakchott (Saharan zone) and Hodh Elgharbi region (Sahelian zone). Circumsporozoite proteins (CSP) for P. falciparum, P. vivax VK210 and P. vivax VK247 were detected by enzyme-linked immunosorbent assay (ELISA) from the female anopheline mosquitoes. To confirm CSP-ELISA results, polymerase chain reaction (PCR) was also performed. Blood meal identification was performed in all engorged females by partial sequencing of the mitochondrial cytochrome b gene. Molecular assessments of pyrethroid knockdown resistance (kdr) and insensitive acetylcholinesterase resistance (ace-1) were conducted. In Nouakchott, the only species of Anopheles identified during the survey was Anopheles arabiensis (356 specimens). In Hodh Elgharbi, 1016 specimens of Anopheles were collected, including 578 (56.9%) Anopheles rufipes, 410 (40.35%) An. arabiensis, 20 (1.96%) An. gambiae, 5 (0.5%) An. pharoensis and 3 (0.3 %) An. funestus. Three of 186 female An. arabiensis collected in Nouakchott and tested by ELISA were found positive for Plasmodium vivax VK210, corresponding to a sporozoite rate of 1.6%; however PCR confirmed infection by P. vivax sporozoite in only one of these. In Hodh Elgharbi, no mosquito was found positive for Plasmodium spp. infection. There was a statistically significant difference in the percentage of human blood-fed Anopheles spp. between Nouakchott (58.7%, 47 of 80 blood-engorged An. arabiensis females) and Hodh Elgharbi (11.1%, 2 of 18 blood-engorged mosquitoes). Analysis of the kdr polymorphisms showed 48.2% (70/145) of East African kdr mutation (L1014S) in Nouakchott compared to 10% (4/40) in Hodh

  4. 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.

  5. 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

  6. 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.

  7. 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.

  8. 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.

  9. 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

  10. 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.

  11. 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.

  12. 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.

  13. 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

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

    PubMed Central

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

    2001-01-01

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

  15. 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. © The American Society of Tropical Medicine and Hygiene.

  16. 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.…

  17. 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...

  18. 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...

  19. 50 CFR 270.18 - Method of imposing assessments.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 50 Wildlife and Fisheries 9 2011-10-01 2011-10-01 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 COUNCILS...

  20. 50 CFR 270.17 - Authority to impose assessments.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 50 Wildlife and Fisheries 11 2012-10-01 2012-10-01 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 COUNCILS...

  1. 50 CFR 270.18 - Method of imposing assessments.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 50 Wildlife and Fisheries 11 2012-10-01 2012-10-01 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 COUNCILS...

  2. 50 CFR 270.17 - Authority to impose assessments.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 50 Wildlife and Fisheries 11 2013-10-01 2013-10-01 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 COUNCILS...

  3. 50 CFR 270.17 - Authority to impose assessments.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 50 Wildlife and Fisheries 9 2011-10-01 2011-10-01 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 COUNCILS...

  4. 50 CFR 270.17 - Authority to impose assessments.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 50 Wildlife and Fisheries 11 2014-10-01 2014-10-01 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 COUNCILS...

  5. 50 CFR 270.18 - Method of imposing assessments.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

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

  6. 50 CFR 270.18 - Method of imposing assessments.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 50 Wildlife and Fisheries 11 2014-10-01 2014-10-01 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 COUNCILS...

  7. Pure culture response of ectomycorrhizal fungi to imposed water stress

    Treesearch

    Mark D. Coleman; Caroline S. Bledsoe; William Lopushinsky

    1989-01-01

    The ability of ectomycorrhizal fungal isolates to tolerate imposed water stress in pure culture was examined in 55 isolates of 18 species. Water potential treatments, adjusted with polyethylene glycol, were applied to Petri dish units. These units allowed colony diameter measurements of fungi grown on liquid media. Delayed growth initiation and inhibition of growth...

  8. 36 CFR 1256.42 - Who imposes general restrictions?

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... restrictions in accordance with 5 U.S.C. 552, as amended, and 44 U.S.C. 2107(4), 2108, and 2111. ... 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...

  9. 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.

  10. 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.

  11. 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.

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

    PubMed

    Antipenko YeN; Kogut, N N

    1993-10-01

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

  13. 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

  14. 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

  15. Imposed power of breathing associated with use of an impedance threshold device.

    PubMed

    Idris, Ahamed H; Convertino, Victor A; Ratliff, Duane A; Doerr, Donald F; Lurie, Keith G; Gabrielli, Andrea; Banner, Michael J

    2007-02-01

    To measure the imposed power of breathing (imposed work of breathing per minute) associated with spontaneous breathing through an active impedance threshold device and a sham impedance threshold device. Prospective randomized blinded protocol. University medical center. Nineteen healthy, normotensive volunteers (10 males, 9 females, age range 20-56 y, mean +/- SD weight 54.8 +/- 7.7 kg for females, 84 +/- 8 kg for males). The volunteers completed 2 trials of breathing through a face mask fitted with an active impedance threshold device set to open at -7 cm H(2)O pressure, or with a sham impedance threshold device, which was identical to the active device except that it did not contain an inspiratory threshold pressure valve diaphragm. Spontaneous breathing frequency (f), tidal volume (V(T)), exhaled minute ventilation, inspiratory pressure, and inspiratory time were measured with a respiratory monitor, and the data were directed to a laptop computer for real-time calculation of the imposed power of breathing. There were no significant differences in heart rate, respiratory rate, tidal volume, and minute ventilation, with and without inspiratory impedance. For the sham and active impedance threshold device groups, respectively, the mean +/- SD imposed power of breathing values were 0.92 +/- 0.63 J/min and 8.18 +/- 4.52 J/min (p < 0.001), the mean +/- SD inspiratory times were 1.98 +/- 0.86 s and 2.97 +/- 1.1 s (p = 0.001), and the mean +/- SD inspiratory airway/mouth pressures were -1.1 +/- 0.6 cm H(2)O and -11.7 +/- 2.4 cm H(2)O (p < 0.001). Breathing through an active impedance threshold device requires significantly more power than breathing through a sham device. All subjects tolerated the respiratory work load and were able to complete the study protocol.

  16. 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.

  17. Imposed work and oxygen delivery during spontaneous breathing with adult disposable manual ventilators.

    PubMed

    Hess, D; Hirsch, C; Marquis-D'Amico, C; Kacmarek, R M

    1994-11-01

    Manual ventilators (resuscitators) are used primarily to ventilate the lungs of patients lacking spontaneous ventilatory effort. However, in many settings patients are allowed to breathe through the manual ventilator. Although many aspects of manual ventilator function have been studied, very little has been reported on the use of manual ventilators during spontaneous breathing. The purpose of this study was to evaluate inspiratory and expiratory imposed work of breathing and oxygen delivery during spontaneous breathing through disposable manual ventilators. Simulated spontaneous breathing was established with a two-chambered test lung, with one chamber serving as the test chamber and the other as the driving chamber. Imposed work of breathing was evaluated with decelerating inspiratory flow at a rate of 20 breaths/min at tidal volume (VT) 0.25 1 and peak flow 40 l/min, at VT 0.5 l and peak flow 80 l/min, and VT 0.81 and peak flow 120 l/min. Flow (integrated to volume) and pressure were measured between the manual ventilator and test lung, and inspiratory and expiratory imposed work of breathing were calculated by integration of the volume-pressure curve. Oxygen concentration was measured with an oxygen analyzer placed between the manual ventilator and the test lung at 20 breaths/min, VT 0.5 l, and flow 45 l/min. An oxygen flow of 15 l/min was added to the device for all evaluations. Two of the manual ventilators had built-in positive end-expiratory pressure valves, and imposed work was evaluated at 10 cmH2O with these. There were significant differences in imposed work between inspiration and expiration (P < 0.001) and among the three levels of ventilatory demand (P < 0.001). For each ventilatory demand, there was a significant difference in work between manual ventilator brands for inspiratory work and expiratory work (P < 0.001). At a VT of 0.5 l and peak flow of 80 l/min, the pooled inspiratory imposed work for all manual ventilators was 0.44 +/- 0.12 J/l, and

  18. Genetic drift and mutational hazard in the evolution of salamander genomic gigantism.

    PubMed

    Mohlhenrich, Erik Roger; Mueller, Rachel Lockridge

    2016-12-01

    Salamanders have the largest nuclear genomes among tetrapods and, excepting lungfishes, among vertebrates as a whole. Lynch and Conery (2003) have proposed the mutational-hazard hypothesis to explain variation in genome size and complexity. Under this hypothesis, noncoding DNA imposes a selective cost by increasing the target for degenerative mutations (i.e., the mutational hazard). Expansion of noncoding DNA, and thus genome size, is driven by increased levels of genetic drift and/or decreased mutation rates; the former determines the efficiency with which purifying selection can remove excess DNA, whereas the latter determines the level of mutational hazard. Here, we test the hypothesis that salamanders have experienced stronger long-term, persistent genetic drift than frogs, a related clade with more typically sized vertebrate genomes. To test this hypothesis, we compared dN/dS and Kr/Kc values of protein-coding genes between these clades. Our results do not support this hypothesis; we find that salamanders have not experienced stronger genetic drift than frogs. Additionally, we find evidence consistent with a lower nucleotide substitution rate in salamanders. This result, along with previous work showing lower rates of small deletion and ectopic recombination in salamanders, suggests that a lower mutational hazard may contribute to genomic gigantism in this clade. © 2016 The Author(s). Evolution © 2016 The Society for the Study of Evolution.

  19. Self-selected or imposed exercise? A different approach for affective comparisons.

    PubMed

    Oliveira, Bruno Ribeiro Ramalho; Deslandes, Andréa Camaz; Nakamura, Fábio Yuzo; Viana, Bruno Ferreira; Santos, Tony Meireles

    2015-01-01

    The aim of this study was to compare the psychological and physiological responses of self-selected and imposed sessions of equivalent intensities and durations and allowing to participants a free control of pace during the self-selected session. Seventeen participants completed three sessions on a cycle ergometer. Participant's VO2Peak and lactate threshold were measured during an incremental exercise test. During the second and third sessions, participants could view a virtual cyclist on a monitor. During the self-selected session, participants were allowed free control of the intensity and duration. To ensure that the imposed session replicated the self-selected session in intensity, participants were instructed to follow an additional virtual cyclist, which was displayed on a monitor using the CompuTrainer 3D software. Power output and physiological and psychological variables were recorded during the sessions. A two-way ANOVA showed no effect of condition for power output (P = 0.940), heart rate (HR) (P = 0.965), VO2 (P = 0.898), blood lactate (P = 0.667), Feeling Scale (P = 0.877), Felt Arousal Scale (P = 0.924) and CR100 (P = 0.939). A paired t-test showed no significant difference in Physical Activity Enjoyment Scale scores between sessions (P = 0.054). In contrast to previous studies, the self-selected session did not provide better affective responses than the imposed session with same intensity and duration.

  20. 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...

  1. 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...

  2. 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...

  3. 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...

  4. 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.

  5. 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.

  6. 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.

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

    NASA Technical Reports Server (NTRS)

    Oro, J.

    1988-01-01

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

  8. 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

  9. The role of de novo mutations in the development of amyotrophic lateral sclerosis.

    PubMed

    van Doormaal, Perry T C; Ticozzi, Nicola; Weishaupt, Jochen H; Kenna, Kevin; Diekstra, Frank P; Verde, Federico; Andersen, Peter M; Dekker, Annelot M; Tiloca, Cinzia; Marroquin, Nicolai; Overste, Daniel J; Pensato, Viviana; Nürnberg, Peter; Pulit, Sara L; Schellevis, Raymond D; Calini, Daniela; Altmüller, Janine; Francioli, Laurent C; Muller, Bernard; Castellotti, Barbara; Motameny, Susanne; Ratti, Antonia; Wolf, Joachim; Gellera, Cinzia; Ludolph, Albert C; van den Berg, Leonard H; Kubisch, Christian; Landers, John E; Veldink, Jan H; Silani, Vincenzo; Volk, Alexander E

    2017-07-17

    The genetic basis combined with the sporadic occurrence of amyotrophic lateral sclerosis (ALS) suggests a role of de novo mutations in disease pathogenesis. Previous studies provided some evidence for this hypothesis; however, results were conflicting: no genes with recurrent occurring de novo mutations were identified and different pathways were postulated. In this study, we analyzed whole-exome data from 82 new patient-parents trios and combined it with the datasets of all previously published ALS trios (173 trios in total). The per patient de novo rate was not higher than expected based on the general population (P = 0.40). We showed that these mutations are not part of the previously postulated pathways, and gene-gene interaction analysis found no enrichment of interacting genes in this group (P = 0.57). Also, we were able to show that the de novo mutations in ALS patients are located in genes already prone for de novo mutations (P < 1 × 10(-15) ). Although the individual effect of rare de novo mutations in specific genes could not be assessed, our results indicate that, in contrast to previous hypothesis, de novo mutations in general do not impose a major burden on ALS risk. © 2017 Wiley Periodicals, Inc.

  10. 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

  11. 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.

  12. 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

  13. 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.

  14. Gyrotactic cells subject to imposed 3D flows

    NASA Astrophysics Data System (ADS)

    Hill, Nicholas; Richardson, Scott; Baggaley, Andrew

    2014-11-01

    We examine the effect of imposed 3-dimensional test flows, specifically a Taylor-Green Vortex flow and an ABC flow, on the patterns and mixing of suspensions of gyrotactic swimming cells. Numerically solving the deterministic swimming trajectory equations for individual cells with random starting positions, we explore how the surrounding flow and the cell shape determine the long-time patterns. For certain parameter ranges these patterns often take the form of braided ``plume-lie'' structures, even when using the chaotic ABC flow. For various pattern configurations, analysis of the governing equations of motion reveals why they are formed, as analytical solutions of the equations for the swimming cell trajectories can be obtained. These patterns persist when small random perturbations (noise) are added to individual trajectories.

  15. 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).

  16. 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.

  17. 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

  18. 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.

  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. 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.

  1. 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.

  2. 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.

  3. HIV-1 imposes rigidity on blood and semen cytokine networks.

    PubMed

    Lisco, Andrea; Introini, Andrea; Munawwar, Arshi; Vanpouille, Christophe; Grivel, Jean-Charles; Blank, Paul; Singh, Sarman; Margolis, Leonid

    2012-12-01

    Although it is established that the levels of individual cytokines are altered by HIV-1 infection, the changes in cytokine interrelations that organize them into networks have been poorly studied. Here, we evaluated these networks in HIV-infected and HIV-uninfected individuals in fluid compartments that are critical for HIV-1 pathogenesis and transmission, namely blood and semen. In samples collected from therapy-naïve HIV-1-infected and HIV-1-uninfected individuals, we measured HIV-1-load, CD4 cell count, and levels of 21 cytokines using a multiplex bead assay. Cytokine networks in blood and semen were different for HIV-1-infected and HIV-1-uninfected individuals. In both compartments of HIV-1-infected individuals, the cytokine networks were more interlocked than in controls: HIV-1 infection resulted in the establishment of new correlations and in the strengthening of pre-existing correlations between different cytokines. In blood and semen of HIV-infected patients, there were, respectively, 68 and 72 statistically significant correlations between cytokines, while in uninfected individuals, there were 18 and 21 such correlations. HIV-1 infection reorganizes the cytokine networks, establishing new strong correlations between various cytokines and thus imposes a high rigidity on the cytokine network. This rigidity may reflect the impairment of the ability of the immune system to respond to microbial challenges. © 2012 John Wiley & Sons A/S.

  4. HIV-1 imposes rigidity on blood and semen cytokine networks

    PubMed Central

    LISCO, Andrea; INTROINI, Andrea; MUNAWWAR, Arshi; VANPOUILLE, Christope; GRIVEL, Jean-Charles; BLANK, Paul; SINGH, Sarman

    2012-01-01

    Problem Although it is established that the levels of individual cytokines are altered by HIV-1 infection, the changes in cytokine interrelations that organize them into networks have been poorly studied. Here, we evaluated these networks in HIV-infected and -uninfected individuals in fluid compartments that are critical for HIV-1 pathogenesis and transmission, namely blood and semen. Method of Study In samples collected from therapy-naïve HIV-1-infected and HIV-1-uninfected individuals, we measured HIV-1-load, CD4-cell-count, and levels of 21 cytokines using a multiplex bead-assay. Results Cytokine networks in blood and semen were different for HIV-1-infected and -uninfected individuals. In both compartments of HIV-1-infected individuals, the cytokine networks were more interlocked than in controls: HIV -1 infection results in the establishment of new correlations and the strengthening of pre-existing correlations between different cytokines. In blood and semen of HIV-infected patients there were, respectively, 68 and 72 statistically significant correlations between cytokines, while in uninfected individuals there were 18 and 21 such correlations. Conclusions HIV-1 infection reorganizes the cytokine networks, establishing new strong correlations between various cytokines and thus imposing a high rigidity on the cytokine network. This rigidity may reflect the impairment of the ability of the immune system to respond to microbial challenges. PMID:23006048

  5. 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.

  6. 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.

  7. 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

  8. 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.

  9. 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

  10. 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...

  11. 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...

  12. 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...

  13. 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...

  14. 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...

  15. 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...

  16. 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...

  17. 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...

  18. 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...

  19. 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...

  20. 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...

  1. 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 a...

  2. Missed therapeutic and prevention opportunities in women with BRCA-mutated epithelial ovarian cancer and their families due to low referral rates for genetic counseling and BRCA testing: A review of the literature.

    PubMed

    Hoskins, Paul J; Gotlieb, Walter H

    2017-09-07

    Answer questions and earn CME/CNE Fifteen percent of women with epithelial ovarian cancer have inherited mutations in the BRCA breast cancer susceptibility genes. Knowledge of her BRCA status has value both for the woman and for her family. A therapeutic benefit exists for the woman with cancer, because a new family of oral drugs, the poly ADP-ribose polymerase (PARP) inhibitors, has recently been approved, and these drugs have the greatest efficacy in women who carry the mutation. For her family, there is the potential to prevent ovarian cancer in those carrying the mutation by using risk-reducing surgery. Such surgery significantly reduces the chance of developing this, for the most part, incurable cancer. Despite these potential benefits, referral rates for genetic counseling and subsequent BRCA testing are low, ranging from 10% to 30%, indicating that these therapeutic and prevention opportunities are being missed. The authors have reviewed the relevant available literature. Topics discussed are BRCA and its relation to ovarian cancer, the rates of referral for genetic counseling/BRCA testing, reasons for these low rates, potential strategies to improve on those rates, lack of effectiveness of current screening strategies, the pros and cons of risk-reducing surgery, other prevention options, and the role and value of PARP inhibitors. CA Cancer J Clin 2017. © 2017 American Cancer Society. © 2017 American Cancer Society.

  3. 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

  4. 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.

  5. 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.

  6. An Interactive Simulator for Imposing Virtual Musculoskeletal Dynamics.

    PubMed

    Hasson, Christopher

    2017-05-10

    Disease processes are often marked by both neural and muscular changes that alter movement control and execution, but these adaptations are difficult to tease apart because they occur simultaneously. This is addressed by swapping an individual's limb dynamics with a neurally-controlled facsimile using an interactive musculoskeletal simulator (IMS) that allows controlled modifications of musculoskeletal dynamics. This paper details the design and operation of the IMS, quantifies and describes human adaptation to the IMS, and determines whether the IMS allows users to move naturally, a prerequisite for manipulation experiments. Healthy volunteers (n = 4) practiced a swift goal-directed task (back-and-forth elbow flexion/extension) for 90 trials with the IMS off (normal dynamics) and 240 trials with the IMS on, i.e. the actions of a user's personalized electromyography-driven musculoskeletal model are robotically imposed back on to the user. After practicing with the IMS on, subjects could complete the task with end-point errors of 1.56°, close to the speed-matched IMS-off error of 0.57°. Muscle activity, joint torque, and arm kinematics for IMS-on and -off conditions were well matched for three subjects (root-meansquared error [RMSE] = 0.16 Nm), but the error was higher for one subject with a small stature (RMSE = 0.25 Nm). A well-matched musculoskeletal model allowed IMS users to perform a goal-directed task nearly as well as when the IMS was not active. This advancement permits real-time manipulations of musculoskeletal dynamics, which could increase our understanding of muscular and neural co-adaptations to injury, disease, disuse, and aging.

  7. 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

  8. Olaparib monotherapy in patients with advanced relapsed ovarian cancer and a germline BRCA1/2 mutation: a multistudy analysis of response rates and safety.

    PubMed

    Matulonis, U A; Penson, R T; Domchek, S M; Kaufman, B; Shapira-Frommer, R; Audeh, M W; Kaye, S; Molife, L R; Gelmon, K A; Robertson, J D; Mann, H; Ho, T W; Coleman, R L

    2016-06-01

    The PARP inhibitor olaparib (Lynparza™) demonstrates antitumor activity in women with relapsed ovarian cancer and a germline BRCA1/2 mutation (gBRCAm). Data from olaparib monotherapy trials were used to explore the treatment effect of olaparib in patients with gBRCAm ovarian cancer who had received multiple lines of prior chemotherapy. This analysis evaluated pooled data from two phase I trials [NCT00516373 (study 2); NCT00777582 (study 24)] and four phase II trials [NCT00494442 (study 9); NCT00628251 (study 12); NCT00679783 (study 20); NCT01078662 (study 42)] that recruited women with relapsed ovarian, fallopian tube or peritoneal cancer. All patients had a documented gBRCAm and were receiving olaparib 400 mg monotherapy twice daily (capsule formulation) at the time of relapse. Objective response rate (ORR) and duration of response (DoR) were evaluated using original patient outcomes data for patients with measurable disease at baseline. Of the 300 patients in the pooled population, 273 had measurable disease at baseline, of whom 205 (75%) had received ≥3 lines of prior chemotherapy. In the pooled population, the ORR was 36% [95% confidence interval (CI) 30-42] and the median DoR was 7.4 months (95% CI 5.7-9.1). The ORR among patients who had received ≥3 lines of prior chemotherapy was 31% (95% CI 25-38), with a DoR of 7.8 months (95% CI 5.6-9.5). The safety profile of olaparib was similar in patients who had received ≥3 lines of prior chemotherapy compared with the pooled population; grade ≥3 adverse events were reported in 54% and 50% of patients, respectively. Durable responses to olaparib were observed in patients with relapsed gBRCAm ovarian cancer who had received ≥3 lines of prior chemotherapy. NCT00516373; NCT00494442; NCT00628251; NCT00679783; NCT00777582; NCT01078662. © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  9. Fast growth increases the selective advantage of a mutation arising recurrently during evolution under metal limitation.

    PubMed

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

    2009-09-01

    Understanding the evolution of biological systems requires untangling the molecular mechanisms that connect genetic and environmental variations to their physiological consequences. Metal limitation across many environments, ranging from pathogens in the human body to phytoplankton in the oceans, imposes strong selection for improved metal acquisition systems. In this study, we uncovered the genetic and physiological basis of adaptation to metal limitation using experimental populations of Methylobacterium extorquens AM1 evolved in metal-deficient growth media. We identified a transposition mutation arising recurrently in 30 of 32 independent populations that utilized methanol as a carbon source, but not in any of the 8 that utilized only succinate. These parallel insertion events increased expression of a novel transporter system that enhanced cobalt uptake. Such ability ensured the production of vitamin B(12), a cobalt-containing cofactor, to sustain two vitamin B(12)-dependent enzymatic reactions essential to methanol, but not succinate, metabolism. Interestingly, this mutation provided higher selective advantages under genetic backgrounds or incubation temperatures that permit faster growth, indicating growth-rate-dependent epistatic and genotype-by-environment interactions. Our results link beneficial mutations emerging in a metal-limiting environment to their physiological basis in carbon metabolism, suggest that certain molecular features may promote the emergence of parallel mutations, and indicate that the selective advantages of some mutations depend generically upon changes in growth rate that can stem from either genetic or environmental influences.

  10. 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.

  11. 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 gl