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Sample records for ongoing positive selection

  1. Science Selections. Accounts of Ongoing Scientific Research.

    ERIC Educational Resources Information Center

    Kornberg, Warren, Ed.

    This publication is intended to present science teachers with an opportunity to communicate to students the idea that science is an ongoing and never-ending process. The booklet contains supplemental materials, valuable as enrichment materials. A selection of ongoing research in the biological sciences, physics and astronomy, oceanography,…

  2. Evidence for ongoing brain injury in human immunodeficiency virus–positive patients treated with antiretroviral therapy

    PubMed Central

    Cardenas, VA; Meyerhoff, DJ; Studholme, C; Kornak, J; Rothlind, J; Lampiris, H; Neuhaus, J; Grant, RM; Chao, LL; Truran, D; Weiner, MW

    2009-01-01

    Treatment with antiretroviral therapy (ART) has greatly reduced the incidence of dementia. The goal of this longitudinal study was to determine if there are ongoing macrostructural brain changes in human immunodeficiency virus–positive (HIV+) individuals treated with ART. To quantify brain structure, three-dimensional T1-weighted magnetic resonance imaging (MRI) scans were performed at baseline and again after 24 months in 39 HIV+ patients on ART and 30 HIV− controls. Longitudinal changes in brain volume were measured using tissue segmentation within regions of interest and deformation morphometry. Measured by tissue segmentation, HIV+ patients on ART had significantly (all P < .05) greater rates of white matter volume loss than HIV− control individuals. Compared with controls, the subgroup of HIV+ individuals on ART with viral suppression also had significantly greater rates of white matter volume loss. Deformation morphometry confirmed these results with more specific spatial localization. Deformation morphometry also detected greater rates of gray matter and white matter loss in the subgroup of HIV+ individuals with detectable viral loads. These results provide evidence of ongoing brain volume loss in HIV+ individuals on stable ART, possibly suggesting ongoing cerebral injury. The presence of continuing injury raises the possibility that HIV+ individuals—even in the presence of viral suppression in the periphery—are at greater risk for future cognitive impairments and dementia and possibly faster cognitive decline. Therefore, HIV+ individuals on ART should be monitored for cognitive decline, and treatments that reduce ongoing neurological injury should be considered. PMID:19499454

  3. Expectations and positive emotional feelings accompany reductions in ongoing and evoked neuropathic pain following placebo interventions.

    PubMed

    Petersen, Gitte L; Finnerup, Nanna B; Grosen, Kasper; Pilegaard, Hans K; Tracey, Irene; Benedetti, Fabrizio; Price, Donald D; Jensen, Troels S; Vase, Lene

    2014-12-01

    Research on placebo analgesia and nocebo hyperalgesia has primarily included healthy subjects or acute pain patients, and it is unknown whether these effects can be obtained in ongoing pain in patients with chronic pain caused by an identifiable nerve injury. Eighteen patients with postthoracotomy neuropathic pain were exposed to placebo and nocebo manipulations, in which they received open and hidden administrations of pain-relieving (lidocaine) or pain-inducing (capsaicin) treatment controlled for the natural history of pain. Immediately after the open administration, patients rated their expected pain levels on a mechanical visual analogue scale (M-VAS). They also reported their emotional feelings via a quantitative/qualitative experiential method. Subsequently, patients rated their ongoing pain levels on the M-VAS and underwent quantitative sensory testing of evoked pain (brush, pinprick, area of hyperalgesia, wind-up-like pain). There was a significant placebo effect on both ongoing (P=.009 to .019) and evoked neuropathic pain (P=.0005 to .053). Expected pain levels accounted for significant amounts of the variance in ongoing (53.4%) and evoked pain (up to 34.5%) after the open lidocaine administration. Furthermore, patients reported high levels of positive and low levels of negative emotional feelings in the placebo condition compared with the nocebo condition (P⩽.001). Pain increases during nocebo were nonsignificant (P=.394 to 1.000). To our knowledge, this is the first study to demonstrate placebo effects in ongoing neuropathic pain. It provides further evidence for placebo-induced reduction in hyperalgesia and suggests that patients' expectations coexist with emotional feelings about treatments. Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

  4. Missed Opportunities: Poor Linkage into Ongoing Care for HIV-Positive Pregnant Women in Mwanza, Tanzania

    PubMed Central

    Watson-Jones, Deborah; Balira, Rebecca; Ross, David A.; Weiss, Helen A.; Mabey, David

    2012-01-01

    Background Global coverage of prevention of mother-to-child (PMTCT) services reached 53% in 2009. However the number of pregnant women who test positive for HIV in antenatal clinics and who link into long-term HIV care is not known in many resource-poor countries. We measured the proportion of HIV-positive pregnant women in Mwanza city, Tanzania, who completed the cascade of care from antenatal HIV diagnosis to assessment and engagement in care in adult HIV clinics. Methods Thirty antenatal and maternity ward health workers were interviewed about PMTCT activities. Nine antenatal HIV education sessions were observed. A prospective cohort of 403 HIV-positive women was enrolled by specially-trained clinicians and nurses on admission to delivery and followed for four months post-partum. Information was collected on referral and attendance at adult HIV clinics, eligibility for highly active antiretroviral therapy (HAART) and reasons for lack of attendance. Results Overall, 70% of PMTCT health workers referred HIV-positive pregnant women to the HIV clinic for assessment and care. Antenatal HIV education sessions did not cover on-going care for HIV-infected women. Of 310 cohort participants tested in pregnancy, 51% had received an HIV clinic referral pre-delivery. Only 32% of 244 women followed to four months post-partum had attended an HIV clinic and been assessed for HAART eligibility. Non-attendance for HIV care was independently associated with fewer antenatal visits, poor PMTCT prophylaxis compliance, non-disclosure of HIV status, and non-Sukuma ethnicity. Conclusion Most women identified as HIV-positive during pregnancy were not assessed for HAART eligibility during pregnancy or in the first four months post-partum. Initiating HAART at the antenatal clinic, improved counselling and linkages to care between PMTCT and adult HIV treatment services and reducing stigma surrounding disclosure of HIV results would benefit on-going care of HIV-positive pregnant women. PMID

  5. Treatment de-escalation in HPV-positive oropharyngeal carcinoma: ongoing trials, critical issues and perspectives.

    PubMed

    Mirghani, H; Amen, F; Blanchard, P; Moreau, F; Guigay, J; Hartl, D M; Lacau St Guily, J

    2015-04-01

    Due to the generally poor prognosis of head and neck squamous cell carcinoma (HNSCC), treatment has been intensified, these last decades, leading to an increase of serious side effects. High-risk human papillomavirus (HR-HPV) infection has been recently etiologically linked to a subset of oropharyngeal squamous cell carcinoma (OPSCC), which is on the increase. These tumors are different, at the clinical and molecular level, when compared to tumors caused by traditional risk factors. Additionally, their prognosis is much more favorable which has led the medical community to consider new treatment strategies. Indeed, it is possible that less intensive treatment regimens could achieve similar efficacy with less toxicity and improved quality of life. Several clinical trials, investigating different ways to de-escalate treatment, are currently ongoing. In this article, we review these main approaches, discuss the rationale behind them and the issues raised by treatment de-escalation in HPV-positive OPSCC.

  6. Positive outcomes from an immediate and ongoing intervention for child witnesses of intimate partner violence.

    PubMed

    Ernst, Amy A; Weiss, Steven J; Enright-Smith, Shannon; Hansen, J Paul

    2008-05-01

    Children who witness intimate partner violence (IPV) experience many psychological and social problems similar to those of the victimized parent. Intervention programs for children who witness IPV have not been adequately evaluated. Two of the most important target areas in treating the children are to improve understanding that (1) the violence is not their fault and that (2) development of a safety plan is valuable in case of future violence. We evaluated a unique immediate and ongoing intervention program for children who witness adult IPV. This was a retrospective review of progress report results both pre- and postintervention of an ongoing IPV intervention program. POPULATION AND INTERVENTION: The study was completed in a largely Hispanic city of 500,000. The intervention program included a number of unique aspects including immediate intervention at the time of police calls for adult IPV, children's art therapy and sand tray therapy, and a unique coloring book to establish a child safety plan in the event of recurrent IPV. Progress report forms included 16 qualitative questions that evaluated the child's understanding of various important concepts pre- and postintervention. All children who entered the program in the last 3 years and had completed data sets for all 16 questions were included. Responses to questions pre- vs postintervention were compared using Wilcoxon signed ranks test. Fifty-eight children had complete data sets pre- and postintervention. Mean age was 8.5 +/- 3.5 years (range, 3-17), and 49% were male. Mean length of therapy was 7.4 +/- 5.2 months (range, 1-31), with a mean number of sessions of 9.7 +/- 11.7 (range, 1-59). For 15 of the 16 evaluation questions, a statistically significant improvement in postintervention evaluations compared with preintervention evaluations was found (P < .01). This included a significant improvement in the percentage of children who were aware that violence was not their fault (59% preintervention vs 84

  7. X-ray selected Type-2 QSOs: ongoing star formation and obscured accretion.

    NASA Astrophysics Data System (ADS)

    Mainieri, Vincenzo; Cosmos Collaboration

    2009-09-01

    Although the fraction of obscured AGN is found to decrease with luminosity from several studies, a non-negligible population of obscured QSOs is still required by the X-ray background synthesis models. We present a large sample (121 objects) of X-ray selected Type-2 QSOs from the XMM-COSMOS survey: sources with high X-ray luminosity (LX>10^{44} erg s^{-1}) and heavy obscuration (NH>10^{22} cm^{-2}), as derived from a detailed X-ray spectral analysis (see Mainieri et al.,2007, ApJS, 172, 368) of the 1800 X-ray point-like sources in this survey. Few (˜5%) of the Type-2 QSOs are best fitted with a pure reflection model. We have performed optical spectroscopy for ˜ 30% of the sample and for the remaining sources we have derived accurate photometric redshifts. The redshift range covered is wide, 0.30.8).We compare the general properties of the host galaxies with the ongoing accretion in their nuclei. Morphology: using five non-parametric diagnostics (asymmetry, concentration, Gini coefficient, M20, ellipticity) we found that ˜10% of the Type-2 QSOs are in elliptical galaxies, ˜55% in disk galaxies and ˜35% in irregular galaxies. The majority of the irregular hosts can be described as undergoing merger activity or show tidal debris. Stellar masses have been derived from SED fitting to the observed photometry(from 0.3 to 4.5 micron) and star formation rates from the [OII] or Hα line fluxes. The majority (˜75%) of QSO-2 host galaxies have stellar masses above log(Mstar)˜10.5 MSun and have ongoing star formation (˜100 MSun/yr). The value of 10.5 MSun is similar to the characteristic mass for obscured AGN (Kauffmann et al. 2003) and radio-loud AGN (Best et al. 2005) in the SDSS. It is also consistent with the more general result that the fraction of galaxies hosting AGN increases with the stellar mass.

  8. Positive selection on the human genome.

    PubMed

    Vallender, Eric J; Lahn, Bruce T

    2004-10-01

    Positive selection has undoubtedly played a critical role in the evolution of Homo sapiens. Of the many phenotypic traits that define our species--notably the enormous brain, advanced cognitive abilities, complex vocal organs, bipedalism and opposable thumbs--most (if not all) are likely the product of strong positive selection. Many other aspects of human biology not necessarily related to the 'branding' of our species, such as host-pathogen interactions, reproduction, dietary adaptation and physical appearance, have also been the substrate of varying levels of positive selection. Comparative genetics/genomics studies in recent years have uncovered a growing list of genes that might have experienced positive selection during the evolution of human and/or primates. These genes offer valuable inroads into understanding the biological processes specific to humans, and the evolutionary forces that gave rise to them. Here, we present a comprehensive review of these genes, and their implications for human evolution.

  9. Improved haplotype-based detection of ongoing selective sweeps towards an application in Arabidopsis thaliana

    PubMed Central

    2011-01-01

    Background The increasing amount of genome information allows us to address various questions regarding the molecular evolution and population genetics of different species. Such genome-wide data sets including thousands of individuals genotyped at hundreds of thousands of markers require time-efficient and powerful analysis methods. Demography and sampling introduce a bias into present population genetic tests of natural selection, which may confound results. Thus, a modification of test statistics is necessary to introduce time-efficient and unbiased analysis methods. Results We present an improved haplotype-based test of selective sweeps in samples of unequally related individuals. For this purpose, we modified existing tests by weighting the contribution of each individual based on its uniqueness in the entire sample. In contrast to previous tests, this modified test is feasible even for large genome-wide data sets of multiple individuals. We utilize coalescent simulations to estimate the sensitivity of such haplotype-based test statistics to complex demographic scenarios, such as population structure, population growth and bottlenecks. The analysis of empirical data from humans reveals different results compared to previous tests. Additionally, we show that our statistic is applicable to empirical data from Arabidopsis thaliana. Overall, the modified test leads to a slight but significant increase of power to detect selective sweeps among all demographic scenarios. Conclusions The concept of this modification might be applied to other statistics in population genetics to reduce the intrinsic bias of demography and sampling. Additionally, the combination of different test statistics may further improve the performance of tests for natural selection. PMID:21729283

  10. Ongoing characterization of the forced electron beam induced arc discharge ion source for the selective production of exotic species facility

    SciTech Connect

    Manzolaro, M. Andrighetto, A.; Monetti, A.; Scarpa, D.; Rossignoli, M.; Vasquez, J.; Corradetti, S.; Calderolla, M.; Prete, G.; Meneghetti, G.

    2014-02-15

    An intense research and development activity to finalize the design of the target ion source system for the selective production of exotic species (SPES) facility (operating according to the isotope separation on line technique) is at present ongoing at Legnaro National Laboratories. In particular, the characterization of ion sources in terms of ionization efficiency and transversal emittance is currently in progress, and a preliminary set of data is already available. In this work, the off-line ionization efficiency and emittance measurements for the SPES forced electron beam induced arc discharge ion source in the case of a stable Ar beam are presented in detail.

  11. Investigational hormone receptor agonists as ongoing female contraception: a focus on selective progesterone receptor modulators in early clinical development.

    PubMed

    Nelson, Anita L

    2015-01-01

    As efforts are made to continue to increase the safety of contraceptive methods, those without estrogen have attracted new attention. Progestin-only options are available in many delivery systems, but most cause disturbed bleeding patterns. For gynecologic patients, selective progesterone receptor modulators (SPRMs) have been approved for medical abortion, for ovulation suppression in emergency contraception, and for the treatment of heavy menstrual bleeding due to leiomyoma. This article discusses the role of SPRMs in controlling fertility on an ongoing basis with particular emphasis on mifepristone and ulipristal acetate (UPA), since none of the other compounds has progressed out of early Phase I - II testing. It also discusses important information about the mechanisms of action and safety of these two SPRMs. Of all the investigational hormone agonist/antagonists, SPRMs have demonstrated the greatest potential as ongoing female contraceptives. They have the ability to suppress ovulation after initiation of the luteinizing hormone (LH) surge without affecting ovarian production of estrogen or inducing any significant metabolic changes. SPRMs may well be able to provide longer term contraception as oral agents, vaginal rings, and perhaps even intrauterine devices. UPA has the greatest promise. Current research needs to be expanded.

  12. Detecting Amino Acid Sites Under Positive Selection and Purifying Selection

    PubMed Central

    Massingham, Tim; Goldman, Nick

    2005-01-01

    An excess of nonsynonymous over synonymous substitution at individual amino acid sites is an important indicator that positive selection has affected the evolution of a protein between the extant sequences under study and their most recent common ancestor. Several methods exist to detect the presence, and sometimes location, of positively selected sites in alignments of protein-coding sequences. This article describes the “sitewise likelihood-ratio” (SLR) method for detecting nonneutral evolution, a statistical test that can identify sites that are unusually conserved as well as those that are unusually variable. We show that the SLR method can be more powerful than currently published methods for detecting the location of positive selection, especially in difficult cases where the strength of selection is low. The increase in power is achieved while relaxing assumptions about how the strength of selection varies over sites and without elevated rates of false-positive results that have been reported with some other methods. We also show that the SLR method performs well even under circumstances where the results from some previous methods can be misleading. PMID:15654091

  13. Fish oil–based lipid emulsions in the treatment of parenteral nutrition-associated liver disease: An ongoing positive experience

    USDA-ARS?s Scientific Manuscript database

    We previously reported the beneficial effect of fish oil-based lipid emulsions (FOLEs) as monotherapy in the treatment of parenteral nutrition-associated liver disease (PNALD). In this report, we share our ongoing experience at Texas Children's Hospital, Houston, in the use of FOLE in treatment of P...

  14. Positive selection on the killer whale mitogenome.

    PubMed

    Foote, Andrew D; Morin, Phillip A; Durban, John W; Pitman, Robert L; Wade, Paul; Willerslev, Eske; Gilbert, M Thomas P; da Fonseca, Rute R

    2011-02-23

    Mitochondria produce up to 95 per cent of the eukaryotic cell's energy. The coding genes of the mitochondrial DNA may therefore evolve under selection owing to metabolic requirements. The killer whale, Orcinus orca, is polymorphic, has a global distribution and occupies a range of ecological niches. It is therefore a suitable organism for testing this hypothesis. We compared a global dataset of the complete mitochondrial genomes of 139 individuals for amino acid changes that were associated with radical physico-chemical property changes and were influenced by positive selection. Two such selected non-synonymous amino acid changes were found; one in each of two ecotypes that inhabit the Antarctic pack ice. Both substitutions were associated with changes in local polarity, increased steric constraints and α-helical tendencies that could influence overall metabolic performance, suggesting a functional change.

  15. Ongoing Inquiry

    ERIC Educational Resources Information Center

    Ashbrook, Peggy

    2011-01-01

    An in-depth science inquiry is an ongoing investigation in which children are introduced to materials through hands-on experiences and, with teacher guidance, begin to investigate a question that they can answer through their own actions, observations, and with teacher-assisted research. Qualities that make an experience appropriate to include in…

  16. Ongoing Inquiry

    ERIC Educational Resources Information Center

    Ashbrook, Peggy

    2011-01-01

    An in-depth science inquiry is an ongoing investigation in which children are introduced to materials through hands-on experiences and, with teacher guidance, begin to investigate a question that they can answer through their own actions, observations, and with teacher-assisted research. Qualities that make an experience appropriate to include in…

  17. Global Positioning System Satellite Selection Method

    NASA Technical Reports Server (NTRS)

    Niles, Frederick A. (Inventor)

    2001-01-01

    The satellite selection method as utilized by the spaceborne Global Positioning System receiver provides navigational solutions and is designed for use in low Earth orbit. The satellite selection method is a robust algorithm that can be used a GPS receiver to select appropriate GPS satellites for use in calculating point solutions or attitude solutions. The method is takes into account the difficulty of finding a particular GPS satellite phase code, especially when the search range in greatly increased due to Doppler shifts introduced into the carrier frequency. The method starts with an update of the antenna pointing and spacecraft vectors to determine the antenna backplane direction. Next, the GPS satellites that will potentially be in view of the antenna are ranked on a list, whereby the list is generated based on the estimated attitude and position of each GPS satellite. Satellites blocked by the Earth are not entered on this list. A second list is created, whereby the GPS satellites are ranked according to their desirability for use in attitude determination. GPS satellites are ranked according to their orthogonality to the antenna backplane, and according to geometric dilution of precision considerations. After the lists are created, the channels of the spaceborne GPS receiver are assigned to various GPS satellites for acquisition and lock. Preliminary Doppler frequencies for searching are assigned to the various channels.

  18. Guiding transcranial brain stimulation by EEG/MEG to interact with ongoing brain activity and associated functions: A position paper.

    PubMed

    Thut, Gregor; Bergmann, Til Ole; Fröhlich, Flavio; Soekadar, Surjo R; Brittain, John-Stuart; Valero-Cabré, Antoni; Sack, Alexander; Miniussi, Carlo; Antal, Andrea; Siebner, Hartwig Roman; Ziemann, Ulf; Herrmann, Christoph S

    2017-01-29

    Non-invasive transcranial brain stimulation (NTBS) techniques have a wide range of applications but also suffer from a number of limitations mainly related to poor specificity of intervention and variable effect size. These limitations motivated recent efforts to focus on the temporal dimension of NTBS with respect to the ongoing brain activity. Temporal patterns of ongoing neuronal activity, in particular brain oscillations and their fluctuations, can be traced with electro- or magnetoencephalography (EEG/MEG), to guide the timing as well as the stimulation settings of NTBS. These novel, online and offline EEG/MEG-guided NTBS-approaches are tailored to specifically interact with the underlying brain activity. Online EEG/MEG has been used to guide the timing of NTBS (i.e., when to stimulate): by taking into account instantaneous phase or power of oscillatory brain activity, NTBS can be aligned to fluctuations in excitability states. Moreover, offline EEG/MEG recordings prior to interventions can inform researchers and clinicians how to stimulate: by frequency-tuning NTBS to the oscillation of interest, intrinsic brain oscillations can be up- or down-regulated. In this paper, we provide an overview of existing approaches and ideas of EEG/MEG-guided interventions, and their promises and caveats. We point out potential future lines of research to address challenges.

  19. Positive Psychology in Context: Effects of Expressing Gratitude in Ongoing Relationships Depend on Perceptions of Enactor Responsiveness.

    PubMed

    Algoe, Sara B; Zhaoyang, Ruixue

    2016-01-01

    Recent correlational evidence implicates gratitude in personal and relational growth, for both members of ongoing relationships. From these observations, it would be tempting to prescribe interpersonal gratitude exercises to improve relationships. In this experiment, couples were randomly assigned to express gratitude over a month, or to a relationally-active control condition. Results showed modest effects of condition on personal and relational well-being. However, those whose partners were perceived as being particularly responsive when expressing gratitude at the initial lab session showed greater well-being across a range of outcomes, whereas this was not so for people in the control condition. Notably, evidence raises concerns about the effectiveness of artificial injections of gratitude when the partner is perceived to be low in responsiveness. Given the importance of close relationships, this work highlights the need for more theory-driven basic research tested in context before assuming what appears to work naturally will also work artificially.

  20. Positive Psychology in Context: Effects of Expressing Gratitude in Ongoing Relationships Depend on Perceptions of Enactor Responsiveness

    PubMed Central

    Algoe, Sara B.; Zhaoyang, Ruixue

    2016-01-01

    Recent correlational evidence implicates gratitude in personal and relational growth, for both members of ongoing relationships. From these observations, it would be tempting to prescribe interpersonal gratitude exercises to improve relationships. In this experiment, couples were randomly assigned to express gratitude over a month, or to a relationally-active control condition. Results showed modest effects of condition on personal and relational well-being. However, those whose partners were perceived as being particularly responsive when expressing gratitude at the initial lab session showed greater well-being across a range of outcomes, whereas this was not so for people in the control condition. Notably, evidence raises concerns about the effectiveness of artificial injections of gratitude when the partner is perceived to be low in responsiveness. Given the importance of close relationships, this work highlights the need for more theory-driven basic research tested in context before assuming what appears to work naturally will also work artificially. PMID:27800009

  1. Fish oil-based lipid emulsions in the treatment of parenteral nutrition-associated liver disease: an ongoing positive experience.

    PubMed

    Premkumar, Muralidhar H; Carter, Beth A; Hawthorne, Keli M; King, Kristi; Abrams, Steven A

    2014-01-01

    We previously reported the beneficial effect of fish oil-based lipid emulsions (FOLEs) as monotherapy in the treatment of parenteral nutrition-associated liver disease (PNALD). In this report, we share our ongoing experience at Texas Children's Hospital, Houston, Texas in the use of FOLE in treatment of PNALD as presented at the 2013 Experimental Biology meeting. We describe the findings of a single center, prospective, observational study of infants <6 mo of age with PNALD who received parenteral FOLE as monotherapy. A total of 97 infants received FOLE under the compassionate-use protocol for the treatment of PNALD. Eighty-three (86%) survived with resolution of cholestasis and 14 (14%) died. The median conjugated bilirubin (CB) concentration at the initiation of FOLE therapy was 4.8 mg/dL (range 2.1-26). The median time to resolution of cholestasis was 40 d (range 3-158). Compared with infants with mild cholestasis (CB of 2.1-5 mg/dL at the initiation of FOLE), nonsurvivors were significantly more premature and took longer to resolve their cholestasis. Gestational age at birth correlated inversely with CB at the beginning of FOLE and peak CB. Infants with an initial CB >10 mg/dL had a higher mortality rate than infants with an initial CB <5 mg/dL (35% vs. 6%; P < 0.05). Our experience with the use of FOLE in PNALD continues to be encouraging. Prematurity continues to be a major determinant in mortality and severity of cholestasis. This calls for further controlled studies designed to optimize dose and timing of intervention in the use of FOLE in neonates.

  2. Results of the Ongoing Monitoring of the Position of a Geostationary Telecommunication Satellite by the Method of Spatially Separated Basis Receiving of Digital Satellite Television Signals

    NASA Astrophysics Data System (ADS)

    Bushuev, F.; Kaliuzhnyi, M.; Sybiryakova, Y.; Shulga, O.; Moskalenko, S.; Balagura, O.; Kulishenko, V.

    2016-10-01

    The results of the ongoing monitoring of the position of geostationary telecommunication satellite Eutelsat-13B (13° East) are presented in the article. The results were obtained using a radio engineering complex (RC) of four stations receiving digital satellite television and a data processing centre. The stations are located in Kyiv, Mukachevo, Kharkiv and Mykolaiv. The equipment of each station allows synchronous recording (by the GPS) of fragments of DVB-S signal from the quadrature detector output of the satellite television receiver. Samples of the complex signal are archived and sent to the data processing center through the Internet. Here three linearly independent slant range differences (Δr) for three pairs of the stations are determined as a result of correlation processing of received signals. Every second measured values of Δr are used to calculate Cartesian coordinates (XYZ) of the satellite in the coordinate system WGS84 by multilateration method. The time series of Δr, X, Y and Z obtained during continuous observations from March to May 2015 are presented in the article. Single-measurement errors of Δr, X, Y and Z are equal to 2.6 m, 3540 m, 705 m and 455 m, respectively. The complex is compared with known analogues. Ways of reduction of measurement errors of satellite coordinates are considered. The radio engineering complex could be considered a prototype of a system of independent ongoing monitoring of the position of geostationary telecommunication satellites.

  3. Positive selection for loss of tetracycline resistance.

    PubMed Central

    Bochner, B R; Huang, H C; Schieven, G L; Ames, B N

    1980-01-01

    A simple technique has been devised that allows direct plate selection of tetracycline-sensitive clones from a predominantly tetracycline-resistant population. The technique is especially useful in genetic methodologies based on the use of tetracycline resistance transposons, such as Tn10. Potential uses of the method include selection of deletion mutants, fine-structure mapping, generalized mapping, construction of multiply marked strains, elimination of tetracycline resistance transposons and plasmids and cloning. The technique is based on our finding that tetracycline-resistant cells are hypersensitive to lipophilic chelating agents, such as fusaric acid. This finding supports the contention that certain metal ions critically facilitate tetracycline uptake and leads us to suggest possible molecular mechanisms for tetracycline resistance. Images PMID:6259126

  4. What Drives Positive Selection in the Drosophila piRNA Machinery? The Genomic Autoimmunity Hypothesis

    PubMed Central

    Blumenstiel, Justin P.; Erwin, Alexandra A.; Hemmer, Lucas W.

    2016-01-01

    In animals, PIWI-interacting RNAs (piRNAs) play a crucial role in genome defense. Moreover, because piRNAs can be maternally transmitted, they contribute to the epigenetic profile of inheritance. Multiple studies, especially in Drosophila, have demonstrated that the machinery of piRNA biogenesis is often the target of positive selection. Because transposable elements (TEs) are a form of genetic parasite, positive selection in the piRNA machinery is often explained by analogy to the signatures of positive selection commonly observed in genes that play a role in host-parasite dynamics. However, the precise mechanisms that drive positive selection in the piRNA machinery are not known. In this review, we outline several mechanistic models that might explain pervasive positive selection in the piRNA machinery of Drosophila species. We propose that recurrent positive selection in the piRNA machinery can be partly explained by an ongoing tension between selection for sensitivity required by genome defense and selection for specificity to avoid the off-target effects of maladaptive genic silencing by piRNA. PMID:28018141

  5. Positive Selection and the Evolution of izumo Genes in Mammals

    PubMed Central

    Grayson, Phil; Civetta, Alberto

    2012-01-01

    Most genes linked to male reproductive function have been known to evolve rapidly among species and to show signatures of positive selection. Different male species-specific reproductive strategies have been proposed to underlie positive selection, such as sperm competitive advantage and control over females postmating physiology. However, an underexplored aspect potentially affecting male reproductive gene evolution in mammals is the effect of gene duplications. Here we analyze the molecular evolution of members of the izumo gene family in mammals, a family of four genes mostly expressed in the sperm with known and potential roles in sperm-egg fusion. We confirm a previously reported bout of selection for izumo1 and establish that the bout of selection is restricted to the diversification of species of the superorder Laurasiatheria. None of the izumo genes showed evidence of positive selection in Glires (Rodentia and Lagomorpha), and in the case of the non-testes-specific izumo4, rapid evolution was driven by relaxed selection. We detected evidence of positive selection for izumo3 among Primates. Interestingly, positively selected sites include several serine residues suggesting modifications in protein function and/or localization among Primates. Our results suggest that positive selection is driven by aspects related to species-specific adaptations to fertilization rather than sexual selection. PMID:22957301

  6. Positive Selection and the Evolution of izumo Genes in Mammals.

    PubMed

    Grayson, Phil; Civetta, Alberto

    2012-01-01

    Most genes linked to male reproductive function have been known to evolve rapidly among species and to show signatures of positive selection. Different male species-specific reproductive strategies have been proposed to underlie positive selection, such as sperm competitive advantage and control over females postmating physiology. However, an underexplored aspect potentially affecting male reproductive gene evolution in mammals is the effect of gene duplications. Here we analyze the molecular evolution of members of the izumo gene family in mammals, a family of four genes mostly expressed in the sperm with known and potential roles in sperm-egg fusion. We confirm a previously reported bout of selection for izumo1 and establish that the bout of selection is restricted to the diversification of species of the superorder Laurasiatheria. None of the izumo genes showed evidence of positive selection in Glires (Rodentia and Lagomorpha), and in the case of the non-testes-specific izumo4, rapid evolution was driven by relaxed selection. We detected evidence of positive selection for izumo3 among Primates. Interestingly, positively selected sites include several serine residues suggesting modifications in protein function and/or localization among Primates. Our results suggest that positive selection is driven by aspects related to species-specific adaptations to fertilization rather than sexual selection.

  7. Outgroups and Positive Selection: The Nothobranchius furzeri Case.

    PubMed

    Sahm, Arne; Platzer, Matthias; Cellerino, Alessandro

    2016-09-01

    Applications of positive selection analysis increase with the number of species for which genome/transcriptome sequences become available. Using the recently sequenced turquoise killifish (Nothobranchius furzeri) genome as an example, we compare two different approaches based on different outgroup selection. The combination of these two methods allows the origin of positively selected sites in aging-related genes of the N. furzeri genome to be determined.

  8. The SEDIBUD (Sediment Budgets in Cold Environments) Programme: Ongoing activities and selected key tasks for the coming years

    NASA Astrophysics Data System (ADS)

    Beylich, Achim A.; Lamoureux, Scott F.; Decaulne, Armelle

    2012-09-01

    Projected climate change in cold environments is expected to alter melt-season duration and intensity, along with the number of extreme rainfall events, total annual precipitation and the balance between snowfall and rainfall. In addition, changes to the thermal balance are expected to reduce the extent of permafrost and seasonal ground frost and increase active layer depths. The combined effects of these changes will alter surface environments in cold climate regions and change the fluxes of sediments, nutrients and solutes, but the absence of data, coordinated process monitoring and coordinated quantitative analysis to understand the sensitivity of the Earth surface environment are acute in cold climate environments. The International Association of Geomorphologists (I.A.G./A.I.G.) SEDIBUD (Sediment Budgets in Cold Environments) Programme has been formed to address this key knowledge gap and builds on the earlier European Science Foundation (ESF) SEDIFLUX (Sedimentary Source-to-Sink-Fluxes in Cold Environments) Network. Coordinated efforts are carried out to monitor, quantify, compare and model sedimentary fluxes and possible effects of predicted climate change in currently 44 selected SEDIBUD Key Test Sites (cold climate environment catchments) worldwide.

  9. Widespread positive selection in the photosynthetic Rubisco enzyme

    PubMed Central

    Kapralov, Maxim V; Filatov, Dmitry A

    2007-01-01

    Background Rubisco enzyme catalyzes the first step in net photosynthetic CO2 assimilation and photorespiratory carbon oxidation and is responsible for almost all carbon fixation on Earth. The large subunit of Rubisco is encoded by the chloroplast rbcL gene, which is widely used for reconstruction of plant phylogenies due to its conservative nature. Plant systematicists have mainly used rbcL paying little attention to its function, and the question whether it evolves under Darwinian selection has received little attention. The purpose of our study was to evaluate how common is positive selection in Rubisco among the phototrophs and where in the Rubisco structure does positive selection occur. Results We searched for positive selection in rbcL sequences from over 3000 species representing all lineages of green plants and some lineages of other phototrophs, such as brown and red algae, diatoms, euglenids and cyanobacteria. Our molecular phylogenetic analysis found the presence of positive selection in rbcL of most analyzed land plants, but not in algae and cyanobacteria. The mapping of the positively selected residues on the Rubisco tertiary structure revealed that they are located in regions important for dimer-dimer, intradimer, large subunit-small subunit and Rubisco-Rubisco activase interactions, and that some of the positively selected residues are close to the active site. Conclusion Our results demonstrate that despite its conservative nature, Rubisco evolves under positive selection in most lineages of land plants, and after billions of years of evolution Darwinian selection still fine-tunes its performance. Widespread positive selection in rbcL has to be taken into account when this gene is used for phylogenetic reconstructions. PMID:17498284

  10. Patterns of Positive Selection in Seven Ant Genomes

    PubMed Central

    Roux, Julien; Privman, Eyal; Moretti, Sébastien; Daub, Josephine T.; Robinson-Rechavi, Marc; Keller, Laurent

    2014-01-01

    The evolution of ants is marked by remarkable adaptations that allowed the development of very complex social systems. To identify how ant-specific adaptations are associated with patterns of molecular evolution, we searched for signs of positive selection on amino-acid changes in proteins. We identified 24 functional categories of genes which were enriched for positively selected genes in the ant lineage. We also reanalyzed genome-wide data sets in bees and flies with the same methodology to check whether positive selection was specific to ants or also present in other insects. Notably, genes implicated in immunity were enriched for positively selected genes in the three lineages, ruling out the hypothesis that the evolution of hygienic behaviors in social insects caused a major relaxation of selective pressure on immune genes. Our scan also indicated that genes implicated in neurogenesis and olfaction started to undergo increased positive selection before the evolution of sociality in Hymenoptera. Finally, the comparison between these three lineages allowed us to pinpoint molecular evolution patterns that were specific to the ant lineage. In particular, there was ant-specific recurrent positive selection on genes with mitochondrial functions, suggesting that mitochondrial activity was improved during the evolution of this lineage. This might have been an important step toward the evolution of extreme lifespan that is a hallmark of ants. PMID:24782441

  11. Control selection and participation in an ongoing, population-based, case-control study of birth defects: the National Birth Defects Prevention Study.

    PubMed

    Cogswell, Mary E; Bitsko, Rebecca H; Anderka, Marlene; Caton, Alissa R; Feldkamp, Marcia L; Hockett Sherlock, Stacey M; Meyer, Robert E; Ramadhani, Tunu; Robbins, James M; Shaw, Gary M; Mathews, T J; Royle, Marjorie; Reefhuis, Jennita

    2009-10-15

    To evaluate the representativeness of controls in an ongoing, population-based, case-control study of birth defects in 10 centers across the United States, researchers compared 1997-2003 birth certificate data linked to selected controls (n = 6,681) and control participants (n = 4,395) with those from their base populations (n = 2,468,697). Researchers analyzed differences in population characteristics (e.g., percentage of births at > or =2,500 g) for each group. Compared with their base populations, control participants did not differ in distributions of maternal or paternal age, previous livebirths, maternal smoking, or diabetes, but they did differ in other maternal (i.e., race/ethnicity, education, entry into prenatal care) and infant (i.e., birth weight, gestational age, and plurality) characteristics. Differences in distributions of maternal, but not infant, characteristics were associated with participation by selected controls. Absolute differences in infant characteristics for the base population versus control participants were < or =1.3 percentage points. Differences in infant characteristics were greater at centers that selected controls from hospitals compared with centers that selected controls from electronic birth certificates. These findings suggest that control participants in the National Birth Defects Prevention Study generally are representative of their base populations. Hospital-based control selection may slightly underascertain infants affected by certain adverse birth outcomes.

  12. Constructing genomic maps of positive selection in humans: Where do we go from here?

    PubMed Central

    Akey, Joshua M.

    2009-01-01

    Identifying targets of positive selection in humans has, until recently, been frustratingly slow, relying on the analysis of individual candidate genes. Genomics, however, has provided the necessary resources to systematically interrogate the entire genome for signatures of natural selection. To date, 21 genome-wide scans for recent or ongoing positive selection have been performed in humans. A key challenge is to begin synthesizing these newly constructed maps of positive selection into a coherent narrative of human evolutionary history and derive a deeper mechanistic understanding of how natural populations evolve. Here, I chronicle the recent history of the burgeoning field of human population genomics, critically assess genome-wide scans for positive selection in humans, identify important gaps in knowledge, and discuss both short- and long-term strategies for traversing the path from the low-resolution, incomplete, and error-prone maps of selection today to the ultimate goal of a detailed molecular, mechanistic, phenotypic, and population genetics characterization of adaptive alleles. PMID:19411596

  13. Evolution under domestication: ongoing artificial selection and divergence of wild and managed Stenocereus pruinosus (Cactaceae) populations in the Tehuacán Valley, Mexico

    PubMed Central

    Parra, Fabiola; Casas, Alejandro; Peñaloza-Ramírez, Juan Manuel; Cortés-Palomec, Aurea C.; Rocha-Ramírez, Víctor; González-Rodríguez, Antonio

    2010-01-01

    Background and Aims The Tehuacán Valley in Mexico is a principal area of plant domestication in Mesoamerica. There, artificial selection is currently practised on nearly 120 native plant species with coexisting wild, silvicultural and cultivated populations, providing an excellent setting for studying ongoing mechanisms of evolution under domestication. One of these species is the columnar cactus Stenocereus pruinosus, in which we studied how artificial selection is operating through traditional management and whether it has determined morphological and genetic divergence between wild and managed populations. Methods Semi-structured interviews were conducted with 83 households of three villages to investigate motives and mechanisms of artificial selection. Management effects were studied by comparing variation patterns of 14 morphological characters and population genetics (four microsatellite loci) of 264 plants from nine wild, silvicultural and cultivated populations. Key Results Variation in fruit characters was recognized by most people, and was the principal target of artificial selection directed to favour larger and sweeter fruits with thinner or thicker peel, fewer spines and pulp colours others than red. Artificial selection operates in agroforestry systems favouring abundance (through not felling plants and planting branches) of the preferred phenotypes, and acts more intensely in household gardens. Significant morphological divergence between wild and managed populations was observed in fruit characters and plant vigour. On average, genetic diversity in silvicultural populations (HE = 0·743) was higher than in wild (HE = 0·726) and cultivated (HE = 0·700) populations. Most of the genetic variation (90·58 %) occurred within populations. High gene flow (NmFST > 2) was identified among almost all populations studied, but was slightly limited by mountains among wild populations, and by artificial selection among wild and managed populations. Conclusions

  14. Evolution under domestication: ongoing artificial selection and divergence of wild and managed Stenocereus pruinosus (Cactaceae) populations in the Tehuacan Valley, Mexico.

    PubMed

    Parra, Fabiola; Casas, Alejandro; Peñaloza-Ramírez, Juan Manuel; Cortés-Palomec, Aurea C; Rocha-Ramírez, Víctor; González-Rodríguez, Antonio

    2010-09-01

    The Tehuacán Valley in Mexico is a principal area of plant domestication in Mesoamerica. There, artificial selection is currently practised on nearly 120 native plant species with coexisting wild, silvicultural and cultivated populations, providing an excellent setting for studying ongoing mechanisms of evolution under domestication. One of these species is the columnar cactus Stenocereus pruinosus, in which we studied how artificial selection is operating through traditional management and whether it has determined morphological and genetic divergence between wild and managed populations. Semi-structured interviews were conducted with 83 households of three villages to investigate motives and mechanisms of artificial selection. Management effects were studied by comparing variation patterns of 14 morphological characters and population genetics (four microsatellite loci) of 264 plants from nine wild, silvicultural and cultivated populations. Variation in fruit characters was recognized by most people, and was the principal target of artificial selection directed to favour larger and sweeter fruits with thinner or thicker peel, fewer spines and pulp colours other than red. Artificial selection operates in agroforestry systems favouring abundance (through not felling plants and planting branches) of the preferred phenotypes, and acts more intensely in household gardens. Significant morphological divergence between wild and managed populations was observed in fruit characters and plant vigour. On average, genetic diversity in silvicultural populations (H(E) = 0.743) was higher than in wild (H(E) = 0.726) and cultivated (H(E) = 0.700) populations. Most of the genetic variation (90.58 %) occurred within populations. High gene flow (Nm(FST) > 2) was identified among almost all populations studied, but was slightly limited by mountains among wild populations, and by artificial selection among wild and managed populations. Traditional management of S. pruinosus involves

  15. Position paper - peer review and design verification of selected activities

    SciTech Connect

    Stine, M.D.

    1994-09-01

    Position Paper to develop and document a position on the performance of independent peer reviews on selected design and analysis components of the Title I (preliminary) and Title II (detailed) design phases of the Multi-Function Waste Tank Facility project.

  16. Patterns of Positive Selection in Six Mammalian Genomes

    PubMed Central

    Kosiol, Carolin; Vinař, Tomáš; da Fonseca, Rute R.; Hubisz, Melissa J.; Bustamante, Carlos D.; Nielsen, Rasmus; Siepel, Adam

    2008-01-01

    Genome-wide scans for positively selected genes (PSGs) in mammals have provided insight into the dynamics of genome evolution, the genetic basis of differences between species, and the functions of individual genes. However, previous scans have been limited in power and accuracy owing to small numbers of available genomes. Here we present the most comprehensive examination of mammalian PSGs to date, using the six high-coverage genome assemblies now available for eutherian mammals. The increased phylogenetic depth of this dataset results in substantially improved statistical power, and permits several new lineage- and clade-specific tests to be applied. Of ∼16,500 human genes with high-confidence orthologs in at least two other species, 400 genes showed significant evidence of positive selection (FDR<0.05), according to a standard likelihood ratio test. An additional 144 genes showed evidence of positive selection on particular lineages or clades. As in previous studies, the identified PSGs were enriched for roles in defense/immunity, chemosensory perception, and reproduction, but enrichments were also evident for more specific functions, such as complement-mediated immunity and taste perception. Several pathways were strongly enriched for PSGs, suggesting possible co-evolution of interacting genes. A novel Bayesian analysis of the possible “selection histories” of each gene indicated that most PSGs have switched multiple times between positive selection and nonselection, suggesting that positive selection is often episodic. A detailed analysis of Affymetrix exon array data indicated that PSGs are expressed at significantly lower levels, and in a more tissue-specific manner, than non-PSGs. Genes that are specifically expressed in the spleen, testes, liver, and breast are significantly enriched for PSGs, but no evidence was found for an enrichment for PSGs among brain-specific genes. This study provides additional evidence for widespread positive selection in

  17. Erasing Errors due to Alignment Ambiguity When Estimating Positive Selection

    PubMed Central

    Redelings, Benjamin

    2014-01-01

    Current estimates of diversifying positive selection rely on first having an accurate multiple sequence alignment. Simulation studies have shown that under biologically plausible conditions, relying on a single estimate of the alignment from commonly used alignment software can lead to unacceptably high false-positive rates in detecting diversifying positive selection. We present a novel statistical method that eliminates excess false positives resulting from alignment error by jointly estimating the degree of positive selection and the alignment under an evolutionary model. Our model treats both substitutions and insertions/deletions as sequence changes on a tree and allows site heterogeneity in the substitution process. We conduct inference starting from unaligned sequence data by integrating over all alignments. This approach naturally accounts for ambiguous alignments without requiring ambiguously aligned sites to be identified and removed prior to analysis. We take a Bayesian approach and conduct inference using Markov chain Monte Carlo to integrate over all alignments on a fixed evolutionary tree topology. We introduce a Bayesian version of the branch-site test and assess the evidence for positive selection using Bayes factors. We compare two models of differing dimensionality using a simple alternative to reversible-jump methods. We also describe a more accurate method of estimating the Bayes factor using Rao-Blackwellization. We then show using simulated data that jointly estimating the alignment and the presence of positive selection solves the problem with excessive false positives from erroneous alignments and has nearly the same power to detect positive selection as when the true alignment is known. We also show that samples taken from the posterior alignment distribution using the software BAli-Phy have substantially lower alignment error compared with MUSCLE, MAFFT, PRANK, and FSA alignments. PMID:24866534

  18. Selection and the cell cycle: positive Darwinian selection in a well-known DNA damage response pathway.

    PubMed

    O'Connell, Mary J

    2010-12-01

    Cancer is a common occurrence in multi-cellular organisms and is not strictly limited to the elderly in a population. It is therefore possible that individuals with genotypes that protect against early onset cancers have a selective advantage. In this study the patterns of mutation in the proteins of a well-studied DNA damage response pathway have been examined for evidence of adaptive evolutionary change. Using a maximum likelihood framework and the mammalian species phylogeny, together with codon models of evolution, selective pressure variation across the interacting network of proteins has been detected. The presence of signatures of adaptive evolution in BRCA1 and BRCA2 has already been documented but the effect on the entire network of interacting proteins in this damage response pathway has, until now, been unknown. Positive selection is evident throughout the network with a total of 11 proteins out of 15 examined displaying patterns of substitution characteristic of positive selection. It is also shown here that modern human populations display evidence of an ongoing selective sweep in 9 of these DNA damage repair proteins. The results presented here provide the community with new residues that may be relevant to cancer susceptibility while also highlighting those proteins where human and mouse have undergone lineage-specific functional shift. An understanding of this damage response pathway from an evolutionary perspective will undoubtedly contribute to future cancer treatment approaches.

  19. Molecules and mating: positive selection and reproductive behaviour in primates.

    PubMed

    Knapp, Leslie A; Innocent, Simeon H S

    2012-01-01

    Sexual reproduction is generally thought to be more costly than asexual reproduction. However, it does have the advantage of accelerating rates of adaptation through processes such as recombination and positive selection. Comparative studies of the human and nonhuman primate genomes have demonstrated that positive selection has played an important role in the evolutionary history of humans and other primates. To date, many dozens of genes, thought to be affected by positive selection, have been identified. In this chapter, we will focus on genes that are associated with mating behaviours and reproductive processes, concentrating on genes that are most likely to enhance reproductive success and that also show evidence of positive selection. The genes encode phenotypic features that potentially influence mate choice decisions or impact the evolution and function of genes involved in the perception and regulation of, and the response to, phenotypic signals. We will also consider genes that influence precopulatory behavioural traits in humans and nonhuman primates, such as social bonding and aggression. The evolution of post-copulatory strategies such as sperm competition and selective abortion may also evolve in the presence of intense competition and these adaptations will also be considered. Although behaviour may not be solely determined by genes, the evidence suggests that the genes discussed in this chapter have some influence on human and nonhuman primate behaviour and that positive selection on these genes results in some degree of population differentiation and diversity.

  20. Genes associated with SLE are targets of recent positive selection.

    PubMed

    Ramos, Paula S; Shaftman, Stephanie R; Ward, Ralph C; Langefeld, Carl D

    2014-01-01

    The reasons for the ethnic disparities in the prevalence of systemic lupus erythematosus (SLE) and the relative high frequency of SLE risk alleles in the population are not fully understood. Population genetic factors such as natural selection alter allele frequencies over generations and may help explain the persistence of such common risk variants in the population and the differential risk of SLE. In order to better understand the genetic basis of SLE that might be due to natural selection, a total of 74 genomic regions with compelling evidence for association with SLE were tested for evidence of recent positive selection in the HapMap and HGDP populations, using population differentiation, allele frequency, and haplotype-based tests. Consistent signs of positive selection across different studies and statistical methods were observed at several SLE-associated loci, including PTPN22, TNFSF4, TET3-DGUOK, TNIP1, UHRF1BP1, BLK, and ITGAM genes. This study is the first to evaluate and report that several SLE-associated regions show signs of positive natural selection. These results provide corroborating evidence in support of recent positive selection as one mechanism underlying the elevated population frequency of SLE risk loci and supports future research that integrates signals of natural selection to help identify functional SLE risk alleles.

  1. A Demonstration of Regression False Positive Selection in Data Mining

    ERIC Educational Resources Information Center

    Pinder, Jonathan P.

    2014-01-01

    Business analytics courses, such as marketing research, data mining, forecasting, and advanced financial modeling, have substantial predictive modeling components. The predictive modeling in these courses requires students to estimate and test many linear regressions. As a result, false positive variable selection ("type I errors") is…

  2. A Demonstration of Regression False Positive Selection in Data Mining

    ERIC Educational Resources Information Center

    Pinder, Jonathan P.

    2014-01-01

    Business analytics courses, such as marketing research, data mining, forecasting, and advanced financial modeling, have substantial predictive modeling components. The predictive modeling in these courses requires students to estimate and test many linear regressions. As a result, false positive variable selection ("type I errors") is…

  3. Methods and reagents. Reducing background colonies with positive selection vectors.

    PubMed

    Hengen, P N

    1997-03-01

    Methods and reagents is a unique monthly column that highlights current discussions in the newsgroup bionet.molbio.methds-reagnts, available on the Internet. This month's column discusses the pros and cons of eliminating unwanted background colonies by using the positive selection vector pZErO. For details on how to partake in the newsgroup, see the accompanying box.

  4. The effect of selective availability on differential GPS positioning

    NASA Astrophysics Data System (ADS)

    Tolman, Brian W.; Coco, David S.; Leach, Mark P.; Clynch, James R.

    The effect of Selective Availability (SA) on differential positioning is considered, using an extensive two-frequency P code data set which was collected during two periods: a publicly announced test of the GPS constellation in October, 1989, and after it was announced that SA had been implemented, in April 1990. The data were collected with the cooperation of several organizations, using TI 4100 receivers and atomic clocks at 6 sites, spanning baselines from 8 to 1350 kilometers, over a total of more than 25 days. A subset of this data set shows strong characteristics which are probably due to SA. Differential positions which have been computed using this 'unhealthy' data are compared to truth positions, and to identically computed positions using apparently 'healthy' data from the same period. The results and their implications for the impact that SA could have on differential positioning are presented.

  5. Chromatographic selectivity study of 4-fluorophenylacetic acid positional isomers separation.

    PubMed

    Chasse, Tyson; Wenslow, Robert; Bereznitski, Yuri

    2007-07-13

    Unique properties of the fluorine atom stimulate widespread use and development of new organofluorine compounds in agrochemistry, biotechnology and pharmacology applications. However, relatively few synthetic methods exhibit a high degree of fluorination selectivity, which ultimately results in the presence of structurally related fluorinated isomers in the synthetic product. This outcome is undesirable from a pharmaceutical perspective as positional isomers possess different reactivity, biological activity and toxicity as compared to the desired product. It is advantageous to control positional isomers in the early stages of the synthetic process, as rejection and analysis of these isomers will likely become more difficult in later stages. The current work reports the development of a chromatographic analysis of 2- and 3-fluorophenylacetic acid positional isomer impurities in 4-fluorophenylacetic acid (4-FPAA), a building block in the synthesis of an active pharmaceutical ingredient. The method is employed as a part of a Quality by Design Approach to control purity of the starting material in order to eliminate the presence of undesirable positional isomers in the final drug substance. During method development, a wide range of chromatographic conditions and structurally related positional isomer probe molecules were exploited in an effort to gain insight into the specifics of the separation mechanism. For the systems studied it was shown that the choice of organic modifier played a key role in achieving acceptable separation. Further studies encompassed investigation of temperature influence on retention and selectivity of the FPAA isomers separation. Thermodynamic analysis of these data showed that the selectivity of the 2- and 4- fluorophenylacetic acids separation was dominated by an enthalpic process, while the selectivity of the 4- and 3-fluorophenylacetic acids separation was exclusively entropy driven (Delta(DeltaH degrees approximately 0). Studies of

  6. Positive selection in glycolysis among Australasian stick insects.

    PubMed

    Dunning, Luke T; Dennis, Alice B; Thomson, Geoffrey; Sinclair, Brent J; Newcomb, Richard D; Buckley, Thomas R

    2013-09-30

    The glycolytic pathway is central to cellular energy production. Selection on individual enzymes within glycolysis, particularly phosphoglucose isomerase (Pgi), has been associated with metabolic performance in numerous organisms. Nonetheless, how whole energy-producing pathways evolve to allow organisms to thrive in different environments and adopt new lifestyles remains little explored. The Lanceocercata radiation of Australasian stick insects includes transitions from tropical to temperate climates, lowland to alpine habitats, and winged to wingless forms. This permits a broad investigation to determine which steps within glycolysis and what sites within enzymes are the targets of positive selection. To address these questions we obtained transcript sequences from seven core glycolysis enzymes, including two Pgi paralogues, from 29 Lanceocercata species. Using maximum likelihood methods a signature of positive selection was inferred in two core glycolysis enzymes. Pgi and Glyceraldehyde 3-phosphate dehydrogenase (Gaphd) genes both encode enzymes linking glycolysis to the pentose phosphate pathway. Positive selection among Pgi paralogues and orthologues predominately targets amino acids with residues exposed to the protein's surface, where changes in physical properties may alter enzyme performance. Our results suggest that, for Lancerocercata stick insects, adaptation to new stressful lifestyles requires a balance between maintaining cellular energy production, efficiently exploiting different energy storage pools and compensating for stress-induced oxidative damage.

  7. Positive selection in glycolysis among Australasian stick insects

    PubMed Central

    2013-01-01

    Background The glycolytic pathway is central to cellular energy production. Selection on individual enzymes within glycolysis, particularly phosphoglucose isomerase (Pgi), has been associated with metabolic performance in numerous organisms. Nonetheless, how whole energy-producing pathways evolve to allow organisms to thrive in different environments and adopt new lifestyles remains little explored. The Lanceocercata radiation of Australasian stick insects includes transitions from tropical to temperate climates, lowland to alpine habitats, and winged to wingless forms. This permits a broad investigation to determine which steps within glycolysis and what sites within enzymes are the targets of positive selection. To address these questions we obtained transcript sequences from seven core glycolysis enzymes, including two Pgi paralogues, from 29 Lanceocercata species. Results Using maximum likelihood methods a signature of positive selection was inferred in two core glycolysis enzymes. Pgi and Glyceraldehyde 3-phosphate dehydrogenase (Gaphd) genes both encode enzymes linking glycolysis to the pentose phosphate pathway. Positive selection among Pgi paralogues and orthologues predominately targets amino acids with residues exposed to the protein’s surface, where changes in physical properties may alter enzyme performance. Conclusion Our results suggest that, for Lancerocercata stick insects, adaptation to new stressful lifestyles requires a balance between maintaining cellular energy production, efficiently exploiting different energy storage pools and compensating for stress-induced oxidative damage. PMID:24079656

  8. Positively selected sites in cetacean myoglobins contribute to protein stability.

    PubMed

    Dasmeh, Pouria; Serohijos, Adrian W R; Kepp, Kasper P; Shakhnovich, Eugene I

    2013-01-01

    Since divergence ∼50 Ma ago from their terrestrial ancestors, cetaceans underwent a series of adaptations such as a ∼10-20 fold increase in myoglobin (Mb) concentration in skeletal muscle, critical for increasing oxygen storage capacity and prolonging dive time. Whereas the O2-binding affinity of Mbs is not significantly different among mammals (with typical oxygenation constants of ∼0.8-1.2 µM(-1)), folding stabilities of cetacean Mbs are ∼2-4 kcal/mol higher than for terrestrial Mbs. Using ancestral sequence reconstruction, maximum likelihood and bayesian tests to describe the evolution of cetacean Mbs, and experimentally calibrated computation of stability effects of mutations, we observe accelerated evolution in cetaceans and identify seven positively selected sites in Mb. Overall, these sites contribute to Mb stabilization with a conditional probability of 0.8. We observe a correlation between Mb folding stability and protein abundance, suggesting that a selection pressure for stability acts proportionally to higher expression. We also identify a major divergence event leading to the common ancestor of whales, during which major stabilization occurred. Most of the positively selected sites that occur later act against other destabilizing mutations to maintain stability across the clade, except for the shallow divers, where late stability relaxation occurs, probably due to the shorter aerobic dive limits of these species. The three main positively selected sites 66, 5, and 35 undergo changes that favor hydrophobic folding, structural integrity, and intra-helical hydrogen bonds.

  9. Selective assessment and positivity bias in environmental valuation.

    PubMed

    Posavac, Steven S; Brakus, J Josko; Jain, Shailendra Pratap; Cronley, Maria L

    2006-03-01

    The need to determine the value of environmental entities has generated substantial research regarding optimal methods for obtaining valuations from survey respondents. The literature suggests the importance of providing clear, complete descriptions of the entity being valued prior to respondents indicating their valuations. The target entity's attributes are often presented in isolation or in greater detail compared with other entities. Two experiments were conducted to explore whether selective exposure to and assessment of an environmental entity can bias survey respondents' judgments. This article adds to the environmental valuation literature by demonstrating a new process that leads to value overestimates. Specifically, the article shows that (a) when an environmental entity is the focus of assessment in a survey, positively biased evaluations often result; (b) positivity bias in evaluation translates to real monetary allocation decisions; and (c) selective information processing contributes to these effects.

  10. Variation in positive selection in termite GNBPs and Relish.

    PubMed

    Bulmer, Mark S; Crozier, Ross H

    2006-02-01

    Social insects are model organisms for investigating molecular evolution in the innate immune system. Their diversity affords comparative analysis among closely related species, and group living is likely to contribute to the pathogen stress imposed on the immune system. We used different models of nucleotide substitution at nonsynonymous (amino acid altering) and synonymous (silent) sites to compare the different levels and type of selection among three immunity genes in 13 Australian termite species (Nasutitermes). The immunity genes include two encoding pathogen recognition proteins (gram-negative bacterial-binding proteins) that duplicated and diverged before or soon after the evolution of the termites and a transcription factor (Relish), which induces the production of antimicrobial peptides. A comparison of evolutionary models that assign four unrestricted classes of dN/dS (the ratio of the nonsynonymous to synonymous substitution rate) to different Nasutitermes lineages revealed that the occurrence of positive selection (dN/dS > 1) varies among lineages and the three genes. Positive selection appears to have driven the evolution of all three genes in an ancestral lineage of three subterranean termites. It had previously been suggested that there was a transition along this ancestral lineage to termite morphology and ecology associated with a diet of decayed wood, a diet that may expose termites to elevated levels of fungal and bacterial pathogens. Relish appears to have experienced the highest levels of selective pressure for change among all three genes. Positively selected sites in the molecule are located in regions that are important for its activation, which suggests that amino acid substitutions at these sites are a counter response to pathogen mechanisms that disrupt the activation of Relish.

  11. Positive and purifying selection on the Drosophila Y chromosome.

    PubMed

    Singh, Nadia D; Koerich, Leonardo B; Carvalho, Antonio Bernardo; Clark, Andrew G

    2014-10-01

    Y chromosomes, with their reduced effective population size, lack of recombination, and male-limited transmission, present a unique collection of constraints for the operation of natural selection. Male-limited transmission may greatly increase the efficacy of selection for male-beneficial mutations, but the reduced effective size also inflates the role of random genetic drift. Together, these defining features of the Y chromosome are expected to influence rates and patterns of molecular evolution on the Y as compared with X-linked or autosomal loci. Here, we use sequence data from 11 genes in 9 Drosophila species to gain insight into the efficacy of natural selection on the Drosophila Y relative to the rest of the genome. Drosophila is an ideal system for assessing the consequences of Y-linkage for molecular evolution in part because the gene content of Drosophila Y chromosomes is highly dynamic, with orthologous genes being Y-linked in some species whereas autosomal in others. Our results confirm the expectation that the efficacy of natural selection at weakly selected sites is reduced on the Y chromosome. In contrast, purifying selection on the Y chromosome for strongly deleterious mutations does not appear to be compromised. Finally, we find evidence of recurrent positive selection for 4 of the 11 genes studied here. Our results thus highlight the variable nature of the mode and impact of natural selection on the Drosophila Y chromosome. © The Author 2014. 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.

  12. Positive darwinian selection at the imprinted MEDEA locus in plants.

    PubMed

    Spillane, Charles; Schmid, Karl J; Laoueillé-Duprat, Sylvia; Pien, Stéphane; Escobar-Restrepo, Juan-Miguel; Baroux, Célia; Gagliardini, Valeria; Page, Damian R; Wolfe, Kenneth H; Grossniklaus, Ueli

    2007-07-19

    In mammals and seed plants, a subset of genes is regulated by genomic imprinting where an allele's activity depends on its parental origin. The parental conflict theory suggests that genomic imprinting evolved after the emergence of an embryo-nourishing tissue (placenta and endosperm), resulting in an intragenomic parental conflict over the allocation of nutrients from mother to offspring. It was predicted that imprinted genes, which arose through antagonistic co-evolution driven by a parental conflict, should be subject to positive darwinian selection. Here we show that the imprinted plant gene MEDEA (MEA), which is essential for seed development, originated during a whole-genome duplication 35 to 85 million years ago. After duplication, MEA underwent positive darwinian selection consistent with neo-functionalization and the parental conflict theory. MEA continues to evolve rapidly in the out-crossing species Arabidopsis lyrata but not in the self-fertilizing species Arabidopsis thaliana, where parental conflicts are reduced. The paralogue of MEA, SWINGER (SWN; also called EZA1), is not imprinted and evolved under strong purifying selection because it probably retained the ancestral function of the common precursor gene. The evolution of MEA suggests a late origin of genomic imprinting within the Brassicaceae, whereas imprinting is thought to have originated early within the mammalian lineage.

  13. Colon cancer associated genes exhibit signatures of positive selection at functionally significant positions

    PubMed Central

    2012-01-01

    Background Cancer, much like most human disease, is routinely studied by utilizing model organisms. Of these model organisms, mice are often dominant. However, our assumptions of functional equivalence fail to consider the opportunity for divergence conferred by ~180 Million Years (MY) of independent evolution between these species. For a given set of human disease related genes, it is therefore important to determine if functional equivalency has been retained between species. In this study we test the hypothesis that cancer associated genes have different patterns of substitution akin to adaptive evolution in different mammal lineages. Results Our analysis of the current literature and colon cancer databases identified 22 genes exhibiting colon cancer associated germline mutations. We identified orthologs for these 22 genes across a set of high coverage (>6X) vertebrate genomes. Analysis of these orthologous datasets revealed significant levels of positive selection. Evidence of lineage-specific positive selection was identified in 14 genes in both ancestral and extant lineages. Lineage-specific positive selection was detected in the ancestral Euarchontoglires and Hominidae lineages for STK11, in the ancestral primate lineage for CDH1, in the ancestral Murinae lineage for both SDHC and MSH6 genes and the ancestral Muridae lineage for TSC1. Conclusion Identifying positive selection in the Primate, Hominidae, Muridae and Murinae lineages suggests an ancestral functional shift in these genes between the rodent and primate lineages. Analyses such as this, combining evolutionary theory and predictions - along with medically relevant data, can thus provide us with important clues for modeling human diseases. PMID:22788692

  14. Fish Oil–Based Lipid Emulsions in the Treatment of Parenteral Nutrition-Associated Liver Disease: An Ongoing Positive Experience123

    PubMed Central

    Premkumar, Muralidhar H.; Carter, Beth A.; Hawthorne, Keli M.; King, Kristi; Abrams, Steven A.

    2014-01-01

    We previously reported the beneficial effect of fish oil-based lipid emulsions (FOLEs) as monotherapy in the treatment of parenteral nutrition-associated liver disease (PNALD). In this report, we share our ongoing experience at Texas Children’s Hospital, Houston, Texas in the use of FOLE in treatment of PNALD as presented at the 2013 Experimental Biology meeting. We describe the findings of a single center, prospective, observational study of infants <6 mo of age with PNALD who received parenteral FOLE as monotherapy. A total of 97 infants received FOLE under the compassionate-use protocol for the treatment of PNALD. Eighty-three (86%) survived with resolution of cholestasis and 14 (14%) died. The median conjugated bilirubin (CB) concentration at the initiation of FOLE therapy was 4.8 mg/dL (range 2.1–26). The median time to resolution of cholestasis was 40 d (range 3–158). Compared with infants with mild cholestasis (CB of 2.1–5 mg/dL at the initiation of FOLE), nonsurvivors were significantly more premature and took longer to resolve their cholestasis. Gestational age at birth correlated inversely with CB at the beginning of FOLE and peak CB. Infants with an initial CB >10 mg/dL had a higher mortality rate than infants with an initial CB <5 mg/dL (35% vs. 6%; P < 0.05). Our experience with the use of FOLE in PNALD continues to be encouraging. Prematurity continues to be a major determinant in mortality and severity of cholestasis. This calls for further controlled studies designed to optimize dose and timing of intervention in the use of FOLE in neonates. PMID:24425724

  15. A novel xylB-based positive selection vector.

    PubMed

    Stevis, P E; Ho, N W

    1988-07-01

    Expression of a plasmid-borne Escherichia coli xylulokinase gene (xylB) under the control of the lac promoter yields constitutively high levels of xylulokinase activity. When a plasmid containing this lac-xylB fusion (pLEK100) is transformed into a xylB- mutant the Xyl+ phenotype is restored on xylose-containing media. When the same transformants are plated on xylitol medium, growth inhibition is observed. Positive selection is achieved by cloning DNA into the unique restriction sites of pLEK100, to disrupt xylB expression, transforming E. coli, and then plating transformants on xylitol medium. With this protocol only transformants with insert containing plasmids will be obtained. This results in a considerable reduction in the time and effort needed to construct genomic libraries or perform routine DNA cloning experiments. Three unique sites are available which are suitable for positive selection of DNA fragments, via the disruption of translation (BglII) or transcription (HindIII, SalI, and BglII) of the xylB gene.

  16. A Genome Scan for Positive Selection in Thoroughbred Horses

    PubMed Central

    Gu, Jingjing; Orr, Nick; Park, Stephen D.; Katz, Lisa M.; Sulimova, Galina; MacHugh, David E.; Hill, Emmeline W.

    2009-01-01

    Thoroughbred horses have been selected for exceptional racing performance resulting in system-wide structural and functional adaptations contributing to elite athletic phenotypes. Because selection has been recent and intense in a closed population that stems from a small number of founder animals Thoroughbreds represent a unique population within which to identify genomic contributions to exercise-related traits. Employing a population genetics-based hitchhiking mapping approach we performed a genome scan using 394 autosomal and X chromosome microsatellite loci and identified positively selected loci in the extreme tail-ends of the empirical distributions for (1) deviations from expected heterozygosity (Ewens-Watterson test) in Thoroughbred (n = 112) and (2) global differentiation among four geographically diverse horse populations (FST). We found positively selected genomic regions in Thoroughbred enriched for phosphoinositide-mediated signalling (3.2-fold enrichment; P<0.01), insulin receptor signalling (5.0-fold enrichment; P<0.01) and lipid transport (2.2-fold enrichment; P<0.05) genes. We found a significant overrepresentation of sarcoglycan complex (11.1-fold enrichment; P<0.05) and focal adhesion pathway (1.9-fold enrichment; P<0.01) genes highlighting the role for muscle strength and integrity in the Thoroughbred athletic phenotype. We report for the first time candidate athletic-performance genes within regions targeted by selection in Thoroughbred horses that are principally responsible for fatty acid oxidation, increased insulin sensitivity and muscle strength: ACSS1 (acyl-CoA synthetase short-chain family member 1), ACTA1 (actin, alpha 1, skeletal muscle), ACTN2 (actinin, alpha 2), ADHFE1 (alcohol dehydrogenase, iron containing, 1), MTFR1 (mitochondrial fission regulator 1), PDK4 (pyruvate dehydrogenase kinase, isozyme 4) and TNC (tenascin C). Understanding the genetic basis for exercise adaptation will be crucial for the identification of genes

  17. Haplotype structure and positive selection at TLR1

    PubMed Central

    Heffelfinger, Christopher; Pakstis, Andrew J; Speed, William C; Clark, Allison P; Haigh, Eva; Fang, Rixun; Furtado, Mahohar R; Kidd, Kenneth K; Snyder, Michael P

    2014-01-01

    Toll-like receptor 1, when dimerized with Toll-like receptor 2, is a cell surface receptor that, upon recognition of bacterial lipoproteins, activates the innate immune system. Variants in TLR1 associate with the risk of a variety of medical conditions and diseases, including sepsis, leprosy, tuberculosis, and others. The foremost of these is rs5743618 c.2079T>G(p.(Ile602Ser)), the derived allele of which is associated with reduced risk of sepsis, leprosy, and other diseases. Interestingly, 602Ser, which shows signatures of selection, inhibits TLR1 surface trafficking and subsequent activation of NFκB upon recognition of a ligand. This suggests that reduced TLR1 activity may be beneficial for human health. To better understand TLR1 variation and its link to human health, we have typed all 7 high-frequency missense variants (>5% in at least one population) along with 17 other variants in and around TLR1 in 2548 individuals from 56 populations from around the globe. We have also found additional signatures of selection on missense variants not associated with rs5743618, suggesting that there may be multiple functional alleles under positive selection in this gene. PMID:24002163

  18. Selection on Position of Nonsense Codons in Introns.

    PubMed

    Behringer, Megan G; Hall, David W

    2016-11-01

    Introns occasionally remain in mature messenger RNAs (mRNAs) due to splicing errors and the translated, aberrant proteins that result represent a metabolic cost and may have other deleterious consequences. The nonsense-mediated decay (NMD) pathway degrades aberrant mRNAs, which it recognizes by the presence of an in-frame premature termination codon (PTC). We investigated whether selection has shaped the location of PTCs in introns to reduce waste and facilitate NMD. We found across seven model organisms, that in both first and last introns, PTCs occur earlier in introns than expected by chance, suggesting that selection favors earlier position. This pattern is more pronounced in species with larger effective population sizes. The pattern does not hold for last introns in the two mammal species, however, perhaps because in these species NMD is not initiated from 3'-terminal introns. We conclude that there is compelling evidence that the location of PTCs is shaped by selection for reduced waste and efficient degradation of aberrant mRNAs. Copyright © 2016 by the Genetics Society of America.

  19. Positive allometry and the prehistory of sexual selection.

    PubMed

    Tomkins, Joseph L; LeBas, Natasha R; Witton, Mark P; Martill, David M; Humphries, Stuart

    2010-08-01

    The function of the exaggerated structures that adorn many fossil vertebrates remains largely unresolved. One recurrent hypothesis is that these elaborated traits had a role in thermoregulation. This orthodoxy persists despite the observation that traits exaggerated to the point of impracticality in extant organisms are almost invariably sexually selected. We use allometric scaling to investigate the role of sexual selection and thermoregulation in the evolution of exaggerated traits of the crested pterosaur Pteranodon longiceps and the sail-backed eupelycosaurs Dimetrodon and Edaphosaurus. The extraordinarily steep positive allometry of the head crest of Pteranodon rules out all of the current hypotheses for this trait's main function other than sexual signaling. We also find interspecific patterns of allometry and sexual dimorphism in the sails of Dimetrodon and patterns of elaboration in Edaphosaurus consistent with a sexually selected function. Furthermore, small ancestral, sail-backed pelycosaurs would have been too small to need adaptations to thermoregulation. Our results question the popular view that the elaborated structures of these fossil species evolved as thermoregulatory organs and provide evidence in support of the hypothesis that Pteranodon crests and eupelycosaur sails are among the earliest and most extreme examples of elaborate sexual signals in the evolution of terrestrial vertebrates.

  20. The role of positive selection in hepatitis C virus.

    PubMed

    Cuevas, José M; Gonzalez, Michael; Torres-Puente, Manuela; Jiménez-Hernández, Nuria; Bracho, María A; García-Robles, Inmaculada; González-Candelas, Fernando; Moya, Andrés

    2009-09-01

    Hepatitis C virus (HCV) is a major health problem worldwide, infecting an estimated 170 million people. In this study, we have employed a large data set of sequences (14,654 sequences from between 25 and 100 clone sequences per analyzed region and per patient) from 67 patients infected with HCV genotype 1 (23 subtype 1a and 44 subtype 1b). For all patients, a sample prior to combined therapy with alpha interferon plus ribavirin was available, whereas for some patients additional samples after 6 or 12 months of treatment were also available. Twenty-seven patients responded to treatment (12 subtype 1a and 15 subtype 1b) and forty patients did not respond to treatment (11 subtype 1a vs. 29 subtype 1b). Two regions of the HCV genome were analyzed, one compressing the hypervariable regions (HVR1, HVR2 and HVR3) of the envelope 2 glycoprotein and another one including the interferon sensitive determining region (ISDR) and the V3 domain of the NS5A protein. Previously (Cuevas, J.M., Torres-Puente, M., Jiménez-Hernández, N., Bracho, M.A., García-Robles, I., Wrobel, B., Carnicer, F., del Olmo, J., Ortega, E., Moya, A., González-Candelas, F., 2008b. Genetic variability of hepatitis C virus before and after combined therapy of interferon plus ribavirin. Plos One 3 (8), e3058), several amino acid positions in both regions analyzed were detected to be under positive selection. Here, we have compared the amino acid composition of each positively selected position between responder and non-responder patients for both subtypes. If we exclude some non-conclusive cases, no clear differences were detected in any case. In conclusion, identifying specific positions as completely discriminatory of treatment response seems to be a difficult task. Our results, in concordance with previous studies, suggest that HCV evasion strategies are more likely based on a global increased variability, which would yield combinations of mutations with an increased resistance, than on the fixation of

  1. Using two on-going HIV studies to obtain clinical data from before, during and after pregnancy for HIV-positive women

    PubMed Central

    2012-01-01

    Background The UK Collaborative HIV Cohort (UK CHIC) is an observational study that collates data on HIV-positive adults accessing HIV clinical care at (currently) 13 large clinics in the UK but does not collect pregnancy specific data. The National Study of HIV in Pregnancy and Childhood (NSHPC) collates data on HIV-positive women receiving antenatal care from every maternity unit in the UK and Ireland. Both studies collate pseudonymised data and neither dataset contains unique patient identifiers. A methodology was developed to find and match records for women reported to both studies thereby obtaining clinical and treatment data on pregnant HIV-positive women not available from either dataset alone. Results Women in UK CHIC receiving HIV-clinical care in 1996–2009, were found in the NSHPC dataset by initially ‘linking’ records with identical date-of-birth, linked records were then accepted as a genuine ‘match’, if they had further matching fields including CD4 test date. In total, 2063 women were found in both datasets, representing 23.1% of HIV-positive women with a pregnancy in the UK (n = 8932). Clinical data was available in UK CHIC following most pregnancies (92.0%, 2471/2685 pregnancies starting before 2009). There was bias towards matching women with repeat pregnancies (35.9% (741/2063) of women found in both datasets had a repeat pregnancy compared to 21.9% (1502/6869) of women in NSHPC only) and matching women HIV diagnosed before their first reported pregnancy (54.8% (1131/2063) compared to 47.7% (3278/6869), respectively). Conclusions Through the use of demographic data and clinical dates, records from two independent studies were successfully matched, providing data not available from either study alone. PMID:22839414

  2. Using two on-going HIV studies to obtain clinical data from before, during and after pregnancy for HIV-positive women.

    PubMed

    Huntington, Susie E; Bansi, Loveleen K; Thorne, Claire; Anderson, Jane; Newell, Marie-Louise; Taylor, Graham P; Pillay, Deenan; Hill, Teresa; Tookey, Pat A; Sabin, Caroline A

    2012-07-28

    The UK Collaborative HIV Cohort (UK CHIC) is an observational study that collates data on HIV-positive adults accessing HIV clinical care at (currently) 13 large clinics in the UK but does not collect pregnancy specific data. The National Study of HIV in Pregnancy and Childhood (NSHPC) collates data on HIV-positive women receiving antenatal care from every maternity unit in the UK and Ireland. Both studies collate pseudonymised data and neither dataset contains unique patient identifiers. A methodology was developed to find and match records for women reported to both studies thereby obtaining clinical and treatment data on pregnant HIV-positive women not available from either dataset alone. Women in UK CHIC receiving HIV-clinical care in 1996-2009, were found in the NSHPC dataset by initially 'linking' records with identical date-of-birth, linked records were then accepted as a genuine 'match', if they had further matching fields including CD4 test date. In total, 2063 women were found in both datasets, representing 23.1% of HIV-positive women with a pregnancy in the UK (n = 8932). Clinical data was available in UK CHIC following most pregnancies (92.0%, 2471/2685 pregnancies starting before 2009). There was bias towards matching women with repeat pregnancies (35.9% (741/2063) of women found in both datasets had a repeat pregnancy compared to 21.9% (1502/6869) of women in NSHPC only) and matching women HIV diagnosed before their first reported pregnancy (54.8% (1131/2063) compared to 47.7% (3278/6869), respectively). Through the use of demographic data and clinical dates, records from two independent studies were successfully matched, providing data not available from either study alone.

  3. Drcd-1 related: a positively selected spermatogenesis retrogene in Drosophila.

    PubMed

    Quezada-Díaz, Jorge Ernesto; Muliyil, Taniya; Río, Javier; Betrán, Esther

    2010-10-01

    Gene duplication is a major force driving genome evolution, and examples of this mode of evolution and of the functions of duplicated genes are needed to reveal general patterns. Here, our study focuses on a particular retrogene (i.e., CG9573) that originated about 5-13 million years ago that we have named Drcd-1 related. It originated in Drosophila through retroposition of the parental gene Required for cell differentiation 1 of Drosophila (Drcd-1; CG14213), which is a known transcription cofactor. Drcd-1r is only present in D. melanogaster, D. simulans, D. sechellia, and D. mauritiana. Drcd-1r is an X to autosome retroposition event. Many retrogenes are X to autosome copies and it has been shown that positive selection underlies this bias. We sought to understand Drcd-1r mode of evolution and function to contribute to the understanding of the selective pressures acting on X to autosome retrogenes. Drcd-1r overlaps with another gene, it is within the 3' UTR of the gene CG13102 and is encoded in the opposite orientation. We have studied the characteristics of the transcripts and quantified expression of CG13102 and Drcd-1r in wild-type flies. We found that Drcd-1r is transcribed specifically in testes. We also studied the molecular evolution of Drcd-1r and Drcd-1 and found that the parental gene has evolved under very strong purifying selection but the retrogene has evolved very rapidly (Ka/Ks ~1) under both positive and purifying selection, as revealed using divergence and polymorphism data. These results indicate that Drcd-1r has a novel function in the Drosophila testes. To further explore Drcd-1r function we used a strain containing a P element inserted in the region where CG13102 and Drcd-1r are located that shows recessive male sterility. Analysis of this strain reveals the difficulties that can be encountered in studying the functions of genes with overlapping transcripts. Avenues for studying of the function of this gene are proposed.

  4. Positive selection driving diversification in plant secondary metabolism

    PubMed Central

    Benderoth, Markus; Textor, Susanne; Windsor, Aaron J.; Mitchell-Olds, Thomas; Gershenzon, Jonathan; Kroymann, Juergen

    2006-01-01

    In Arabidopsis thaliana and related plants, glucosinolates are a major component in the blend of secondary metabolites and contribute to resistance against herbivorous insects. Methylthioalkylmalate synthases (MAM) encoded at the MAM gene cluster control an early step in the biosynthesis of glucosinolates and, therefore, are central to the diversification of glucosinolate metabolism. We sequenced bacterial artificial chromosomes containing the MAM cluster from several Arabidopsis relatives, conducted enzyme assays with heterologously expressed MAM genes, and analyzed MAM nucleotide variation patterns. Our results show that gene duplication, neofunctionalization, and positive selection provide the mechanism for biochemical adaptation in plant defense. These processes occur repeatedly in the history of the MAM gene family, indicating their fundamental importance for the evolution of plant metabolic diversity both within and among species. PMID:16754868

  5. Evidence of recombination and positive selection in cetacean papillomaviruses.

    PubMed

    Robles-Sikisaka, Refugio; Rivera, Rebecca; Nollens, Hendrik H; St Leger, Judy; Durden, Wendy N; Stolen, Megan; Burchell, Jennifer; Wellehan, James F X

    2012-06-05

    Papillomaviruses (PVs) are small DNA viruses that have been associated with increased epithelial proliferation. Over one hundred PV types have been identified in humans; however, only three have been identified in bottlenose dolphins (Tursiops truncatus) to date. Using rolling circle amplification and degenerate PCR, we identified four novel PV genomes of bottlenose dolphins. TtPV4, TtPV5 and TtPV6 were identified in genital lesions while TtPV7 was identified in normal genital mucosa. Bayesian analysis of the full-length L1 genes found that TtPV4 and TtPV7 group within the Upsilonpapillomavirus genus while TtPV5 and TtPV6 group with Omikronpapillomavirus. However, analysis of the E1 gene did not distinguish these genera, implying that these genes may not share a common history, consistent with recombination. Recombination analyses identified several probable events. Signals of positive selection were found mostly in the E1 and E2 genes. Recombination and diversifying selection pressures constitute important driving forces of cetacean PV evolution.

  6. Evidence of recombination and positive selection in cetacean papillomaviruses

    SciTech Connect

    Robles-Sikisaka, Refugio; Rivera, Rebecca; Nollens, Hendrik H.; St Leger, Judy; Durden, Wendy N.; Stolen, Megan; Burchell, Jennifer; Wellehan, James F.X.

    2012-06-05

    Papillomaviruses (PVs) are small DNA viruses that have been associated with increased epithelial proliferation. Over one hundred PV types have been identified in humans; however, only three have been identified in bottlenose dolphins (Tursiops truncatus) to date. Using rolling circle amplification and degenerate PCR, we identified four novel PV genomes of bottlenose dolphins. TtPV4, TtPV5 and TtPV6 were identified in genital lesions while TtPV7 was identified in normal genital mucosa. Bayesian analysis of the full-length L1 genes found that TtPV4 and TtPV7 group within the Upsilonpapillomavirus genus while TtPV5 and TtPV6 group with Omikronpapillomavirus. However, analysis of the E1 gene did not distinguish these genera, implying that these genes may not share a common history, consistent with recombination. Recombination analyses identified several probable events. Signals of positive selection were found mostly in the E1 and E2 genes. Recombination and diversifying selection pressures constitute important driving forces of cetacean PV evolution.

  7. Effect of sound similarity and word position on lexical selection

    PubMed Central

    Reilly, Megan; Blumstein, Sheila E.

    2014-01-01

    Spoken word production research has shown that phonological information influences lexical selection. It remains unclear, however, whether this phonological information is specified for its phonological environment (e.g., word position) or its phonetic (allophonic) realization. To examine this, two definition naming experiments were performed during which subjects produced lexical targets (e.g., “balcony”) in response to the targets’ definitions (“deck higher than a building’s first floor”) after naming a series of phonologically related or unrelated primes. Subjects produced target responses significantly more often when the primes were phonologically related to the target, regardless of whether the phonologically related primes matched the target’s word position or did not. For example, subjects were equally primed to produce the target “balcony” after the prime “ballast” or “unbalanced” relative to unrelated primes. Moreover, equal priming occurred irrespective of phonological environment or phonetic realization. The results support models of spoken word production which include context-independent phonological representations. PMID:25436217

  8. Rapidly evolving genes in pathogens: methods for detecting positive selection and examples among fungi, bacteria, viruses and protists.

    PubMed

    Aguileta, Gabriela; Refrégier, Guislaine; Yockteng, Roxana; Fournier, Elisabeth; Giraud, Tatiana

    2009-07-01

    The ongoing coevolutionary struggle between hosts and pathogens, with hosts evolving to escape pathogen infection and pathogens evolving to escape host defences, can generate an 'arms race', i.e., the occurrence of recurrent selective sweeps that each favours a novel resistance or virulence allele that goes to fixation. Host-pathogen coevolution can alternatively lead to a 'trench warfare', i.e., balancing selection, maintaining certain alleles at loci involved in host-pathogen recognition over long time scales. Recently, technological and methodological progress has enabled detection of footprints of selection directly on genes, which can provide useful insights into the processes of coevolution. This knowledge can also have practical applications, for instance development of vaccines or drugs. Here we review the methods for detecting genes under positive selection using divergence data (i.e., the ratio of nonsynonymous to synonymous substitution rates, d(N)/d(S)). We also review methods for detecting selection using polymorphisms, such as methods based on F(ST) measures, frequency spectrum, linkage disequilibrium and haplotype structure. In the second part, we review examples where targets of selection have been identified in pathogens using these tests. Genes under positive selection in pathogens have mostly been sought among viruses, bacteria and protists, because of their paramount importance for human health. Another focus is on fungal pathogens owing to their agronomic importance. We finally discuss promising directions in pathogen studies, such as detecting selection in non-coding regions.

  9. Transcriptome Sequencing and Positive Selected Genes Analysis of Bombyx mandarina

    PubMed Central

    Wu, Yuqian; Long, Renwen; Liu, Chun; Xia, Qingyou

    2015-01-01

    The wild silkworm Bombyx mandarina is widely believed to be an ancestor of the domesticated silkworm, Bombyx mori. Silkworms are often used as a model for studying the mechanism of species domestication. Here, we performed transcriptome sequencing of the wild silkworm using an Illumina HiSeq2000 platform. We produced 100,004,078 high-quality reads and assembled them into 50,773 contigs with an N50 length of 1764 bp and a mean length of 941.62 bp. A total of 33,759 unigenes were identified, with 12,805 annotated in the Nr database, 8273 in the Pfam database, and 9093 in the Swiss-Prot database. Expression profile analysis found significant differential expression of 1308 unigenes between the middle silk gland (MSG) and posterior silk gland (PSG). Three sericin genes (sericin 1, sericin 2, and sericin 3) were expressed specifically in the MSG and three fibroin genes (fibroin-H, fibroin-L, and fibroin/P25) were expressed specifically in the PSG. In addition, 32,297 Single-nucleotide polymorphisms (SNPs) and 361 insertion-deletions (INDELs) were detected. Comparison with the domesticated silkworm p50/Dazao identified 5,295 orthologous genes, among which 400 might have experienced or to be experiencing positive selection by Ka/Ks analysis. These data and analyses presented here provide insights into silkworm domestication and an invaluable resource for wild silkworm genomics research. PMID:25806526

  10. Impact of selected troposphere models on Precise Point Positioning convergence

    NASA Astrophysics Data System (ADS)

    Kalita, Jakub; Rzepecka, Zofia

    2016-04-01

    The Precise Point Positioning (PPP) absolute method is currently intensively investigated in order to reach fast convergence time. Among various sources that influence the convergence of the PPP, the tropospheric delay is one of the most important. Numerous models of tropospheric delay are developed and applied to PPP processing. However, with rare exceptions, the quality of those models does not allow fixing the zenith path delay tropospheric parameter, leaving difference between nominal and final value to the estimation process. Here we present comparison of several PPP result sets, each of which based on different troposphere model. The respective nominal values are adopted from models: VMF1, GPT2w, MOPS and ZERO-WET. The PPP solution admitted as reference is based on the final troposphere product from the International GNSS Service (IGS). The VMF1 mapping function was used for all processing variants in order to provide capability to compare impact of applied nominal values. The worst case initiates zenith wet delay with zero value (ZERO-WET). Impact from all possible models for tropospheric nominal values should fit inside both IGS and ZERO-WET border variants. The analysis is based on data from seven IGS stations located in mid-latitude European region from year 2014. For the purpose of this study several days with the most active troposphere were selected for each of the station. All the PPP solutions were determined using gLAB open-source software, with the Kalman filter implemented independently by the authors of this work. The processing was performed on 1 hour slices of observation data. In addition to the analysis of the output processing files, the presented study contains detailed analysis of the tropospheric conditions for the selected data. The overall results show that for the height component the VMF1 model outperforms GPT2w and MOPS by 35-40% and ZERO-WET variant by 150%. In most of the cases all solutions converge to the same values during first

  11. Ongoing Space Nuclear Activities

    NASA Technical Reports Server (NTRS)

    Houts, Michael G.

    2007-01-01

    Most ongoing US activities related to space nuclear power and propulsion are sponsored by NASA. NASA-spons0red space nuclear work is currently focused on evaluating potential fission surface power (FSP) systems and on radioisotope power systems (RPS). In addition, significant efforts related to nuclear thermal propulsion (NTP) systems have been completed and will provide a starting point for potential future NTP work.

  12. Autonomous site selection and instrument positioning for sample acquisition

    NASA Astrophysics Data System (ADS)

    Shaw, A.; Barnes, D.; Pugh, S.

    The European Space Agency Aurora Exploration Program aims to establish a European long-term programme for the exploration of Space, culminating in a human mission to space in the 2030 timeframe. Two flagship missions, namely Mars Sample Return and ExoMars, have been proposed as recognised steps along the way. The Exomars Rover is the first of these flagship missions and includes a rover carrying the Pasteur Payload, a mobile exobiology instrumentation package, and the Beagle 2 arm. The primary objective is the search for evidence of past or present life on mars, but the payload will also study the evolution of the planet and the atmosphere, look for evidence of seismological activity and survey the environment in preparation for future missions. The operation of rovers in unknown environments is complicated, and requires large resources not only on the planet but also in ground based operations. Currently, this can be very labour intensive, and costly, if large teams of scientists and engineers are required to assess mission progress, plan mission scenarios, and construct a sequence of events or goals for uplink. Furthermore, the constraints in communication imposed by the time delay involved over such large distances, and line-of-sight required, make autonomy paramount to mission success, affording the ability to operate in the event of communications outages and be opportunistic with respect to scientific discovery. As part of this drive to reduce mission costs and increase autonomy the Space Robotics group at the University of Wales, Aberystwyth is researching methods of autonomous site selection and instrument positioning, directly applicable to the ExoMars mission. The site selection technique used builds on the geometric reasoning algorithms used previously for localisation and navigation [Shaw 03]. It is proposed that a digital elevation model (DEM) of the local surface, generated during traverse and without interaction from ground based operators, can be

  13. Extensive Positive Selection Drives the Evolution of Nonstructural Proteins in Lineage C Betacoronaviruses

    PubMed Central

    Cagliani, Rachele; Mozzi, Alessandra; Pozzoli, Uberto; Al-Daghri, Nasser; Clerici, Mario; Sironi, Manuela

    2016-01-01

    ABSTRACT Middle East respiratory syndrome-related coronavirus (MERS-CoV) spreads to humans via zoonotic transmission from camels. MERS-CoV belongs to lineage C of betacoronaviruses (betaCoVs), which also includes viruses isolated from bats and hedgehogs. A large portion of the betaCoV genome consists of two open reading frames (ORF1a and ORF1b) that are translated into polyproteins. These are cleaved by viral proteases to generate 16 nonstructural proteins (nsp1 to nsp16) which compose the viral replication-transcription complex. We investigated the evolution of ORF1a and ORF1b in lineage C betaCoVs. Results indicated widespread positive selection, acting mostly on ORF1a. The proportion of positively selected sites in ORF1a was much higher than that previously reported for the surface-exposed spike protein. Selected sites were unevenly distributed, with nsp3 representing the preferential target. Several pairs of coevolving sites were also detected, possibly indicating epistatic interactions; most of these were located in nsp3. Adaptive evolution at nsp3 is ongoing in MERS-CoV strains, and two selected sites (G720 and R911) were detected in the protease domain. While position 720 is variable in camel-derived viruses, suggesting that the selective event does not represent a specific adaptation to humans, the R911C substitution was observed only in human-derived MERS-CoV isolates, including the viral strain responsible for the recent South Korean outbreak. It will be extremely important to assess whether these changes affect host range or other viral phenotypes. More generally, data herein indicate that CoV nsp3 represents a major selection target and that nsp3 sequencing should be envisaged in monitoring programs and field surveys. IMPORTANCE Both severe acute respiratory syndrome coronavirus (SARS-CoV) and MERS-CoV originated in bats and spread to humans via an intermediate host. This clearly highlights the potential for coronavirus host shifting and the relevance

  14. Whole genome detection of signature of positive selection in African cattle reveals selection for thermotolerance.

    PubMed

    Taye, Mengistie; Lee, Wonseok; Caetano-Anolles, Kelsey; Dessie, Tadelle; Hanotte, Olivier; Mwai, Okeyo Ally; Kemp, Stephen; Cho, Seoae; Oh, Sung Jong; Lee, Hak-Kyo; Kim, Heebal

    2017-07-27

    As African indigenous cattle evolved in a hot tropical climate, they have developed an inherent thermotolerance; survival mechanisms include a light-colored and shiny coat, increased sweating, and cellular and molecular mechanisms to cope with high environmental temperature. Here, we report the positive selection signature of genes in African cattle breeds which contribute for their heat tolerance mechanisms. We compared the genomes of five indigenous African cattle breeds with the genomes of four commercial cattle breeds using cross-population composite likelihood ratio (XP-CLR) and cross-population extended haplotype homozygosity (XP-EHH) statistical methods. We identified 296 (XP-EHH) and 327 (XP-CLR) positively selected genes. Gene ontology analysis resulted in 41 biological process terms and six Kyoto Encyclopedia of Genes and Genomes pathways. Several genes and pathways were found to be involved in oxidative stress response, osmotic stress response, heat shock response, hair and skin properties, sweat gland development and sweating, feed intake and metabolism, and reproduction functions. The genes and pathways identified directly or indirectly contribute to the superior heat tolerance mechanisms in African cattle populations. The result will improve our understanding of the biological mechanisms of heat tolerance in African cattle breeds and opens an avenue for further study. © 2017 Japanese Society of Animal Science.

  15. Immunology (1955-1975): the natural selection theory, the two signal hypothesis and positive repertoire selection.

    PubMed

    Forsdyke, Donald R

    2012-01-01

    Observations suggesting the existence of natural antibody prior to exposure of an organism to the corresponding antigen, led to the natural selection theory of antibody formation of Jerne in 1955, and to the two signal hypothesis of Forsdyke in 1968. Aspects of these were not only first discoveries but also foundational discoveries in that they influenced contemporaries in a manner that, from our present vantage point, appears to have been constructive. Jerne's later hypothesis (1971, European Journal of Immunology 1: 1-9), that antibody-like receptors on lymphocytes were selected over evolutionary time for reactivity with the major histocompatibility complex (MHC) antigens of the species, was a first, but it was incorrect, and was foundational only to the extent that it emphasized the need to explain the Simonsen phenomenon. Although easily construed as derivative of Jerne (1971), the affinity/avidity model of Forsdyke (1975, Journal of Theoretical Biology 52: 187-198), which predicted that cell-surface components, including MHC antigens, would restrict antigen-reactivity by somatically shaping lymphocyte repertoires, was actually an extension of the two signal hypothesis. While presenting a mechanism for the positive selection of lymphocyte repertoires, and explaining the Simonsen phenomenon, the affinity/avidity model was not foundational in that it had to be independently rediscovered. For science to advance optimally we must seek to close temporal gaps so that first discoveries are also foundational. Listening to young scientists may be part of the solution.

  16. Positive Selection of Iris, a Retroviral Envelope–Derived Host Gene in Drosophila melanogaster

    PubMed Central

    Malik, Harmit S; Henikoff, Steven

    2005-01-01

    vertebrates. It is also the first example of a retroviral envelope gene that has been found to be subject to positive selection following its domestication. The unusual selective pressures acting on Iris suggest that it is an active participant in an ongoing genetic conflict. We propose a model in which Iris has “switched sides,” having been recruited by host genomes to combat baculoviruses and retroviruses, which employ homologous envelope genes to mediate infection. PMID:16244705

  17. Selecting Reinforcers for Positive Classroom Projects in Inner City Schools.

    ERIC Educational Resources Information Center

    Reyes, Donald

    1981-01-01

    Suggests several positive reinforcement methods that teachers may employ with inner-city students to improve student responsibility, organization, and motivation. These methods include offering incentives for grade improvement, tangible and nontangible reinforcers, token systems, and social reinforcement. (GC)

  18. Reliable automatic plan selection for visual robotic positioning

    NASA Technical Reports Server (NTRS)

    Mcinroy, John E.; Saridis, George N.

    1991-01-01

    Reliability analysis techniques developed for robotics are applied to a six-DOF (degree-of-freedom) visual positioning system. The task is to measure an object's pose and then grip the object reliably subject to time and accuracy constraints. Errors due to pixel truncation in the stadimetric vision system, forward kinematic and inverse kinematic uncertainties, and joint position and velocity noise are stochastically modeled. Simulation results for PUMA 500 kinematic and dynamic characteristics are presented.

  19. Reduced purifying selection prevails over positive selection in human copy number variant evolution.

    PubMed

    Nguyen, Duc-Quang; Webber, Caleb; Hehir-Kwa, Jayne; Pfundt, Rolph; Veltman, Joris; Ponting, Chris P

    2008-11-01

    Copy number variation is a dominant contributor to genomic variation and may frequently underlie an individual's variable susceptibilities to disease. Here we question our previous proposition that copy number variants (CNVs) are often retained in the human population because of their adaptive benefit. We show that genic biases of CNVs are best explained, not by positive selection, but by reduced efficiency of selection in eliminating deleterious changes from the human population. Of four CNV data sets examined, three exhibit significant increases in protein evolutionary rates. These increases appear to be attributable to the frequent coincidence of CNVs with segmental duplications (SDs) that recombine infrequently. Furthermore, human orthologs of mouse genes, which, when disrupted, result in pre- or postnatal lethality, are unusually depleted in CNVs. Together, these findings support a model of reduced purifying selection (Hill-Robertson interference) within copy number variable regions that are enriched in nonessential genes, allowing both the fixation of slightly deleterious substitutions and increased drift of CNV alleles. Additionally, all four CNV sets exhibited increased rates of interspecies chromosomal rearrangement and nucleotide substitution and an increased gene density. We observe that sequences with high G+C contents are most prone to copy number variation. In particular, frequently duplicated human SD sequence, or CNVs that are large and/or observed frequently, tend to be elevated in G+C content. In contrast, SD sequences that appear fixed in the human population lie more frequently within low G+C sequence. These findings provide an overarching view of how CNVs arise and segregate in the human population.

  20. Automatic Omega Station and LOP (Line of Position) Selection,

    DTIC Science & Technology

    1987-09-01

    huit postes de transmission r~partis autour du globe. La diff~rence de phase entre les signaux de deux postes donne un ligne de position (LDP) sur la... puissance du signal. Ce rapport d~crit ces facteurs et leur 6valuation. Il d6crit 6galement l’ensemble des algorithmes employ6 par MINS pour s4lectionner

  1. The role of Parenting and Goal Selection in Positive Youth Development: A Person-Centered Approach

    ERIC Educational Resources Information Center

    Napolitano, Christopher M.; Bowers, Edmond P.; Gestsdottir, Steinunn; Depping, Miriam; von Eye, Alexander; Chase, Paul; Lerner, Jacqueline V.

    2011-01-01

    Using a person-centered approach, we examined the relations between goal selection, various indicators of parenting, and positive development among 510 Grades 9 to 11 participants (68% female) in the 4-H Study of Positive Youth Development (PYD), a longitudinal study involving U.S. adolescents. Goal selection was operationalized by the "Selection"…

  2. The role of Parenting and Goal Selection in Positive Youth Development: A Person-Centered Approach

    ERIC Educational Resources Information Center

    Napolitano, Christopher M.; Bowers, Edmond P.; Gestsdottir, Steinunn; Depping, Miriam; von Eye, Alexander; Chase, Paul; Lerner, Jacqueline V.

    2011-01-01

    Using a person-centered approach, we examined the relations between goal selection, various indicators of parenting, and positive development among 510 Grades 9 to 11 participants (68% female) in the 4-H Study of Positive Youth Development (PYD), a longitudinal study involving U.S. adolescents. Goal selection was operationalized by the "Selection"…

  3. How to select and apply positive-displacement rotary pumps

    SciTech Connect

    Neerken, R.F.

    1980-04-07

    The advantages of rotary pumps for process applications are promoted by these practical guidelines concerning the types available, facts about their operation and performance, and the fluid systems in which they can be used. Basic types of rotary pumps discussed include internal gear, sliding vane, single-screw (progressing cavity), cam and piston, flexible tube, flexible liner, external gear, circumferential piston, twin screw, triple screw, single lobe, and 3 lobe. Factors which are examined to make pump selection include suction requirements, viscosity of fluids, temperature at which process fluid is handled, working and allowable pressures, pump capacity, pump horsepower, materials of construction, and intended applications.

  4. Identifying relevant positions in proteins by Critical Variable Selection.

    PubMed

    Grigolon, Silvia; Franz, Silvio; Marsili, Matteo

    2016-06-21

    Evolution in its course has found a variety of solutions to the same optimisation problem. The advent of high-throughput genomic sequencing has made available extensive data from which, in principle, one can infer the underlying structure on which biological functions rely. In this paper, we present a new method aimed at the extraction of sites encoding structural and functional properties from a set of protein primary sequences, namely a multiple sequence alignment. The method, called critical variable selection, is based on the idea that subsets of relevant sites correspond to subsequences that occur with a particularly broad frequency distribution in the dataset. By applying this algorithm to in silico sequences, to the response regulator receiver and to the voltage sensor domain of ion channels, we show that this procedure recovers not only the information encoded in single site statistics and pairwise correlations but also captures dependencies going beyond pairwise correlations. The method proposed here is complementary to statistical coupling analysis, in that the most relevant sites predicted by the two methods differ markedly. We find robust and consistent results for datasets as small as few hundred sequences that reveal a hidden hierarchy of sites that are consistent with the present knowledge on biologically relevant sites and evolutionary dynamics. This suggests that critical variable selection is capable of identifying a core of sites encoding functional and structural information in a multiple sequence alignment.

  5. A scan for positively selected genes in the genomes of humans and chimpanzees.

    PubMed

    Nielsen, Rasmus; Bustamante, Carlos; Clark, Andrew G; Glanowski, Stephen; Sackton, Timothy B; Hubisz, Melissa J; Fledel-Alon, Adi; Tanenbaum, David M; Civello, Daniel; White, Thomas J; J Sninsky, John; Adams, Mark D; Cargill, Michele

    2005-06-01

    Since the divergence of humans and chimpanzees about 5 million years ago, these species have undergone a remarkable evolution with drastic divergence in anatomy and cognitive abilities. At the molecular level, despite the small overall magnitude of DNA sequence divergence, we might expect such evolutionary changes to leave a noticeable signature throughout the genome. We here compare 13,731 annotated genes from humans to their chimpanzee orthologs to identify genes that show evidence of positive selection. Many of the genes that present a signature of positive selection tend to be involved in sensory perception or immune defenses. However, the group of genes that show the strongest evidence for positive selection also includes a surprising number of genes involved in tumor suppression and apoptosis, and of genes involved in spermatogenesis. We hypothesize that positive selection in some of these genes may be driven by genomic conflict due to apoptosis during spermatogenesis. Genes with maximal expression in the brain show little or no evidence for positive selection, while genes with maximal expression in the testis tend to be enriched with positively selected genes. Genes on the X chromosome also tend to show an elevated tendency for positive selection. We also present polymorphism data from 20 Caucasian Americans and 19 African Americans for the 50 annotated genes showing the strongest evidence for positive selection. The polymorphism analysis further supports the presence of positive selection in these genes by showing an excess of high-frequency derived nonsynonymous mutations.

  6. Positive Selection within a Diatom Species Acts on Putative Protein Interactions and Transcriptional Regulation

    PubMed Central

    Koester, Julie A.; Swanson, Willie J.; Armbrust, E. Virginia

    2013-01-01

    Diatoms are the most species-rich group of microalgae, and their contribution to marine primary production is important on a global scale. Diatoms can form dense blooms through rapid asexual reproduction; mutations acquired and propagated during blooms likely provide the genetic, and thus phenotypic, variability upon which natural selection may act. Positive selection was tested using genome and transcriptome-wide pair-wise comparisons of homologs in three genera of diatoms (Pseudo-nitzschia, Ditylum, and Thalassiosira) that represent decreasing phylogenetic distances. The signal of positive selection was greatest between two strains of Thalassiosira pseudonana. Further testing among seven strains of T. pseudonana yielded 809 candidate genes of positive selection, which are 7% of the protein-coding genes. Orphan genes and genes encoding protein-binding domains and transcriptional regulators were enriched within the set of positively selected genes relative to the genome as a whole. Positively selected genes were linked to the potential selective pressures of nutrient limitation and sea surface temperature based on analysis of gene expression profiles and identification of positively selected genes in subsets of strains from locations with similar environmental conditions. The identification of positively selected genes presents an opportunity to test new hypotheses in natural populations and the laboratory that integrate selected genotypes in T. pseudonana with their associated phenotypes and selective forces. PMID:23097498

  7. Positive Selection Drives Preferred Segment Combinations during Influenza Virus Reassortment

    PubMed Central

    Zeldovich, Konstantin B.; Liu, Ping; Renzette, Nicholas; Foll, Matthieu; Pham, Serena T.; Venev, Sergey V.; Gallagher, Glen R.; Bolon, Daniel N.; Kurt-Jones, Evelyn A.; Jensen, Jeffrey D.; Caffrey, Daniel R.; Schiffer, Celia A.; Kowalik, Timothy F.; Wang, Jennifer P.; Finberg, Robert W.

    2015-01-01

    Influenza A virus (IAV) has a segmented genome that allows for the exchange of genome segments between different strains. This reassortment accelerates evolution by breaking linkage, helping IAV cross species barriers to potentially create highly virulent strains. Challenges associated with monitoring the process of reassortment in molecular detail have limited our understanding of its evolutionary implications. We applied a novel deep sequencing approach with quantitative analysis to assess the in vitro temporal evolution of genomic reassortment in IAV. The combination of H1N1 and H3N2 strains reproducibly generated a new H1N2 strain with the hemagglutinin and nucleoprotein segments originating from H1N1 and the remaining six segments from H3N2. By deep sequencing the entire viral genome, we monitored the evolution of reassortment, quantifying the relative abundance of all IAV genome segments from the two parent strains over time and measuring the selection coefficients of the reassorting segments. Additionally, we observed several mutations coemerging with reassortment that were not found during passaging of pure parental IAV strains. Our results demonstrate how reassortment of the segmented genome can accelerate viral evolution in IAV, potentially enabled by the emergence of a small number of individual mutations. PMID:25713211

  8. Factors affecting motorcycle helmet use: size selection, stability, and position.

    PubMed

    Thai, Kim T; McIntosh, Andrew S; Pang, Toh Yen

    2015-01-01

    One of the main requirements of a protective helmet is to provide and maintain appropriate and adequate coverage to the head. A helmet that is poorly fitted or fastened may become displaced during normal use or even ejected during a crash. Observations and measurements of head dimensions, helmet position, adjustment, and stability were made on 216 motorcyclists. Helmet details were recorded. Participants completed a questionnaire on helmet usability and their riding history. Helmet stability was assessed quasistatically. Differences between the dimensions of ISO headforms and equivalent sized motorcyclists' heads were observed, especially head width. Almost all (94%) of the helmets were labeled to be compliant with AS/NZS 1698 (2006). The majority of riders were satisfied with the comfort, fit, and usability aspects of their helmets. The majority of helmets were deemed to have been worn correctly. Using quasistatic pull tests, it was found that helmet type (open-face or full-face) and the wearing correctness were among factors that affected the loads at which helmets became displaced. The forces required to displace the helmet were low, around 25 N. The size of the in-use motorcycle helmets did not correspond well to the predicted size based on head dimensions, although motorcyclists were generally satisfied with comfort and fit. The in vivo stability tests appear to overpredict that helmets will come off in a crash, based on the measured forces, tangential forces measured in the oblique impact tests, and the actual rate of helmet ejection.

  9. Positive selection of lactase persistence among people of Southern Arabia.

    PubMed

    Bayoumi, Riad; De Fanti, Sara; Sazzini, Marco; Giuliani, Cristina; Quagliariello, Andrea; Bortolini, Eugenio; Boattini, Alessio; Al-Habori, Molham; Al-Zubairi, Adel Sharaf; Rose, Jeffrey I; Romeo, Giovanni; Al-Abri, Abdulrahim; Luiselli, Donata

    2016-12-01

    Frequency patterns of the lactase persistence (LP)-associated -13,915 G allele and archaeological records pointing to substantial role played by southern regions in the peopling and domestication processes that involved the Arabian Peninsula suggest that Southern Arabia plausibly represented the center of diffusion of such adaptive variant. Nevertheless, a well-defined scenario for evolution of Arabian LP is still to be elucidated and the burgeoning archaeological picture of complex human migrations occurred through the peninsula is not matched by an equivalent high-resolution description of genetic variation underlying this adaptive trait. To fill this gap, we investigated diversity at a wide genomic interval surrounding the LCT gene in different Southern Arabian populations. 40 SNPs were genotyped to characterize LCT profiles of 630 Omani and Yemeni individuals to perform population structure, linkage disequilibrium, population differentiation-based and haplotype-based analyses. Typical Arabian LP-related variation was found in Dhofaris and Yemenis, being characterized by private haplotypes carrying the -13,915 G allele, unusual differentiation with respect to northern groups and conserved homozygous haplotype-blocks, suggesting that the adaptive allele was likely introduced in the Arabian gene pool in southern populations and was then subjected to prolonged selective pressure. By pointing to Yemen as one of the best candidate centers of diffusion of the Arabian-specific adaptive variant, obtained results indicate the spread of indigenous groups as the main process underlying dispersal of LP along the Arabian Peninsula, supporting a refugia model for Arabian demic movements occurred during the Terminal Pleistocene and Early Holocene. © 2016 Wiley Periodicals, Inc.

  10. Selective reduction of CAD false-positive findings

    NASA Astrophysics Data System (ADS)

    Camarlinghi, N.; Gori, I.; Retico, A.; Bagagli, F.

    2010-03-01

    Computer-Aided Detection (CAD) systems are becoming widespread supporting tools to radiologists' diagnosis, especially in screening contexts. However, a large amount of false positive (FP) alarms would inevitably lead both to an undesired possible increase in time for diagnosis, and to a reduction in radiologists' confidence in CAD as a useful tool. Most CAD systems implement as final step of the analysis a classifier which assigns a score to each entry of a list of findings; by thresholding this score it is possible to define the system performance on an annotated validation dataset in terms of a FROC curve (sensitivity vs. FP per scan). To use a CAD as a supportive tool for most clinical activities, an operative point has to be chosen on the system FROC curve, according to the obvious criterion of keeping the sensitivity as high as possible, while maintaining the number of FP alarms still acceptable. The strategy proposed in this study is to choose an operative point with high sensitivity on the CAD FROC curve, then to implement in cascade a further classification step, constituted by a smarter classifier. The key issue of this approach is that the smarter classifier is actually a meta-classifier of more then one decision system, each specialized in rejecting a particular type of FP findings generated by the CAD. The application of this approach to a dataset of 16 lung CT scans previously processed by the VBNACAD system is presented. The lung CT VBNACAD performance of 87.1% sensitivity to juxtapleural nodules with 18.5 FP per scan is improved up to 10.1 FP per scan while maintaining the same value of sensitivity. This work has been carried out in the framework of the MAGIC-V collaboration.

  11. Patterns of Positive Selection of the Myogenic Regulatory Factor Gene Family in Vertebrates

    PubMed Central

    Zhao, Xiao; Yu, Qi; Huang, Ling; Liu, Qing-Xin

    2014-01-01

    The functional divergence of transcriptional factors is critical in the evolution of transcriptional regulation. However, the mechanism of functional divergence among these factors remains unclear. Here, we performed an evolutionary analysis for positive selection in members of the myogenic regulatory factor (MRF) gene family of vertebrates. We selected 153 complete vertebrate MRF nucleotide sequences from our analyses, which revealed substantial evidence of positive selection. Here, we show that sites under positive selection were more frequently detected and identified from the genes encoding the myogenic differentiation factors (MyoG and Myf6) than the genes encoding myogenic determination factors (Myf5 and MyoD). Additionally, the functional divergence within the myogenic determination factors or differentiation factors was also under positive selection pressure. The positive selection sites were more frequently detected from MyoG and MyoD than Myf6 and Myf5, respectively. Amino acid residues under positive selection were identified mainly in their transcription activation domains and on the surface of protein three-dimensional structures. These data suggest that the functional gain and divergence of myogenic regulatory factors were driven by distinct positive selection of their transcription activation domains, whereas the function of the DNA binding domains was conserved in evolution. Our study evaluated the mechanism of functional divergence of the transcriptional regulation factors within a family, whereby the functions of their transcription activation domains diverged under positive selection during evolution. PMID:24651579

  12. Human and Non-Human Primate Genomes Share Hotspots of Positive Selection

    PubMed Central

    Enard, David; Depaulis, Frantz; Roest Crollius, Hugues

    2010-01-01

    Among primates, genome-wide analysis of recent positive selection is currently limited to the human species because it requires extensive sampling of genotypic data from many individuals. The extent to which genes positively selected in human also present adaptive changes in other primates therefore remains unknown. This question is important because a gene that has been positively selected independently in the human and in other primate lineages may be less likely to be involved in human specific phenotypic changes such as dietary habits or cognitive abilities. To answer this question, we analysed heterozygous Single Nucleotide Polymorphisms (SNPs) in the genomes of single human, chimpanzee, orangutan, and macaque individuals using a new method aiming to identify selective sweeps genome-wide. We found an unexpectedly high number of orthologous genes exhibiting signatures of a selective sweep simultaneously in several primate species, suggesting the presence of hotspots of positive selection. A similar significant excess is evident when comparing genes positively selected during recent human evolution with genes subjected to positive selection in their coding sequence in other primate lineages and identified using a different test. These findings are further supported by comparing several published human genome scans for positive selection with our findings in non-human primate genomes. We thus provide extensive evidence that the co-occurrence of positive selection in humans and in other primates at the same genetic loci can be measured with only four species, an indication that it may be a widespread phenomenon. The identification of positive selection in humans alongside other primates is a powerful tool to outline those genes that were selected uniquely during recent human evolution. PMID:20140238

  13. Positive selection and functional divergence of farnesyl pyrophosphate synthase genes in plants.

    PubMed

    Qian, Jieying; Liu, Yong; Chao, Naixia; Ma, Chengtong; Chen, Qicong; Sun, Jian; Wu, Yaosheng

    2017-02-04

    Farnesyl pyrophosphate synthase (FPS) belongs to the short-chain prenyltransferase family, and it performs a conserved and essential role in the terpenoid biosynthesis pathway. However, its classification, evolutionary history, and the forces driving the evolution of FPS genes in plants remain poorly understood. Phylogeny and positive selection analysis was used to identify the evolutionary forces that led to the functional divergence of FPS in plants, and recombinant detection was undertaken using the Genetic Algorithm for Recombination Detection (GARD) method. The dataset included 68 FPS variation pattern sequences (2 gymnosperms, 10 monocotyledons, 54 dicotyledons, and 2 outgroups). This study revealed that the FPS gene was under positive selection in plants. No recombinant within the FPS gene was found. Therefore, it was inferred that the positive selection of FPS had not been influenced by a recombinant episode. The positively selected sites were mainly located in the catalytic center and functional areas, which indicated that the 98S and 234D were important positively selected sites for plant FPS in the terpenoid biosynthesis pathway. They were located in the FPS conserved domain of the catalytic site. We inferred that the diversification of FPS genes was associated with functional divergence and could be driven by positive selection. It was clear that protein sequence evolution via positive selection was able to drive adaptive diversification in plant FPS proteins. This study provides information on the classification and positive selection of plant FPS genes, and the results could be useful for further research on the regulation of triterpenoid biosynthesis.

  14. Molecular evolution and positive Darwinian selection of the chloroplast maturase matK.

    PubMed

    Hao, Da Cheng; Chen, Shi Lin; Xiao, Pei Gen

    2010-03-01

    It is not clear whether matK evolves under Darwinian selection. In this study, 70 plant groups, representing 2,279 species at various evolutionary levels, were used to illustrate the molecular adaptation and evolutionary dynamics of gene divergence in matKs. Selective influences were investigated using standard dN/dS ratio methods. Analyses revealed the presence of positive selection in matKs of 32 plant groups. More positively selected sites were detected in the N-terminal region than in the RT domain and domain X of matK. Moreover, removing amino acid sites that are under positive selection has a significant effect on the bootstrap values of phylogenetic reconstruction. Our results suggest that the rapidly evolving matK evolves under positive selection in some lineages of land plants. Several regions of matK have experienced molecular adaptation, which fine-tunes maturase performance.

  15. Maximum-likelihood approaches reveal signatures of positive selection in IL genes in mammals.

    PubMed

    Neves, Fabiana; Abrantes, Joana; Steinke, John W; Esteves, Pedro J

    2014-02-01

    ILs are part of the immune system and are involved in multiple biological activities. ILs have been shown to evolve under positive selection; however, little information exists regarding which codons are specifically selected. By using different codon-based maximum-likelihood (ML) approaches, signatures of positive selection in mammalian ILs were searched for. Sequences of 46 ILs were retrieved from publicly available databases of mammalian genomes to detect signatures of positive selection in individual codons. Evolutionary analyses were conducted under two ML frameworks, the HyPhy package implemented in the Data Monkey Web Server and CODEML implemented in PAML. Signatures of positive selection were found in 28 ILs: IL-1A and B; IL-2, IL-4 to IL-10, IL-12A and B; IL-14 to IL-17A and C; IL-18, IL-20 to IL-22, IL-25, IL-26, IL-27B, IL-31, IL-34, IL-36A; and G. Codons under positive selection varied between 1 and 15. No evidence of positive selection was detected in IL-13; IL-17B and F; IL-19, IL-23, IL-24, IL-27A; or IL-29. Most mammalian ILs have sites evolving under positive selection, which may be explained by the multitude of biological processes in which ILs are enrolled. The results obtained raise hypotheses concerning the ILs functions, which should be pursued by using mutagenesis and crystallographic approaches.

  16. Positive Darwinian selection drives the evolution of several female reproductive proteins in mammals

    PubMed Central

    Swanson, Willie J.; Yang, Ziheng; Wolfner, Mariana F.; Aquadro, Charles F.

    2001-01-01

    Rapid evolution driven by positive Darwinian selection is a recurrent theme in male reproductive protein evolution. In contrast, positive selection has never been demonstrated for female reproductive proteins. Here, we perform phylogeny-based tests on three female mammalian fertilization proteins and demonstrate positive selection promoting their divergence. Two of these female fertilization proteins, the zona pellucida glycoproteins ZP2 and ZP3, are part of the mammalian egg coat. Several sites identified in ZP3 as likely to be under positive selection are located in a region previously demonstrated to be involved in species-specific sperm-egg interaction, suggesting the selective pressure is related to male-female interaction. The results provide long-sought evidence for two evolutionary hypotheses: sperm competition and sexual conflict. PMID:11226269

  17. Basal DNA repair machinery is subject to positive selection in ionizing-radiation-resistant bacteria.

    PubMed

    Sghaier, Haïtham; Ghedira, Kaïs; Benkahla, Alia; Barkallah, Insaf

    2008-06-21

    Ionizing-radiation-resistant bacteria (IRRB) show a surprising capacity for adaptation to ionizing radiation and desiccation. Positive Darwinian selection is expected to play an important role in this trait, but no data are currently available regarding the role of positive adaptive selection in resistance to ionizing-radiation and tolerance of desiccation. We analyzed the four known genome sequences of IRRB (Deinococcus geothermalis, Deinococcus radiodurans, Kineococcus radiotolerans, and Rubrobacter xylanophilus) to determine the role of positive Darwinian selection in the evolution of resistance to ionizing radiation and tolerance of desiccation. We used the programs MultiParanoid and DnaSP to deduce the sets of orthologs that potentially evolved due to positive Darwinian selection in IRRB. We find that positive selection targets 689 ortholog sets of IRRB. Among these, 58 ortholog sets are absent in ionizing-radiation-sensitive bacteria (IRSB: Escherichia coli and Thermus thermophilus). The most striking finding is that all basal DNA repair genes in IRRB, unlike many of their orthologs in IRSB, are subject to positive selection. Our results provide the first in silico prediction of positively selected genes with potential roles in the molecular basis of resistance to gamma-radiation and tolerance of desiccation in IRRB. Identification of these genes provides a basis for future experimental work aimed at understanding the metabolic networks in which they participate.

  18. PSP: rapid identification of orthologous coding genes under positive selection across multiple closely related prokaryotic genomes.

    PubMed

    Su, Fei; Ou, Hong-Yu; Tao, Fei; Tang, Hongzhi; Xu, Ping

    2013-12-27

    With genomic sequences of many closely related bacterial strains made available by deep sequencing, it is now possible to investigate trends in prokaryotic microevolution. Positive selection is a sub-process of microevolution, in which a particular mutation is favored, causing the allele frequency to continuously shift in one direction. Wide scanning of prokaryotic genomes has shown that positive selection at the molecular level is much more frequent than expected. Genes with significant positive selection may play key roles in bacterial adaption to different environmental pressures. However, selection pressure analyses are computationally intensive and awkward to configure. Here we describe an open access web server, which is designated as PSP (Positive Selection analysis for Prokaryotic genomes) for performing evolutionary analysis on orthologous coding genes, specially designed for rapid comparison of dozens of closely related prokaryotic genomes. Remarkably, PSP facilitates functional exploration at the multiple levels by assignments and enrichments of KO, GO or COG terms. To illustrate this user-friendly tool, we analyzed Escherichia coli and Bacillus cereus genomes and found that several genes, which play key roles in human infection and antibiotic resistance, show significant evidence of positive selection. PSP is freely available to all users without any login requirement at: http://db-mml.sjtu.edu.cn/PSP/. PSP ultimately allows researchers to do genome-scale analysis for evolutionary selection across multiple prokaryotic genomes rapidly and easily, and identify the genes undergoing positive selection, which may play key roles in the interactions of host-pathogen and/or environmental adaptation.

  19. Exploring evidence of positive selection signatures in cattle breeds selected for different traits.

    PubMed

    Taye, Mengistie; Lee, Wonseok; Jeon, Soomin; Yoon, Joon; Dessie, Tadelle; Hanotte, Olivier; Mwai, Okeyo Ally; Kemp, Stephen; Cho, Seoae; Oh, Sung Jong; Lee, Hak-Kyo; Kim, Heebal

    2017-09-13

    Since domestication, the genome landscape of cattle has been changing due to natural and artificial selection forces resulting in several general and specialized cattle breeds of the world. Identifying genomic regions affected due to these forces in livestock gives an insight into the history of selection for economically important traits and genetic adaptation to specific environments of the populations under consideration. This study explores the genes/genomic regions under selection in relation to the phenotypes of Holstein, Hanwoo, and N'Dama cattle breeds using Tajima's D, XP-CLR, and XP-EHH population statistical methods. The whole genomes of 10 Holstein (South Korea), 11 Hanwoo (South Korea), and 10 N'Dama (West Africa-Guinea) cattle breeds re-sequenced to ~11x coverage and retained 37 million SNPs were used for the study. Selection signature analysis revealed 441, 512, and 461 genes under selection from Holstein, Hanwoo, and N'Dama cattle breeds, respectively. Among all these, seven genes including ARFGAP3, SNORA70, and other RNA genes were common between the breeds. From each of the gene lists, significant functional annotation cluster terms including milk protein and thyroid hormone signaling pathway (Holstein), histone acetyltransferase activity (Hanwoo), and renin secretion (N'Dama) were enriched. Genes that are related to the phenotypes of the respective breeds were also identified. Moreover, significant breed-specific missense variants were identified in CSN3, PAPPA2 (Holstein), C1orf116 (Hanwoo), and COMMD1 (N'Dama) genes. The genes identified from this study provide an insight into the biological mechanisms and pathways that are important in cattle breeds selected for different traits of economic significance.

  20. Identification of positive selection in disease response genes within members of the Poaceae.

    PubMed

    Rech, Gabriel E; Vargas, Walter A; Sukno, Serenella A; Thon, Michael R

    2012-12-01

    Millions of years of coevolution between plants and pathogens can leave footprints on their genomes and genes involved on this interaction are expected to show patterns of positive selection in which novel, beneficial alleles are rapidly fixed within the population. Using information about upregulated genes in maize during Colletotrichum graminicola infection and resources available in the Phytozome database, we looked for evidence of positive selection in the Poaceae lineage, acting on protein coding sequences related with plant defense. We found six genes with evidence of positive selection and another eight with sites showing episodic selection. Some of them have already been described as evolving under positive selection, but others are reported here for the first time including genes encoding isocitrate lyase, dehydrogenases, a multidrug transporter, a protein containing a putative leucine-rich repeat and other proteins with unknown functions. Mapping positively selected residues onto the predicted 3-D structure of proteins showed that most of them are located on the surface, where proteins are in contact with other molecules. We present here a set of Poaceae genes that are likely to be involved in plant defense mechanisms and have evidence of positive selection. These genes are excellent candidates for future functional validation.

  1. Identification of positive selection in disease response genes within members of the Poaceae

    PubMed Central

    Rech, Gabriel E.; Vargas, Walter A.; Sukno, Serenella A.; Thon, Michael R.

    2012-01-01

    Millions of years of coevolution between plants and pathogens can leave footprints on their genomes and genes involved on this interaction are expected to show patterns of positive selection in which novel, beneficial alleles are rapidly fixed within the population. Using information about upregulated genes in maize during Colletotrichum graminicola infection and resources available in the Phytozome database, we looked for evidence of positive selection in the Poaceae lineage, acting on protein coding sequences related with plant defense. We found six genes with evidence of positive selection and another eight with sites showing episodic selection. Some of them have already been described as evolving under positive selection, but others are reported here for the first time including genes encoding isocitrate lyase, dehydrogenases, a multidrug transporter, a protein containing a putative leucine-rich repeat and other proteins with unknown functions. Mapping positively selected residues onto the predicted 3-D structure of proteins showed that most of them are located on the surface, where proteins are in contact with other molecules. We present here a set of Poaceae genes that are likely to be involved in plant defense mechanisms and have evidence of positive selection. These genes are excellent candidates for future functional validation. PMID:23073005

  2. Genome-wide signals of positive selection in strongylocentrotid sea urchins.

    PubMed

    Kober, Kord M; Pogson, Grant H

    2017-07-21

    Comparative genomics studies investigating the signals of positive selection among groups of closely related species are still rare and limited in taxonomic breadth. Such studies show great promise in advancing our knowledge about the proportion and the identity of genes experiencing diversifying selection. However, methodological challenges have led to high levels of false positives in past studies. Here, we use the well-annotated genome of the purple sea urchin, Strongylocentrotus purpuratus, as a reference to investigate the signals of positive selection at 6520 single-copy orthologs from nine sea urchin species belonging to the family Strongylocentrotidae paying careful attention to minimizing false positives. We identified 1008 (15.5%) candidate positive selection genes (PSGs). Tests for positive selection along the nine terminal branches of the phylogeny identified 824 genes that showed lineage-specific adaptive diversification (1.67% of branch-sites tests performed). Positively selected codons were not enriched at exon borders or near regions containing missing data, suggesting a limited contribution of false positives caused by alignment or annotation errors. Alignments were validated at 10 loci with re-sequencing using Sanger methods. No differences were observed in the rates of synonymous substitution (d S), GC content, and codon bias between the candidate PSGs and those not showing positive selection. However, the candidate PSGs had 68% higher rates of nonsynonymous substitution (d N) and 33% lower levels of heterozygosity, consistent with selective sweeps and opposite to that expected by a relaxation of selective constraint. Although positive selection was identified at reproductive proteins and innate immunity genes, the strongest signals of adaptive diversification were observed at extracellular matrix proteins, cell adhesion molecules, membrane receptors, and ion channels. Many candidate PSGs have been widely implicated as targets of pathogen binding

  3. More genes underwent positive selection in chimpanzee evolution than in human evolution

    PubMed Central

    Bakewell, Margaret A.; Shi, Peng; Zhang, Jianzhi

    2007-01-01

    Observations of numerous dramatic and presumably adaptive phenotypic modifications during human evolution prompt the common belief that more genes have undergone positive Darwinian selection in the human lineage than in the chimpanzee lineage since their evolutionary divergence 6–7 million years ago. Here, we test this hypothesis by analyzing nearly 14,000 genes of humans and chimps. To ensure an accurate and unbiased comparison, we select a proper outgroup, avoid sequencing errors, and verify statistical methods. Our results show that the number of positively selected genes is substantially smaller in humans than in chimps, despite a generally higher nonsynonymous substitution rate in humans. These observations are explainable by the reduced efficacy of natural selection in humans because of their smaller long-term effective population size but refute the anthropocentric view that a grand enhancement in Darwinian selection underlies human origins. Although human and chimp positively selected genes have different molecular functions and participate in different biological processes, the differences do not ostensibly correspond to the widely assumed adaptations of these species, suggesting how little is currently known about which traits have been under positive selection. Our analysis of the identified positively selected genes lends support to the association between human Mendelian diseases and past adaptations but provides no evidence for either the chromosomal speciation hypothesis or the widespread brain-gene acceleration hypothesis of human origins. PMID:17449636

  4. On the Choice of Access Point Selection Criterion and Other Position Estimation Characteristics for WLAN-Based Indoor Positioning

    PubMed Central

    Laitinen, Elina; Lohan, Elena Simona

    2016-01-01

    The positioning based on Wireless Local Area Networks (WLAN) is one of the most promising technologies for indoor location-based services, generally using the information carried by Received Signal Strengths (RSS). One challenge, however, is the huge amount of data in the radiomap database due to the enormous number of hearable Access Points (AP) that could make the positioning system very complex. This paper concentrates on WLAN-based indoor location by comparing fingerprinting, path loss and weighted centroid based positioning approaches in terms of complexity and performance and studying the effects of grid size and AP reduction with several choices for appropriate selection criterion. All results are based on real field measurements in three multi-floor buildings. We validate our earlier findings concerning several different AP selection criteria and conclude that the best results are obtained with a maximum RSS-based criterion, which also proved to be the most consistent among the different investigated approaches. We show that the weighted centroid based low-complexity method is very sensitive to AP reduction, while the path loss-based method is also very robust to high percentage removals. Indeed, for fingerprinting, 50% of the APs can be removed safely with a properly chosen removal criterion without increasing the positioning error much. PMID:27213395

  5. Isolating "Unknown" Bacteria in the Introductory Microbiology Laboratory: A New Selective Medium for Gram-Positives.

    ERIC Educational Resources Information Center

    McKillip, John L.; Drake, MaryAnne

    1999-01-01

    Describes the development, preparation, and use of a medium that can select against a wide variety of Gram-negative bacteria while still allowing growth and differentiation of a wide range of Gram-positives. (WRM)

  6. Isolating "Unknown" Bacteria in the Introductory Microbiology Laboratory: A New Selective Medium for Gram-Positives.

    ERIC Educational Resources Information Center

    McKillip, John L.; Drake, MaryAnne

    1999-01-01

    Describes the development, preparation, and use of a medium that can select against a wide variety of Gram-negative bacteria while still allowing growth and differentiation of a wide range of Gram-positives. (WRM)

  7. Recent Positive Selection in Genes of the Mammalian Epidermal Differentiation Complex Locus

    PubMed Central

    Goodwin, Zane A.; de Guzman Strong, Cristina

    2017-01-01

    The epidermal differentiation complex (EDC) is the most rapidly evolving locus in the human genome compared to that of the chimpanzee. Yet the EDC genes that are undergoing positive selection across mammals and in humans are not known. We sought to identify the positively selected genetic variants and determine the evolutionary events of the EDC using mammalian-wide and clade-specific branch- and branch-site likelihood ratio tests and a genetic algorithm (GA) branch test. Significant non-synonymous substitutions were found in filaggrin, SPRR4, LELP1, and S100A2 genes across 14 mammals. By contrast, we identified recent positive selection in SPRR4 in primates. Additionally, the GA branch test discovered lineage-specific evolution for distinct EDC genes occurring in each of the nodes in the 14-mammal phylogenetic tree. Multiple instances of positive selection for FLG, TCHHL1, SPRR4, LELP1, and S100A2 were noted among the primate branch nodes. Branch-site likelihood ratio tests further revealed positive selection in specific sites in SPRR4, LELP1, filaggrin, and repetin across 14 mammals. However, in addition to continuous evolution of SPRR4, site-specific positive selection was also found in S100A11, KPRP, SPRR1A, S100A7L2, and S100A3 in primates and filaggrin, filaggrin2, and S100A8 in great apes. Very recent human positive selection was identified in the filaggrin2 L41 site that was present in Neanderthal. Together, our results identifying recent positive selection in distinct EDC genes reveal an underappreciated evolution of epidermal skin barrier function in primates and humans. PMID:28119736

  8. Recent Positive Selection in Genes of the Mammalian Epidermal Differentiation Complex Locus.

    PubMed

    Goodwin, Zane A; de Guzman Strong, Cristina

    2016-01-01

    The epidermal differentiation complex (EDC) is the most rapidly evolving locus in the human genome compared to that of the chimpanzee. Yet the EDC genes that are undergoing positive selection across mammals and in humans are not known. We sought to identify the positively selected genetic variants and determine the evolutionary events of the EDC using mammalian-wide and clade-specific branch- and branch-site likelihood ratio tests and a genetic algorithm (GA) branch test. Significant non-synonymous substitutions were found in filaggrin, SPRR4, LELP1, and S100A2 genes across 14 mammals. By contrast, we identified recent positive selection in SPRR4 in primates. Additionally, the GA branch test discovered lineage-specific evolution for distinct EDC genes occurring in each of the nodes in the 14-mammal phylogenetic tree. Multiple instances of positive selection for FLG, TCHHL1, SPRR4, LELP1, and S100A2 were noted among the primate branch nodes. Branch-site likelihood ratio tests further revealed positive selection in specific sites in SPRR4, LELP1, filaggrin, and repetin across 14 mammals. However, in addition to continuous evolution of SPRR4, site-specific positive selection was also found in S100A11, KPRP, SPRR1A, S100A7L2, and S100A3 in primates and filaggrin, filaggrin2, and S100A8 in great apes. Very recent human positive selection was identified in the filaggrin2 L41 site that was present in Neanderthal. Together, our results identifying recent positive selection in distinct EDC genes reveal an underappreciated evolution of epidermal skin barrier function in primates and humans.

  9. Positive selection neighboring functionally essential sites and disease-implicated regions of mammalian reproductive proteins

    PubMed Central

    2010-01-01

    Background Reproductive proteins are central to the continuation of all mammalian species. The evolution of these proteins has been greatly influenced by environmental pressures induced by pathogens, rival sperm, sexual selection and sexual conflict. Positive selection has been demonstrated in many of these proteins with particular focus on primate lineages. However, the mammalia are a diverse group in terms of mating habits, population sizes and germ line generation times. We have examined the selective pressures at work on a number of novel reproductive proteins across a wide variety of mammalia. Results We show that selective pressures on reproductive proteins are highly varied. Of the 10 genes analyzed in detail, all contain signatures of positive selection either across specific sites or in specific lineages or a combination of both. Our analysis of SP56 and Col1a1 are entirely novel and the results show positively selected sites present in each gene. Our findings for the Col1a1 gene are suggestive of a link between positive selection and severe disease type. We find evidence in our dataset to suggest that interacting proteins are evolving in symphony: most likely to maintain interacting functionality. Conclusion Our in silico analyses show positively selected sites are occurring near catalytically important regions suggesting selective pressure to maximize efficient fertilization. In those cases where a mechanism of protein function is not fully understood, the sites presented here represent ideal candidates for mutational study. This work has highlighted the widespread rate heterogeneity in mutational rates across the mammalia and specifically has shown that the evolution of reproductive proteins is highly varied depending on the species and interacting partners. We have shown that positive selection and disease are closely linked in the Col1a1 gene. PMID:20149245

  10. Widespread signatures of recent selection linked to nucleosome positioning in the human lineage.

    PubMed

    Prendergast, James G D; Semple, Colin A M

    2011-11-01

    In this study we investigated the strengths and modes of selection associated with nucleosome positioning in the human lineage through the comparison of interspecies and intraspecies rates of divergence. We identify significant evidence for both positive and negative selection linked to human nucleosome positioning for the first time, implicating a widespread and important role for DNA sequence in the location of well-positioned nucleosomes. Selection appears to be acting on particular base substitutions to maintain optimum GC compositions in core and linker regions, with, e.g., unexpectedly elevated rates of C→T substitutions during recent human evolution at linker regions 60-90 bp from the nucleosome dyad but significant depletion of the same substitutions within nucleosome core regions. These patterns are strikingly consistent with the known relationships between genomic sequence composition and nucleosome assembly. By stratifying nucleosomes according to the GC content of their genomic neighborhood, we also show that the strength and direction of selection detected is dictated by local GC content. Intriguingly these signatures of selection are not restricted to nucleosomes in close proximity to exons, suggesting the correct positioning of nucleosomes is not only important in and around coding regions. This analysis provides strong evidence that the genomic sequences associated with nucleosomes are not evolving neutrally, and suggests that underlying DNA sequence is an important factor in nucleosome positioning. Recent signatures of selection linked to genomic features as ubiquitous as the nucleosome have important implications for human genome evolution and disease.

  11. HDAC3 Is Required for the Downregulation of RORγt during Thymocyte Positive Selection.

    PubMed

    Philips, Rachael L; Chen, Meibo W; McWilliams, Douglas C; Belmonte, Paul J; Constans, Megan M; Shapiro, Virginia Smith

    2016-07-15

    To generate functional peripheral T cells, proper gene regulation during T cell development is critical. In this study, we found that histone deacetylase (HDAC) 3 is required for T cell development. T cell development in CD2-icre HDAC3 conditional knockout (cKO) mice (HDAC3-cKO) was blocked at positive selection, resulting in few CD4 and CD8 T cells, and it could not be rescued by a TCR transgene. These single-positive thymocytes failed to upregulate Bcl-2, leading to increased apoptosis. HDAC3-cKO mice failed to downregulate retinoic acid-related orphan receptor (ROR) γt during positive selection, similar to the block in positive selection in RORγt transgenic mice. In the absence of HDAC3, the RORC promoter was hyperacetylated. In the periphery, the few CD4 T cells present were skewed toward RORγt(+) IL-17-producing Th17 cells, leading to inflammatory bowel disease. Positive selection of CD8 single-positive thymocytes was restored in RORγt-KO Bcl-xL transgenic HDAC3-cKO mice, demonstrating that HDAC3 is required at positive selection to downregulate RORγt.

  12. Positive Darwinian selection at single amino acid sites conferring plant virus resistance

    USDA-ARS?s Scientific Manuscript database

    Explicit evaluation of the accuracy and power of Maximum Likelihood and Bayesian methods for detecting site-specific positive Darwinian selection presents a challenge because selective consequences of single amino acid changes are generally unknown. We exploit extensive molecular and functional cha...

  13. Continental-Scale Footprint of Balancing and Positive Selection in a Small Rodent (Microtus arvalis)

    PubMed Central

    Fischer, Martin C.; Foll, Matthieu; Heckel, Gerald; Excoffier, Laurent

    2014-01-01

    Genetic adaptation to different environmental conditions is expected to lead to large differences between populations at selected loci, thus providing a signature of positive selection. Whereas balancing selection can maintain polymorphisms over long evolutionary periods and even geographic scale, thus leads to low levels of divergence between populations at selected loci. However, little is known about the relative importance of these two selective forces in shaping genomic diversity, partly due to difficulties in recognizing balancing selection in species showing low levels of differentiation. Here we address this problem by studying genomic diversity in the European common vole (Microtus arvalis) presenting high levels of differentiation between populations (average FST = 0.31). We studied 3,839 Amplified Fragment Length Polymorphism (AFLP) markers genotyped in 444 individuals from 21 populations distributed across the European continent and hence over different environmental conditions. Our statistical approach to detect markers under selection is based on a Bayesian method specifically developed for AFLP markers, which treats AFLPs as a nearly codominant marker system, and therefore has increased power to detect selection. The high number of screened populations allowed us to detect the signature of balancing selection across a large geographic area. We detected 33 markers potentially under balancing selection, hence strong evidence of stabilizing selection in 21 populations across Europe. However, our analyses identified four-times more markers (138) being under positive selection, and geographical patterns suggest that some of these markers are probably associated with alpine regions, which seem to have environmental conditions that favour adaptation. We conclude that despite favourable conditions in this study for the detection of balancing selection, this evolutionary force seems to play a relatively minor role in shaping the genomic diversity of the

  14. Continental-scale footprint of balancing and positive selection in a small rodent (Microtus arvalis).

    PubMed

    Fischer, Martin C; Foll, Matthieu; Heckel, Gerald; Excoffier, Laurent

    2014-01-01

    Genetic adaptation to different environmental conditions is expected to lead to large differences between populations at selected loci, thus providing a signature of positive selection. Whereas balancing selection can maintain polymorphisms over long evolutionary periods and even geographic scale, thus leads to low levels of divergence between populations at selected loci. However, little is known about the relative importance of these two selective forces in shaping genomic diversity, partly due to difficulties in recognizing balancing selection in species showing low levels of differentiation. Here we address this problem by studying genomic diversity in the European common vole (Microtus arvalis) presenting high levels of differentiation between populations (average F ST = 0.31). We studied 3,839 Amplified Fragment Length Polymorphism (AFLP) markers genotyped in 444 individuals from 21 populations distributed across the European continent and hence over different environmental conditions. Our statistical approach to detect markers under selection is based on a Bayesian method specifically developed for AFLP markers, which treats AFLPs as a nearly codominant marker system, and therefore has increased power to detect selection. The high number of screened populations allowed us to detect the signature of balancing selection across a large geographic area. We detected 33 markers potentially under balancing selection, hence strong evidence of stabilizing selection in 21 populations across Europe. However, our analyses identified four-times more markers (138) being under positive selection, and geographical patterns suggest that some of these markers are probably associated with alpine regions, which seem to have environmental conditions that favour adaptation. We conclude that despite favourable conditions in this study for the detection of balancing selection, this evolutionary force seems to play a relatively minor role in shaping the genomic diversity of the

  15. The role of positive selection in determining the molecular cause of species differences in disease

    PubMed Central

    2008-01-01

    Background Related species, such as humans and chimpanzees, often experience the same disease with varying degrees of pathology, as seen in the cases of Alzheimer's disease, or differing symptomatology as in AIDS. Furthermore, certain diseases such as schizophrenia, epithelial cancers and autoimmune disorders are far more frequent in humans than in other species for reasons not associated with lifestyle. Genes that have undergone positive selection during species evolution are indicative of functional adaptations that drive species differences. Thus we investigate whether biomedical disease differences between species can be attributed to positively selected genes. Results We identified genes that putatively underwent positive selection during the evolution of humans and four mammals which are often used to model human diseases (mouse, rat, chimpanzee and dog). We show that genes predicted to have been subject to positive selection pressure during human evolution are implicated in diseases such as epithelial cancers, schizophrenia, autoimmune diseases and Alzheimer's disease, all of which differ in prevalence and symptomatology between humans and their mammalian relatives. In agreement with previous studies, the chimpanzee lineage was found to have more genes under positive selection than any of the other lineages. In addition, we found new evidence to support the hypothesis that genes that have undergone positive selection tend to interact with each other. This is the first such evidence to be detected widely among mammalian genes and may be important in identifying molecular pathways causative of species differences. Conclusion Our dataset of genes predicted to have been subject to positive selection in five species serves as an informative resource that can be consulted prior to selecting appropriate animal models during drug target validation. We conclude that studying the evolution of functional and biomedical disease differences between species is an

  16. Nonstructural Proteins Are Preferential Positive Selection Targets in Zika Virus and Related Flaviviruses.

    PubMed

    Sironi, Manuela; Forni, Diego; Clerici, Mario; Cagliani, Rachele

    2016-09-01

    The Flavivirus genus comprises several human pathogens such as dengue virus (DENV), Japanese encephalitis virus (JEV), and Zika virus (ZIKV). Although ZIKV usually causes mild symptoms, growing evidence is linking it to congenital birth defects and to increased risk of Guillain-Barré syndrome. ZIKV encodes a polyprotein that is processed to produce three structural and seven nonstructural (NS) proteins. We investigated the evolution of the viral polyprotein in ZIKV and in related flaviviruses (DENV, Spondweni virus, and Kedougou virus). After accounting for saturation issues, alignment uncertainties, and recombination, we found evidence of episodic positive selection on the branch that separates DENV from the other flaviviruses. NS1 emerged as the major selection target, and selected sites were located in immune epitopes or in functionally important protein regions. Three of these sites are located in an NS1 region that interacts with structural proteins and is essential for virion biogenesis. Analysis of the more recent evolutionary history of ZIKV lineages indicated that positive selection acted on NS5 and NS4B, this latter representing the preferential target. All selected sites were located in the N-terminal portion of NS4B, which inhibits interferon response. One of the positively selected sites (26M/I/T/V) in ZIKV also represents a selection target in sylvatic DENV2 isolates, and a nearby residue evolves adaptively in JEV. Two additional positively selected sites are within a protein region that interacts with host (e.g. STING) and viral (i.e. NS1, NS4A) proteins. Notably, mutations in the NS4B region of other flaviviruses modulate neurovirulence and/or neuroinvasiveness. These results suggest that the positively selected sites we identified modulate viral replication and contribute to immune evasion. These sites should be prioritized in future experimental studies. However, analyses herein detected no selective events associated to the spread of the Asian

  17. Nonstructural Proteins Are Preferential Positive Selection Targets in Zika Virus and Related Flaviviruses

    PubMed Central

    Sironi, Manuela; Forni, Diego; Clerici, Mario; Cagliani, Rachele

    2016-01-01

    The Flavivirus genus comprises several human pathogens such as dengue virus (DENV), Japanese encephalitis virus (JEV), and Zika virus (ZIKV). Although ZIKV usually causes mild symptoms, growing evidence is linking it to congenital birth defects and to increased risk of Guillain-Barré syndrome. ZIKV encodes a polyprotein that is processed to produce three structural and seven nonstructural (NS) proteins. We investigated the evolution of the viral polyprotein in ZIKV and in related flaviviruses (DENV, Spondweni virus, and Kedougou virus). After accounting for saturation issues, alignment uncertainties, and recombination, we found evidence of episodic positive selection on the branch that separates DENV from the other flaviviruses. NS1 emerged as the major selection target, and selected sites were located in immune epitopes or in functionally important protein regions. Three of these sites are located in an NS1 region that interacts with structural proteins and is essential for virion biogenesis. Analysis of the more recent evolutionary history of ZIKV lineages indicated that positive selection acted on NS5 and NS4B, this latter representing the preferential target. All selected sites were located in the N-terminal portion of NS4B, which inhibits interferon response. One of the positively selected sites (26M/I/T/V) in ZIKV also represents a selection target in sylvatic DENV2 isolates, and a nearby residue evolves adaptively in JEV. Two additional positively selected sites are within a protein region that interacts with host (e.g. STING) and viral (i.e. NS1, NS4A) proteins. Notably, mutations in the NS4B region of other flaviviruses modulate neurovirulence and/or neuroinvasiveness. These results suggest that the positively selected sites we identified modulate viral replication and contribute to immune evasion. These sites should be prioritized in future experimental studies. However, analyses herein detected no selective events associated to the spread of the Asian

  18. Population differentiation as an indicator of recent positive selection in humans: an empirical evaluation.

    PubMed

    Xue, Yali; Zhang, Xuelong; Huang, Ni; Daly, Allan; Gillson, Christopher J; Macarthur, Daniel G; Yngvadottir, Bryndis; Nica, Alexandra C; Woodwark, Cara; Chen, Yuan; Conrad, Donald F; Ayub, Qasim; Mehdi, S Qasim; Li, Pu; Tyler-Smith, Chris

    2009-11-01

    We have evaluated the extent to which SNPs identified by genomewide surveys as showing unusually high levels of population differentiation in humans have experienced recent positive selection, starting from a set of 32 nonsynonymous SNPs in 27 genes highlighted by the HapMap1 project. These SNPs were genotyped again in the HapMap samples and in the Human Genome Diversity Project-Centre d'Etude du Polymorphisme Humain (HGDP-CEPH) panel of 52 populations representing worldwide diversity; extended haplotype homozygosity was investigated around all of them, and full resequence data were examined for 9 genes (5 from public sources and 4 from new data sets). For 7 of the genes, genotyping errors were responsible for an artifactual signal of high population differentiation and for 2, the population differentiation did not exceed our significance threshold. For the 18 genes with confirmed high population differentiation, 3 showed evidence of positive selection as measured by unusually extended haplotypes within a population, and 7 more did in between-population analyses. The 9 genes with resequence data included 7 with high population differentiation, and 5 showed evidence of positive selection on the haplotype carrying the nonsynonymous SNP from skewed allele frequency spectra; in addition, 2 showed evidence of positive selection on unrelated haplotypes. Thus, in humans, high population differentiation is (apart from technical artifacts) an effective way of enriching for recently selected genes, but is not an infallible pointer to recent positive selection supported by other lines of evidence.

  19. T cell positive selection by a high density, low affinity ligand

    PubMed Central

    Liu, Chih-Pin; Crawford, Frances; Marrack, Philippa; Kappler, John

    1998-01-01

    Interaction of the αβ T cell receptor (TCR) with major histocompatibility (MHC) molecules occupied with any of a large collection of peptides derived from self proteins is a critical step in driving T cell “positive” selection in the thymus. Interaction with this same pool of self-peptide/MHC ligands deletes T cells with potential self-reactivity. To examine how T cells survive both of these processes to form a self-tolerant mature repertoire, mice were constructed whose entire class II MHC IEk specific repertoire was positively selected on a single peptide covalently attached to the IEk molecule. In these mice T cells were identified that could respond to a variant of the positively selecting peptide bound to IEk. The affinities of the TCRs from these T cells for the positively selecting ligand were extremely low and at least 10-fold less than those for the activating ligand. These results support the theory that positive selection is driven by TCR affinities lower than those involved in T cell deletion or activation and that, if present at high concentration, even very low affinity ligands can positively select. PMID:9539770

  20. Gasp, a Grb2-associating protein, is critical for positive selection of thymocytes

    PubMed Central

    Patrick, Michael S.; Oda, Hiroyo; Hayakawa, Kunihiro; Sato, Yoshinori; Eshima, Koji; Kirikae, Teruo; Iemura, Shun-ichiro; Shirai, Mutsunori; Abe, Takaya; Natsume, Tohru; Sasazuki, Takehiko; Suzuki, Harumi

    2009-01-01

    T cells develop in the thymus through positive and negative selection, which are responsible for shaping the T cell receptor (TCR) repertoire. To elucidate the molecular mechanisms involved in selection remains an area of intense interest. Here, we identified and characterized a gene product Gasp (Grb2-associating protein, also called Themis) that is critically required for positive selection. Gasp is a cytosolic protein with no known functional motifs that is expressed only in T cells, especially immature CD4/CD8 double positive (DP) thymocytes. In the absence of Gasp, differentiation of both CD4 and CD8 single positive cells in the thymus was severely inhibited, whereas all other TCR-induced events such as β-selection, negative selection, peripheral activation, and homeostatic proliferation were unaffected. We found that Gasp constitutively associates with Grb2 via its N-terminal Src homology 3 domain, suggesting that Gasp acts as a thymocyte-specific adaptor for Grb2 or regulates Ras signaling in DP thymocytes. Collectively, we have described a gene called Gasp that is critical for positive selection. PMID:19805304

  1. Voluntary strategy suppresses the positive impact of preferential selection in prisoner’s dilemma

    NASA Astrophysics Data System (ADS)

    Sun, Lei; Lin, Pei-jie; Chen, Ya-shan

    2014-11-01

    Impact of aspiration is ubiquitous in social and biological disciplines. In this work, we try to explore the impact of such a trait on voluntary prisoners’ dilemma game via a selection parameter w. w=0 returns the traditional version of random selection. For positive w, the opponent of high payoff will be selected; while negative w means that the partner of low payoff will be chosen. We find that for positive w, cooperation will be greatly promoted in the interval of small b, at variance cooperation is inhibited with large b. For negative w, cooperation is fully restrained, irrespective of b value. It is found that the positive impact of preferential selection is suppressed by the voluntary strategy in prisoner’s dilemma. These observations can be supported by the spatial patterns. Our work may shed light on the emergence and persistence of cooperation with voluntary participation in social dilemma.

  2. Positive selection drives accelerated evolution of mosquito salivary genes associated with blood-feeding

    PubMed Central

    Arcà, Bruno; Struchiner, Cláudio J.; Pham, Van M.; Sferra, Gabriella; Lombardo, Fabrizio; Pombi, Marco; Ribeiro, José M. C.

    2013-01-01

    Saliva of bloodsucking animals contains dozens to hundreds of proteins that counteract their hosts’ hemostasis, inflammation, and immunity. It was previously observed that salivary proteins involved in hematophagy are much more divergent in their primary sequence than those of housekeeping function, when comparisons were made between closely related organisms. While this pattern of evolution could result from relaxed selection or drift, it could alternatively be the result of positive selection driven by the intense pressure of the host immune system. We investigated the polymorphism of five different genes associated with blood feeding in the mosquito Anopheles gambiae and obtained evidence in four genes for sites with signatures of positive selection. These results add salivary gland genes from bloodsucking arthropods to the small list of genes driven by positive selection. PMID:24237399

  3. dbPSHP: a database of recent positive selection across human populations.

    PubMed

    Li, Mulin Jun; Wang, Lily Yan; Xia, Zhengyuan; Wong, Maria P; Sham, Pak Chung; Wang, Junwen

    2014-01-01

    The dbPSHP database (http://jjwanglab.org/dbpshp) aims to help researchers to efficiently identify, validate and visualize putative positively selected loci in human evolution and further discover the mechanism governing these natural selections. Recent evolution of human populations at the genomic level reflects the adaptations to the living environments, including climate change and availability and stability of nutrients. Many genetic regions under positive selection have been identified, which assist us to understand how natural selection has shaped population differences. Here, we manually collect recent positive selections in different human populations, consisting of 15,472 loci from 132 publications. We further compiled a database that used 15 statistical terms of different evolutionary attributes for single nucleotide variant sites from the HapMap 3 and 1000 Genomes Project to identify putative regions under positive selection. These attributes include variant allele/genotype properties, variant heterozygosity, within population diversity, long-range haplotypes, pairwise population differentiation and evolutionary conservation. We also provide interactive pages for visualization and annotation of different selective signals. The database is freely available to the public and will be frequently updated.

  4. Determination of Azimuth Angle at Burnout for Placing a Satellite Over a Selected Earth Position

    NASA Technical Reports Server (NTRS)

    Skopinski, T. H.; Johnson, Katherine G.

    1960-01-01

    Expressions are presented for relating the satellite position in the orbital plane with the projected latitude and longitude on a rotating earth surface. An expression is also presented for determining the azimuth angle at a given burnout position on the basis of a selected passage position on the earth's surface. Examples are presented of a satellite launched eastward and one launched westward, each passing over a selected position sometime after having completed three orbits. Incremental changes from the desired latitude and longitude due to the earth's oblateness are included in the iteration for obtaining the azimuth angles of the two examples. The results for both cases are then compared with those obtained from a computing program using an oblate rotating earth. Changes from the selected latitude and longitude resulting from incremental changes from the burn-out azimuth angle and latitude are also analyzed.

  5. Positive Evolutionary Selection On the RIG-I-Like Receptor Genes in Mammals

    PubMed Central

    Lemos de Matos, Ana; McFadden, Grant; Esteves, Pedro J.

    2013-01-01

    The mammalian RIG-I-like receptors, RIG-I, MDA5 and LGP2, are a family of DExD/H box RNA helicases responsible for the cytoplasmic detection of viral RNA. These receptors detect a variety of RNA viruses, or DNA viruses that express unusual RNA species, many of which are responsible for a great number of severe and lethal diseases. Host innate sentinel proteins involved in pathogen recognition must rapidly evolve in a dynamic arms race with pathogens, and thus are subjected to long-term positive selection pressures to avoid potential infections. Using six codon-based Maximum Likelihood methods, we were able to identify specific codons under positive selection in each of these three genes. The highest number of positively selected codons was detected in MDA5, but a great percentage of these codons were located outside of the currently defined protein domains for MDA5, which likely reflects the imposition of both functional and structural constraints. Additionally, our results support LGP2 as being the least prone to evolutionary change, since the lowest number of codons under selection was observed for this gene. On the other hand, the preponderance of positively selected codons for RIG-I were detected in known protein functional domains, suggesting that pressure has been imposed by the vast number of viruses that are recognized by this RNA helicase. Furthermore, the RIG-I repressor domain, the region responsible for recognizing and binding to its RNA substrates, exhibited the strongest evidence of selective pressures. Branch-site analyses were performed and several species branches on the three receptor gene trees showed evidence of episodic positive selection. In conclusion, by looking for evidence of positive evolutionary selection on mammalian RIG-I-like receptor genes, we propose that a multitude of viruses have crafted the receptors biological function in host defense, specifically for the RIG-I gene, contributing to the innate species-specific resistance

  6. Widespread signatures of positive selection in common risk alleles associated to autism spectrum disorder

    PubMed Central

    2017-01-01

    The human brain is the outcome of innumerable evolutionary processes; the systems genetics of psychiatric disorders could bear their signatures. On this basis, we analyzed five psychiatric disorders, attention deficit hyperactivity disorder, autism spectrum disorder (ASD), bipolar disorder, major depressive disorder, and schizophrenia (SCZ), using GWAS summary statistics from the Psychiatric Genomics Consortium. Machine learning-derived scores were used to investigate two natural-selection scenarios: complete selection (loci where a selected allele reached fixation) and incomplete selection (loci where a selected allele has not yet reached fixation). ASD GWAS results positively correlated with incomplete-selection (p = 3.53*10−4). Variants with ASD GWAS p<0.1 were shown to have a 19%-increased probability to be in the top-5% for incomplete-selection score (OR = 1.19, 95%CI = 1.11–1.8, p = 9.56*10−7). Investigating the effect directions of minor alleles, we observed an enrichment for positive associations in SNPs with ASD GWAS p<0.1 and top-5% incomplete-selection score (permutation p<10−4). Considering the set of these ASD-positive-associated variants, we observed gene-expression enrichments for brain and pituitary tissues (p = 2.3*10−5 and p = 3*10−5, respectively) and 53 gene ontology (GO) enrichments, such as nervous system development (GO:0007399, p = 7.57*10−12), synapse organization (GO:0050808, p = 8.29*10−7), and axon guidance (GO:0007411, p = 1.81*10−7). Previous genetic studies demonstrated that ASD positively correlates with childhood intelligence, college completion, and years of schooling. Accordingly, we hypothesize that certain ASD risk alleles were under positive selection during human evolution due to their involvement in neurogenesis and cognitive ability. PMID:28187187

  7. Positive selection underlies the species-specific binding of Plasmodium falciparum RH5 to human basigin.

    PubMed

    Forni, Diego; Pontremoli, Chiara; Cagliani, Rachele; Pozzoli, Uberto; Clerici, Mario; Sironi, Manuela

    2015-09-01

    Plasmodium falciparum, the causative agent of the deadliest form of malaria, is a member of the Laverania subgenus, which includes ape-infecting parasites. P. falciparum is thought to have originated in gorillas, although infection is now restricted to humans. Laverania parasites display remarkable host-specificity, which is partially mediated by the interaction between parasite ligands and host receptors. We analyse the evolution of BSG (basigin) and GYPA (glycophorin A) in primates/hominins, as well as of their Plasmodium-encoded ligands, PfRH5 and PfEBA175. We show that, in primates, positive selection targeted two sites in BSG (F27 and H102), both involved in PfRH5 binding. A population genetics-phylogenetics approach detected the strongest selection for the gorilla lineage: one of the positively selected sites (K191) is a major determinant of PfRH5 binding affinity. Analysis of RH5 genes indicated episodic selection on the P. falciparum branch; the positively selected W447 site is known to stabilize the interaction with human basigin. Conversely, we detect no selection in the receptor-binding region of EBA175 in the P. falciparum lineage. Its host receptor, GYPA, shows evidence of positive selection in all hominid lineages; selected codons include glycosylation sites that modulate PfEBA175 binding affinity. Data herein provide an evolutionary explanation for species-specific binding of the PfRH5-BSG ligand-receptor pair and support the hypothesis that positive selection at these genes drove the host shift leading to the emergence of P. falciparum as a human pathogen. © 2015 John Wiley & Sons Ltd.

  8. Evidence for positive selection in the gene fruitless in Anastrepha fruit flies

    PubMed Central

    2010-01-01

    Background Many genes involved in the sex determining cascade have indicated signals of positive selection and rapid evolution across different species. Even though fruitless is an important gene involved mostly in several aspects of male courtship behavior, the few studies so far have explained its high rates of evolution by relaxed selective constraints. This would indicate that a large portion of this gene has evolved neutrally, contrary to what has been observed for other genes in the sex cascade. Results Here we test whether the fruitless gene has evolved neutrally or under positive selection in species of Anastrepha (Tephritidae: Diptera) using two different approaches, a long-term evolutionary analysis and a populational genetic data analysis. The first analysis was performed by using sequences of three species of Anastrepha and sequences from several species of Drosophila using the ratio of nonsynonymous to synonymous rates of evolution in PAML, which revealed that the fru region here studied has evolved by positive selection. Using Bayes Empirical Bayes we estimated that 16 sites located in the connecting region of the fruitless gene were evolving under positive selection. We also investigated for signs of this positive selection using populational data from 50 specimens from three species of Anastrepha from different localities in Brazil. The use of standard tests of selection and a new test that compares patterns of differential survival between synonymous and nonsynonymous in evolutionary time also provide evidence of positive selection across species and of a selective sweep for one of the species investigated. Conclusions Our data indicate that the high diversification of fru connecting region in Anastrepha flies is due at least in part to positive selection, not merely as a consequence of relaxed selective constraint. These conclusions are based not only on the comparison of distantly related taxa that show long-term divergence time, but also on

  9. A Novel Method for Optimum Global Positioning System Satellite Selection Based on a Modified Genetic Algorithm

    PubMed Central

    Song, Jiancai; Xue, Guixiang; Kang, Yanan

    2016-01-01

    In this paper, a novel method for selecting a navigation satellite subset for a global positioning system (GPS) based on a genetic algorithm is presented. This approach is based on minimizing the factors in the geometric dilution of precision (GDOP) using a modified genetic algorithm (MGA) with an elite conservation strategy, adaptive selection, adaptive mutation, and a hybrid genetic algorithm that can select a subset of the satellites represented by specific numbers in the interval (4 ∼ n) while maintaining position accuracy. A comprehensive simulation demonstrates that the MGA-based satellite selection method effectively selects the correct number of optimal satellite subsets using receiver autonomous integrity monitoring (RAIM) or fault detection and exclusion (FDE). This method is more adaptable and flexible for GPS receivers, particularly for those used in handset equipment and mobile phones. PMID:26943638

  10. A Novel Method for Optimum Global Positioning System Satellite Selection Based on a Modified Genetic Algorithm.

    PubMed

    Song, Jiancai; Xue, Guixiang; Kang, Yanan

    2016-01-01

    In this paper, a novel method for selecting a navigation satellite subset for a global positioning system (GPS) based on a genetic algorithm is presented. This approach is based on minimizing the factors in the geometric dilution of precision (GDOP) using a modified genetic algorithm (MGA) with an elite conservation strategy, adaptive selection, adaptive mutation, and a hybrid genetic algorithm that can select a subset of the satellites represented by specific numbers in the interval (4 ∼ n) while maintaining position accuracy. A comprehensive simulation demonstrates that the MGA-based satellite selection method effectively selects the correct number of optimal satellite subsets using receiver autonomous integrity monitoring (RAIM) or fault detection and exclusion (FDE). This method is more adaptable and flexible for GPS receivers, particularly for those used in handset equipment and mobile phones.

  11. Weak negative and positive selection and the drift load at splice sites.

    PubMed

    Denisov, Stepan V; Bazykin, Georgii A; Sutormin, Roman; Favorov, Alexander V; Mironov, Andrey A; Gelfand, Mikhail S; Kondrashov, Alexey S

    2014-05-14

    Splice sites (SSs) are short sequences that are crucial for proper mRNA splicing in eukaryotic cells, and therefore can be expected to be shaped by strong selection. Nevertheless, in mammals and in other intron-rich organisms, many of the SSs often involve nonconsensus (Nc), rather than consensus (Cn), nucleotides, and beyond the two critical nucleotides, the SSs are not perfectly conserved between species. Here, we compare the SS sequences between primates, and between Drosophila fruit flies, to reveal the pattern of selection acting at SSs. Cn-to-Nc substitutions are less frequent, and Nc-to-Cn substitutions are more frequent, than neutrally expected, indicating, respectively, negative and positive selection. This selection is relatively weak (1 < |4Nes| < 4), and has a similar efficiency in primates and in Drosophila. Within some nucleotide positions, the positive selection in favor of Nc-to-Cn substitutions is weaker than the negative selection maintaining already established Cn nucleotides; this difference is due to site-specific negative selection favoring current Nc nucleotides. In general, however, the strength of negative selection protecting the Cn alleles is similar in magnitude to the strength of positive selection favoring replacement of Nc alleles, as expected under the simple nearly neutral turnover. In summary, although a fraction of the Nc nucleotides within SSs is maintained by selection, the abundance of deleterious nucleotides in this class suggests a substantial genome-wide drift load. © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

  12. Tracing evolutionary relicts of positive selection on eight malaria-related immune genes in mammals.

    PubMed

    Huang, Bing-Hong; Liao, Pei-Chun

    2015-07-01

    Plasmodium-induced malaria widely infects primates and other mammals. Multiple past studies have revealed that positive selection could be the main evolutionary force triggering the genetic diversity of anti-malaria resistance-associated genes in human or primates. However, researchers focused most of their attention on the infra-generic and intra-specific genome evolution rather than analyzing the complete evolutionary history of mammals. Here we extend previous research by testing the evolutionary link of natural selection on eight candidate genes associated with malaria resistance in mammals. Three of the eight genes were detected to be affected by recombination, including TNF-α, iNOS and DARC. Positive selection was detected in the rest five immunogenes multiple times in different ancestral lineages of extant species throughout the mammalian evolution. Signals of positive selection were exposed in four malaria-related immunogenes in primates: CCL2, IL-10, HO1 and CD36. However, selection signals of G6PD have only been detected in non-primate eutherians. Significantly higher evolutionary rates and more radical amino acid replacement were also detected in primate CD36, suggesting its functional divergence from other eutherians. Prevalent positive selection throughout the evolutionary trajectory of mammalian malaria-related genes supports the arms race evolutionary hypothesis of host genetic response of mammalian immunogenes to infectious pathogens.

  13. Expression Divergence Is Correlated with Sequence Evolution but Not Positive Selection in Conifers.

    PubMed

    Hodgins, Kathryn A; Yeaman, Sam; Nurkowski, Kristin A; Rieseberg, Loren H; Aitken, Sally N

    2016-06-01

    The evolutionary and genomic determinants of sequence evolution in conifers are poorly understood, and previous studies have found only limited evidence for positive selection. Using RNAseq data, we compared gene expression profiles to patterns of divergence and polymorphism in 44 seedlings of lodgepole pine (Pinus contorta) and 39 seedlings of interior spruce (Picea glauca × engelmannii) to elucidate the evolutionary forces that shape their genomes and their plastic responses to abiotic stress. We found that rapidly diverging genes tend to have greater expression divergence, lower expression levels, reduced levels of synonymous site diversity, and longer proteins than slowly diverging genes. Similar patterns were identified for the untranslated regions, but with some exceptions. We found evidence that genes with low expression levels had a larger fraction of nearly neutral sites, suggesting a primary role for negative selection in determining the association between evolutionary rate and expression level. There was limited evidence for differences in the rate of positive selection among genes with divergent versus conserved expression profiles and some evidence supporting relaxed selection in genes diverging in expression between the species. Finally, we identified a small number of genes that showed evidence of site-specific positive selection using divergence data alone. However, estimates of the proportion of sites fixed by positive selection (α) were in the range of other plant species with large effective population sizes suggesting relatively high rates of adaptive divergence among conifers.

  14. Physicochemical evolution and positive selection of the gymnosperm matK proteins.

    PubMed

    Hao, Da Cheng; Mu, Jun; Chen, Shi Lin; Xiao, Pei Gen

    2010-04-01

    It is not clear whether matK evolves under Darwinian selection. In this study, the gymnosperm Taxaceae, Cephalotaxaceae and Pinaceae were used to illustrate the physicochemical evolution, molecular adaptation and evolutionary dynamics of gene divergence in matKs. matK sequences were amplified from 27 Taxaceae and 12 Cephalotaxaceae species. matK sequences of 19 Pinaceae species were retrieved from GenBank. The phylogenetic tree was generated using conceptual-translated amino acid sequences. Selective influences were investigated using standard dN/dS ratio methods and more sensitive techniques investigating the amino acid property changes resulting from nonsynonymous replacements in a phylogenetic context. Analyses revealed the presence of positive selection in matKs (N-terminal region, RT domain and domain X) of Taxaceae and Pinaceae,and found positive destabilizing selection in N-terminal region and RT domain of Cephalotaxaceae matK. Moreover, various amino acid properties were found to be influenced by destabilizing positive selection. Amino acid sites relating to these properties and to different secondary structures were found and have the potential to affect group II intron maturase function. Despite the evolutionary constraint on the rapidly evolving matK, this protein evolves under positive selection in gymnosperm. Several regions of matK have experienced molecular adaptation which fine-tunes maturase performance.

  15. Characterising private and shared signatures of positive selection in 37 Asian populations.

    PubMed

    Liu, Xuanyao; Lu, Dongsheng; Saw, Woei-Yuh; Shaw, Philip J; Wangkumhang, Pongsakorn; Ngamphiw, Chumpol; Fucharoen, Suthat; Lert-Itthiporn, Worachart; Chin-Inmanu, Kwanrutai; Chau, Tran Nguyen Bich; Anders, Katie; Kasturiratne, Anuradhani; de Silva, H Janaka; Katsuya, Tomohiro; Kimura, Ryosuke; Nabika, Toru; Ohkubo, Takayoshi; Tabara, Yasuharu; Takeuchi, Fumihiko; Yamamoto, Ken; Yokota, Mitsuhiro; Mamatyusupu, Dolikun; Yang, Wenjun; Chung, Yeun-Jun; Jin, Li; Hoh, Boon-Peng; Wickremasinghe, Ananda R; Ong, RickTwee-Hee; Khor, Chiea-Chuen; Dunstan, Sarah J; Simmons, Cameron; Tongsima, Sissades; Suriyaphol, Prapat; Kato, Norihiro; Xu, Shuhua; Teo, Yik-Ying

    2017-04-01

    The Asian Diversity Project (ADP) assembled 37 cosmopolitan and ethnic minority populations in Asia that have been densely genotyped across over half a million markers to study patterns of genetic diversity and positive natural selection. We performed population structure analyses of the ADP populations and divided these populations into four major groups based on their genographic information. By applying a highly sensitive algorithm haploPS to locate genomic signatures of positive selection, 140 distinct genomic regions exhibiting evidence of positive selection in at least one population were identified. We examined the extent of signal sharing for regions that were selected in multiple populations and observed that populations clustered in a similar fashion to that of how the ancestry clades were phylogenetically defined. In particular, populations predominantly located in South Asia underwent considerably different adaptation as compared with populations from the other geographical regions. Signatures of positive selection present in multiple geographical regions were predicted to be older and have emerged prior to the separation of the populations in the different regions. In contrast, selection signals present in a single population group tended to be of lower frequencies and thus can be attributed to recent evolutionary events.

  16. Detection of Pathways Affected by Positive Selection in Primate Lineages Ancestral to Humans

    PubMed Central

    Moretti, S.; Davydov, I.I.; Excoffier, L.

    2017-01-01

    Abstract Gene set enrichment approaches have been increasingly successful in finding signals of recent polygenic selection in the human genome. In this study, we aim at detecting biological pathways affected by positive selection in more ancient human evolutionary history. Focusing on four branches of the primate tree that lead to modern humans, we tested all available protein coding gene trees of the Primates clade for signals of adaptation in these branches, using the likelihood-based branch site test of positive selection. The results of these locus-specific tests were then used as input for a gene set enrichment test, where whole pathways are globally scored for a signal of positive selection, instead of focusing only on outlier “significant” genes. We identified signals of positive selection in several pathways that are mainly involved in immune response, sensory perception, metabolism, and energy production. These pathway-level results are highly significant, even though there is no functional enrichment when only focusing on top scoring genes. Interestingly, several gene sets are found significant at multiple levels in the phylogeny, but different genes are responsible for the selection signal in the different branches. This suggests that the same function has been optimized in different ways at different times in primate evolution. PMID:28333345

  17. A Genome-Wide Identification of Genes Undergoing Recombination and Positive Selection in Neisseria

    PubMed Central

    Jin, Yuan; Yin, Zhiqiu; Ren, Hongguang; Zhou, Wei

    2014-01-01

    Currently, there is particular interest in the molecular mechanisms of adaptive evolution in bacteria. Neisseria is a genus of gram negative bacteria, and there has recently been considerable focus on its two human pathogenic species N. meningitidis and N. gonorrhoeae. Until now, no genome-wide studies have attempted to scan for the genes related to adaptive evolution. For this reason, we selected 18 Neisseria genomes (14 N. meningitidis, 3 N. gonorrhoeae and 1 commensal N. lactamics) to conduct a comparative genome analysis to obtain a comprehensive understanding of the roles of natural selection and homologous recombination throughout the history of adaptive evolution. Among the 1012 core orthologous genes, we identified 635 genes with recombination signals and 10 genes that showed significant evidence of positive selection. Further functional analyses revealed that no functional bias was found in the recombined genes. Positively selected genes are prone to DNA processing and iron uptake, which are essential for the fundamental life cycle. Overall, the results indicate that both recombination and positive selection play crucial roles in the adaptive evolution of Neisseria genomes. The positively selected genes and the corresponding amino acid sites provide us with valuable targets for further research into the detailed mechanisms of adaptive evolution in Neisseria. PMID:25180194

  18. A survey of methods and tools to detect recent and strong positive selection.

    PubMed

    Pavlidis, Pavlos; Alachiotis, Nikolaos

    2017-12-01

    Positive selection occurs when an allele is favored by natural selection. The frequency of the favored allele increases in the population and due to genetic hitchhiking the neighboring linked variation diminishes, creating so-called selective sweeps. Detecting traces of positive selection in genomes is achieved by searching for signatures introduced by selective sweeps, such as regions of reduced variation, a specific shift of the site frequency spectrum, and particular LD patterns in the region. A variety of methods and tools can be used for detecting sweeps, ranging from simple implementations that compute summary statistics such as Tajima's D, to more advanced statistical approaches that use combinations of statistics, maximum likelihood, machine learning etc. In this survey, we present and discuss summary statistics and software tools, and classify them based on the selective sweep signature they detect, i.e., SFS-based vs. LD-based, as well as their capacity to analyze whole genomes or just subgenomic regions. Additionally, we summarize the results of comparisons among four open-source software releases (SweeD, SweepFinder, SweepFinder2, and OmegaPlus) regarding sensitivity, specificity, and execution times. In equilibrium neutral models or mild bottlenecks, both SFS- and LD-based methods are able to detect selective sweeps accurately. Methods and tools that rely on LD exhibit higher true positive rates than SFS-based ones under the model of a single sweep or recurrent hitchhiking. However, their false positive rate is elevated when a misspecified demographic model is used to represent the null hypothesis. When the correct (or similar to the correct) demographic model is used instead, the false positive rates are considerably reduced. The accuracy of detecting the true target of selection is decreased in bottleneck scenarios. In terms of execution time, LD-based methods are typically faster than SFS-based methods, due to the nature of required arithmetic.

  19. Protein kinase D regulates positive selection of CD4+ thymocytes through phosphorylation of SHP-1

    PubMed Central

    Ishikawa, Eri; Kosako, Hidetaka; Yasuda, Tomoharu; Ohmuraya, Masaki; Araki, Kimi; Kurosaki, Tomohiro; Saito, Takashi; Yamasaki, Sho

    2016-01-01

    Thymic selection shapes an appropriate T cell antigen receptor (TCR) repertoire during T cell development. Here, we show that a serine/threonine kinase, protein kinase D (PKD), is crucial for thymocyte positive selection. In T cell-specific PKD-deficient (PKD2/PKD3 double-deficient) mice, the generation of CD4 single positive thymocytes is abrogated. This defect is likely caused by attenuated TCR signalling during positive selection and incomplete CD4 lineage specification in PKD-deficient thymocytes; however, TCR-proximal tyrosine phosphorylation is not affected. PKD is activated in CD4+CD8+ double positive (DP) thymocytes on stimulation with positively selecting peptides. By phosphoproteomic analysis, we identify SH2-containing protein tyrosine phosphatase-1 (SHP-1) as a direct substrate of PKD. Substitution of wild-type SHP-1 by phosphorylation-defective mutant (SHP-1S557A) impairs generation of CD4+ thymocytes. These results suggest that the PKD–SHP-1 axis positively regulates TCR signalling to promote CD4+ T cell development. PMID:27670070

  20. Functional role of positively selected amino acid substitutions in mammalian rhodopsin evolution.

    PubMed

    Fernández-Sampedro, Miguel A; Invergo, Brandon M; Ramon, Eva; Bertranpetit, Jaume; Garriga, Pere

    2016-02-11

    Visual rhodopsins are membrane proteins that function as light photoreceptors in the vertebrate retina. Specific amino acids have been positively selected in visual pigments during mammal evolution, which, as products of adaptive selection, would be at the base of important functional innovations. We have analyzed the top candidates for positive selection at the specific amino acids and the corresponding reverse changes (F13M, Q225R and A346S) in order to unravel the structural and functional consequences of these important sites in rhodopsin evolution. We have constructed, expressed and immunopurified the corresponding mutated pigments and analyzed their molecular phenotypes. We find that position 13 is very important for the folding of the receptor and also for proper protein glycosylation. Position 225 appears to be important for the function of the protein affecting the G-protein activation process, and position 346 would also regulate functionality of the receptor by enhancing G-protein activation and presumably affecting protein phosphorylation by rhodopsin kinase. Our results represent a link between the evolutionary analysis, which pinpoints the specific amino acid positions in the adaptive process, and the structural and functional analysis, closer to the phenotype, making biochemical sense of specific selected genetic sequences in rhodopsin evolution.

  1. Functional role of positively selected amino acid substitutions in mammalian rhodopsin evolution

    PubMed Central

    Fernández-Sampedro, Miguel A.; Invergo, Brandon M.; Ramon, Eva; Bertranpetit, Jaume; Garriga, Pere

    2016-01-01

    Visual rhodopsins are membrane proteins that function as light photoreceptors in the vertebrate retina. Specific amino acids have been positively selected in visual pigments during mammal evolution, which, as products of adaptive selection, would be at the base of important functional innovations. We have analyzed the top candidates for positive selection at the specific amino acids and the corresponding reverse changes (F13M, Q225R and A346S) in order to unravel the structural and functional consequences of these important sites in rhodopsin evolution. We have constructed, expressed and immunopurified the corresponding mutated pigments and analyzed their molecular phenotypes. We find that position 13 is very important for the folding of the receptor and also for proper protein glycosylation. Position 225 appears to be important for the function of the protein affecting the G-protein activation process, and position 346 would also regulate functionality of the receptor by enhancing G-protein activation and presumably affecting protein phosphorylation by rhodopsin kinase. Our results represent a link between the evolutionary analysis, which pinpoints the specific amino acid positions in the adaptive process, and the structural and functional analysis, closer to the phenotype, making biochemical sense of specific selected genetic sequences in rhodopsin evolution. PMID:26865329

  2. Keeping It Local: Evidence for Positive Selection in Swedish Arabidopsis thaliana

    PubMed Central

    Huber, Christian D.; Nordborg, Magnus; Hermisson, Joachim; Hellmann, Ines

    2014-01-01

    Detecting positive selection in species with heterogeneous habitats and complex demography is notoriously difficult and prone to statistical biases. The model plant Arabidopsis thaliana exemplifies this problem: In spite of the large amounts of data, little evidence for classic selective sweeps has been found. Moreover, many aspects of the demography are unclear, which makes it hard to judge whether the few signals are indeed signs of selection, or false positives caused by demographic events. Here, we focus on Swedish A. thaliana and we find that the demography can be approximated as a two-population model. Careful analysis of the data shows that such a two island model is characterized by a very old split time that significantly predates the last glacial maximum followed by secondary contact with strong migration. We evaluate selection based on this demography and find that this secondary contact model strongly affects the power to detect sweeps. Moreover, it affects the power differently for northern Sweden (more false positives) as compared with southern Sweden (more false negatives). However, even when the demographic history is accounted for, sweep signals in northern Sweden are stronger than in southern Sweden, with little or no positional overlap. Further simulations including the complex demography and selection confirm that this is not compatible with global selection acting on both populations, and thus can be taken as evidence for local selection within subpopulations of Swedish A. thaliana. This study demonstrates the necessity of combining demographic analyses and sweep scans for the detection of selection, particularly when selection acts predominantly local. PMID:25158800

  3. The influence of phylogenetic uncertainty on the detection of positive Darwinian selection.

    PubMed

    Pie, Marcio R

    2006-12-01

    The power of maximum likelihood tests of positive selection on protein-coding genes depends heavily on detecting and accounting for potential biases in the studied data set. Although the influence of transition:transversion and codon biases have been investigated in detail, little is known about how inaccuracy in the phylogeny used during the calculations affects the performance of these tests. In this study, 3 empirical data sets are analyzed using sets of simulated topologies corresponding to low, intermediate, and high levels of phylogenetic uncertainty. The detection of positive selection was largely unaffected by errors in the underlying phylogeny. However, the number of sites identified as being under positive selection tended to be overestimated.

  4. Transcriptome Sequencing of Lima Bean (Phaseolus lunatus) to Identify Putative Positive Selection in Phaseolus and Legumes

    PubMed Central

    Li, Fengqi; Cao, Depan; Liu, Yang; Yang, Ting; Wang, Guirong

    2015-01-01

    The identification of genes under positive selection is a central goal of evolutionary biology. Many legume species, including Phaseolus vulgaris (common bean) and Phaseolus lunatus (lima bean), have important ecological and economic value. In this study, we sequenced and assembled the transcriptome of one Phaseolus species, lima bean. A comparison with the genomes of six other legume species, including the common bean, Medicago, lotus, soybean, chickpea, and pigeonpea, revealed 15 and 4 orthologous groups with signatures of positive selection among the two Phaseolus species and among the seven legume species, respectively. Characterization of these positively selected genes using Non redundant (nr) annotation, gene ontology (GO) classification, GO term enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that these genes are mostly involved in thylakoids, photosynthesis and metabolism. This study identified genes that may be related to the divergence of the Phaseolus and legume species. These detected genes are particularly good candidates for subsequent functional studies. PMID:26151849

  5. Significant Selective Constraint at 4-Fold Degenerate Sites in the Avian Genome and Its Consequence for Detection of Positive Selection

    PubMed Central

    Künstner, Axel; Nabholz, Benoit; Ellegren, Hans

    2011-01-01

    A major conclusion from comparative genomics is that many sequences that do not code for proteins are conserved beyond neutral expectations, indicating that they evolve under the influence of purifying selection and are likely to have functional roles. Due to the degeneracy of the genetic code, synonymous sites within protein-coding genes have previously been seen as “silent” with respect to function and thereby invisible to selection. However, there are indications that synonymous sites of vertebrate genomes are also subject to selection and this is not necessarily because of potential codon bias. We used divergence in ancestral repeats as a neutral reference to estimate the constraint on 4-fold degenerate sites of avian genes in a whole-genome approach. In the pairwise comparison of chicken and zebra finch, constraint was estimated at 24–32%. Based on three-species alignments of chicken, turkey, and zebra finch, lineage-specific estimates of constraint were 43%, 29%, and 24%, respectively. The finding of significant constraint at 4-fold degenerate sites from data on interspecific divergence was replicated in an analysis of intraspecific diversity in the chicken genome. These observations corroborate recent data from mammalian genomes and call for a reappraisal of the use of synonymous substitution rates as neutral standards in molecular evolutionary analysis, for example, in the use of the well-known dN/dS ratio and in inferences on positive selection. We show by simulations that the rate of false positives in the detection of positively selected genes and sites increases several-fold at the levels of constraint at 4-fold degenerate sites found in this study. PMID:22042333

  6. SAR studies on carboxylic acid series M(1) selective positive allosteric modulators (PAMs).

    PubMed

    Kuduk, Scott D; Beshore, Douglas C

    2014-01-01

    There is mounting evidence from preclinical and early proof-of-concept studies suggesting that selective modulation of the M1 muscarinic receptor is efficacious in cognitive models of Alzheimer's disease (AD). A number of nonselective M1 muscarinic agonists have previously shown positive effects on cognitive function in AD patients, but were limited due to cholinergic adverse events thought to be mediated by pan activation of the M2 to M5 sub-types. Thus, there is a need to identify selective activators of the M1 receptor to evaluate their potential in cognitive disorders. One strategy to confer selectivity for M1 is the identification of allosteric agonists or positive allosteric modulators, which would target an allosteric site on the M1 receptor rather than the highly conserved orthosteric acetylcholine binding site. BQCA has been identified as a highly selective carboxylic acid M1 PAM and this review focuses on an extensive lead optimization campaign undertaken on this compound.

  7. Episodic positive selection at mitochondrial genome in an introduced biological control agent.

    PubMed

    Li, Hao-Sen; Liang, Xin-Yu; Zou, Shang-Jun; Liu, Yang; De Clercq, Patrick; Ślipiński, Adam; Pang, Hong

    2016-05-01

    Artificial introduction in classical biological control provides a unique opportunity to understand mitochondrial evolution driving adaptation to novel environments. We studied mitochondrial genomes of a world-wide introduced agent, Cryptolaemus montrouzieri. We detected positive selection in complex I genes (ND5 and ND4) against a background of widespread negative selection. We further detected significant signals in neutrality tests within 11 populations at ND5 gene, indicating a recent selective sweep/positive selection. Our results imply that these candidate mutations may contribute local adaptation of exotic biological control agents and these provide new insights into the improvement of classical biological control programs. Copyright © 2016 Elsevier B.V. and Mitochondria Research Society. All rights reserved.

  8. Selective anion exchange with nanogated isoreticular positive metal-organic frameworks.

    PubMed

    Zhao, Xiang; Bu, Xianhui; Wu, Tao; Zheng, Shou-Tian; Wang, Le; Feng, Pingyun

    2013-01-01

    Crystalline porous materials, especially inorganic porous solids such as zeolites, usually have negative frameworks with extra-framework mobile cations and are widely used for cation exchange. It is highly desirable to develop new materials with positive frameworks for selective anion exchange and separation or storage and delivery. Recent advances in metal-organic framework synthesis have created new opportunities in this direction. Here we report the synthesis of a series of positive indium metal-organic frameworks and their utilization as a platform for the anion exchange-based separation process. This process is capable of size- or charge-selective ion-exchange of organic dyes and may form the basis for size-selective ion chromatography. Ion-exchange dynamics of a series of organic dyes and their selective encapsulation and release are also studied, highlighting the advantages of metal-organic framework compositions for designing host materials tailored for applications in anion separation and purification.

  9. Positive selection sites in tertiary structure of Leguminosae chalcone isomerase 1.

    PubMed

    Wang, R K; Zhan, S F; Zhao, T J; Zhou, X L; Wang, C E

    2015-03-20

    Isoflavonoids and the related synthesis enzyme, chalcone isomerase 1 (CHI1), are unique in the Leguminosae, with diverse biological functions. Among the Leguminosae, the soybean is an important oil, protein crop, and model plant. In this study, we aimed to detect the generation pattern of Leguminosae CHI1. Genome-wide sequence analysis of CHI in 3 Leguminosae and 3 other closely related model plants was performed; the expression levels of soybean chalcone isomerases were also analyzed. By comparing positively selected sites and their protein structures, we retrieved the evolution patterns for Leguminosae CHI1. A total of 28 CHI and 7 FAP3 (CHI4) genes were identified and separated into 4 clades: CHI1, CHI2, CHI3, and FAP3. Soybean genes belonging to the same chalcone isomerase subfamily had similar expression patterns. CHI1, the unique chalcone isomerase subfamily in Leguminosae, showed signs of significant positive selection as well as special expression characteristics, indicating an accelerated evolution throughout its divergence. Eight sites were identified as undergoing positive selection with high confidence. When mapped onto the tertiary structure of CHI1, these 8 sites were observed surrounding the enzyme substrate only; some of them connected to the catalytic core of CHI. Thus, we inferred that the generation of Leguminosae CHI1 is dependent on the positively selected amino acids surrounding its catalytic substrate. In other words, the evolution of CHI1 was driven by specific selection or processing conditions within the substrate.

  10. Tuning transport selectivity of ionic species by phosphoric acid gradient in positively charged nanochannel membranes.

    PubMed

    Yang, Meng; Yang, Xiaohai; Wang, Kemin; Wang, Qing; Fan, Xin; Liu, Wei; Liu, Xizhen; Liu, Jianbo; Huang, Jin

    2015-02-03

    The transport of ionic species through a nanochannel plays important roles in fundamental research and practical applications of the nanofluidic device. Here, we demonstrated that ionic transport selectivity of a positively charged nanochannel membrane can be tuned under a phosphoric acid gradient. When phosphoric acid solution and analyte solution were connected by the positively charged nanochannel membrane, the faster-moving analyte through the positively charged nanochannel membrane was the positively charged dye (methylviologen, MV(2+)) instead of the negatively charged dye (1,5-naphthalene disulfonate, NDS(2-)). In other words, a reversed ion selectivity of the nanochannel membranes can be found. It can be explained as a result of the combination of diffusion, induced electroosmosis, and induced electrophoresis. In addition, the influencing factors of transport selectivity, including concentration of phosphoric acid, penetration time, and volume of feed solution, were also investigated. The results showed that the transport selectivity can further be tuned by adjusting these factors. As a method of tuning ionic transport selectivity by establishing phosphoric acid gradient, it will be conducive to improving the separation of ionic species.

  11. Automatic segmentation of zona pellucida and its application in cleavage-stage embryo biopsy position selection.

    PubMed

    Wang, Zenan; Ang, Wei Tech; Tan, Steven Yih Min; Latt, Win Tun

    2015-01-01

    A very important step of Pre-implantation genetic diagnosis (PGD) is embryo biopsy, in which process the zona pellucida (ZP) is cut open partially and a part of cellular material is extracted from the embryo. Recognition of the ZP is necessary not only for embryo biopsy, but also for other applications such as zona pellucida thickness variation (ZPTV), embryo dissection, etc. The ZP opening position is closely related to the cell survival rate after the biopsy. Selection of an unsuitable position may cause blastomere lysis after the ZP opening. Normal procedures of ZP recognition and biopsy position selection involve a skilled human embryologist. In order to make the process automatic, we introduce an automatic segmentation method for ZP recognition by using edge detection and ellipse fitting with a value adjustment algorithm in this paper. An application of ZP recognition in embryo biopsy position selection is also introduced. Our ZP recognition algorithm was able to correctly segment 43 out of 45 sample embryo images, achieving a success rate of 96%. Its application in embryo biopsy position selection achieved a success rate of 93%.

  12. Positive and Purifying Selection Influence the Evolution of Doublesex in the Anastrepha fraterculus Species Group

    PubMed Central

    Sobrinho, Iderval S.; de Brito, Reinaldo A.

    2012-01-01

    The gene doublesex (dsx) is considered to be under strong selective constraint along its evolutionary history because of its central role in somatic sex differentiation in insects. However, previous studies of dsx used global estimates of evolutionary rates to investigate its molecular evolution, which potentially miss signals of adaptive changes in generally conserved genes. In this work, we investigated the molecular evolution of dsx in the Anastrepha fraterculus species group (Diptera, Tephritidae), and test the hypothesis that this gene evolved solely by purifying selection using divergence-based and population-based methods. In the first approach, we compared sequences from Anastrepha and other Tephritidae with other Muscomorpha species, analyzed variation in nonsynonymous to synonymous rate ratios (dN/dS) in the Tephritidae, and investigated radical and conservative changes in amino acid physicochemical properties. We show a general selective constraint on dsx, but with signs of positive selection mainly in the common region. Such changes were localized in alpha-helices previously reported to be involved in dimer formation in the OD2 domain and near the C-terminal of the OD1 domain. In the population-based approach, we amplified a region of 540 bp that spanned almost all of the region common to both sexes from 32 different sites in Brazil. We investigated patterns of selection using neutrality tests based on the frequency spectrum and locations of synonymous and nonsynonymous mutations in a haplotype network. As in the divergence-based approach, these analyses showed that dsx has evolved under an overall selective constraint, but with some events of positive selection. In contrast to previous studies, our analyses indicate that even though dsx has indeed evolved as a conserved gene, the common region of dsx has also experienced bouts of positive selection, perhaps driven by sexual selection, during its evolution. PMID:22428050

  13. Evolution of the core and pan-genome of Streptococcus: positive selection, recombination, and genome composition

    PubMed Central

    Lefébure, Tristan; Stanhope, Michael J

    2007-01-01

    Background The genus Streptococcus is one of the most diverse and important human and agricultural pathogens. This study employs comparative evolutionary analyses of 26 Streptococcus genomes to yield an improved understanding of the relative roles of recombination and positive selection in pathogen adaptation to their hosts. Results Streptococcus genomes exhibit extreme levels of evolutionary plasticity, with high levels of gene gain and loss during species and strain evolution. S. agalactiae has a large pan-genome, with little recombination in its core-genome, while S. pyogenes has a smaller pan-genome and much more recombination of its core-genome, perhaps reflecting the greater habitat, and gene pool, diversity for S. agalactiae compared to S. pyogenes. Core-genome recombination was evident in all lineages (18% to 37% of the core-genome judged to be recombinant), while positive selection was mainly observed during species differentiation (from 11% to 34% of the core-genome). Positive selection pressure was unevenly distributed across lineages and biochemical main role categories. S. suis was the lineage with the greatest level of positive selection pressure, the largest number of unique loci selected, and the largest amount of gene gain and loss. Conclusion Recombination is an important evolutionary force in shaping Streptococcus genomes, not only in the acquisition of significant portions of the genome as lineage specific loci, but also in facilitating rapid evolution of the core-genome. Positive selection, although undoubtedly a slower process, has nonetheless played an important role in adaptation of the core-genome of different Streptococcus species to different hosts. PMID:17475002

  14. Thinking too positive? Revisiting current methods of population genetic selection inference.

    PubMed

    Bank, Claudia; Ewing, Gregory B; Ferrer-Admettla, Anna; Foll, Matthieu; Jensen, Jeffrey D

    2014-12-01

    In the age of next-generation sequencing, the availability of increasing amounts and improved quality of data at decreasing cost ought to allow for a better understanding of how natural selection is shaping the genome than ever before. However, alternative forces, such as demography and background selection (BGS), obscure the footprints of positive selection that we would like to identify. In this review, we illustrate recent developments in this area, and outline a roadmap for improved selection inference. We argue (i) that the development and obligatory use of advanced simulation tools is necessary for improved identification of selected loci, (ii) that genomic information from multiple time points will enhance the power of inference, and (iii) that results from experimental evolution should be utilized to better inform population genomic studies.

  15. Evidence of positive selection in mitochondrial complexes I and V of the African elephant.

    PubMed

    Finch, Tabitha M; Zhao, Nan; Korkin, Dmitry; Frederick, Katy H; Eggert, Lori S

    2014-01-01

    As species evolve, they become adapted to their local environments. Detecting the genetic signature of selection and connecting that to the phenotype of the organism, however, is challenging. Here we report using an integrative approach that combines DNA sequencing with structural biology analyses to assess the effect of selection on residues in the mitochondrial DNA of the two species of African elephants. We detected evidence of positive selection acting on residues in complexes I and V, and we used homology protein structure modeling to assess the effect of the biochemical properties of the selected residues on the enzyme structure. Given the role these enzymes play in oxidative phosphorylation, we propose that the selected residues may contribute to the metabolic adaptation of forest and savanna elephants to their unique habitats.

  16. Evidence of Positive Selection in Mitochondrial Complexes I and V of the African Elephant

    PubMed Central

    Finch, Tabitha M.; Zhao, Nan; Korkin, Dmitry; Frederick, Katy H.; Eggert, Lori S.

    2014-01-01

    As species evolve, they become adapted to their local environments. Detecting the genetic signature of selection and connecting that to the phenotype of the organism, however, is challenging. Here we report using an integrative approach that combines DNA sequencing with structural biology analyses to assess the effect of selection on residues in the mitochondrial DNA of the two species of African elephants. We detected evidence of positive selection acting on residues in complexes I and V, and we used homology protein structure modeling to assess the effect of the biochemical properties of the selected residues on the enzyme structure. Given the role these enzymes play in oxidative phosphorylation, we propose that the selected residues may contribute to the metabolic adaptation of forest and savanna elephants to their unique habitats. PMID:24695069

  17. Positive Selection or Free to Vary? Assessing the Functional Significance of Sequence Change Using Molecular Dynamics

    PubMed Central

    Allison, Jane R.; Lechner, Marcus; Hoeppner, Marc P.; Poole, Anthony M.

    2016-01-01

    Evolutionary arms races between pathogens and their hosts may be manifested as selection for rapid evolutionary change of key genes, and are sometimes detectable through sequence-level analyses. In the case of protein-coding genes, such analyses frequently predict that specific codons are under positive selection. However, detecting positive selection can be non-trivial, and false positive predictions are a common concern in such analyses. It is therefore helpful to place such predictions within a structural and functional context. Here, we focus on the p19 protein from tombusviruses. P19 is a homodimer that sequesters siRNAs, thereby preventing the host RNAi machinery from shutting down viral infection. Sequence analysis of the p19 gene is complicated by the fact that it is constrained at the sequence level by overprinting of a viral movement protein gene. Using homology modeling, in silico mutation and molecular dynamics simulations, we assess how non-synonymous changes to two residues involved in forming the dimer interface—one invariant, and one predicted to be under positive selection—impact molecular function. Interestingly, we find that both observed variation and potential variation (where a non-synonymous change to p19 would be synonymous for the overprinted movement protein) does not significantly impact protein structure or RNA binding. Consequently, while several methods identify residues at the dimer interface as being under positive selection, MD results suggest they are functionally indistinguishable from a site that is free to vary. Our analyses serve as a caveat to using sequence-level analyses in isolation to detect and assess positive selection, and emphasize the importance of also accounting for how non-synonymous changes impact structure and function. PMID:26871901

  18. Positioning.

    ERIC Educational Resources Information Center

    Conone, Ruth M.

    The key to positioning is the creation of a clear benefit image in the consumer's mind. One positioning strategy is creating in the prospect's mind a position that takes into consideration the company's or agency's strengths and weaknesses as well as those of its competitors. Another strategy is to gain entry into a position ladder owned by…

  19. Signatures of positive selection in East African Shorthorn Zebu: a genome-wide SNP analysis

    USDA-ARS?s Scientific Manuscript database

    The small East African Shorthorn Zebu is the main indigenous cattle across East Africa. A recent genome wide SNPs analysis has revealed their ancient stable African taurine x Asian zebu admixture. Here, we assess the presence of candidate signature of positive selection in their genome, with the aim...

  20. Positive selection of T-lymphocytes induced by intrathymic injection of a thymic epithelial cell line

    PubMed Central

    Vukmanović, Stanislav; Grandea, Andres G.; Faas, Susan J.; Knowles, Barbara B.; Bevan, Michael J.

    2009-01-01

    Tlymphocytes recognize antigens as peptide fragments associated with molecules encoded by the major histocompatibility complex (MHC) and expressed on the surface of antigen-presenting cells1. In the thymus, T cells bearing αβ receptors that react with the MHC molecules expressed by radioresistant stromal elements are positively selected for maturation2–5. In (A × B → A) bone marrow chimaeras, T cells restricted to the MHC-A haplotype are positively selected, whereas MHC-B-reactive thymocytes are not. We investigated whether the introduction of particular thymic stromal elements bearing MHC-B molecules could alter the fate of B-reactive T cells in these (A × B → A) chimaeras. Thymic epithelial cell (TEC) lines expressing H-2b were introduced by intrathymic injection into (H-2b/s → H2S) bone marrow chimaeras and we measured their ability to generate H-2b-restricted cytotoxic T-lymphocytes (CTLs). We report here that one TEC line, 427.1, was able positively to select CTLs specific for influenza and vesicular stomatitis virus antigens in association with class I H–2b molecules. In addition, line 427.1 can process cytoplasmic proteins for presentation to H–2Kb- and H-2Db-restricted CTLs. Thus, a TEC line capable of normal class I MHC antigen processing and presentation in vitro can induce positive selection after intrathymic injection. PMID:1331804

  1. A powerful score test to detect positive selection in genome-wide scans

    PubMed Central

    Zhong, Ming; Lange, Kenneth; Papp, Jeanette C; Fan, Ruzong

    2010-01-01

    One of the surest signatures of recent positive selection is a local elevation of advantageous allele frequency and linkage disequilibrium (LD). We proposed to detect such hitchhiking effects by using extended stretches of homozygosity as a surrogate indicator of recent positive selection. An extended haplotype-based homozygosity score test (EHHST) was developed to detect excess homozygosity. The EHHST conditioned on existing LD and it tested the haplotype version of the Hardy–Weinberg equilibrium. Compared with existing popular tests, which usually lack clear distribution, the EHHST is asymptotically normal, which makes analysis and applications easier. In particular, the EHHST facilitates the computation of an asymptotic P-value instead of an empirical P-value, using simulations. We evaluated by simulation that the EHHST led to appropriate false-positive rates, and it had higher or similar power as the existing popular methods. The method was applied to HapMap Phase II data. We were able to replicate previous findings of strong positive selection in 17 autosome genomic regions out of 20 reported candidates. On the basis of high EHHST values and population differentiations, we identified 15 new candidate regions that could undergo recent selection. PMID:20461112

  2. Multifunctionalized iron oxide nanoparticles for selective drug delivery to CD44-positive cancer cells

    NASA Astrophysics Data System (ADS)

    Aires, Antonio; Ocampo, Sandra M.; Simões, Bruno M.; Josefa Rodríguez, María; Cadenas, Jael F.; Couleaud, Pierre; Spence, Katherine; Latorre, Alfonso; Miranda, Rodolfo; Somoza, Álvaro; Clarke, Robert B.; Carrascosa, José L.; Cortajarena, Aitziber L.

    2016-02-01

    Nanomedicine nowadays offers novel solutions in cancer therapy and diagnosis by introducing multimodal treatments and imaging tools in one single formulation. Nanoparticles acting as nanocarriers change the solubility, biodistribution and efficiency of therapeutic molecules, reducing their side effects. In order to successfully apply these novel therapeutic approaches, efforts are focused on the biological functionalization of the nanoparticles to improve the selectivity towards cancer cells. In this work, we present the synthesis and characterization of novel multifunctionalized iron oxide magnetic nanoparticles (MNPs) with antiCD44 antibody and gemcitabine derivatives, and their application for the selective treatment of CD44-positive cancer cells. The lymphocyte homing receptor CD44 is overexpressed in a large variety of cancer cells, but also in cancer stem cells (CSCs) and circulating tumor cells (CTCs). Therefore, targeting CD44-overexpressing cells is a challenging and promising anticancer strategy. Firstly, we demonstrate the targeting of antiCD44 functionalized MNPs to different CD44-positive cancer cell lines using a CD44-negative non-tumorigenic cell line as a control, and verify the specificity by ultrastructural characterization and downregulation of CD44 expression. Finally, we show the selective drug delivery potential of the MNPs by the killing of CD44-positive cancer cells using a CD44-negative non-tumorigenic cell line as a control. In conclusion, the proposed multifunctionalized MNPs represent an excellent biocompatible nanoplatform for selective CD44-positive cancer therapy in vitro.

  3. Positive Darwinian selection results in resistance to cardioactive toxins in true toads (Anura: Bufonidae)

    PubMed Central

    Moore, David J.; Halliday, Damien C. T.; Rowell, David M.; Robinson, Anthony J.; Keogh, J. Scott

    2009-01-01

    Members of the Family Bufonidae, true toads, are famous for their endogenously synthesized cardioactive steroids that serve as defensive toxins. Evolution of resistance to these toxins is not understood. We sequenced a key region of the toxin's binding site in the Na+/K+ ATPase for relevant taxa representing Hyloidea (including bufonids), Ranoidea and Archaeobatrachia and tested for positive selection in a phylogenetic context. Bufonidae were distinct from other Hyloidea at 4–6 of 12 sites and, with one exception, had a homologous amino acid sequence. Melanophryniscus stelzneri had a distinct sequence, consistent with other independent evidence for a differentiated toxin. Tests within Bufonidae detected positive selection within the binding region, providing, to our knowledge, the first evidence of this type for positive selection within Amphibia. There was no evidence for positive selection on Bufonidae or M. stelzneri lineages. Sequence change in Leptodactylus ocellatus, a leptodactylid predator of Bufonidae, provides a molecular basis for predator resistance possibly associated with gene duplication. PMID:19465576

  4. Genome-wide detection and characterization of positive selection in human populations.

    PubMed

    Sabeti, Pardis C; Varilly, Patrick; Fry, Ben; Lohmueller, Jason; Hostetter, Elizabeth; Cotsapas, Chris; Xie, Xiaohui; Byrne, Elizabeth H; McCarroll, Steven A; Gaudet, Rachelle; Schaffner, Stephen F; Lander, Eric S; Frazer, Kelly A; Ballinger, Dennis G; Cox, David R; Hinds, David A; Stuve, Laura L; Gibbs, Richard A; Belmont, John W; Boudreau, Andrew; Hardenbol, Paul; Leal, Suzanne M; Pasternak, Shiran; Wheeler, David A; Willis, Thomas D; Yu, Fuli; Yang, Huanming; Zeng, Changqing; Gao, Yang; Hu, Haoran; Hu, Weitao; Li, Chaohua; Lin, Wei; Liu, Siqi; Pan, Hao; Tang, Xiaoli; Wang, Jian; Wang, Wei; Yu, Jun; Zhang, Bo; Zhang, Qingrun; Zhao, Hongbin; Zhao, Hui; Zhou, Jun; Gabriel, Stacey B; Barry, Rachel; Blumenstiel, Brendan; Camargo, Amy; Defelice, Matthew; Faggart, Maura; Goyette, Mary; Gupta, Supriya; Moore, Jamie; Nguyen, Huy; Onofrio, Robert C; Parkin, Melissa; Roy, Jessica; Stahl, Erich; Winchester, Ellen; Ziaugra, Liuda; Altshuler, David; Shen, Yan; Yao, Zhijian; Huang, Wei; Chu, Xun; He, Yungang; Jin, Li; Liu, Yangfan; Shen, Yayun; Sun, Weiwei; Wang, Haifeng; Wang, Yi; Wang, Ying; Xiong, Xiaoyan; Xu, Liang; Waye, Mary M Y; Tsui, Stephen K W; Xue, Hong; Wong, J Tze-Fei; Galver, Luana M; Fan, Jian-Bing; Gunderson, Kevin; Murray, Sarah S; Oliphant, Arnold R; Chee, Mark S; Montpetit, Alexandre; Chagnon, Fanny; Ferretti, Vincent; Leboeuf, Martin; Olivier, Jean-François; Phillips, Michael S; Roumy, Stéphanie; Sallée, Clémentine; Verner, Andrei; Hudson, Thomas J; Kwok, Pui-Yan; Cai, Dongmei; Koboldt, Daniel C; Miller, Raymond D; Pawlikowska, Ludmila; Taillon-Miller, Patricia; Xiao, Ming; Tsui, Lap-Chee; Mak, William; Song, You Qiang; Tam, Paul K H; Nakamura, Yusuke; Kawaguchi, Takahisa; Kitamoto, Takuya; Morizono, Takashi; Nagashima, Atsushi; Ohnishi, Yozo; Sekine, Akihiro; Tanaka, Toshihiro; Tsunoda, Tatsuhiko; Deloukas, Panos; Bird, Christine P; Delgado, Marcos; Dermitzakis, Emmanouil T; Gwilliam, Rhian; Hunt, Sarah; Morrison, Jonathan; Powell, Don; Stranger, Barbara E; Whittaker, Pamela; Bentley, David R; Daly, Mark J; de Bakker, Paul I W; Barrett, Jeff; Chretien, Yves R; Maller, Julian; McCarroll, Steve; Patterson, Nick; Pe'er, Itsik; Price, Alkes; Purcell, Shaun; Richter, Daniel J; Sabeti, Pardis; Saxena, Richa; Schaffner, Stephen F; Sham, Pak C; Varilly, Patrick; Altshuler, David; Stein, Lincoln D; Krishnan, Lalitha; Smith, Albert Vernon; Tello-Ruiz, Marcela K; Thorisson, Gudmundur A; Chakravarti, Aravinda; Chen, Peter E; Cutler, David J; Kashuk, Carl S; Lin, Shin; Abecasis, Gonçalo R; Guan, Weihua; Li, Yun; Munro, Heather M; Qin, Zhaohui Steve; Thomas, Daryl J; McVean, Gilean; Auton, Adam; Bottolo, Leonardo; Cardin, Niall; Eyheramendy, Susana; Freeman, Colin; Marchini, Jonathan; Myers, Simon; Spencer, Chris; Stephens, Matthew; Donnelly, Peter; Cardon, Lon R; Clarke, Geraldine; Evans, David M; Morris, Andrew P; Weir, Bruce S; Tsunoda, Tatsuhiko; Johnson, Todd A; Mullikin, James C; Sherry, Stephen T; Feolo, Michael; Skol, Andrew; Zhang, Houcan; Zeng, Changqing; Zhao, Hui; Matsuda, Ichiro; Fukushima, Yoshimitsu; Macer, Darryl R; Suda, Eiko; Rotimi, Charles N; Adebamowo, Clement A; Ajayi, Ike; Aniagwu, Toyin; Marshall, Patricia A; Nkwodimmah, Chibuzor; Royal, Charmaine D M; Leppert, Mark F; Dixon, Missy; Peiffer, Andy; Qiu, Renzong; Kent, Alastair; Kato, Kazuto; Niikawa, Norio; Adewole, Isaac F; Knoppers, Bartha M; Foster, Morris W; Clayton, Ellen Wright; Watkin, Jessica; Gibbs, Richard A; Belmont, John W; Muzny, Donna; Nazareth, Lynne; Sodergren, Erica; Weinstock, George M; Wheeler, David A; Yakub, Imtaz; Gabriel, Stacey B; Onofrio, Robert C; Richter, Daniel J; Ziaugra, Liuda; Birren, Bruce W; Daly, Mark J; Altshuler, David; Wilson, Richard K; Fulton, Lucinda L; Rogers, Jane; Burton, John; Carter, Nigel P; Clee, Christopher M; Griffiths, Mark; Jones, Matthew C; McLay, Kirsten; Plumb, Robert W; Ross, Mark T; Sims, Sarah K; Willey, David L; Chen, Zhu; Han, Hua; Kang, Le; Godbout, Martin; Wallenburg, John C; L'Archevêque, Paul; Bellemare, Guy; Saeki, Koji; Wang, Hongguang; An, Daochang; Fu, Hongbo; Li, Qing; Wang, Zhen; Wang, Renwu; Holden, Arthur L; Brooks, Lisa D; McEwen, Jean E; Guyer, Mark S; Wang, Vivian Ota; Peterson, Jane L; Shi, Michael; Spiegel, Jack; Sung, Lawrence M; Zacharia, Lynn F; Collins, Francis S; Kennedy, Karen; Jamieson, Ruth; Stewart, John

    2007-10-18

    With the advent of dense maps of human genetic variation, it is now possible to detect positive natural selection across the human genome. Here we report an analysis of over 3 million polymorphisms from the International HapMap Project Phase 2 (HapMap2). We used 'long-range haplotype' methods, which were developed to identify alleles segregating in a population that have undergone recent selection, and we also developed new methods that are based on cross-population comparisons to discover alleles that have swept to near-fixation within a population. The analysis reveals more than 300 strong candidate regions. Focusing on the strongest 22 regions, we develop a heuristic for scrutinizing these regions to identify candidate targets of selection. In a complementary analysis, we identify 26 non-synonymous, coding, single nucleotide polymorphisms showing regional evidence of positive selection. Examination of these candidates highlights three cases in which two genes in a common biological process have apparently undergone positive selection in the same population:LARGE and DMD, both related to infection by the Lassa virus, in West Africa;SLC24A5 and SLC45A2, both involved in skin pigmentation, in Europe; and EDAR and EDA2R, both involved in development of hair follicles, in Asia.

  5. Genome-wide detection and characterization of positive selection in human populations

    PubMed Central

    Sabeti, Pardis C.; Varilly, Patrick; Fry, Ben; Lohmueller, Jason; Hostetter, Elizabeth; Cotsapas, Chris; Xie, Xiaohui; Byrne, Elizabeth H.; McCarroll, Steven A.; Gaudet, Rachelle; Schaffner, Stephen F.; Lander, Eric S.

    2009-01-01

    With the advent of dense maps of human genetic variation, it is now possible to detect positive natural selection across the human genome. Here we report an analysis of over 3 million polymorphisms from the International HapMap Project Phase 2 (HapMap2)1. We used ‘long-range haplotype’ methods, which were developed to identify alleles segregating in a population that have undergone recent selection2, and we also developed new methods that are based on cross-population comparisons to discover alleles that have swept to near-fixation within a population. The analysis reveals more than 300 strong candidate regions. Focusing on the strongest 22 regions, we develop a heuristic for scrutinizing these regions to identify candidate targets of selection. In a complementary analysis, we identify 26 non-synonymous, coding, single nucleotide polymorphisms showing regional evidence of positive selection. Examination of these candidates highlights three cases in which two genes in a common biological process have apparently undergone positive selection in the same population: LARGE and DMD, both related to infection by the Lassa virus3, in West Africa; SLC24A5 and SLC45A2, both involved in skin pigmentation4,5, in Europe; and EDAR and EDA2R, both involved in development of hair follicles6, in Asia. PMID:17943131

  6. A method to infer positive selection from marker dynamics in an asexual population.

    PubMed

    Illingworth, Christopher J R; Mustonen, Ville

    2012-03-15

    The observation of positive selection acting on a mutant indicates that the corresponding mutation has some form of functional relevance. Determining the fitness effects of mutations thus has relevance to many interesting biological questions. One means of identifying beneficial mutations in an asexual population is to observe changes in the frequency of marked subsets of the population. We here describe a method to estimate the establishment times and fitnesses of beneficial mutations from neutral marker frequency data. The method accurately reproduces complex marker frequency trajectories. In simulations for which positive selection is close to 5% per generation, we obtain correlations upwards of 0.91 between correct and inferred haplotype establishment times. Where mutation selection coefficients are exponentially distributed, the inferred distribution of haplotype fitnesses is close to being correct. Applied to data from a bacterial evolution experiment, our method reproduces an observed correlation between evolvability and initial fitness defect.

  7. Genomic Analysis Identifies Targets of Convergent Positive Selection in Drug Resistant Mycobacterium tuberculosis

    PubMed Central

    Farhat, Maha R; Shapiro, B Jesse; Kieser, Karen J; Sultana, Razvan; Jacobson, Karen R; Victor, Thomas C; Warren, Robin M; Streicher, Elizabeth M; Calver, Alistair; Sloutsky, Alex; Kaur, Devinder; Posey, Jamie E; Plikaytis, Bonnie; Oggioni, Marco R; Gardy, Jennifer L; Johnston, James C; Rodrigues, Mabel; Tang, Patrick K C; Kato-Maeda, Midori; Borowsky, Mark L; Muddukrishna, Bhavana; Kreiswirth, Barry N; Kurepina, Natalia; Galagan, James; Gagneux, Sebastien; Birren, Bruce; Rubin, Eric J; Lander, Eric S; Sabeti, Pardis C; Murray, Megan

    2013-01-01

    Mycobacterium tuberculosis is successfully evolving antibiotic resistance, threatening attempts at tuberculosis epidemic control. Mechanisms of resistance, including the genetic changes favored by selection in resistant isolates, are incompletely understood. Using 116 newly and 7 previously sequenced M. tuberculosis genomes, we identified genomewide signatures of positive selection specific to the 47 resistant genomes. By searching for convergent evolution, the independent fixation of mutations at the same nucleotide site or gene, we recovered 100% of a set of known resistance markers. We also found evidence of positive selection in an additional 39 genomic regions in resistant isolates. These regions encode pathways of cell wall biosynthesis, transcriptional regulation and DNA repair. Mutations in these regions could directly confer resistance or compensate for fitness costs associated with resistance. Functional genetic analysis of mutations in one gene, ponA1, demonstrated an in vitro growth advantage in the presence of the drug rifampicin. PMID:23995135

  8. Selection of electrode positions for an EEG-based brain computer interface (BCI).

    PubMed

    Pregenzer, M; Pfurtscheller, G; Flotzinger, D

    1994-10-01

    One major question in designing an EEG-based Brain Computer Interface to bypass the normal motor pathways is the selection of proper electrode positions. This study investigates electrode selection with a Distinction Sensitive Learning Vector Quantizer (DSLVQ). DSLVQ is an extended Learning Vector Quantizer (LVQ) which employs a weighted distance function for dynamical scaling and feature selection. The data analysed and classified were 56-channel EEG recordings over sensorimotor areas during preparation for discrete left or right index finger flexions. Data from 3 subjects are reported. It was found by DSLVQ that the most important electrode positions for differentiation between planning of left and right finger movement overlie cortical finger/hand areas over both hemispheres.

  9. Positive manifold limits the relevance of content-matching strategies for validating selection test batteries.

    PubMed

    Murphy, Kevin R; Dzieweczynski, Jessica L; Zhang, Yang

    2009-07-01

    Inferences about the relationships between scores on selection tests and measures of job performance are often made on the basis of an assessment of the match between the content of the test and the content of the job. However, there is little evidence that these test-to-job comparisons have any bearing on the criterion-related validity of selection tests. The authors show that conclusions reached in analyses of cognitive tests-that content matching is largely irrelevant to criterion-related validity-can be generalized to most sets of selection tests (e.g., psychomotor and performance tests, interview ratings, biodata scores, knowledge tests, work sample tests) that are positively correlated with one another and with the criterion. When the universe of potential predictors shows positive manifold, almost all possible sets of test batteries will yield similar outcomes and show similar validities, regardless of whether the content of these tests matches the content of the job.

  10. Functional Consequence of Positive Selection Revealed through Rational Mutagenesis of Human Myeloperoxidase

    PubMed Central

    Loughran, Noeleen B.; Hinde, Sara; McCormick-Hill, Sally; Leidal, Kevin G.; Bloomberg, Sarah; Loughran, Sinéad T.; O’Connor, Brendan; Ó'Fágáin, Ciarán; Nauseef, William M.; O’Connell, Mary J.

    2012-01-01

    Myeloperoxidase (MPO) is a member of the mammalian heme peroxidase (MHP) multigene family. Whereas all MHPs oxidize specific halides to generate the corresponding hypohalous acid, MPO is unique in its capacity to oxidize chloride at physiologic pH to produce hypochlorous acid (HOCl), a potent microbicide that contributes to neutrophil-mediated host defense against infection. We have previously resolved the evolutionary relationships in this functionally diverse multigene family and predicted in silico that positive Darwinian selection played a major role in the observed functional diversities (Loughran NB, O'Connor B, O'Fagain C, O'Connell MJ. 2008. The phylogeny of the mammalian heme peroxidases and the evolution of their diverse functions. BMC Evol Biol. 8:101). In this work, we have replaced positively selected residues asparagine 496 (N496), tyrosine 500 (Y500), and leucine 504 (L504) with the amino acids present in the ancestral MHP and have examined the effects on the structure, biosynthesis, and activity of MPO. Analysis in silico predicted that N496F, Y500F, or L504T would perturb hydrogen bonding in the heme pocket of MPO and thus disrupt the structural integrity of the enzyme. Biosynthesis of the mutants stably expressed in human embryonic kidney 293 cells yielded apoproMPO, the heme-free, enzymatically inactive precursor of MPO, that failed to undergo normal maturation or proteolytic processing. As a consequence of the maturational arrest at the apoproMPO stage of development, cells expressing MPO with mutations N496F, Y500F, L504T, individually or in combination, lacked normal peroxidase or chlorinating activity. Taken together, our data provide further support for the in silico predictions of positive selection and highlight the correlation between positive selection and functional divergence. Our data demonstrate that directly probing the functional importance of positive selection can provide important insights into understanding protein evolution

  11. Superoxide dismutase 1 is positively selected to minimize protein aggregation in great apes.

    PubMed

    Dasmeh, Pouria; Kepp, Kasper P

    2017-08-01

    Positive (adaptive) selection has recently been implied in human superoxide dismutase 1 (SOD1), a highly abundant antioxidant protein with energy signaling and antiaging functions, one of very few examples of direct selection on a human protein product (exon); the molecular drivers of this selection are unknown. We mapped 30 extant SOD1 sequences to the recently established mammalian species tree and inferred ancestors, key substitutions, and signatures of selection during the protein's evolution. We detected elevated substitution rates leading to great apes (Hominidae) at ~1 per 2 million years, significantly higher than in other primates and rodents, although these paradoxically generally evolve much faster. The high evolutionary rate was partly due to relaxation of some selection pressures and partly to distinct positive selection of SOD1 in great apes. We then show that higher stability and net charge and changes at the dimer interface were selectively introduced upon separation from old world monkeys and lesser apes (gibbons). Consequently, human, chimpanzee and gorilla SOD1s have a net charge of -6 at physiological pH, whereas the closely related gibbons and macaques have -3. These features consistently point towards selection against the malicious aggregation effects of elevated SOD1 levels in long-living great apes. The findings mirror the impact of human SOD1 mutations that reduce net charge and/or stability and cause ALS, a motor neuron disease characterized by oxidative stress and SOD1 aggregates and triggered by aging. Our study thus marks an example of direct selection for a particular chemical phenotype (high net charge and stability) in a single human protein with possible implications for the evolution of aging.

  12. Positive Selection Underlies Faster-Z Evolution of Gene Expression in Birds.

    PubMed

    Dean, Rebecca; Harrison, Peter W; Wright, Alison E; Zimmer, Fabian; Mank, Judith E

    2015-10-01

    The elevated rate of evolution for genes on sex chromosomes compared with autosomes (Fast-X or Fast-Z evolution) can result either from positive selection in the heterogametic sex or from nonadaptive consequences of reduced relative effective population size. Recent work in birds suggests that Fast-Z of coding sequence is primarily due to relaxed purifying selection resulting from reduced relative effective population size. However, gene sequence and gene expression are often subject to distinct evolutionary pressures; therefore, we tested for Fast-Z in gene expression using next-generation RNA-sequencing data from multiple avian species. Similar to studies of Fast-Z in coding sequence, we recover clear signatures of Fast-Z in gene expression; however, in contrast to coding sequence, our data indicate that Fast-Z in expression is due to positive selection acting primarily in females. In the soma, where gene expression is highly correlated between the sexes, we detected Fast-Z in both sexes, although at a higher rate in females, suggesting that many positively selected expression changes in females are also expressed in males. In the gonad, where intersexual correlations in expression are much lower, we detected Fast-Z for female gene expression, but crucially, not males. This suggests that a large amount of expression variation is sex-specific in its effects within the gonad. Taken together, our results indicate that Fast-Z evolution of gene expression is the product of positive selection acting on recessive beneficial alleles in the heterogametic sex. More broadly, our analysis suggests that the adaptive potential of Z chromosome gene expression may be much greater than that of gene sequence, results which have important implications for the role of sex chromosomes in speciation and sexual selection. © The Author 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

  13. Positive Selection Underlies Faster-Z Evolution of Gene Expression in Birds

    PubMed Central

    Dean, Rebecca; Harrison, Peter W.; Wright, Alison E.; Zimmer, Fabian; Mank, Judith E.

    2015-01-01

    The elevated rate of evolution for genes on sex chromosomes compared with autosomes (Fast-X or Fast-Z evolution) can result either from positive selection in the heterogametic sex or from nonadaptive consequences of reduced relative effective population size. Recent work in birds suggests that Fast-Z of coding sequence is primarily due to relaxed purifying selection resulting from reduced relative effective population size. However, gene sequence and gene expression are often subject to distinct evolutionary pressures; therefore, we tested for Fast-Z in gene expression using next-generation RNA-sequencing data from multiple avian species. Similar to studies of Fast-Z in coding sequence, we recover clear signatures of Fast-Z in gene expression; however, in contrast to coding sequence, our data indicate that Fast-Z in expression is due to positive selection acting primarily in females. In the soma, where gene expression is highly correlated between the sexes, we detected Fast-Z in both sexes, although at a higher rate in females, suggesting that many positively selected expression changes in females are also expressed in males. In the gonad, where intersexual correlations in expression are much lower, we detected Fast-Z for female gene expression, but crucially, not males. This suggests that a large amount of expression variation is sex-specific in its effects within the gonad. Taken together, our results indicate that Fast-Z evolution of gene expression is the product of positive selection acting on recessive beneficial alleles in the heterogametic sex. More broadly, our analysis suggests that the adaptive potential of Z chromosome gene expression may be much greater than that of gene sequence, results which have important implications for the role of sex chromosomes in speciation and sexual selection. PMID:26067773

  14. Pervasive, genome-wide positive selection leading to functional divergence in the bacterial genus Campylobacter

    PubMed Central

    Lefébure, Tristan; Stanhope, Michael J.

    2009-01-01

    An open question in bacterial genomics is the role that adaptive evolution of the core genome plays in diversification and adaptation of bacterial species, and how this might differ between groups of bacteria occupying different environmental circumstances. The genus Campylobacter encompasses several important human and animal enteric pathogens, with genome sequence data available for eight species. We estimate the Campylobacter core genome at 647 genes, with 92.5% of the nonrecombinant core genome loci under positive selection in at least one lineage and the same gene frequently under positive selection in multiple lineages. Tests are provided that reject recombination, saturation, and variation in codon usage bias as factors contributing to this high level of selection. We suggest this genome-wide adaptive evolution may result from a Red Queen macroevolutionary dynamic, in which species are involved in competition for resources within the mammalian and/or vertebrate gastrointestinal tract. Much reduced levels of positive selection evident in Streptococcus, as reported by the authors in an earlier work, may be a consequence of these taxa inhabiting less species-rich habitats, and more unique niches. Despite many common loci under positive selection in multiple Campylobacter lineages, we found no evidence for molecular adaptive convergence at the level of the same or adjacent codons, or even protein domains. Taken collectively, these results describe the diversification of a bacterial genus that involves pervasive natural selection pressure across virtually the entire genome, with this adaptation occurring in different ways in different lineages, despite the species tendency toward a common gastrointestinal habitat. PMID:19304960

  15. Thymoproteasome subunit-β5T generates peptide-MHC complexes specialized for positive selection

    PubMed Central

    Xing, Yan; Jameson, Stephen C.; Hogquist, Kristin A.

    2013-01-01

    Cortical thymic epithelial cells (cTECs) express a unique thymoproteasome subunit-β5T that plays an essential role in the development of CD8 T cells. In contrast, the immunoproteasome subunit-β5i is expressed in other thymic antigen-presenting cells (APCs). The thymoproteasome may generate peptides that are specialized for positive selection, or it may simply serve to generate peptides that are distinct from other APCs that cause negative selection, thereby promoting an overall larger number of surviving clones to mature and function in the immune system. To distinguish these models, we genetically engineered mice to express distinct peptide repertoires in cTECs vs. other APCs without expressing β5T, by generating β5t5i knockin mice, in which β5i replaced β5T in cTECs. When such animals were crossed to β5i−/− mice, β5i was exclusively expressed in cTECs, whereas β5 was expressed in other cells. However, this mouse did not support normal positive selection, suggesting that β5T generates peptides that are intrinsically better for positive selection (i.e., β5i could not replace β5T) and not merely because these peptides are distinct from peptides presented by other APCs. Finally, using an Nur77GFP reporter, we show that the T cells generated in the absence of β5T have higher reactivity to self, generating predominantly CD44hi memory phenotype peripheral CD8+ T cells. Altogether, our results suggest that the thymoproteasome supports positive selection by generating peptides that are optimized for the selection of weakly self-reactive, naïve T-cell clones. PMID:23569244

  16. Cancer Evolution Is Associated with Pervasive Positive Selection on Globally Expressed Genes

    PubMed Central

    Ostrow, Sheli L.; Barshir, Ruth; DeGregori, James; Yeger-Lotem, Esti; Hershberg, Ruth

    2014-01-01

    Cancer is an evolutionary process in which cells acquire new transformative, proliferative and metastatic capabilities. A full understanding of cancer requires learning the dynamics of the cancer evolutionary process. We present here a large-scale analysis of the dynamics of this evolutionary process within tumors, with a focus on breast cancer. We show that the cancer evolutionary process differs greatly from organismal (germline) evolution. Organismal evolution is dominated by purifying selection (that removes mutations that are harmful to fitness). In contrast, in the cancer evolutionary process the dominance of purifying selection is much reduced, allowing for a much easier detection of the signals of positive selection (adaptation). We further show that, as a group, genes that are globally expressed across human tissues show a very strong signal of positive selection within tumors. Indeed, known cancer genes are enriched for global expression patterns. Yet, positive selection is prevalent even on globally expressed genes that have not yet been associated with cancer, suggesting that globally expressed genes are enriched for yet undiscovered cancer related functions. We find that the increased positive selection on globally expressed genes within tumors is not due to their expression in the tissue relevant to the cancer. Rather, such increased adaptation is likely due to globally expressed genes being enriched in important housekeeping and essential functions. Thus, our results suggest that tumor adaptation is most often mediated through somatic changes to those genes that are important for the most basic cellular functions. Together, our analysis reveals the uniqueness of the cancer evolutionary process and the particular importance of globally expressed genes in driving cancer initiation and progression. PMID:24603726

  17. Genome-wide scans provide evidence for positive selection of genes implicated in Lassa fever.

    PubMed

    Andersen, Kristian G; Shylakhter, Ilya; Tabrizi, Shervin; Grossman, Sharon R; Happi, Christian T; Sabeti, Pardis C

    2012-03-19

    Rapidly evolving viruses and other pathogens can have an immense impact on human evolution as natural selection acts to increase the prevalence of genetic variants providing resistance to disease. With the emergence of large datasets of human genetic variation, we can search for signatures of natural selection in the human genome driven by such disease-causing microorganisms. Based on this approach, we have previously hypothesized that Lassa virus (LASV) may have been a driver of natural selection in West African populations where Lassa haemorrhagic fever is endemic. In this study, we provide further evidence for this notion. By applying tests for selection to genome-wide data from the International Haplotype Map Consortium and the 1000 Genomes Consortium, we demonstrate evidence for positive selection in LARGE and interleukin 21 (IL21), two genes implicated in LASV infectivity and immunity. We further localized the signals of selection, using the recently developed composite of multiple signals method, to introns and putative regulatory regions of those genes. Our results suggest that natural selection may have targeted variants giving rise to alternative splicing or differential gene expression of LARGE and IL21. Overall, our study supports the hypothesis that selective pressures imposed by LASV may have led to the emergence of particular alleles conferring resistance to Lassa fever, and opens up new avenues of research pursuit.

  18. Ongoing Progress in Spacecraft Controls

    NASA Technical Reports Server (NTRS)

    Ghosh, Dave (Editor)

    1992-01-01

    This publication is a collection of papers presented at the Mars Mission Research Center workshop on Ongoing Progress in Spacecraft Controls. The technical program addressed additional Mars mission control problems that currently exist in robotic missions in addition to human missions. Topics include control systems design in the presence of large time delays, fuel-optimal propulsive control, and adaptive control to handle a variety of unknown conditions.

  19. The effects of alignment error and alignment filtering on the sitewise detection of positive selection.

    PubMed

    Jordan, Gregory; Goldman, Nick

    2012-04-01

    When detecting positive selection in proteins, the prevalence of errors resulting from misalignment and the ability of alignment filters to mitigate such errors are not well understood, but filters are commonly applied to try to avoid false positive results. Focusing on the sitewise detection of positive selection across a wide range of divergence levels and indel rates, we performed simulation experiments to quantify the false positives and false negatives introduced by alignment error and the ability of alignment filters to improve performance. We found that some aligners led to many false positives, whereas others resulted in very few. False negatives were a problem for all aligners, increasing with sequence divergence. Of the aligners tested, PRANK's codon-based alignments consistently performed the best and ClustalW performed the worst. Of the filters tested, GUIDANCE performed the best and Gblocks performed the worst. Although some filters showed good ability to reduce the error rates from ClustalW and MAFFT alignments, none were found to substantially improve the performance of PRANK alignments under most conditions. Our results revealed distinct trends in error rates and power levels for aligners and filters within a biologically plausible parameter space. With the best aligner, a low false positive rate was maintained even with extremely divergent indel-prone sequences. Controls using the true alignment and an optimal filtering method suggested that performance improvements could be gained by improving aligners or filters to reduce the prevalence of false negatives, especially at higher divergence levels and indel rates.

  20. Signatures of positive selection in Toll-like receptor (TLR) genes in mammals

    PubMed Central

    2011-01-01

    Background Toll-like receptors (TLRs) are a major class of pattern recognition receptors (PRRs) expressed in the cell surface or membrane compartments of immune and non-immune cells. TLRs are encoded by a multigene family and represent the first line of defense against pathogens by detecting foreigner microbial molecular motifs, the pathogen-associated molecular patterns (PAMPs). TLRs are also important by triggering the adaptive immunity in vertebrates. They are characterized by the presence of leucine-rich repeats (LRRs) in the ectodomain, which are associated with the PAMPs recognition. The direct recognition of different pathogens by TLRs might result in different evolutionary adaptations important to understand the dynamics of the host-pathogen interplay. Ten mammal TLR genes, viral (TLR3, 7, 8, 9) and non-viral (TLR1-6, 10), were selected to identify signatures of positive selection that might have been imposed by interacting pathogens and to clarify if viral and non-viral TLRs might display different patterns of molecular evolution. Results By using Maximum Likelihood approaches, evidence of positive selection was found in all the TLRs studied. The number of positively selected codons (PSC) ranged between 2-26 codons (0.25%-2.65%) with the non-viral TLR4 as the receptor with higher percentage of positively selected codons (2.65%), followed by the viral TLR8 (2.50%). The results indicated that viral and non-viral TLRs are similarly under positive selection. Almost all TLRs have at least one PSC located in the LRR ectodomain which underlies the importance of the pathogen recognition by this region. Conclusions Our results are not in line with previous studies on primates and birds that identified more codons under positive selection in non-viral TLRs. This might be explained by the fact that both primates and birds are homogeneous groups probably being affected by only a restricted number of related viruses with equivalent motifs to be recognized. The analyses

  1. Three-dimensional window analysis for detecting positive selection at structural regions of proteins.

    PubMed

    Suzuki, Yoshiyuki

    2004-12-01

    Detection of natural selection operating at the amino acid sequence level is important in the study of molecular evolution. Single-site analysis and one-dimensional window analysis can be used to detect selection when the biological functions of amino acid sites are unknown. Single-site analysis is useful when selection operates more or less constantly over evolutionary time, but less so when selection operates temporarily. One-dimensional window analysis is more sensitive than single-site analysis when the functions of amino acid sites in close proximity in the linear sequence are similar, although this is not always the case. Here I present a three-dimensional window analysis method for detecting selection given the three-dimensional structure of the protein of interest. In the three-dimensional structure, the window is defined as the sphere centered on the alpha-carbon of an amino acid site. The window size is the radius of the sphere. The sites whose alpha-carbons are included in the window are grouped for the neutrality test. The window is moved within the three-dimensional structure by sequentially moving the central site along the primary amino acid sequence. To detect positive selection, it may also be useful to group the surface-exposed sites in the window separately. Three-dimensional window analysis appears not only to be more sensitive than single-site analysis and one-dimensional window analysis but also to provide similar specificity for inferring positive selection in the analyses of the hemagglutinin and neuraminidase genes of human influenza A viruses. This method, however, may fail to detect selection when it operates only on a particular site, in which case single-site analysis may be preferred, although a large number of sequences is required.

  2. 'Obesity' is healthy for cetaceans? Evidence from pervasive positive selection in genes related to triacylglycerol metabolism.

    PubMed

    Wang, Zhengfei; Chen, Zhuo; Xu, Shixia; Ren, Wenhua; Zhou, Kaiya; Yang, Guang

    2015-09-18

    Cetaceans are a group of secondarily adapted marine mammals with an enigmatic history of transition from terrestrial to fully aquatic habitat and subsequent adaptive radiation in waters around the world. Numerous physiological and morphological cetacean characteristics have been acquired in response to this drastic habitat transition; for example, the thickened blubber is one of the most striking changes that increases their buoyancy, supports locomotion, and provides thermal insulation. However, the genetic basis underlying the blubber thickening in cetaceans remains poorly explored. Here, 88 candidate genes associated with triacylglycerol metabolism were investigated in representative cetaceans and other mammals to test whether the thickened blubber matched adaptive evolution of triacylglycerol metabolism-related genes. Positive selection was detected in 41 of the 88 candidate genes, and functional characterization of these genes indicated that these are involved mainly in triacylglycerol synthesis and lipolysis processes. In addition, some essential regulatory genes underwent significant positive selection in cetacean-specific lineages, whereas no selection signal was detected in the counterpart terrestrial mammals. The extensive occurrence of positive selection in triacylglycerol metabolism-related genes is suggestive of their essential role in secondary adaptation to an aquatic life, and further implying that 'obesity' might be an indicator of good health for cetaceans.

  3. Detecting signatures of positive selection associated with musical aptitude in the human genome

    PubMed Central

    Liu, Xuanyao; Kanduri, Chakravarthi; Oikkonen, Jaana; Karma, Kai; Raijas, Pirre; Ukkola-Vuoti, Liisa; Teo, Yik-Ying; Järvelä, Irma

    2016-01-01

    Abilities related to musical aptitude appear to have a long history in human evolution. To elucidate the molecular and evolutionary background of musical aptitude, we compared genome-wide genotyping data (641 K SNPs) of 148 Finnish individuals characterized for musical aptitude. We assigned signatures of positive selection in a case-control setting using three selection methods: haploPS, XP-EHH and FST. Gene ontology classification revealed that the positive selection regions contained genes affecting inner-ear development. Additionally, literature survey has shown that several of the identified genes were known to be involved in auditory perception (e.g. GPR98, USH2A), cognition and memory (e.g. GRIN2B, IL1A, IL1B, RAPGEF5), reward mechanisms (RGS9), and song perception and production of songbirds (e.g. FOXP1, RGS9, GPR98, GRIN2B). Interestingly, genes related to inner-ear development and cognition were also detected in a previous genome-wide association study of musical aptitude. However, the candidate genes detected in this study were not reported earlier in studies of musical abilities. Identification of genes related to language development (FOXP1 and VLDLR) support the popular hypothesis that music and language share a common genetic and evolutionary background. The findings are consistent with the evolutionary conservation of genes related to auditory processes in other species and provide first empirical evidence for signatures of positive selection for abilities that contribute to musical aptitude. PMID:26879527

  4. Detecting signatures of positive selection associated with musical aptitude in the human genome.

    PubMed

    Liu, Xuanyao; Kanduri, Chakravarthi; Oikkonen, Jaana; Karma, Kai; Raijas, Pirre; Ukkola-Vuoti, Liisa; Teo, Yik-Ying; Järvelä, Irma

    2016-02-16

    Abilities related to musical aptitude appear to have a long history in human evolution. To elucidate the molecular and evolutionary background of musical aptitude, we compared genome-wide genotyping data (641 K SNPs) of 148 Finnish individuals characterized for musical aptitude. We assigned signatures of positive selection in a case-control setting using three selection methods: haploPS, XP-EHH and FST. Gene ontology classification revealed that the positive selection regions contained genes affecting inner-ear development. Additionally, literature survey has shown that several of the identified genes were known to be involved in auditory perception (e.g. GPR98, USH2A), cognition and memory (e.g. GRIN2B, IL1A, IL1B, RAPGEF5), reward mechanisms (RGS9), and song perception and production of songbirds (e.g. FOXP1, RGS9, GPR98, GRIN2B). Interestingly, genes related to inner-ear development and cognition were also detected in a previous genome-wide association study of musical aptitude. However, the candidate genes detected in this study were not reported earlier in studies of musical abilities. Identification of genes related to language development (FOXP1 and VLDLR) support the popular hypothesis that music and language share a common genetic and evolutionary background. The findings are consistent with the evolutionary conservation of genes related to auditory processes in other species and provide first empirical evidence for signatures of positive selection for abilities that contribute to musical aptitude.

  5. Orexin A/hypocretin-1 selectively promotes motivation for positive reinforcers.

    PubMed

    Borgland, Stephanie L; Chang, Shao-Ju; Bowers, M Scott; Thompson, Jennifer L; Vittoz, Nicole; Floresco, Stan B; Chou, Jonathan; Chen, Billy T; Bonci, Antonello

    2009-09-09

    Orexin A/hypocretin-1 (oxA/hcrt-1) is known to be a modulator of dopamine-dependent neuronal activity and behaviors. However, the role of this system in driving motivated behaviors remains poorly understood. Here, we show that orexin/hypocretin receptor-1 (ox/hcrt-1R) signaling is important for motivation for highly salient, positive reinforcement. Blockade of ox/hcrt-1R selectively reduced work to self-administer cocaine or high fat food pellets. Moreover, oxA/hcrt-1 strengthened presynaptic glutamatergic inputs to the ventral tegmental area (VTA) only in cocaine or high fat self-administering rats. Finally, oxA/hcrt-1-mediated excitatory synaptic transmission onto VTA neurons was not potentiated following an arousing, aversive stimulus, suggesting that oxA/hcrt-1-mediated glutamatergic synaptic transmission was potentiated selectively with highly salient positive reinforcers. These experiments provide evidence for a selective role of oxA/hcrt-1 signaling in motivation for highly salient reinforcers and may represent a unique opportunity to design novel therapies that selectively reduce excessive drive to consume positive reinforcers of high salience.

  6. Evidence for the fixation of gene duplications by positive selection in Drosophila

    PubMed Central

    Cardoso-Moreira, Margarida; Arguello, J. Roman; Gottipati, Srikanth; Harshman, L.G.; Grenier, Jennifer K.; Clark, Andrew G.

    2016-01-01

    Gene duplications play a key role in the emergence of novel traits and in adaptation. But despite their centrality to evolutionary processes, it is still largely unknown how new gene duplicates are initially fixed within populations and later maintained in genomes. Long-standing debates on the evolution of gene duplications could be settled by determining the relative importance of genetic drift vs. positive selection in the fixation of new gene duplicates. Using the Drosophila Global Diversity Lines (GDL), we have combined genome-wide SNP polymorphism data with a novel set of copy number variant calls and gene expression profiles to characterize the polymorphic phase of new genes. We found that approximately half of the roughly 500 new complete gene duplications segregating in the GDL lead to significant increases in the expression levels of the duplicated genes and that these duplications are more likely to be found at lower frequencies, suggesting a negative impact on fitness. However, we also found that six of the nine gene duplications that are fixed or close to fixation in at least one of the five populations in our study show signs of being under positive selection, and that these duplications are likely beneficial because of dosage effects, with a possible role for additional mutations in two duplications. Our work suggests that in Drosophila, theoretical models that posit that gene duplications are immediately beneficial and fixed by positive selection are most relevant to explain the long-term evolution of gene duplications in this species. PMID:27197209

  7. Evidence for Positive Selection on the Leptin Gene in Cetacea and Pinnipedia

    PubMed Central

    Zhang, Xin; Wang, Ding; Zheng, Jin-song; Yang, Guang; Xu, Shi-xia; Cho, Soochin; Zhang, Ya-ping

    2011-01-01

    The leptin gene has received intensive attention and scientific investigation for its importance in energy homeostasis and reproductive regulation in mammals. Furthermore, study of the leptin gene is of crucial importance for public health, particularly for its role in obesity, as well as for other numerous physiological roles that it plays in mammals. In the present work, we report the identification of novel leptin genes in 4 species of Cetacea, and a comparison with 55 publicly available leptin sequences from mammalian genome assemblies and previous studies. Our study provides evidence for positive selection in the suborder Odontoceti (toothed whales) of the Cetacea and the family Phocidae (earless seals) of the Pinnipedia. We also detected positive selection in several leptin gene residues in these two lineages. To test whether leptin and its receptor evolved in a coordinated manner, we analyzed 24 leptin receptor gene (LPR) sequences from available mammalian genome assemblies and other published data. Unlike the case of leptin, our analyses did not find evidence of positive selection for LPR across the Cetacea and Pinnipedia lineages. In line with this, positively selected sites identified in the leptin genes of these two lineages were located outside of leptin receptor binding sites, which at least partially explains why co-evolution of leptin and its receptor was not observed in the present study. Our study provides interesting insights into current understanding of the evolution of mammalian leptin genes in response to selective pressures from life in an aquatic environment, and leads to a hypothesis that new tissue specificity or novel physiologic functions of leptin genes may have arisen in both odontocetes and phocids. Additional data from other species encompassing varying life histories and functional tests of the adaptive role of the amino acid changes identified in this study will help determine the factors that promote the adaptive evolution of the

  8. Evidence for positive selection on the leptin gene in Cetacea and Pinnipedia.

    PubMed

    Yu, Li; Jin, Wei; Zhang, Xin; Wang, Ding; Zheng, Jin-song; Yang, Guang; Xu, Shi-xia; Cho, Soochin; Zhang, Ya-ping

    2011-01-01

    The leptin gene has received intensive attention and scientific investigation for its importance in energy homeostasis and reproductive regulation in mammals. Furthermore, study of the leptin gene is of crucial importance for public health, particularly for its role in obesity, as well as for other numerous physiological roles that it plays in mammals. In the present work, we report the identification of novel leptin genes in 4 species of Cetacea, and a comparison with 55 publicly available leptin sequences from mammalian genome assemblies and previous studies. Our study provides evidence for positive selection in the suborder Odontoceti (toothed whales) of the Cetacea and the family Phocidae (earless seals) of the Pinnipedia. We also detected positive selection in several leptin gene residues in these two lineages. To test whether leptin and its receptor evolved in a coordinated manner, we analyzed 24 leptin receptor gene (LPR) sequences from available mammalian genome assemblies and other published data. Unlike the case of leptin, our analyses did not find evidence of positive selection for LPR across the Cetacea and Pinnipedia lineages. In line with this, positively selected sites identified in the leptin genes of these two lineages were located outside of leptin receptor binding sites, which at least partially explains why co-evolution of leptin and its receptor was not observed in the present study. Our study provides interesting insights into current understanding of the evolution of mammalian leptin genes in response to selective pressures from life in an aquatic environment, and leads to a hypothesis that new tissue specificity or novel physiologic functions of leptin genes may have arisen in both odontocetes and phocids. Additional data from other species encompassing varying life histories and functional tests of the adaptive role of the amino acid changes identified in this study will help determine the factors that promote the adaptive evolution of the

  9. Positive selection in the SLC11A1 gene in the family Equidae.

    PubMed

    Bayerova, Zuzana; Janova, Eva; Matiasovic, Jan; Orlando, Ludovic; Horin, Petr

    2016-05-01

    Immunity-related genes are a suitable model for studying effects of selection at the genomic level. Some of them are highly conserved due to functional constraints and purifying selection, while others are variable and change quickly to cope with the variation of pathogens. The SLC11A1 gene encodes a transporter protein mediating antimicrobial activity of macrophages. Little is known about the patterns of selection shaping this gene during evolution. Although it is a typical evolutionarily conserved gene, functionally important polymorphisms associated with various diseases were identified in humans and other species. We analyzed the genomic organization, genetic variation, and evolution of the SLC11A1 gene in the family Equidae to identify patterns of selection within this important gene. Nucleotide SLC11A1 sequences were shown to be highly conserved in ten equid species, with more than 97 % sequence identity across the family. Single nucleotide polymorphisms (SNPs) were found in the coding and noncoding regions of the gene. Seven codon sites were identified to be under strong purifying selection. Codons located in three regions, including the glycosylated extracellular loop, were shown to be under diversifying selection. A 3-bp indel resulting in a deletion of the amino acid 321 in the predicted protein was observed in all horses, while it has been maintained in all other equid species. This codon comprised in an N-glycosylation site was found to be under positive selection. Interspecific variation in the presence of predicted N-glycosylation sites was observed.

  10. Synthesis and applications of RNAs with position-selective labeling and mosaic composition

    PubMed Central

    Liu, Yu; Holmstrom, Erik; Zhang, Jinwei; Yu, Ping; Wang, Jinbu; Dyba, Marzena A.; Chen, De; Ying, Jinfa; Lockett, Stephen; Nesbitt, David J.; Ferré-D'Amaré, Adrian R.; Sousa, Rui; Stagno, Jason R.; Wang, Yun-Xing

    2015-01-01

    Knowledge of the structure and dynamics of RNA molecules is critical to understand their many biological functions. Furthermore, synthetic RNAs have applications as therapeutics and molecular sensors. Both research and technological applications of RNA would be significantly enhanced by methods that enable incorporation of modified or labeled nucleotides into specifically designated positions or regions of RNA. However, the synthesis of tens of milligrams of such RNAs using existing methods has been impossible. We have developed a hybrid solid-liquid phase transcription method and automated robotic platform for the synthesis of RNAs with position-selective labeling. We demonstrate its utility by successfully preparing various isotope- or fluorescently-labeled versions of the 71-nucleotide aptamer domain of an adenine riboswitch1 for nuclear magnetic resonance (NMR) spectroscopy or single molecule Förster resonance-energy transfer (smFRET), respectively. Those RNAs include molecules that were selectively isotope-labeled in specific loops, linkers, a helix, several discrete positions, or a single internal position, as well as RNA molecules that were fluorescently-labeled in and near kissing loops. These selectively labeled RNAs have the same fold as those transcribed using conventional methods, but greatly simplified the interpretation of NMR spectra. The single-position isotope-labeled and fluorescently-labeled RNA samples revealed multiple conformational states of the adenine riboswitch. Lastly, we describe a robotic platform and the operation that automates this technology. Our selective labeling method may be useful for studying RNA structure and dynamics and for making RNA sensors for a variety of applications including cell-biological studies, substance detection2 and disease diagnostics3,4. PMID:25938715

  11. Diversification of the ant odorant receptor gene family and positive selection on candidate cuticular hydrocarbon receptors.

    PubMed

    Engsontia, Patamarerk; Sangket, Unitsa; Robertson, Hugh M; Satasook, Chutamas

    2015-08-27

    Chemical communication plays important roles in the social behavior of ants making them one of the most successful groups of animals on earth. However, the molecular evolutionary process responsible for their chemosensory adaptation is still elusive. Recent advances in genomic studies have led to the identification of large odorant receptor (Or) gene repertoires from ant genomes providing fruitful materials for molecular evolution analysis. The aim of this study was to test the hypothesis that diversification of this gene family is involved in olfactory adaptation of each species. We annotated the Or genes from the genome sequences of two leaf-cutter ants, Acromyrmex echinatior and Atta cephalotes (385 and 376 putative functional genes, respectively). These were used, together with Or genes from Camponotus floridanus, Harpegnathos saltator, Pogonomyrmex barbatus, Linepithema humile, Cerapachys biroi, Solenopsis invicta and Apis mellifera, in molecular evolution analysis. Like the Or family in other insects, ant Or genes evolve by the birth-and-death model of gene family evolution. Large gene family expansions involving tandem gene duplications, and gene gains outnumbering losses, are observed. Codon analysis of genes in lineage-specific expansion clades revealed signatures of positive selection on the candidate cuticular hydrocarbon receptor genes (9-exon subfamily) of Cerapachys biroi, Camponotus floridanus, Acromyrmex echinatior and Atta cephalotes. Positively selected amino acid positions are primarily in transmembrane domains 3 and 6, which are hypothesized to contribute to the odor-binding pocket, presumably mediating changing ligand specificity. This study provides support for the hypothesis that some ant lineage-specific Or genes have evolved under positive selection. Newly duplicated genes particularly in the candidate cuticular hydrocarbon receptor clade that have evolved under positive selection may contribute to the highly sophisticated lineage

  12. Detecting recent positive selection with high accuracy and reliability by conditional coalescent tree.

    PubMed

    Wang, Minxian; Huang, Xin; Li, Ran; Xu, Hongyang; Jin, Li; He, Yungang

    2014-11-01

    Studies of natural selection, followed by functional validation, are shedding light on understanding of genetic mechanisms underlying human evolution and adaptation. Classic methods for detecting selection, such as the integrated haplotype score (iHS) and Fay and Wu's H statistic, are useful for candidate gene searching underlying positive selection. These methods, however, have limited capability to localize causal variants in selection target regions. In this study, we developed a novel method based on conditional coalescent tree to detect recent positive selection by counting unbalanced mutations on coalescent gene genealogies. Extensive simulation studies revealed that our method is more robust than many other approaches against biases due to various demographic effects, including population bottleneck, expansion, or stratification, while not sacrificing its power. Furthermore, our method demonstrated its superiority in localizing causal variants from massive linked genetic variants. The rate of successful localization was about 20-40% higher than that of other state-of-the-art methods on simulated data sets. On empirical data, validated functional causal variants of four well-known positive selected genes were all successfully localized by our method, such as ADH1B, MCM6, APOL1, and HBB. Finally, the computational efficiency of this new method was much higher than that of iHS implementations, that is, 24-66 times faster than the REHH package, and more than 10,000 times faster than the original iHS implementation. These magnitudes make our method suitable for applying on large sequencing data sets. Software can be downloaded from https://github.com/wavefancy/scct.

  13. Evidence of Positive Selection of Aquaporins Genes from Pontoporia blainvillei during the Evolutionary Process of Cetaceans.

    PubMed

    São Pedro, Simone Lima; Alves, João Marcelo Pereira; Barreto, André Silva; Lima, André Oliveira de Souza

    2015-01-01

    Marine mammals are well adapted to their hyperosmotic environment. Several morphological and physiological adaptations for water conservation and salt excretion are known to be present in cetaceans, being responsible for regulating salt balance. However, most previous studies have focused on the unique renal physiology of marine mammals, but the molecular bases of these mechanisms remain poorly explored. Many genes have been identified to be involved in osmotic regulation, including the aquaporins. Considering that aquaporin genes were potentially subject to strong selective pressure, the aim of this study was to analyze the molecular evolution of seven aquaporin genes (AQP1, AQP2, AQP3, AQP4, AQP6, AQP7, and AQP9) comparing the lineages of cetaceans and terrestrial mammals. Our results demonstrated strong positive selection in cetacean-specific lineages acting only in the gene for AQP2 (amino acids 23, 83, 107,179, 180, 181, 182), whereas no selection was observed in terrestrial mammalian lineages. We also analyzed the changes in the 3D structure of the aquaporin 2 protein. Signs of strong positive selection in AQP2 sites 179, 180, 181, and 182 were unexpectedly identified only in the baiji lineage, which was the only river dolphin examined in this study. Positive selection in aquaporins AQP1 (45), AQP4 (74), AQP7 (342, 343, 356) was detected in cetaceans and artiodactyls, suggesting that these events are not related to maintaining water and electrolyte homeostasis in seawater. Our results suggest that the AQP2 gene might reflect different selective pressures in maintaining water balance in cetaceans, contributing to the passage from the terrestrial environment to the aquatic. Further studies are necessary, especially those including other freshwater dolphins, who exhibit osmoregulatory mechanisms different from those of marine cetaceans for the same essential task of maintaining serum electrolyte balance.

  14. Evidence of Positive Selection of Aquaporins Genes from Pontoporia blainvillei during the Evolutionary Process of Cetaceans

    PubMed Central

    São Pedro, Simone Lima; Alves, João Marcelo Pereira; Barreto, André Silva; Lima, André Oliveira de Souza

    2015-01-01

    Background Marine mammals are well adapted to their hyperosmotic environment. Several morphological and physiological adaptations for water conservation and salt excretion are known to be present in cetaceans, being responsible for regulating salt balance. However, most previous studies have focused on the unique renal physiology of marine mammals, but the molecular bases of these mechanisms remain poorly explored. Many genes have been identified to be involved in osmotic regulation, including the aquaporins. Considering that aquaporin genes were potentially subject to strong selective pressure, the aim of this study was to analyze the molecular evolution of seven aquaporin genes (AQP1, AQP2, AQP3, AQP4, AQP6, AQP7, and AQP9) comparing the lineages of cetaceans and terrestrial mammals. Results Our results demonstrated strong positive selection in cetacean-specific lineages acting only in the gene for AQP2 (amino acids 23, 83, 107,179, 180, 181, 182), whereas no selection was observed in terrestrial mammalian lineages. We also analyzed the changes in the 3D structure of the aquaporin 2 protein. Signs of strong positive selection in AQP2 sites 179, 180, 181, and 182 were unexpectedly identified only in the baiji lineage, which was the only river dolphin examined in this study. Positive selection in aquaporins AQP1 (45), AQP4 (74), AQP7 (342, 343, 356) was detected in cetaceans and artiodactyls, suggesting that these events are not related to maintaining water and electrolyte homeostasis in seawater. Conclusions Our results suggest that the AQP2 gene might reflect different selective pressures in maintaining water balance in cetaceans, contributing to the passage from the terrestrial environment to the aquatic. Further studies are necessary, especially those including other freshwater dolphins, who exhibit osmoregulatory mechanisms different from those of marine cetaceans for the same essential task of maintaining serum electrolyte balance. PMID:26226365

  15. Positive Selection Pressure Drives Variation on the Surface-Exposed Variable Proteins of the Pathogenic Neisseria

    PubMed Central

    Hill, Stuart

    2016-01-01

    Pathogenic species of Neisseria utilize variable outer membrane proteins to facilitate infection and proliferation within the human host. However, the mechanisms behind the evolution of these variable alleles remain largely unknown due to analysis of previously limited datasets. In this study, we have expanded upon the previous analyses to substantially increase the number of analyzed sequences by including multiple diverse strains, from various geographic locations, to determine whether positive selective pressure is exerted on the evolution of these variable genes. Although Neisseria are naturally competent, this analysis indicates that only intrastrain horizontal gene transfer among the pathogenic Neisseria principally account for these genes exhibiting linkage equilibrium which drives the polymorphisms evidenced within these alleles. As the majority of polymorphisms occur across species, the divergence of these variable genes is dependent upon the species and is independent of geographical location, disease severity, or serogroup. Tests of neutrality were able to detect strong selection pressures acting upon both the opa and pil gene families, and were able to locate the majority of these sites within the exposed variable regions of the encoded proteins. Evidence of positive selection acting upon the hypervariable domains of Opa contradicts previous beliefs and provides evidence for selection of receptor binding. As the pathogenic Neisseria reside exclusively within the human host, the strong selection pressures acting upon both the opa and pil gene families provide support for host immune system pressure driving sequence polymorphisms within these variable genes. PMID:27532335

  16. FOXP2 targets show evidence of positive selection in European populations.

    PubMed

    Ayub, Qasim; Yngvadottir, Bryndis; Chen, Yuan; Xue, Yali; Hu, Min; Vernes, Sonja C; Fisher, Simon E; Tyler-Smith, Chris

    2013-05-02

    Forkhead box P2 (FOXP2) is a highly conserved transcription factor that has been implicated in human speech and language disorders and plays important roles in the plasticity of the developing brain. The pattern of nucleotide polymorphisms in FOXP2 in modern populations suggests that it has been the target of positive (Darwinian) selection during recent human evolution. In our study, we searched for evidence of selection that might have followed FOXP2 adaptations in modern humans. We examined whether or not putative FOXP2 targets identified by chromatin-immunoprecipitation genomic screening show evidence of positive selection. We developed an algorithm that, for any given gene list, systematically generates matched lists of control genes from the Ensembl database, collates summary statistics for three frequency-spectrum-based neutrality tests from the low-coverage resequencing data of the 1000 Genomes Project, and determines whether these statistics are significantly different between the given gene targets and the set of controls. Overall, there was strong evidence of selection of FOXP2 targets in Europeans, but not in the Han Chinese, Japanese, or Yoruba populations. Significant outliers included several genes linked to cellular movement, reproduction, development, and immune cell trafficking, and 13 of these constituted a significant network associated with cardiac arteriopathy. Strong signals of selection were observed for CNTNAP2 and RBFOX1, key neurally expressed genes that have been consistently identified as direct FOXP2 targets in multiple studies and that have themselves been associated with neurodevelopmental disorders involving language dysfunction.

  17. Positive Selection Pressure Drives Variation on the Surface-Exposed Variable Proteins of the Pathogenic Neisseria.

    PubMed

    Wachter, Jenny; Hill, Stuart

    2016-01-01

    Pathogenic species of Neisseria utilize variable outer membrane proteins to facilitate infection and proliferation within the human host. However, the mechanisms behind the evolution of these variable alleles remain largely unknown due to analysis of previously limited datasets. In this study, we have expanded upon the previous analyses to substantially increase the number of analyzed sequences by including multiple diverse strains, from various geographic locations, to determine whether positive selective pressure is exerted on the evolution of these variable genes. Although Neisseria are naturally competent, this analysis indicates that only intrastrain horizontal gene transfer among the pathogenic Neisseria principally account for these genes exhibiting linkage equilibrium which drives the polymorphisms evidenced within these alleles. As the majority of polymorphisms occur across species, the divergence of these variable genes is dependent upon the species and is independent of geographical location, disease severity, or serogroup. Tests of neutrality were able to detect strong selection pressures acting upon both the opa and pil gene families, and were able to locate the majority of these sites within the exposed variable regions of the encoded proteins. Evidence of positive selection acting upon the hypervariable domains of Opa contradicts previous beliefs and provides evidence for selection of receptor binding. As the pathogenic Neisseria reside exclusively within the human host, the strong selection pressures acting upon both the opa and pil gene families provide support for host immune system pressure driving sequence polymorphisms within these variable genes.

  18. Selective Androgen Receptor Modulator in a Patient With Hormone-Positive Metastatic Breast Cancer.

    PubMed

    Vontela, Namratha; Koduri, Vamsi; Schwartzberg, Lee S; Vidal, Gregory A

    2017-03-01

    Androgen receptors (ARs) are highly coexpressed in estrogen receptor (ER)-positive breast cancers. Their role in breast tumorigenesis has been postulated, but the mechanism is not yet well-characterized. Steroidal androgens were previously used as an anticancer strategy but fell out of favor because of toxicity and the discovery of alternative therapies. Recent attempts to modulate androgen pathway signaling have focused on AR inhibitors. This report discusses a case using a well-tolerated selective AR modulator to treat a highly pretreated patient with ER-positive breast cancer, which resulted in a durable partial response. Copyright © 2017 by the National Comprehensive Cancer Network.

  19. Positive and purifying selection in mitochondrial genomes of a bird with mitonuclear discordance.

    PubMed

    Morales, Hernán E; Pavlova, Alexandra; Joseph, Leo; Sunnucks, Paul

    2015-06-01

    Diversifying selection on metabolic pathways can reduce intraspecific gene flow and promote population divergence. An opportunity to explore this arises from mitonuclear discordance observed in an Australian bird Eopsaltria australis. Across >1500 km, nuclear differentiation is low and latitudinally structured by isolation by distance, whereas two highly divergent, parapatric mitochondrial lineages (>6.6% in ND2) show a discordant longitudinal geographic pattern and experience different climates. Vicariance, incomplete lineage sorting and sex-biased dispersal were shown earlier to be unlikely drivers of the mitonuclear discordance; instead, natural selection on a female-linked trait was the preferred hypothesis. Accordingly, here we tested for signals of positive, divergent selection on mitochondrial genes in E. australis. We used codon models and physicochemical profiles of amino acid replacements to analyse complete mitochondrial genomes of the two mitochondrial lineages in E. australis, its sister species Eopsaltria griseogularis, and outgroups. We found evidence of positive selection on at least five amino acids, encoded by genes of two oxidative phosphorylation pathway complexes NADH dehydrogenase (ND4 and ND4L) and cytochrome bc1 (cyt-b) against a background of widespread purifying selection on all mitochondrial genes. Three of these amino acid replacements were fixed in ND4 of the geographically most widespread E. australis lineage. The other two replacements were fixed in ND4L and cyt-b of the geographically more restricted E. australis lineage. We discuss whether this selection may reflect local environmental adaptation, a by-product of other selective processes, or genetic incompatibilities, and propose how these hypotheses can be tested in future.

  20. Transient inflammation-induced ongoing pain is driven by TRPV1 sensitive afferents.

    PubMed

    Okun, Alec; DeFelice, Milena; Eyde, Nathan; Ren, Jiyang; Mercado, Ramon; King, Tamara; Porreca, Frank

    2011-01-10

    Tissue injury elicits both hypersensitivity to evoked stimuli and ongoing, stimulus-independent pain. We previously demonstrated that pain relief elicits reward in nerve-injured rats. This approach was used to evaluate the temporal and mechanistic features of inflammation-induced ongoing pain. Intraplantar Complete Freund's Adjuvant (CFA) produced thermal hyperalgesia and guarding behavior that was reliably observed within 24 hrs and maintained, albeit diminished, 4 days post-administration. Spinal clonidine produced robust conditioned place preference (CPP) in CFA treated rats 1 day, but not 4 days following CFA administration. However, spinal clonidine blocked CFA-induced thermal hyperalgesia at both post-CFA days 1 and 4, indicating different time-courses of ongoing and evoked pain. Peripheral nerve block by lidocaine administration into the popliteal fossa 1 day following intraplantar CFA produced a robust preference for the lidocaine paired chamber, indicating that injury-induced ongoing pain is driven by afferent fibers innervating the site of injury. Pretreatment with resiniferatoxin (RTX), an ultrapotent capsaicin analogue known to produce long-lasting desensitization of TRPV1 positive afferents, fully blocked CFA-induced thermal hypersensitivity and abolished the CPP elicited by administration of popliteal fossa lidocaine 24 hrs post-CFA. In addition, RTX pretreatment blocked guarding behavior observed 1 day following intraplantar CFA. In contrast, administration of the selective TRPV1 receptor antagonist, AMG9810, at a dose that reversed CFA-induced thermal hyperalgesia failed to reduce CFA-induced ongoing pain or guarding behavior. These data demonstrate that inflammation induces both ongoing pain and evoked hypersensitivity that can be differentiated on the basis of time course. Ongoing pain (a) is transient, (b) driven by peripheral input resulting from the injury, (c) dependent on TRPV1 positive fibers and (d) not blocked by TRPV1 receptor antagonism

  1. Positive selection moments identify potential functional residues in human olfactory receptors

    NASA Technical Reports Server (NTRS)

    Singer, M. S.; Weisinger-Lewin, Y.; Lancet, D.; Shepherd, G. M.

    1996-01-01

    Correlated mutation analysis and molecular models of olfactory receptors have provided evidence that residues in the transmembrane domains form a binding pocket for odor ligands. As an independent test of these results, we have calculated positive selection moments for the alpha-helical sixth transmembrane domain (TM6) of human olfactory receptors. The moments can be used to identify residues that have been preferentially affected by positive selection and are thus likely to interact with odor ligands. The results suggest that residue 622, which is commonly a serine or threonine, could form critical H-bonds. In some receptors a dual-serine subsite, formed by residues 622 and 625, could bind hydroxyl determinants on odor ligands. The potential importance of these residues is further supported by site-directed mutagenesis in the beta-adrenergic receptor. The findings should be of practical value for future physiological studies, binding assays, and site-directed mutagenesis.

  2. Positive selection moments identify potential functional residues in human olfactory receptors

    NASA Technical Reports Server (NTRS)

    Singer, M. S.; Weisinger-Lewin, Y.; Lancet, D.; Shepherd, G. M.

    1996-01-01

    Correlated mutation analysis and molecular models of olfactory receptors have provided evidence that residues in the transmembrane domains form a binding pocket for odor ligands. As an independent test of these results, we have calculated positive selection moments for the alpha-helical sixth transmembrane domain (TM6) of human olfactory receptors. The moments can be used to identify residues that have been preferentially affected by positive selection and are thus likely to interact with odor ligands. The results suggest that residue 622, which is commonly a serine or threonine, could form critical H-bonds. In some receptors a dual-serine subsite, formed by residues 622 and 625, could bind hydroxyl determinants on odor ligands. The potential importance of these residues is further supported by site-directed mutagenesis in the beta-adrenergic receptor. The findings should be of practical value for future physiological studies, binding assays, and site-directed mutagenesis.

  3. Evolutionary analysis of TLR9 genes reveals the positive selection of extant teleosts in Perciformes.

    PubMed

    Zhu, Zhihuang; Sun, Yuena; Wang, Rixin; Xu, Tianjun

    2013-08-01

    The innate immune system can recognize non-self through pattern recognition receptors. Toll-like receptors were the best-known members of these receptors, and they could sense, recognize, and bind pathogen-associated molecular patterns. TLRs played an important role in innate immune system and were conserved in both invertebrate and vertebrate lineages. Thereinto, TLR9 could detect unmethylated CpG motifs in dsDNA and was expected to undergo coevolution with its microbial ligands. It was known that aquatic and terrestrial organisms dwelled in different environments which contained different pathogens, and they had to adapt to their local environmental conditions. Therefore, we collected TLR9 genes from invertebrate to vertebrate to further explore whether the huge differences between aquatic and terrestrial environments affected the TLR9s evolution between aquatic and terrestrial organisms. Molecular evolution analysis detected positively selected sites in the ancestral lineages of vertebrates, teleosts, and Perciformes but not in the ancestral lineage of mammals. In PAML, site model revealed that extant mammalian TLR9 genes underwent positive selection. However, the positive selection of extant teleosts appeared primarily in Perciformes in which there were 14 positively selected sites. Among these sites, two of them were located on the amino acid insertions of the leucine-rich repeats which could create DNA binding sites, three were found on the convex surface which might possibly affect the flexibility of the TLR solenoids, and six were located on the β-face of concave surface which contained the ligand-binding sites of the TLR solenoids. In other ML methods, we also found three sites under selection that coincided with the codons identified by M8 and these sites were all located in LRRs. The diverse aquatic and terrestrial environments might possess different pathogens to make the living organisms adapt to their local environmental conditions. The positive

  4. Positive selection is the main driving force for evolution of citrus canker-causing Xanthomonas.

    PubMed

    Zhang, Yunzeng; Jalan, Neha; Zhou, Xiaofeng; Goss, Erica; Jones, Jeffrey B; Setubal, João C; Deng, Xiaoling; Wang, Nian

    2015-10-01

    Understanding the evolutionary history and potential of bacterial pathogens is critical to prevent the emergence of new infectious bacterial diseases. Xanthomonas axonopodis subsp. citri (Xac) (synonym X. citri subsp. citri), which causes citrus canker, is one of the hardest-fought plant bacterial pathogens in US history. Here, we sequenced 21 Xac strains (14 XacA, 3 XacA* and 4 XacA(w)) with different host ranges from North America and Asia and conducted comparative genomic and evolutionary analyses. Our analyses suggest that acquisition of beneficial genes and loss of detrimental genes most likely allowed XacA to infect a broader range of hosts as compared with XacA(w) and XacA*. Recombination was found to have occurred frequently on the relative ancient branches, but rarely on the young branches of the clonal genealogy. The ratio of recombination/mutation ρ/θ was 0.0790±0.0005, implying that the Xac population was clonal in structure. Positive selection has affected 14% (395 out of 2822) of core genes of the citrus canker-causing Xanthomonas. The genes affected are enriched in 'carbohydrate transport and metabolism' and 'DNA replication, recombination and repair' genes (P<0.05). Many genes related to virulence, especially genes involved in the type III secretion system and effectors, are affected by positive selection, further highlighting the contribution of positive selection to the evolution of citrus canker-causing Xanthomonas. Our results suggest that both metabolism and virulence genes provide advantages to endow XacA with higher virulence and a wider host range. Our analysis advances our understanding of the genomic basis of specialization by positive selection in bacterial evolution.

  5. Relation between flexibility and positively selected HIV-1 protease mutants against inhibitors.

    PubMed

    Braz, Antônio S K; Tufanetto, Patrícia; Perahia, David; Scott, Luis P B

    2012-12-01

    The antiretroviral chemotherapy helps to reduce the mortality of HIVs infected patients. However, RNA dependant virus replication has a high mutation rate. Human immunodeficiency virus Type 1 protease plays an essential role in viral replication cycle. This protein is an important target for therapy with viral protein inhibitors. There are few works using normal mode analysis to investigate this problem from the structural changes viewpoint. The investigation of protein flexibility may be important for the study of processes associated with conformational changes and state transitions. The normal mode analysis allowed us to investigate structural changes in the protease (such as flexibility) in a straightforward way and try to associate these changes with the increase of fitness for each positively selected HIV-1 mutant protease of patients treated with several protease inhibitors (saquinavir, indinavir, ritonavir, nelfinavir, lopinavir, fosamprenavir, atazanavir, darunavir, and tripanavir) in combination or separately. These positively selected mutations introduce significant flexibility in important regions such as the active site cavity and flaps. These mutations were also able to cause changes in accessible solvent area. This study showed that the majority of HIV-1 protease mutants can be grouped into two main classes of protein flexibility behavior. We presented a new approach to study structural changes caused by positively selected mutations in a pathogen protein, for instance the HIV-1 protease and their relationship with their resistance mechanism against known inhibitors. The method can be applied to any pharmaceutically relevant pathogen proteins and could be very useful to understand the effects of positively selected mutations in the context of structural changes.

  6. Positive selection is the main driving force for evolution of citrus canker-causing Xanthomonas

    PubMed Central

    Zhang, Yunzeng; Jalan, Neha; Zhou, Xiaofeng; Goss, Erica; Jones, Jeffrey B; Setubal, João C; Deng, Xiaoling; Wang, Nian

    2015-01-01

    Understanding the evolutionary history and potential of bacterial pathogens is critical to prevent the emergence of new infectious bacterial diseases. Xanthomonas axonopodis subsp. citri (Xac) (synonym X. citri subsp. citri), which causes citrus canker, is one of the hardest-fought plant bacterial pathogens in US history. Here, we sequenced 21 Xac strains (14 XacA, 3 XacA* and 4 XacAw) with different host ranges from North America and Asia and conducted comparative genomic and evolutionary analyses. Our analyses suggest that acquisition of beneficial genes and loss of detrimental genes most likely allowed XacA to infect a broader range of hosts as compared with XacAw and XacA*. Recombination was found to have occurred frequently on the relative ancient branches, but rarely on the young branches of the clonal genealogy. The ratio of recombination/mutation ρ/θ was 0.0790±0.0005, implying that the Xac population was clonal in structure. Positive selection has affected 14% (395 out of 2822) of core genes of the citrus canker-causing Xanthomonas. The genes affected are enriched in ‘carbohydrate transport and metabolism' and ‘DNA replication, recombination and repair' genes (P<0.05). Many genes related to virulence, especially genes involved in the type III secretion system and effectors, are affected by positive selection, further highlighting the contribution of positive selection to the evolution of citrus canker-causing Xanthomonas. Our results suggest that both metabolism and virulence genes provide advantages to endow XacA with higher virulence and a wider host range. Our analysis advances our understanding of the genomic basis of specialization by positive selection in bacterial evolution. PMID:25689023

  7. High amino acid diversity and positive selection at a putative coral immunity gene (tachylectin-2)

    PubMed Central

    2010-01-01

    Background Genes involved in immune functions, including pathogen recognition and the activation of innate defense pathways, are among the most genetically variable known, and the proteins that they encode are often characterized by high rates of amino acid substitutions, a hallmark of positive selection. The high levels of variation characteristic of immunity genes make them useful tools for conservation genetics. To date, highly variable immunity genes have yet to be found in corals, keystone organisms of the world's most diverse marine ecosystem, the coral reef. Here, we examine variation in and selection on a putative innate immunity gene from Oculina, a coral genus previously used as a model for studies of coral disease and bleaching. Results In a survey of 244 Oculina alleles, we find high nonsynonymous variation and a signature of positive selection, consistent with a putative role in immunity. Using computational protein structure prediction, we generate a structural model of the Oculina protein that closely matches the known structure of tachylectin-2 from the Japanese horseshoe crab (Tachypleus tridentatus), a protein with demonstrated function in microbial recognition and agglutination. We also demonstrate that at least three other genera of anthozoan cnidarians (Acropora, Montastrea and Nematostella) possess proteins structurally similar to tachylectin-2. Conclusions Taken together, the evidence of high amino acid diversity, positive selection and structural correspondence to the horseshoe crab tachylectin-2 suggests that this protein is 1) part of Oculina's innate immunity repertoire, and 2) evolving adaptively, possibly under selective pressure from coral-associated microorganisms. Tachylectin-2 may serve as a candidate locus to screen coral populations for their capacity to respond adaptively to future environmental change. PMID:20482872

  8. Positive selection at a seminal fluid gene within a QTL for conspecific sperm precedence.

    PubMed

    Civetta, Alberto; Reimer, Angela

    2014-12-01

    The role of sexual selection in driving the rapid evolution of male reproductive proteins has been tested in a wide variety of organisms. Sperm competition is a form of postmating sexual selection that can contribute to reproductive isolation between species by biasing the proportion of progeny fathered by conspecific over heterospecific males. This phenomenon is known as conspecific sperm precedence (CSP). A previous quantitative trait loci study between Drosophila simulans and D. sechellia identified a locus associated with CSP within the second chromosome centered at the 53 cytogenetic map position. Male accessory gland proteins (ACPs) are associated with triggering postmating physiological responses in D. melanogaster females that can contribute to differential male reproductive success. Moreover, a large number of ACPs evolve rapidly and under positive selection among closely-related species of Drosophila. Here we have sequenced five candidate Acp genes (Acp53C14a, Acp53C14b, Acp53C14c, Acp53Ea and Acp54A1) within the previously mapped D. simulans-D. sechellia CSP locus from different D. simulans and D. sechellia strains. Polymorphism data analysis shows evidence of a selective sweep at Acp53Ea within D. simulans. In the context of CSP, the combined use of polymorphism and interspecies sequence divergence shows that Acp53C14c gene tree topology separates D. simulans and D. sechellia. Moreover, Acp53C14c is the only gene showing evidence of positive selection with five fixed amino acid substitutions between species. Our results highlight Acp53C14c as a candidate gene for future gene targeting studies to elucidate its role in CSP between D. simulans and D. sechellia.

  9. Positive selection on the gene RNASEL: correlation between patterns of evolution and function.

    PubMed

    Jin, Wei; Wu, Dong-Dong; Zhang, Xin; Irwin, David M; Zhang, Ya-Ping

    2012-10-01

    RNASEL is a 2-5A-dependent endoribonuclease that is a component of the interferon-induced 2-5A system, which plays a crucial role in the antiviral and apoptotic activities of interferons. In humans, many polymorphic sites within the RNASEL gene have been associated with an increased risk of developing prostate cancer. Here, we obtained coding sequences for the RNASEL gene from 11 primates and found evidence that positive selection has operated on the C-terminal endoribonuclease domain and the N-terminal ankyrin repeats domain of the protein, domains that directly interact with virus (i.e., ankyrin repeats are responsible for receiving environmental signals, and the endoribonuclease catalyses the destruction of the pathogenic viral RNA). To extend this finding, we studied variation within this gene in modern human populations by resequencing alleles from 144 individuals representing four separate populations. Interestingly, the frequency of the 541D allele shows a negative association with the incidence rate of prostate cancer in worldwide populations, and haplotypes containing the 541D polymorphisms demonstrate signatures of positive selection. RNASEL variants having the 541D haplotype likely have a greater ability to defend against infections by viruses, thus the loss of this activity may be associated with the development of prostate cancer. We provide evidence that positive selection has operated on the RNASEL gene, and its evolution is correlated with its function in pathogen defense and cancer association.

  10. Warning signals are under positive frequency-dependent selection in nature.

    PubMed

    Chouteau, Mathieu; Arias, Mónica; Joron, Mathieu

    2016-02-23

    Positive frequency-dependent selection (FDS) is a selection regime where the fitness of a phenotype increases with its frequency, and it is thought to underlie important adaptive strategies resting on signaling and communication. However, whether and how positive FDS truly operates in nature remains unknown, which hampers our understanding of signal diversity. Here, we test for positive FDS operating on the warning color patterns of chemically defended butterflies forming multiple coexisting mimicry assemblages in the Amazon. Using malleable prey models placed in localities showing differences in the relative frequencies of warningly colored prey, we demonstrate that the efficiency of a warning signal increases steadily with its local frequency in the natural community, up to a threshold where protection stabilizes. The shape of this relationship is consistent with the direct effect of the local abundance of each warning signal on the corresponding avoidance knowledge of the local predator community. This relationship, which differs from purifying selection acting on each mimetic pattern, indicates that predator knowledge, integrated over the entire community, is saturated only for the most common warning signals. In contrast, among the well-established warning signals present in local prey assemblages, most are incompletely known to local predators and enjoy incomplete protection. This incomplete predator knowledge should generate strong benefits to life history traits that enhance warning efficiency by increasing the effective frequency of prey visible to predators. Strategies such as gregariousness or niche convergence between comimics may therefore readily evolve through their effects on predator knowledge and warning efficiency.

  11. Evolutionary Dynamics of MERS-CoV: Potential Recombination, Positive Selection and Transmission

    PubMed Central

    Zhang, Zhao; Shen, Libing; Gu, Xun

    2016-01-01

    Middle East respiratory syndrome coronavirus (MERS-CoV) belongs to beta group of coronavirus and was first discovered in 2012. MERS-CoV can infect multiple host species and cause severe diseases in human. We conducted a series of phylogenetic and bioinformatic analyses to study the evolution dynamics of MERS-CoV among different host species with genomic data. Our analyses show: 1) 28 potential recombinant sequences were detected and they can be classified into seven potential recombinant types; 2) The spike (S) protein of MERS-CoV was under strong positive selection when MERS-CoV transmitted from their natural host to human; 3) Six out of nine positive selection sites detected in spike (S) protein are located in its receptor-binding domain which is in direct contact with host cells; 4) MERS-CoV frequently transmitted back and forth between human and camel after it had acquired the human-camel infection capability. Together, these results suggest that potential recombination events might have happened frequently during MERS-CoV’s evolutionary history and the positive selection sites in MERS-CoV’s S protein might enable it to infect human. PMID:27142087

  12. Warning signals are under positive frequency-dependent selection in nature

    PubMed Central

    Chouteau, Mathieu; Arias, Mónica; Joron, Mathieu

    2016-01-01

    Positive frequency-dependent selection (FDS) is a selection regime where the fitness of a phenotype increases with its frequency, and it is thought to underlie important adaptive strategies resting on signaling and communication. However, whether and how positive FDS truly operates in nature remains unknown, which hampers our understanding of signal diversity. Here, we test for positive FDS operating on the warning color patterns of chemically defended butterflies forming multiple coexisting mimicry assemblages in the Amazon. Using malleable prey models placed in localities showing differences in the relative frequencies of warningly colored prey, we demonstrate that the efficiency of a warning signal increases steadily with its local frequency in the natural community, up to a threshold where protection stabilizes. The shape of this relationship is consistent with the direct effect of the local abundance of each warning signal on the corresponding avoidance knowledge of the local predator community. This relationship, which differs from purifying selection acting on each mimetic pattern, indicates that predator knowledge, integrated over the entire community, is saturated only for the most common warning signals. In contrast, among the well-established warning signals present in local prey assemblages, most are incompletely known to local predators and enjoy incomplete protection. This incomplete predator knowledge should generate strong benefits to life history traits that enhance warning efficiency by increasing the effective frequency of prey visible to predators. Strategies such as gregariousness or niche convergence between comimics may therefore readily evolve through their effects on predator knowledge and warning efficiency. PMID:26858416

  13. Positive and strongly relaxed purifying selection drive the evolution of repeats in proteins

    PubMed Central

    Persi, Erez; Wolf, Yuri I.; Koonin, Eugene V

    2016-01-01

    Protein repeats are considered hotspots of protein evolution, associated with acquisition of new functions and novel phenotypic traits, including disease. Paradoxically, however, repeats are often strongly conserved through long spans of evolution. To resolve this conundrum, it is necessary to directly compare paralogous (horizontal) evolution of repeats within proteins with their orthologous (vertical) evolution through speciation. Here we develop a rigorous methodology to identify highly periodic repeats with significant sequence similarity, for which evolutionary rates and selection (dN/dS) can be estimated, and systematically characterize their evolution. We show that horizontal evolution of repeats is markedly accelerated compared with their divergence from orthologues in closely related species. This observation is universal across the diversity of life forms and implies a biphasic evolutionary regime whereby new copies experience rapid functional divergence under combined effects of strongly relaxed purifying selection and positive selection, followed by fixation and conservation of each individual repeat. PMID:27857066

  14. A Novel Positive Selection for Identifying Cold-Sensitive Myosin II Mutants in Dictyostelium

    PubMed Central

    Patterson, B.; Spudich, J. A.

    1995-01-01

    We developed a positive selection for myosin heavy chain mutants in Dictyostelium. This selection is based on the fact that brief exposure to azide causes wild-type cells to release from the substrate, whereas myosin null cells remain adherent. This procedure assays myosin function on a time scale of minutes and has therefore allowed us to select rapid-onset cold-sensitive mutants after random chemical mutagenesis of Dictyostelium cells. We developed a rapid technique for determining which mutations lie in sequences of the myosin gene that encode the head (motor) domain and localized 27 of 34 mutants to this domain. We recovered the appropriate sequences from five of the mutants and demonstrated that they retain their cold-sensitive properties when expressed from extrachromosomal plasmids. PMID:7498732

  15. Distinguishing Positive Selection From Neutral Evolution: Boosting the Performance of Summary Statistics

    PubMed Central

    Lin, Kao; Li, Haipeng; Schlötterer, Christian; Futschik, Andreas

    2011-01-01

    Summary statistics are widely used in population genetics, but they suffer from the drawback that no simple sufficient summary statistic exists, which captures all information required to distinguish different evolutionary hypotheses. Here, we apply boosting, a recent statistical method that combines simple classification rules to maximize their joint predictive performance. We show that our implementation of boosting has a high power to detect selective sweeps. Demographic events, such as bottlenecks, do not result in a large excess of false positives. A comparison to other neutrality tests shows that our boosting implementation performs well compared to other neutrality tests. Furthermore, we evaluated the relative contribution of different summary statistics to the identification of selection and found that for recent sweeps integrated haplotype homozygosity is very informative whereas older sweeps are better detected by Tajima's π. Overall, Watterson's θ was found to contribute the most information for distinguishing between bottlenecks and selection. PMID:21041556

  16. Involvement of p21ras distinguishes positive and negative selection in thymocytes.

    PubMed Central

    Swan, K A; Alberola-Ila, J; Gross, J A; Appleby, M W; Forbush, K A; Thomas, J F; Perlmutter, R M

    1995-01-01

    Small molecular weight GTP binding proteins of the ras family have been implicated in signal transduction from the T cell antigen receptor (TCR). To test the importance of p21ras in the control of thymocyte development, we generated mice expressing a dominant-negative p21ras protein (H-rasN17) in T lineage cells under the control of the lck proximal promoter. Proliferation of thymocytes from lck-H-rasN17 mice in response to TCR stimulation was nearly completely blocked, confirming the importance of p21ras in mediating TCR-derived signals in mature CD4+8- or CD8+4- thymocytes. In contrast, some TCR-derived signals proceeded unimpaired in the CD4+8+ thymocytes of mice expressing dominant-negative p21ras. Analysis of thymocyte development in mice made doubly transgenic for the H-Y-specific TCR and lck-H-rasN17 demonstrated that antigen-specific negative selection occurs normally in the presence of p21H-rasN17. Superantigen-induced negative selection in vivo also proceeded unhindered in H-rasN17 thymocytes. In contrast, positive selection of thymocytes in the H-Y mice was severely compromised by the presence of p21H-rasN17. These observations demonstrate that positive and negative selection, two conceptually antithetical consequences of TCR stimulation, are biochemically distinguishable. Images PMID:7835338

  17. Detecting and characterizing genomic signatures of positive selection in global populations.

    PubMed

    Liu, Xuanyao; Ong, Rick Twee-Hee; Pillai, Esakimuthu Nisha; Elzein, Abier M; Small, Kerrin S; Clark, Taane G; Kwiatkowski, Dominic P; Teo, Yik-Ying

    2013-06-06

    Natural selection is a significant force that shapes the architecture of the human genome and introduces diversity across global populations. The question of whether advantageous mutations have arisen in the human genome as a result of single or multiple mutation events remains unanswered except for the fact that there exist a handful of genes such as those that confer lactase persistence, affect skin pigmentation, or cause sickle cell anemia. We have developed a long-range-haplotype method for identifying genomic signatures of positive selection to complement existing methods, such as the integrated haplotype score (iHS) or cross-population extended haplotype homozygosity (XP-EHH), for locating signals across the entire allele frequency spectrum. Our method also locates the founder haplotypes that carry the advantageous variants and infers their corresponding population frequencies. This presents an opportunity to systematically interrogate the whole human genome whether a selection signal shared across different populations is the consequence of a single mutation process followed subsequently by gene flow between populations or of convergent evolution due to the occurrence of multiple independent mutation events either at the same variant or within the same gene. The application of our method to data from 14 populations across the world revealed that positive-selection events tend to cluster in populations of the same ancestry. Comparing the founder haplotypes for events that are present across different populations revealed that convergent evolution is a rare occurrence and that the majority of shared signals stem from the same evolutionary event.

  18. Positive selection at reproductive ADAM genes with potential intercellular binding activity.

    PubMed

    Glassey, Barb; Civetta, Alberto

    2004-05-01

    Many genes with a role in reproduction, including those implicated in fertilization and spermatogenesis, have been shown to evolve at a faster rate relative to genes associated with other functions and tissues. These survey studies usually group a wide variety of genes with different characteristics and evolutionary histories as reproductive genes based on their site of expression or function. We have examined the molecular evolution of the ADAM (a disintegrin and metalloprotease) gene family, a structurally and functionally diverse group of genes expressed in reproductive and somatic tissue to test whether a variety of protein characteristics such as phylogenetic clusters, tissue of expression, and proteolytic and adhesive function can group fast evolving ADAM genes. We found that all genes were evolving under purifying selection (d(N)/d(S) < 1), although reproductive ADAMs, including those implicated in fertilization and spermatogenesis, evolved at the fastest rate. Genes with a role in binding to cell receptors in endogenous tissue appear to be evolving under purifying selection, regardless of the tissue of expression. In contrast, positive selection of codon sites in the disintegrin/cysteine-rich adhesion domains was detected exclusively in ADAMs 2 and 32, two genes expressed in the testis with a potential role in sperm-egg adhesion. Positive selection was detected in the transmembrane/cytosolic tail region of ADAM genes expressed in a variety of tissues.

  19. Signatures of purifying and local positive selection in human miRNAs.

    PubMed

    Quach, Hélène; Barreiro, Luis B; Laval, Guillaume; Zidane, Nora; Patin, Etienne; Kidd, Kenneth K; Kidd, Judith R; Bouchier, Christiane; Veuille, Michel; Antoniewski, Christophe; Quintana-Murci, Lluís

    2009-03-01

    MicroRNAs (miRNAs) are noncoding RNAs involved in posttranscriptional gene repression, and their role in diverse physiological processes is increasingly recognized. Yet, few efforts have been devoted to evolutionary studies of human miRNAs. Knowledge about the way in which natural selection has targeted miRNAs should provide insight into their functional relevance as well as their mechanisms of action. Here we used miRNAs as a model system for investigating the influence of natural selection on gene regulation by characterizing the full spectrum of naturally occurring sequence variation of 117 human miRNAs from different populations worldwide. We found that purifying selection has globally constrained the diversity of miRNA-containing regions and has strongly targeted the mature miRNA. This observation emphasizes that mutations in these molecules are likely to be deleterious, and therefore they can have severe phenotypic consequences on human health. More importantly, we obtained evidence of population-specific events of positive selection acting on a number of miRNA-containing regions. Notably, our analysis revealed that positive selection has targeted a "small-RNA-rich island" on chromosome 14, harboring both miRNAs and small nucleolar RNAs, in Europeans and East Asians. These observations support the notion that the tuning of gene expression contributes to the processes by which populations adapt to specific environments. These findings will fuel future investigations exploring how genetic and functional variation of miRNAs under selection affects the repression of their mRNA targets, increasing our understanding of the role of gene regulation in population adaptation and human disease.

  20. Genetic Variation and Recent Positive Selection in Worldwide Human Populations: Evidence from Nearly 1 Million SNPs

    PubMed Central

    Theunert, Christoph; Pugach, Irina; Li, Jing; Nandineni, Madhusudan R.; Gross, Arnd; Scholz, Markus; Stoneking, Mark

    2009-01-01

    Background Genome-wide scans of hundreds of thousands of single-nucleotide polymorphisms (SNPs) have resulted in the identification of new susceptibility variants to common diseases and are providing new insights into the genetic structure and relationships of human populations. Moreover, genome-wide data can be used to search for signals of recent positive selection, thereby providing new insights into the genetic adaptations that occurred as modern humans spread out of Africa and around the world. Methodology We genotyped approximately 500,000 SNPs in 255 individuals (5 individuals from each of 51 worldwide populations) from the Human Genome Diversity Panel (HGDP-CEPH). When merged with non-overlapping SNPs typed previously in 250 of these same individuals, the resulting data consist of over 950,000 SNPs. We then analyzed the genetic relationships and ancestry of individuals without assigning them to populations, and we also identified candidate regions of recent positive selection at both the population and regional (continental) level. Conclusions Our analyses both confirm and extend previous studies; in particular, we highlight the impact of various dispersals, and the role of substructure in Africa, on human genetic diversity. We also identified several novel candidate regions for recent positive selection, and a gene ontology (GO) analysis identified several GO groups that were significantly enriched for such candidate genes, including immunity and defense related genes, sensory perception genes, membrane proteins, signal receptors, lipid binding/metabolism genes, and genes involved in the nervous system. Among the novel candidate genes identified are two genes involved in the thyroid hormone pathway that show signals of selection in African Pygmies that may be related to their short stature. PMID:19924308

  1. Species-specific activity of HIV-1 Vpu and positive selection of tetherin transmembrane domain variants.

    PubMed

    McNatt, Matthew W; Zang, Trinity; Hatziioannou, Theodora; Bartlett, Mackenzie; Fofana, Ismael Ben; Johnson, Welkin E; Neil, Stuart J D; Bieniasz, Paul D

    2009-02-01

    Tetherin/BST-2/CD317 is a recently identified antiviral protein that blocks the release of nascent retrovirus, and other virus, particles from infected cells. An HIV-1 accessory protein, Vpu, acts as an antagonist of tetherin. Here, we show that positive selection is evident in primate tetherin sequences and that HIV-1 Vpu appears to have specifically adapted to antagonize variants of tetherin found in humans and chimpanzees. Tetherin variants found in rhesus macaques (rh), African green monkeys (agm) and mice were able to inhibit HIV-1 particle release, but were resistant to antagonism by HIV-1 Vpu. Notably, reciprocal exchange of transmembrane domains between human and monkey tetherins conferred sensitivity and resistance to Vpu, identifying this protein domain as a critical determinant of Vpu function. Indeed, differences between hu-tetherin and rh-tetherin at several positions in the transmembrane domain affected sensitivity to antagonism by Vpu. Two alterations in the hu-tetherin transmembrane domain, that correspond to differences found in rh- and agm-tetherin proteins, were sufficient to render hu-tetherin completely resistant to HIV-1 Vpu. Interestingly, transmembrane and cytoplasmic domain sequences in primate tetherins exhibit variation at numerous codons that is likely the result of positive selection, and some of these changes coincide with determinants of HIV-1 Vpu sensitivity. Overall, these data indicate that tetherin could impose a barrier to viral zoonosis as a consequence of positive selection that has been driven by ancient viral antagonists, and that the HIV-1 Vpu protein has specialized to target the transmembrane domains found in human/chimpanzee tetherin proteins.

  2. Species-Specific Activity of HIV-1 Vpu and Positive Selection of Tetherin Transmembrane Domain Variants

    PubMed Central

    McNatt, Matthew W.; Zang, Trinity; Hatziioannou, Theodora; Bartlett, Mackenzie; Fofana, Ismael Ben; Johnson, Welkin E.; Neil, Stuart J. D.; Bieniasz, Paul D.

    2009-01-01

    Tetherin/BST-2/CD317 is a recently identified antiviral protein that blocks the release of nascent retrovirus, and other virus, particles from infected cells. An HIV-1 accessory protein, Vpu, acts as an antagonist of tetherin. Here, we show that positive selection is evident in primate tetherin sequences and that HIV-1 Vpu appears to have specifically adapted to antagonize variants of tetherin found in humans and chimpanzees. Tetherin variants found in rhesus macaques (rh), African green monkeys (agm) and mice were able to inhibit HIV-1 particle release, but were resistant to antagonism by HIV-1 Vpu. Notably, reciprocal exchange of transmembrane domains between human and monkey tetherins conferred sensitivity and resistance to Vpu, identifying this protein domain as a critical determinant of Vpu function. Indeed, differences between hu-tetherin and rh-tetherin at several positions in the transmembrane domain affected sensitivity to antagonism by Vpu. Two alterations in the hu-tetherin transmembrane domain, that correspond to differences found in rh- and agm-tetherin proteins, were sufficient to render hu-tetherin completely resistant to HIV-1 Vpu. Interestingly, transmembrane and cytoplasmic domain sequences in primate tetherins exhibit variation at numerous codons that is likely the result of positive selection, and some of these changes coincide with determinants of HIV-1 Vpu sensitivity. Overall, these data indicate that tetherin could impose a barrier to viral zoonosis as a consequence of positive selection that has been driven by ancient viral antagonists, and that the HIV-1 Vpu protein has specialized to target the transmembrane domains found in human/chimpanzee tetherin proteins. PMID:19214216

  3. A Comparison by Gender of Selected Educational Administration Positions Represented by NBTA Membership in the Province of New Brunswick.

    ERIC Educational Resources Information Center

    Crabb, Sharon A.

    Although more women are entering positions of educational administration in Canada, men hold a greater variety of administrative positions than do women, and men occupy those positions in greater numbers. This paper presents findings of a study that examined the relationship between the selected educational administrative positions of principal,…

  4. Using the CRISPR-Cas System to Positively Select Mutants in Genes Essential for Its Function.

    PubMed

    Yosef, Ido; Goren, Moran G; Edgar, Rotem; Qimron, Udi

    2015-01-01

    The clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR associated proteins (Cas) comprise a prokaryotic adaptive defense system against foreign nucleic acids. This defense is mediated by Cas proteins, which are guided by sequences flanked by the repeats, called spacers, to target nucleic acids. Spacers designed against the prokaryotic self chromosome are lethal to the prokaryotic cell. This self-killing of the bacterium by its own CRISPR-Cas system can be used to positively select genes that participate in this killing, as their absence will result in viable cells. Here we describe a positive selection assay that uses this feature to identify E. coli mutants encoding an inactive CRISPR-Cas system. The procedure includes establishment of an assay that detects this self-killing, generation of transposon insertion mutants in random genes, and selection of viable mutants, suspected as required for this lethal activity. This procedure enabled us to identify a novel gene, htpG, that is required for the activity of the CRISPR-Cas system. The procedures described here can be adjusted to various organisms to identify genes required for their CRISPR-Cas activity.

  5. Widespread Positive Selection Drives Differentiation of Centromeric Proteins in the Drosophila melanogaster subgroup

    PubMed Central

    Beck, Emily A.; Llopart, Ana

    2015-01-01

    Rapid evolution of centromeric satellite repeats is thought to cause compensatory amino acid evolution in interacting centromere-associated kinetochore proteins. Cid, a protein that mediates kinetochore/centromere interactions, displays particularly high amino acid turnover. Rapid evolution of both Cid and centromeric satellite repeats led us to hypothesize that the apparent compensatory evolution may extend to interacting partners in the Condensin I complex (i.e., SMC2, SMC4, Cap-H, Cap-D2, and Cap-G) and HP1s. Missense mutations in these proteins often result in improper centromere formation and aberrant chromosome segregation, thus selection for maintained function and coevolution among proteins of the complex is likely strong. Here, we report evidence of rapid evolution and recurrent positive selection in seven centromere-associated proteins in species of the Drosophila melanogaster subgroup, and further postulate that positive selection on these proteins could be a result of centromere drive and compensatory changes, with kinetochore proteins competing for optimal spindle attachment. PMID:26603658

  6. Suppressors of RNAi from plant viruses are subject to episodic positive selection

    PubMed Central

    Murray, Gemma G. R.; Kosakovsky Pond, Sergei L.; Obbard, Darren J.

    2013-01-01

    Viral suppressors of RNAi (VSRs) are proteins that actively inhibit the antiviral RNA interference (RNAi) immune response, providing an immune evasion route for viruses. It has been hypothesized that VSRs are engaged in a molecular ‘arms race’ with RNAi pathway genes. Two lines of evidence support this. First, VSRs from plant viruses display high sequence diversity, and are frequently gained and lost over evolutionary time scales. Second, Drosophila antiviral RNAi genes show high rates of adaptive evolution. Here, we investigate whether VSRs diversify faster than other genes and, if so, whether this is a result of positive selection, as might be expected in an arms race. By analysis of 12 plant RNA viruses, we show that the relative rate of protein evolution is higher for VSRs than for other genes, but that this is not attributable to pervasive positive selection. We argue that, because evolutionary time scales are extremely different for viruses and eukaryotes, it is improbable that viral adaptation (as measured by the ratio of non-synonymous to synonymous change) will be dominated by one-to-one coevolution with eukaryotes. Instead, for plant virus VSRs, we find strong evidence of episodic selection—diversifying selection that acts on a subset of lineages—which might be attributable to frequent shifts between different host genotypes or species. PMID:23804618

  7. Characterization of two paralogous myostatin genes and evidence for positive selection in Tibet fish: Gymnocypris przewalskii.

    PubMed

    Tong, Chao; Zhang, Cunfang; Shi, Jianquan; Qi, Hongfang; Zhang, Renyi; Tang, Yongtao; Li, Guogang; Feng, Chenguang; Zhao, Kai

    2015-07-10

    Myostatin (mstn) is an important member of TGF-β superfamily, a muscle growth inhibitor. Though mstn has been identified in many organisms, little is known about this gene in highland fish, Gymnocypris przewalskii endemic to the Qinghai-Tibetan Plateau. In this study, we first cloned two paralogous mstn genes (mstn1 and mstn2) from G. przewalskii through homologue cloning. The 3D structures of both Mstn proteins varied in the numbers of β-sheets and conformations of α-helices. The branch-site model showed that mstn1 has undergone positive selection, and two positively selected sites (107M and 181T) were located on the random coils of the 3D protein structure. Expression patterns indicated that the mstn1 expressed widely, while the mstn2 only expressed in the muscle and brain. During the early stage of embryo development, the expression levels of both mstn paralogous genes showed different increasing trends. These results suggest that it is diverging in two mstn paralogues of G. przewalskii via specific differences in gene structure, protein structure, selection pressure and gene expression patterns. Taken together, this study provides novel contribution on the research topics of growth related gene function and mechanism of highland fish in extreme aquatic environment on the Qinghai-Tibetan Plateau.

  8. Widespread Positive Selection Drives Differentiation of Centromeric Proteins in the Drosophila melanogaster subgroup.

    PubMed

    Beck, Emily A; Llopart, Ana

    2015-11-25

    Rapid evolution of centromeric satellite repeats is thought to cause compensatory amino acid evolution in interacting centromere-associated kinetochore proteins. Cid, a protein that mediates kinetochore/centromere interactions, displays particularly high amino acid turnover. Rapid evolution of both Cid and centromeric satellite repeats led us to hypothesize that the apparent compensatory evolution may extend to interacting partners in the Condensin I complex (i.e., SMC2, SMC4, Cap-H, Cap-D2, and Cap-G) and HP1s. Missense mutations in these proteins often result in improper centromere formation and aberrant chromosome segregation, thus selection for maintained function and coevolution among proteins of the complex is likely strong. Here, we report evidence of rapid evolution and recurrent positive selection in seven centromere-associated proteins in species of the Drosophila melanogaster subgroup, and further postulate that positive selection on these proteins could be a result of centromere drive and compensatory changes, with kinetochore proteins competing for optimal spindle attachment.

  9. Cytosine deaminase MX cassettes as positive/negative selectable markers in Saccharomyces cerevisiae.

    PubMed

    Hartzog, Phillip E; Nicholson, Bradly P; McCusker, John H

    2005-07-30

    We describe positive/negative selectable cytosine deaminase MX cassettes for use in Saccharomyces cerevisiae. The basis of positive selection for cytosine deaminase (Fcy1) activity is that (a) fcy1 strains are unable to grow on medium containing cytosine as a sole nitrogen source and (b) fcy1 ura3 strains are unable to grow on medium containing cytosine as the sole pyrimidine source. Conversely, as 5-fluorocytosine (5FC) is toxic to cytosine deaminase-producing cells, fcy1 strains are resistant to 5FC. FCY1MX and FCA1MX cassettes, containing open reading frames (ORFs) of S. cerevisiae FCY1 and Candida albicans FCA1, respectively, were constructed and used to disrupt targeted genes in S. cerevisiae fcy1 strains. In addition, new direct repeat cassettes, kanPR, FCA1PR, FCY1PR and CaURA3PR, were developed to allow efficient deletion of target genes in cells containing MX3 repeats. Finally, the FCY1- and FCA1MX3 or PR direct repeat cassettes can be readily recycled after 5FC counter-selection on both synthetic and rich media.

  10. Positive selection of a gene family during the emergence of humans and African apes.

    PubMed

    Johnson, M E; Viggiano, L; Bailey, J A; Abdul-Rauf, M; Goodwin, G; Rocchi, M; Eichler, E E

    2001-10-04

    Gene duplication followed by adaptive evolution is one of the primary forces for the emergence of new gene function. Here we describe the recent proliferation, transposition and selection of a 20-kilobase (kb) duplicated segment throughout 15 Mb of the short arm of human chromosome 16. The dispersal of this segment was accompanied by considerable variation in chromosomal-map location and copy number among hominoid species. In humans, we identified a gene family (morpheus) within the duplicated segment. Comparison of putative protein-encoding exons revealed the most extreme case of positive selection among hominoids. The major episode of enhanced amino-acid replacement occurred after the separation of human and great-ape lineages from the orangutan. Positive selection continued to alter amino-acid composition after the divergence of human and chimpanzee lineages. The rapidity and bias for amino-acid-altering nucleotide changes suggest adaptive evolution of the morpheus gene family during the emergence of humans and African apes. Moreover, some genes emerge and evolve very rapidly, generating copies that bear little similarity to their ancestral precursors. Consequently, a small fraction of human genes may not possess discernible orthologues within the genomes of model organisms.

  11. Mitogenomic analyses propose positive selection in mitochondrial genes for high-altitude adaptation in galliform birds.

    PubMed

    Zhou, Taicheng; Shen, Xuejuan; Irwin, David M; Shen, Yongyi; Zhang, Yaping

    2014-09-01

    Galliform birds inhabit very diverse habitats, including plateaus that are above 3000 m in altitude. At high altitude, lower temperature and hypoxia are two important factors influencing survival. Mitochondria, as the ultimate oxygen transductor, play an important role in aerobic respiration through oxidative phosphorylation (OXPHOS). We analyzed the mitochondrial genomes of six high-altitude phasianidae birds and sixteen low-altitude relatives in an attempt to determine the role of mitochondrial genes in high-altitude adaptation. We reconstructed the phylogenetic relationships of these phasianidae birds and relatives and found at least four lineages that independently occupied this high-altitude habitat. Selective analyses revealed significant evidence for positive selection in the genes ND2, ND4, and ATP6 in three of the high-altitude lineages. This result strongly suggests that adaptive evolution of mitochondrial genes played a critical role during the independent acclimatization to high altitude by galliform birds.

  12. Audition electives during surgical residency and selection for post-residency fellowship positions.

    PubMed

    Tzarnas, Chris D; Fessenden, John

    2002-01-01

    This study sought to determine the impact of surgical resident elective rotations, termed "audition" electives, upon the selection processes of surgical subspecialty residency positions, and to establish the incidence and character of resident personal contact before selection with the program where they ultimately located in order to appropriately council residents in achieving their educational and professional goals. A national survey of all surgical subspecialty programs for academic year 1999/2000 was conducted to determine whether the current first-year subspecialty residents had been on a clinical rotation of the subspecialty at their institution during their general surgery residency, had participated in research efforts of the specific subspecialty at their institution, and whether the resident's prerequisite general surgery training was obtained at their parent sponsoring institution. Seventy-two percent of 348 programs responded, representing 396 beginning surgical subspecialty residents for the surveyed academic year. Overall, 73% of first-year surgical subspecialty residents did not have direct prior personal contact with their subspecialty program either through a clinical rotation at the institution or through research as a general surgery resident. Eighty-four percent of first-year surgical subspecialty residents did not complete their general surgery residency at the parent sponsoring institution of the subspecialty program. An audition elective does not appear to significantly influence the process of surgical subspecialty resident selection. The findings further validate the fairness of the selection processes.

  13. Area-Selective Atomic Layer Deposition: Conformal Coating, Subnanometer Thickness Control, and Smart Positioning.

    PubMed

    Fang, Ming; Ho, Johnny C

    2015-09-22

    Transistors have already been made three-dimensional (3D), with device channels (i.e., fins in trigate field-effect transistor (FinFET) technology) that are taller, thinner, and closer together in order to enhance device performance and lower active power consumption. As device scaling continues, these transistors will require more advanced, fabrication-enabling technologies for the conformal deposition of high-κ dielectric layers on their 3D channels with accurate position alignment and thickness control down to the subnanometer scale. Among many competing techniques, area-selective atomic layer deposition (AS-ALD) is a promising method that is well suited to the requirements without the use of complicated, complementary metal-oxide semiconductor (CMOS)-incompatible processes. However, further progress is limited by poor area selectivity for thicker films formed via a higher number of ALD cycles as well as the prolonged processing time. In this issue of ACS Nano, Professor Stacy Bent and her research group demonstrate a straightforward self-correcting ALD approach, combining selective deposition with a postprocess mild chemical etching, which enables selective deposition of dielectric films with thicknesses and processing times at least 10 times larger and 48 times shorter, respectively, than those obtained by conventional AS-ALD processes. These advances present an important technological breakthrough that may drive the AS-ALD technique a step closer toward industrial applications in electronics, catalysis, and photonics, etc. where more efficient device fabrication processes are needed.

  14. Rapid intrahost evolution of human cytomegalovirus is shaped by demography and positive selection.

    PubMed

    Renzette, Nicholas; Gibson, Laura; Bhattacharjee, Bornali; Fisher, Donna; Schleiss, Mark R; Jensen, Jeffrey D; Kowalik, Timothy F

    2013-01-01

    Populations of human cytomegalovirus (HCMV), a large DNA virus, are highly polymorphic in patient samples, which may allow for rapid evolution within human hosts. To understand HCMV evolution, longitudinally sampled genomic populations from the urine and plasma of 5 infants with symptomatic congenital HCMV infection were analyzed. Temporal and compartmental variability of viral populations were quantified using high throughput sequencing and population genetics approaches. HCMV populations were generally stable over time, with ~88% of SNPs displaying similar frequencies. However, samples collected from plasma and urine of the same patient at the same time were highly differentiated with approximately 1700 consensus sequence SNPs (1.2% of the genome) identified between compartments. This inter-compartment differentiation was comparable to the differentiation observed in unrelated hosts. Models of demography (i.e., changes in population size and structure) and positive selection were evaluated to explain the observed patterns of variation. Evidence for strong bottlenecks (>90% reduction in viral population size) was consistent among all patients. From the timing of the bottlenecks, we conclude that fetal infection occurred between 13-18 weeks gestational age in patients analyzed, while colonization of the urine compartment followed roughly 2 months later. The timing of these bottlenecks is consistent with the clinical histories of congenital HCMV infections. We next inferred that positive selection plays a small but measurable role in viral evolution within a single compartment. However, positive selection appears to be a strong and pervasive driver of evolution associated with compartmentalization, affecting ≥ 34 of the 167 open reading frames (~20%) of the genome. This work offers the most detailed map of HCMV in vivo evolution to date and provides evidence that viral populations can be stable or rapidly differentiate, depending on host environment. The

  15. Ancestral resurrection of anthropoid estrogen receptor β demonstrates functional consequences of positive selection.

    PubMed

    Weckle, Amy; McGowen, Michael R; Xing, Jun; Chen, Caoyi; Sterner, Kirstin N; Hou, Zhuo-Cheng; Romero, Roberto; Wildman, Derek E

    2017-09-13

    Anthropoid primates arose during the Eocene approximately 55 million years ago (mya), and extant anthropoids share a most recent common ancestor ∼40mya. Paleontology has been very successful at describing the morphological phenotypes of extinct anthropoids. Less well understood is the molecular biology of these extinct species as well as the phenotypic consequences of evolutionary variation in their genomes. Here we resurrect the most recent common ancestral anthropoid estrogen receptor β gene (ESR2) and demonstrate that the function of this ancestral estrogen receptor has been maintained during human descent but was altered during early New World monkey (NWM) evolution by becoming a more potent transcriptional activator. We tested hypotheses of adaptive evolution in the protein coding sequences of ESR2, and determined that ESR2 evolved via episodic positive selection on the NWM stem lineage. We separately co-transfected ESR2 constructs for human, NWM, and the anthropoid ancestor along with reporter gene vectors and performed hormone binding dose response experiments that measure transactivation activity. We found the transactivation potentials of the ancestral and human sequences to be significantly lower (p<0.0001 in each comparison) than that of the NWM when treated with estradiol, the most prevalent estrogen. We conclude the difference in fold activation is due to positive selection in the NWM ERβ ligand binding domain. Our study validates inferential methods for detecting adaptive evolution that predict functional consequences of nucleotide substitutions and points a way toward examining the functional consequences of positive Darwinian selection. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Positive selection on panpulmonate mitogenomes provide new clues on adaptations to terrestrial life.

    PubMed

    Romero, Pedro E; Weigand, Alexander M; Pfenninger, Markus

    2016-08-22

    Transitions from marine to intertidal and terrestrial habitats resulted in a significant adaptive radiation within the Panpulmonata (Gastropoda: Heterobranchia). This clade comprises several groups that invaded the land realm independently and in different time periods, e.g., Ellobioidea, Systellomatophora, and Stylommatophora. Thus, mitochondrial genomes of panpulmonate gastropods are promising to screen for adaptive molecular signatures related to land invasions. We obtained three complete mitochondrial genomes of terrestrial panpulmonates, i.e., the ellobiid Carychium tridentatum, and the stylommatophorans Arion rufus and Helicella itala. Our dataset consisted of 50 mitogenomes comprising almost all major panpulmonate lineages. The phylogenetic tree based on mitochondrial genes supports the monophyly of the clade Panpulmonata. Terrestrial lineages were sampled from Ellobioidea (1 sp.) and Stylommatophora (9 spp.). The branch-site test of positive selection detected significant non-synonymous changes in the terrestrial branches leading to Carychium (Ellobiodea) and Stylommatophora. These convergent changes occurred in the cob and nad5 genes (OXPHOS complex III and I, respectively). The convergence of the non-synonymous changes in cob and nad5 suggest possible ancient episodes of positive selection related to adaptations to non-marine habitats. The positively selected sites in our data are in agreement with previous results in vertebrates suggesting a general pattern of adaptation to the new metabolic requirements. The demand for energy due to the colonization of land (for example, to move and sustain the body mass in the new habitat) and the necessity to tolerate new conditions of abiotic stress may have changed the physiological constraints in the early terrestrial panpulmonates and triggered adaptations at the mitochondrial level.

  17. Non-gated laser-induced breakdown spectroscopy in bulk water by position-selective detection

    SciTech Connect

    Tian, Ye; Xue, Boyang; Song, Jiaojian; Lu, Yuan; Zheng, Ronger

    2015-09-14

    Temporal and spatial evolutions of the laser-induced plasma in bulk water are investigated using fast imaging and emission spectroscopic techniques. By tightly focusing a single-pulse nanosecond Nd: YAG laser beam into the bulk water, we generate a strongly expanded plasma with high reproducibility. Such a strong expanding plasma enables us to obtain well-resolved spectral lines by means of position-selective detection; hence, the time-gated detector becomes abdicable. The present results suggest not only a possible non-gated approach for underwater laser-induced breakdown spectroscopy but also give an insight into the plasma generation and expansion in bulk water.

  18. Delineation of plant caleosin residues critical for functional divergence, positive selection and coevolution

    PubMed Central

    2014-01-01

    Background The caleosin genes encode proteins with a single conserved EF hand calcium-binding domain and comprise small gene families found in a wide range of plant species. These proteins may be involved in many cellular and biological processes coupled closely to the synthesis, degradation, or stability of oil bodies. Although previous studies of this protein family have been reported for Arabidopsis and other species, understanding of the evolution of the caleosin gene family in plants remains inadequate. Results In this study, comparative genomic analysis was performed to investigate the phylogenetic relationships, evolutionary history, functional divergence, positive selection, and coevolution of caleosins. First, 84 caleosin genes were identified from five main lineages that included 15 species. Phylogenetic analysis placed these caleosins into five distinct subfamilies (sub I–V), including two subfamilies that have not been previously identified. Among these subfamilies, sub II coincided with the distinct P-caleosin isoform recently identified in the pollen oil bodies of lily; caleosin genes from the same lineage tended to be clustered together in the phylogenetic tree. A special motif was determined to be related with the classification of caleosins, which may have resulted from a deletion in sub I and sub III occurring after the evolutionary divergence of monocot and dicot species. Additionally, several segmentally and tandem-duplicated gene pairs were identified from seven species, and further analysis revealed that caleosins of different species did not share a common expansion model. The ages of each pair of duplications were calculated, and most were consistent with the time of genome-wide duplication events in each species. Functional divergence analysis showed that changes in functional constraints have occurred between subfamilies I/IV, II/IV, and II/V, and some critical amino acid sites were identified during the functional divergence. Additional

  19. New Positive Ca2+-Activated K+ Channel Gating Modulators with Selectivity for KCa3.1

    PubMed Central

    Coleman, Nichole; Brown, Brandon M.; Oliván-Viguera, Aida; Singh, Vikrant; Olmstead, Marilyn M.; Valero, Marta Sofia; Köhler, Ralf

    2014-01-01

    Small-conductance (KCa2) and intermediate-conductance (KCa3.1) calcium-activated K+ channels are voltage-independent and share a common calcium/calmodulin-mediated gating mechanism. Existing positive gating modulators like EBIO, NS309, or SKA-31 activate both KCa2 and KCa3.1 channels with similar potency or, as in the case of CyPPA and NS13001, selectively activate KCa2.2 and KCa2.3 channels. We performed a structure-activity relationship (SAR) study with the aim of optimizing the benzothiazole pharmacophore of SKA-31 toward KCa3.1 selectivity. We identified SKA-111 (5-methylnaphtho[1,2-d]thiazol-2-amine), which displays 123-fold selectivity for KCa3.1 (EC50 111 ± 27 nM) over KCa2.3 (EC50 13.7 ± 6.9 μM), and SKA-121 (5-methylnaphtho[2,1-d]oxazol-2-amine), which displays 41-fold selectivity for KCa3.1 (EC50 109 nM ± 14 nM) over KCa2.3 (EC50 4.4 ± 1.6 μM). Both compounds are 200- to 400-fold selective over representative KV (KV1.3, KV2.1, KV3.1, and KV11.1), NaV (NaV1.2, NaV1.4, NaV1.5, and NaV1.7), as well as CaV1.2 channels. SKA-121 is a typical positive-gating modulator and shifts the calcium-concentration response curve of KCa3.1 to the left. In blood pressure telemetry experiments, SKA-121 (100 mg/kg i.p.) significantly lowered mean arterial blood pressure in normotensive and hypertensive wild-type but not in KCa3.1−/− mice. SKA-111, which was found in pharmacokinetic experiments to have a much longer half-life and to be much more brain penetrant than SKA-121, not only lowered blood pressure but also drastically reduced heart rate, presumably through cardiac and neuronal KCa2 activation when dosed at 100 mg/kg. In conclusion, with SKA-121, we generated a KCa3.1-specific positive gating modulator suitable for further exploring the therapeutical potential of KCa3.1 activation. PMID:24958817

  20. GABAB Receptor Positive Modulation Decreases Selective Molecular and Behavioral Effects of Cocaine

    PubMed Central

    Lhuillier, Loic; Mombereau, Cedric; Cryan, John F.; Kaupmann, Klemens

    2006-01-01

    Exposure to cocaine induces selective behavioral and molecular adaptations. In rodents, acute cocaine induces increased locomotor activity whereas prolonged drug exposure results in behavioral locomotor sensitization, which is thought to be a consequence of drug–induced neuroadaptive changes. Recent attention has been given to compounds activating GABAB receptors as potential anti-addictive therapies. In particular the principle of allosteric positive GABAB receptor modulators is very promising in this respect, as positive modulators lack the sedative and muscle relaxant properties of full GABAB receptor agonists such as baclofen. Here we investigated the effects of systemic application of the GABAB receptor positive modulator GS39783 in animals treated with acute and chronic cocaine administration. Both GS39783 and baclofen dose-dependently attenuated acute cocaine-induced hyperlocomotion. Furthermore, both compounds also efficiently blocked cocaine-induced Fos induction in the striatal complex. In chronic studies GS39783 induced a modest attenuation of cocaine-induced locomotor sensitization. Chronic cocaine induces the accumulation of the transcription factor ΔFosB and up regulates cAMP-response-element-binding-protein (CREB) and dopamine-and-cAMP-regulated-phosphoprotein of 32 kd (DARPP-32). GS39783 blocked the induction/activation of DARPP-32 and CREB in the nucleus accumbens and dorsal striatum and partially inhibited ΔFosB accumulation in the dorsal striatum. In summary our data provide evidence that GS39783 attenuates the acute behavioral effects of cocaine exposure in rodents and in addition prevents the induction of selective long-term adaptive changes in dopaminergic signaling pathways. Further investigation of GABAB receptor positive modulation as a novel therapeutic strategy for the treatment of cocaine dependence and possibly other drugs of abuse is therefore warranted. PMID:16710312

  1. Positive Evolutionary Selection of an HD Motif on Alzheimer Precursor Protein Orthologues Suggests a Functional Role

    PubMed Central

    Miklós, István; Zádori, Zoltán

    2012-01-01

    HD amino acid duplex has been found in the active center of many different enzymes. The dyad plays remarkably different roles in their catalytic processes that usually involve metal coordination. An HD motif is positioned directly on the amyloid beta fragment (Aβ) and on the carboxy-terminal region of the extracellular domain (CAED) of the human amyloid precursor protein (APP) and a taxonomically well defined group of APP orthologues (APPOs). In human Aβ HD is part of a presumed, RGD-like integrin-binding motif RHD; however, neither RHD nor RXD demonstrates reasonable conservation in APPOs. The sequences of CAEDs and the position of the HD are not particularly conserved either, yet we show with a novel statistical method using evolutionary modeling that the presence of HD on CAEDs cannot be the result of neutral evolutionary forces (p<0.0001). The motif is positively selected along the evolutionary process in the majority of APPOs, despite the fact that HD motif is underrepresented in the proteomes of all species of the animal kingdom. Position migration can be explained by high probability occurrence of multiple copies of HD on intermediate sequences, from which only one is kept by selective evolutionary forces, in a similar way as in the case of the “transcription binding site turnover.” CAED of all APP orthologues and homologues are predicted to bind metal ions including Amyloid-like protein 1 (APLP1) and Amyloid-like protein 2 (APLP2). Our results suggest that HDs on the CAEDs are most probably key components of metal-binding domains, which facilitate and/or regulate inter- or intra-molecular interactions in a metal ion-dependent or metal ion concentration-dependent manner. The involvement of naturally occurring mutations of HD (Tottori (D7N) and English (H6R) mutations) in early onset Alzheimer's disease gives additional support to our finding that HD has an evolutionary preserved function on APPOs. PMID:22319430

  2. Oligopolyphenylenevinylene-conjugated oligoelectrolyte membrane insertion molecules selectively disrupt cell envelopes of Gram-positive bacteria.

    PubMed

    Hinks, Jamie; Poh, Wee Han; Chu, Justin Jang Hann; Loo, Joachim Say Chye; Bazan, Guillermo C; Hancock, Lynn E; Wuertz, Stefan

    2015-03-01

    The modification of microbial membranes to achieve biotechnological strain improvement with exogenous small molecules, such as oligopolyphenylenevinylene-conjugated oligoelectrolyte (OPV-COE) membrane insertion molecules (MIMs), is an emerging biotechnological field. Little is known about the interactions of OPV-COEs with their target, the bacterial envelope. We studied the toxicity of three previously reported OPV-COEs with a selection of Gram-negative and Gram-positive organisms and demonstrated that Gram-positive bacteria are more sensitive to OPV-COEs than Gram-negative bacteria. Transmission electron microscopy demonstrated that these MIMs disrupt microbial membranes and that this occurred to a much greater degree in Gram-positive organisms. We used a number of mutants to probe the nature of MIM interactions with the microbial envelope but were unable to align the membrane perturbation effects of these compounds to previously reported membrane disruption mechanisms of, for example, cationic antimicrobial peptides. Instead, the data support the notion that OPV-COEs disrupt microbial membranes through a suspected interaction with diphosphatidylglycerol (DPG), a major component of Gram-positive membranes. The integrity of model membranes containing elevated amounts of DPG was disrupted to a greater extent by MIMs than those prepared from Escherichia coli total lipid extracts alone.

  3. Investigation of some selected strategies for multi-GNSS instantaneous RTK positioning

    NASA Astrophysics Data System (ADS)

    Paziewski, Jacek; Wielgosz, Pawel

    2017-01-01

    It is clear that we can benefit from multi-constellation GNSS in precise relative positioning. On the other hand, it is still an open problem how to combine multi-GNSS signals in a single functional model. This study presents methodology and quality assessment of selected methods allowing for multi-GNSS observations combining in relative kinematic positioning using baselines up to tens of kilometers. In specific, this paper characterizes loose and tight integration strategies applied to the ionosphere and troposphere weighted model. Performance assessment of the established strategies was based on the analyses of the integer ambiguity resolution and rover coordinates' repeatability obtained in the medium range instantaneous RTK positioning with the use of full constellation dual frequency GPS and Galileo signals. Since full constellation of Galileo satellites is not yet available, the observational data were obtained from a hardware GNSS signal simulator using regular geodetic GNSS receivers. The results indicate on similar and high performance of the loose, and tight integration with calibrated receiver ISBs strategies. These approaches have undeniable advantage over single system positioning in terms of reliability of the integer ambiguity resolution as well as rover coordinate repeatability.

  4. Oligopolyphenylenevinylene-Conjugated Oligoelectrolyte Membrane Insertion Molecules Selectively Disrupt Cell Envelopes of Gram-Positive Bacteria

    PubMed Central

    Poh, Wee Han; Chu, Justin Jang Hann; Loo, Joachim Say Chye; Bazan, Guillermo C.; Hancock, Lynn E.

    2015-01-01

    The modification of microbial membranes to achieve biotechnological strain improvement with exogenous small molecules, such as oligopolyphenylenevinylene-conjugated oligoelectrolyte (OPV-COE) membrane insertion molecules (MIMs), is an emerging biotechnological field. Little is known about the interactions of OPV-COEs with their target, the bacterial envelope. We studied the toxicity of three previously reported OPV-COEs with a selection of Gram-negative and Gram-positive organisms and demonstrated that Gram-positive bacteria are more sensitive to OPV-COEs than Gram-negative bacteria. Transmission electron microscopy demonstrated that these MIMs disrupt microbial membranes and that this occurred to a much greater degree in Gram-positive organisms. We used a number of mutants to probe the nature of MIM interactions with the microbial envelope but were unable to align the membrane perturbation effects of these compounds to previously reported membrane disruption mechanisms of, for example, cationic antimicrobial peptides. Instead, the data support the notion that OPV-COEs disrupt microbial membranes through a suspected interaction with diphosphatidylglycerol (DPG), a major component of Gram-positive membranes. The integrity of model membranes containing elevated amounts of DPG was disrupted to a greater extent by MIMs than those prepared from Escherichia coli total lipid extracts alone. PMID:25576607

  5. Ongoing hydrothermal activities within Enceladus.

    PubMed

    Hsu, Hsiang-Wen; Postberg, Frank; Sekine, Yasuhito; Shibuya, Takazo; Kempf, Sascha; Horányi, Mihály; Juhász, Antal; Altobelli, Nicolas; Suzuki, Katsuhiko; Masaki, Yuka; Kuwatani, Tatsu; Tachibana, Shogo; Sirono, Sin-iti; Moragas-Klostermeyer, Georg; Srama, Ralf

    2015-03-12

    Detection of sodium-salt-rich ice grains emitted from the plume of the Saturnian moon Enceladus suggests that the grains formed as frozen droplets from a liquid water reservoir that is, or has been, in contact with rock. Gravitational field measurements suggest a regional south polar subsurface ocean of about 10 kilometres thickness located beneath an ice crust 30 to 40 kilometres thick. These findings imply rock-water interactions in regions surrounding the core of Enceladus. The resulting chemical 'footprints' are expected to be preserved in the liquid and subsequently transported upwards to the near-surface plume sources, where they eventually would be ejected and could be measured by a spacecraft. Here we report an analysis of silicon-rich, nanometre-sized dust particles (so-called stream particles) that stand out from the water-ice-dominated objects characteristic of Saturn. We interpret these grains as nanometre-sized SiO2 (silica) particles, initially embedded in icy grains emitted from Enceladus' subsurface waters and released by sputter erosion in Saturn's E ring. The composition and the limited size range (2 to 8 nanometres in radius) of stream particles indicate ongoing high-temperature (>90 °C) hydrothermal reactions associated with global-scale geothermal activity that quickly transports hydrothermal products from the ocean floor at a depth of at least 40 kilometres up to the plume of Enceladus.

  6. School Discipline: The Ongoing Crisis

    ERIC Educational Resources Information Center

    Whiteside, Marilyn

    1975-01-01

    The positive and negative aspects of classroom punishment were compared and the characteristics of teachers who did not experience discipline problems with their students were discussed. Additionally, programs for overcoming discipline difficulties were presented. (RK)

  7. Rapid positive selection of stable integrants following transfection of Plasmodium falciparum.

    PubMed

    Wang, Ping; Wang, Qi; Sims, Paul F G; Hyde, John E

    2002-08-07

    With the near-completion of the genome sequence of Plasmodium falciparum, further understanding of this major human pathogen urgently requires more effective genetic tools. These must include faster and more reliable gene replacement or gene knockout techniques, essential for the analysis of gene function. We describe a serial system which uses the blasticidin S deaminase (bsd) gene of Aspergillus and the neomycin phosphotransferase II (neo) gene from transposon Tn5 as selectable markers for, respectively, transient transfection of malaria parasites and the selection of stable integrants. Challenge with blasticidin S (BS) enriches the parasite population transiently expressing the bsd gene, laying the foundation for the subsequent, much less frequent, integration event. Positive selection for this rare event is enormously facilitated by fusing the neo gene in frame to the replacement or knockout targeting gene. The sequence employed for the targeting (the polymorphic pppk-dhps gene of P. falciparum, as a model system) is truncated at the 5' end with no promoter located upstream, therefore neo cannot be expressed without specifically integrating within the genomic copy of the target gene. After BS selection, the culture is immediately exposed to geneticin (G418), leading to an apparently homogenous population of mutant parasites. As well as excluding spurious integrants at non-targeted sequences, this system greatly reduces the lengthy selection period for obtaining the desired mutants by eliminating the drug-on and drug-off cycles for the production of stable integrants, which are normally required by the single marker systems currently in use for transfection of malaria parasites.

  8. Imbalanced positive selection maintains the functional divergence of duplicated DIHYDROKAEMPFEROL 4-REDUCTASE genes

    PubMed Central

    Huang, Bing-Hong; Chen, Yi-Wen; Huang, Chia-Lung; Gao, Jian; Liao, Pei-Chun

    2016-01-01

    Gene duplication could be beneficial by functional division but might increase the risk of genetic load. The dynamics of duplicated paralogs number could involve recombination, positive selection, and functional divergence. Duplication of DIHYDROFLAVONOL 4-REDUCTASE (DFR) has been reported in several organisms and may have been retained by escape from adaptive conflict (EAC). In this study, we screened the angiosperm DFR gene focusing on a diversified genus Scutellaria to investigate how these duplicated genes are retained. We deduced that gene duplication involved multiple independent events in angiosperms, but the duplication of DFR was before the divergence of Scutellaria. Asymmetric positive selective pressures resulted in different evolutionary rates between the duplicates. Different numbers of regulatory elements, differential codon usages, radical amino acid changes, and differential gene expressions provide evidences of functional divergence between the two DFR duplicates in Scutellaria, implying adaptive subfunctionalization between duplicates. The discovery of pseudogenes accompanying a reduced replacement rate in one DFR paralogous gene suggested possibly leading to “loss of function” due to dosage imbalance after the transient adaptive subfunctionalization in the early stage of duplication. Notwithstanding, episodic gene duplication and functional divergence may be relevant to the diversification of ecological function of DFR gene in Scutellaria. PMID:27966614

  9. Positive selection at the ASPM gene coincides with brain size enlargements in cetaceans.

    PubMed

    Xu, Shixia; Chen, Yuan; Cheng, Yuefeng; Yang, Dan; Zhou, Xuming; Xu, Junxiao; Zhou, Kaiya; Yang, Guang

    2012-11-07

    The enlargement of cetacean brain size represents an enigmatic event in mammalian evolution, yet its genetic basis remains poorly explored. One candidate gene associated with brain size evolution is the abnormal spindle-like microcephaly associated (ASPM), as mutations in this gene cause severe reductions in the cortical size of humans. Here, we investigated the ASPM gene in representative cetacean lineages and previously published sequences from other mammals to test whether the expansion of the cetacean brain matched adaptive ASPM evolution patterns. Our analyses yielded significant evidence of positive selection on the ASPM gene during cetacean evolution, especially for the Odontoceti and Delphinoidea lineages. These molecular patterns were associated with two major events of relative brain size enlargement in odontocetes and delphinoids. It is of particular interest to find that positive selection was restricted to cetaceans and primates, two distant lineages both characterized by a massive expansion of brain size. This result is suggestive of convergent molecular evolution, although no site-specific convergence at the amino acid level was found.

  10. Evidence of positive selection associated with placental loss in tiger sharks.

    PubMed

    Swift, Dominic G; Dunning, Luke T; Igea, Javier; Brooks, Edward J; Jones, Catherine S; Noble, Leslie R; Ciezarek, Adam; Humble, Emily; Savolainen, Vincent

    2016-06-14

    All vertebrates initially feed their offspring using yolk reserves. In some live-bearing species these yolk reserves may be supplemented with extra nutrition via a placenta. Sharks belonging to the Carcharhinidae family are all live-bearing, and with the exception of the tiger shark (Galeocerdo cuvier), develop placental connections after exhausting yolk reserves. Phylogenetic relationships suggest the lack of placenta in tiger sharks is due to secondary loss. This represents a dramatic shift in reproductive strategy, and is likely to have left a molecular footprint of positive selection within the genome. We sequenced the transcriptome of the tiger shark and eight other live-bearing shark species. From this data we constructed a time-calibrated phylogenetic tree estimating the tiger shark lineage diverged from the placental carcharhinids approximately 94 million years ago. Along the tiger shark lineage, we identified five genes exhibiting a signature of positive selection. Four of these genes have functions likely associated with brain development (YWHAE and ARL6IP5) and sexual reproduction (VAMP4 and TCTEX1D2). Our results indicate the loss of placenta in tiger sharks may be associated with subsequent adaptive changes in brain development and sperm production.

  11. Increased mitochondrial mutation frequency after an island colonization: positive selection or accumulation of slightly deleterious mutations?

    PubMed

    Hardouin, Emilie A; Tautz, Diethard

    2013-04-23

    Island colonizations are excellent models for studying early processes of evolution. We found in a previous study on mice that had colonized the sub-Antarctic Kerguelen Archipelago about 200 years ago that they were derived from a single founder lineage and that this showed an unexpectedly large number of new mutations in the mitochondrial D-loop. To assess whether positive selection has played a role in the emergence of these variants, we have obtained 16 full mitochondrial genome sequences from these mice. For comparison, we have compiled 57 mitochondrial genome sequences from laboratory inbred lines that became established about 100 years ago, also starting from a single founder lineage. We find that the island mice and the laboratory lines show very similar mutation frequencies and patterns. None of the patterns in the Kerguelen mice provides evidence for positive selection. We conclude that nearly neutral evolutionary processes that assume the presence of slightly deleterious variants can fully explain the patterns. This supports the notion of time-dependency of molecular evolution and provides a new calibration point. Based on the observed mutation frequency, we calculate an average evolutionary rate of 0.23 substitutions per site per Myr for the earliest time frame of divergence, which is about six times higher than the long-term rate of 0.037 substitutions per site per Myr.

  12. High burden and pervasive positive selection of somatic mutations in normal human skin

    PubMed Central

    Martincorena, Iñigo; Roshan, Amit; Gerstung, Moritz; Ellis, Peter; Van Loo, Peter; McLaren, Stuart; Wedge, David C.; Fullam, Anthony; Alexandrov, Ludmil B.; Tubio, Jose M.; Stebbings, Lucy; Menzies, Andrew; Widaa, Sara; Stratton, Michael R.; Jones, Philip H.; Campbell, Peter J.

    2015-01-01

    How somatic mutations accumulate in normal cells is central to understanding cancer development, but is poorly understood. We performed ultra-deep sequencing of 74 cancer genes in small (0.8-4.7mm2) biopsies of normal skin. Across 234 biopsies of sun-exposed eyelid epidermis from four individuals, the burden of somatic mutations averaged 2-6 mutations/megabase/cell, similar to many cancers, and exhibited characteristic signatures of ultraviolet light exposure. Remarkably, multiple cancer genes are under strong positive selection even in physiologically normal skin, including most of the key drivers of cutaneous squamous cell carcinomas. Positively selected ‘driver’ mutations were found in 18-32% of normal skin cells at a density of ~140/cm2. We observed variability in the driver landscape among individuals and variability in sizes of clonal expansions across genes. Thus, aged, sun-exposed skin is a patchwork of thousands of evolving clones, with over a quarter of cells carrying cancer-causing mutations while maintaining the physiological functions of epidermis. PMID:25999502

  13. Selective nucleolus organizer inactivation in Arabidopsis is a chromosome position-effect phenomenon

    PubMed Central

    Mohannath, Gireesha; Pontvianne, Frederic

    2016-01-01

    Nucleolus organizer regions (NORs) are chromosomal loci where hundreds of rRNA genes are clustered. Despite being nearly identical in sequence, specific rRNA genes are selected for silencing during development via choice mechanism(s) that remain unclear. In Arabidopsis thaliana, rRNA gene subtypes that are silenced during development were recently mapped to the NOR on chromosome 2, NOR2, whereas active rRNA genes map to NOR4, on chromosome 4. In a mutant line deficient for ATXR5 or ATXR6-dependent histone H3 lysine 27 (H3K27) monomethylation, we show that millions of base pairs of chromosome 4, including the telomere, TEL4N, and much of NOR4, have been converted to the corresponding sequences of chromosome 2. This genomic change places rRNA genes of NOR2, which are normally silenced, at the position on chromosome 4 where active rRNA genes are normally located. At their new location, NOR2-derived rRNA genes escape silencing, independent of the atxr mutations, indicating that selective rRNA gene silencing is chromosome 2-specific. The chromosome 2 position effect is not explained by the NOR2-associated telomere, TEL2N, which remains linked to the translocated NOR, implicating centromere-proximal sequences in silencing. PMID:27821753

  14. Positive Diversifying Selection on the Plasmodium falciparum surf4.1 Gene in Thailand

    PubMed Central

    Xangsayarath, Phonepadith; Kaewthamasorn, Morakot; Yahata, Kazuhide; Nakazawa, Shusuke; Sattabongkot, Jetsumon; Udomsangpetch, Rachanee; Kaneko, Osamu

    2012-01-01

    Plasmodium falciparum SURFIN4.1 is a type I transmembrane protein thought to locate on the merozoite surface and to be responsible for a reversible adherence to the erythrocyte before invasion. In this study, we evaluated surf4.1 gene segment encoding extracellular region for polymorphism, the signature of positive selection, the degree of linkage disequilibrium, and temporal change in allele frequency distribution in P. falciparum isolates from Thailand in 1988–89, 2003, and 2005. We found that SURFIN4.1 is highly polymorphic, particularly at the C-terminal side of the variable region located just before a predicted transmembrane region. A signature of positive diversifying selection on the variable region was detected by multiple tests and, to a lesser extent, on conserved N-terminally located cysteine-rich domain by Tajima’s D test. Linkage disequilibrium between sites over a long distance (> 1.5 kb) was detected, and multiple SURFIN4.1 haplotype sequences detected in 1988/89 still circulated in 2003. Few of the single amino acid polymorphism allele frequency distributions were significantly different between the 1988/89 and 2003 groups, suggesting that the frequency distribution of SURFIN4.1 extracellular region remained stable over 14 years. PMID:23264727

  15. Ongoing incestuous abuse during adulthood.

    PubMed

    Middleton, Warwick

    2013-01-01

    Individual cases of adult incestuous abuse have surfaced repeatedly in the lay and professional literature of the past 1.5 centuries without it occasioning systematic investigation, such as the reporting of a case series of individuals subjected to such extreme abuse. Yet substantial numbers of patients with dissociative identity disorder at the time of presentation report incestuous abuse continuing into the adult years, and for many the abuse is ongoing. Data relating to a series of 10 such incestuously abused women are presented. These patients were sexually abused from a very early age (typically from before age 3), with the manipulation of their sexual response a key component in conditioning an enduring sexualized attachment. Shame and fear were also used to ensure compliance and silence. The women, when able to speak of it, describe the induction by their paternal abuser of orgasm at an early age, typically around the age of 6. The women have high indices of self-harm and suicidality and are prone to placing themselves in dangerous reenactment scenarios. The average duration of incestuous abuse for this group of women was 31 years, and the average estimate of total episodes of sexual abuse was 3,320. Most women do not feel that they own their body and experience being "fused" to their father. Their mother was reported as an active participant in the sexual abuse or as having done nothing to protect their daughter despite seeing obvious evidence of incest. The fathers, despite a propensity to use or threaten violence, were generally outwardly productively employed, financially comfortable, and stably married and half had close church involvement. However, suicide and murder occurred within the 1st- or 2nd-degree relatives of these women at a high frequency. All 10 had been sexually abused by various groupings of individuals connected to their fathers.

  16. Molecular evolution of GYPC: evidence for recent structural innovation and positive selection in humans.

    PubMed

    Wilder, Jason A; Hewett, Elizabeth K; Gansner, Meredith E

    2009-12-01

    GYPC encodes two erythrocyte surface sialoglycoproteins in humans, glycophorin C and glycophorin D (GPC and GPD), via initiation of translation at two start codons on a single transcript. The malaria-causing parasite Plasmodium falciparum uses GPC as a means of invasion into the human red blood cell. Here, we examine the molecular evolution of GYPC among the Hominoidea (Greater and Lesser Apes) and also the pattern of polymorphism at the locus in a global human sample. We find an excess of nonsynonymous divergence among species that appears to be caused solely by accelerated evolution of GYPC in the human lineage. Moreover, we find that the ability of GYPC to encode both GPC and GPD is a uniquely human trait, caused by the evolution of the GPC start codon in the human lineage. The pattern of polymorphism among humans is consistent with a hitchhiking event at the locus, suggesting that positive natural selection affected GYPC in the relatively recent past. Because GPC is exploited by P. falciparum for invasion of the red blood cell, we hypothesize that selection for evasion of P. falciparum has caused accelerated evolution of GYPC in humans (relative to other primates) and that this positive selection has continued to act in the recent evolution of our species. These data suggest that malaria has played a powerful role in shaping molecules on the surface of the human red blood cell. In addition, our examination of GYPC reveals a novel mechanism of protein evolution: co-option of untranslated region (UTR) sequence following the formation of a new start codon. In the case of human GYPC, the ancestral protein (GPD) continues to be produced through leaky translation. Because leaky translation is a widespread phenomenon among genes and organisms, we suggest that co-option of UTR sequence may be an important source of protein innovation.

  17. Exploring signatures of positive selection in pigmentation candidate genes in populations of East Asian ancestry.

    PubMed

    Hider, Jessica L; Gittelman, Rachel M; Shah, Tapan; Edwards, Melissa; Rosenbloom, Arnold; Akey, Joshua M; Parra, Esteban J

    2013-07-12

    Currently, there is very limited knowledge about the genes involved in normal pigmentation variation in East Asian populations. We carried out a genome-wide scan of signatures of positive selection using the 1000 Genomes Phase I dataset, in order to identify pigmentation genes showing putative signatures of selective sweeps in East Asia. We applied a broad range of methods to detect signatures of selection including: 1) Tests designed to identify deviations of the Site Frequency Spectrum (SFS) from neutral expectations (Tajima's D, Fay and Wu's H and Fu and Li's D* and F*), 2) Tests focused on the identification of high-frequency haplotypes with extended linkage disequilibrium (iHS and Rsb) and 3) Tests based on genetic differentiation between populations (LSBL). Based on the results obtained from a genome wide analysis of 25 kb windows, we constructed an empirical distribution for each statistic across all windows, and identified pigmentation genes that are outliers in the distribution. Our tests identified twenty genes that are relevant for pigmentation biology. Of these, eight genes (ATRN, EDAR, KLHL7, MITF, OCA2, TH, TMEM33 and TRPM1,) were extreme outliers (top 0.1% of the empirical distribution) for at least one statistic, and twelve genes (ADAM17, BNC2, CTSD, DCT, EGFR, LYST, MC1R, MLPH, OPRM1, PDIA6, PMEL (SILV) and TYRP1) were in the top 1% of the empirical distribution for at least one statistic. Additionally, eight of these genes (BNC2, EGFR, LYST, MC1R, OCA2, OPRM1, PMEL (SILV) and TYRP1) have been associated with pigmentary traits in association studies. We identified a number of putative pigmentation genes showing extremely unusual patterns of genetic variation in East Asia. Most of these genes are outliers for different tests and/or different populations, and have already been described in previous scans for positive selection, providing strong support to the hypothesis that recent selective sweeps left a signature in these regions. However, it will

  18. Molecular phylogenetic and positive selection analysis of Japanese encephalitis virus strains isolated from pigs in China.

    PubMed

    Liu, Wen-Jun; Zhu, Ming; Pei, Jing-Jing; Dong, Xiao-Ying; Liu, Wei; Zhao, Ming-Qiu; Wang, Jia-Ying; Gou, Hong-Chao; Luo, Yong-Wen; Chen, Jin-Ding

    2013-12-26

    Japanese encephalitis virus (JEV) is one of the most important virus which causes encephalitis. This disease is most prevalent in the south, southeast and the east region of Asia. In this study, two JEV strains, named JEV/SW/GD/01/2009 and JEV/SW/GZ/09/2004, were isolated from aborted fetuses and seminal fluid of pigs in China. To determine the characteristic of these virus isolates, the virulence of two newly JEV isolates was investigated, the result evidenced that the JEV/SW/GD/01/2009 did not kill mice, while the JEV/SW/GZ/09/2004 displayed neurovirulence with 0.925log10 p.f.u./LD50. Additionally, the full genome sequences of JEV were determined and compared with other known JEV strains. Results demonstrated that the genome of two JEV isolates was 10,976 nucleotides (nt) in length. As compared to the Chinese vaccine strain SA14-14-2, the JEV/SW/GD/01/2009 and the JEV/SW/GZ/09/2004 showed 99.7% and 97.5% identity at the nucleotide level, 99.6% and 96.7% identity at the amino acid level, respectively. Phylogenetic analysis, based on the full-length genome revealed that two JEV isolates were all clustered into genotype III compared to the reference strains. Furthermore, selection analyses revealed that dominant selective pressure acting on the JEV genome was purifying selection. Four sites under positive selection were identified: codon 521 (amino acid E-227), 2296 (amino acid NS4b-24), 3048 (amino acid NS5-521) and 3055 (amino acid NS5-528). Amino acid E-227 was proved to be related to neurovirulence. Taken together, the molecular epidemiology and functional of positively selected amino acid sites of two newly JEV isolates were fully understood, which might be helpful to predict possible changes in virulence. Copyright © 2013 Elsevier B.V. All rights reserved.

  19. Exploring signatures of positive selection in pigmentation candidate genes in populations of East Asian ancestry

    PubMed Central

    2013-01-01

    Background Currently, there is very limited knowledge about the genes involved in normal pigmentation variation in East Asian populations. We carried out a genome-wide scan of signatures of positive selection using the 1000 Genomes Phase I dataset, in order to identify pigmentation genes showing putative signatures of selective sweeps in East Asia. We applied a broad range of methods to detect signatures of selection including: 1) Tests designed to identify deviations of the Site Frequency Spectrum (SFS) from neutral expectations (Tajima’s D, Fay and Wu’s H and Fu and Li’s D* and F*), 2) Tests focused on the identification of high-frequency haplotypes with extended linkage disequilibrium (iHS and Rsb) and 3) Tests based on genetic differentiation between populations (LSBL). Based on the results obtained from a genome wide analysis of 25 kb windows, we constructed an empirical distribution for each statistic across all windows, and identified pigmentation genes that are outliers in the distribution. Results Our tests identified twenty genes that are relevant for pigmentation biology. Of these, eight genes (ATRN, EDAR, KLHL7, MITF, OCA2, TH, TMEM33 and TRPM1,) were extreme outliers (top 0.1% of the empirical distribution) for at least one statistic, and twelve genes (ADAM17, BNC2, CTSD, DCT, EGFR, LYST, MC1R, MLPH, OPRM1, PDIA6, PMEL (SILV) and TYRP1) were in the top 1% of the empirical distribution for at least one statistic. Additionally, eight of these genes (BNC2, EGFR, LYST, MC1R, OCA2, OPRM1, PMEL (SILV) and TYRP1) have been associated with pigmentary traits in association studies. Conclusions We identified a number of putative pigmentation genes showing extremely unusual patterns of genetic variation in East Asia. Most of these genes are outliers for different tests and/or different populations, and have already been described in previous scans for positive selection, providing strong support to the hypothesis that recent selective sweeps left a

  20. Positive selection of AS3MT to arsenic water in Andean populations

    PubMed Central

    Eichstaedt, Christina A.; Antao, Tiago; Cardona, Alexia; Pagani, Luca; Kivisild, Toomas; Mormina, Maru

    2016-01-01

    Arsenic is a carcinogen associated with skin lesions and cardiovascular diseases. The Colla population from the Puna region in Northwest Argentinean is exposed to levels of arsenic in drinking water exceeding the recommended maximum by a factor of 20. Yet, they thrive in this challenging environment since thousands of years and therefore we hypothesize strong selection signatures in genes involved in arsenic metabolism. We analyzed genome-wide genotype data for 730,000 loci in 25 Collas, considering 24 individuals of the neighbouring Calchaquíes and 24 Wichí from the Gran Chaco region in the Argentine province of Salta as control groups. We identified a strong signal of positive selection in the main arsenic methyltransferase AS3MT gene, which has been previously associated with lower concentrations of the most toxic product of arsenic metabolism monomethylarsonic acid. This study confirms recent studies reporting selection signals in the AS3MT gene albeit using different samples, tests and control populations. PMID:26366667

  1. Influence of Rotational Nucleosome Positioning on Transcription Start Site Selection in Animal Promoters

    PubMed Central

    Ambrosini, Giovanna; Bucher, Philipp

    2016-01-01

    The recruitment of RNA-Pol-II to the transcription start site (TSS) is an important step in gene regulation in all organisms. Core promoter elements (CPE) are conserved sequence motifs that guide Pol-II to the TSS by interacting with specific transcription factors (TFs). However, only a minority of animal promoters contains CPEs. It is still unknown how Pol-II selects the TSS in their absence. Here we present a comparative analysis of promoters’ sequence composition and chromatin architecture in five eukaryotic model organisms, which shows the presence of common and unique DNA-encoded features used to organize chromatin. Analysis of Pol-II initiation patterns uncovers that, in the absence of certain CPEs, there is a strong correlation between the spread of initiation and the intensity of the 10 bp periodic signal in the nearest downstream nucleosome. Moreover, promoters’ primary and secondary initiation sites show a characteristic 10 bp periodicity in the absence of CPEs. We also show that DNA natural variants in the region immediately downstream the TSS are able to affect both the nucleosome-DNA affinity and Pol-II initiation pattern. These findings support the notion that, in addition to CPEs mediated selection, sequence–induced nucleosome positioning could be a common and conserved mechanism of TSS selection in animals. PMID:27716823

  2. Phylogenetic analysis and positive-selection site detecting of vascular endothelial growth factor family in vertebrates.

    PubMed

    He, Wenwu; Tang, Yanyan; Qi, Bin; Lu, Chuansen; Qin, Chao; Wei, Yunfei; Yi, Jiachao; Chen, Mingwu

    2014-02-10

    Vascular endothelial growth factor (VEGF), known to play an important role in vascular homeostasis, vascular integrity and angiogenesis, is little known about the evolutionary relationship of its five members especially the role of gene duplication and natural selection in the evolution of the VEGF family. In this study, seventy-five full-length cDNA sequences from 33 vertebrate species were extracted from the NCBI's GenBank, UniProt protein database and the Ensembl database. By phylogenetic analyses, we investigated the origin, conservation, and evolution of the VEGFs. Five VEGF family members in vertebrates might be formed by gene duplication. The inferred evolutionary transitions that separate members which belong to different gene clusters correlated with changes in functional properties. Selection analysis and protein structure analysis were combined to explain the relationship of the site-specific evolution in the vertebrate VEGF family. Eleven positive selection sites, one transmembrane region and the active sites were detected in this process. © 2013.

  3. Technical note: immunomagnetic procedure for positive selection of macrophages in ovine milk.

    PubMed

    Caroprese, M; Marzano, A; Schena, L; Sevi, A

    2008-05-01

    A simple immunomagnetic procedure was developed to select macrophages from ovine milk by using a non-specific magnetic positive separation technique. Samples of ewe bulk milk were collected during early, mid, and late lactation; milk samples were centrifuged at 2,000 x g for 30 min at 4 degrees C; the fatty fraction and supernatant were removed, and each pellet was dissolved in 500 microL of pH 7.4 phosphate buffered saline + 0.02% NaN(3). Cells were targeted for selection by using mouse-IgG anti-ovine macrophages. Several trials, testing 2 different fluorochrome-conjugated antibodies [i.e., mouse anti-human CD14:R-Phycoerythrin (RPE) (MCA1568PE, Serotec) and F(ab')2 rabbit anti-mouse IgG:RPE (STAR12A, Serotec)] and 3 different labeling procedures, were performed to evaluate the purity of samples by flow cytometry. A morphological test was carried out by direct microscopic count in enriched fraction smears stained with May-Grünwald-Giemsa stain to confirm the presence of macrophages. The method described in the present technical note can be considered an innovative application to obtain a single-cell population of high purity selected from all the somatic cells in milk.

  4. A voltage-gated sodium channel is essential for the positive selection of CD4(+) T cells.

    PubMed

    Lo, Wan-Lin; Donermeyer, David L; Allen, Paul M

    2012-09-01

    The sustained entry of Ca(2+) into CD4(+)CD8(+) double-positive thymocytes is required for positive selection. Here we identified a voltage-gated Na(+) channel (VGSC) that was essential for positive selection of CD4(+) T cells. Pharmacological inhibition of VGSC activity inhibited the sustained Ca(2+) influx induced by positively selecting ligands and the in vitro positive selection of CD4(+) but not CD8(+) T cells. In vivo short hairpin RNA (shRNA)-mediated knockdown of the gene encoding a regulatory β-subunit of a VGSC specifically inhibited the positive selection of CD4(+) T cells. Ectopic expression of VGSC in peripheral AND CD4(+) T cells bestowed the ability to respond to a positively selecting ligand, which directly demonstrated that VGSC expression was responsible for the enhanced sensitivity. Thus, active VGSCs in thymocytes provide a mechanism by which a weak positive selection signal can induce the sustained Ca(2+) signals required for CD4(+) T cell development.

  5. Histidine substitution identifies a surface position and confers Cs+ selectivity on a K+ pore.

    PubMed Central

    De Biasi, M; Drewe, J A; Kirsch, G E; Brown, A M

    1993-01-01

    The amino acid located at position 369 is a key determinant of the ion conduction pathway or pore of the voltage-gated K+ channels, Kv2.1 and a chimeric channel, CHM, constructed by replacing the pore region of Kv2.1 with that of Kv3.1. To determine the orientation of residue 369 with respect to the aqueous lumen of the pore, the nonpolar Ile at 369 in Kv2.1 was replaced with a basic His. This substitution produced a Cs(+)-selective channel with Cs+:K+ permeability ratio of 4 compared to 0.1 in the wild type. Block by external tetraethylammonium (TEA) was reduced about 20-fold, while block by internal TEA was unaffected. External protons and Zn2+, that are known to interact with the imidazole ring of His, blocked the mutant channel much more effectively than the wild type channel. The blockade by Zn2+ and protons was voltage-independent, and the proton blockade had a pKa of about 6.5, consistent with the pKa for His in solution. The histidyl-specific reagent diethylpyrocarbonate produced greatly exaggerated blockade of the mutated channel compared to the wild type. The residue at position 369 appears to form part of the binding site for external TEA and to influence the selectivity for monovalent cations. We suggest that the imidazole side-chain of His369 is exposed to the aqueous lumen at a surface position near the external mouth of the pore. PMID:8241404

  6. Selective Population of Unbound Positive Parity States in 25F and 26F

    NASA Astrophysics Data System (ADS)

    Frank, Nathan; Herman, Jacob; Rabeh, Ali; Tuttle-Timm, Matthew; MoNA Collaboration

    2017-01-01

    Unbound Positive Parity States in 25F and 26F were populated in the one-proton removal reaction from a radioactive 27Ne beam. The experiment was performed at the National Superconducting Cyclotron Laboratory (NSCL), where a 101.3 MeV/u 27Ne ion beam impinged on a liquid deuterium target populating states in 26F. States above the one- and two- neutron separation energies lead to 24F and 25F, respectively. The MoNA/LISA setup at NSCL was used to detect the fragments in coincidence with neutrons and the decay energy spectra of 25F and 26F were reconstructed by invariant mass spectroscopy. Resonance energies of approximately 0.35 MeV and 0.5 MeV for 25F* and 26F*, respectively, were extracted. Based on the calculated spectroscopic strength distribution of negative and positive parity states in 26F and the selectivity of one proton-removal reactions both states were assigned positive parity. NSF Grant #1404236.

  7. Evidence for positive selection and recombination hotspots in Deformed wing virus (DWV)

    PubMed Central

    Dalmon, A.; Desbiez, C.; Coulon, M.; Thomasson, M.; Le Conte, Y.; Alaux, C.; Vallon, J.; Moury, B.

    2017-01-01

    Deformed wing virus (DWV) is considered one of the most damaging pests in honey bees since the spread of its vector, Varroa destructor. In this study, we sequenced the whole genomes of two virus isolates and studied the evolutionary forces that act on DWV genomes. The isolate from a Varroa-tolerant bee colony was characterized by three recombination breakpoints between DWV and the closely related Varroa destructor virus-1 (VDV-1), whereas the variant from the colony using conventional Varroa management was similar to the originally described DWV. From the complete sequence dataset, nine independent DWV-VDV-1 recombination breakpoints were detected, and recombination hotspots were found in the 5′ untranslated region (5′ UTR) and the conserved region encoding the helicase. Partial sequencing of the 5′ UTR and helicase-encoding region in 41 virus isolates suggested that most of the French isolates were recombinants. By applying different methods based on the ratio between non-synonymous (dN) and synonymous (dS) substitution rates, we identified four positions that showed evidence of positive selection. Three of these positions were in the putative leader protein (Lp), and one was in the polymerase. These findings raise the question of the putative role of the Lp in viral evolution. PMID:28120868

  8. Genes Regulated by Vitamin D in Bone Cells Are Positively Selected in East Asians

    PubMed Central

    Chen, Yuan; Xue, Yali; Luiselli, Donata; Tyler-Smith, Chris; Pagani, Luca; Ayub, Qasim

    2015-01-01

    Vitamin D and folate are activated and degraded by sunlight, respectively, and the physiological processes they control are likely to have been targets of selection as humans expanded from Africa into Eurasia. We investigated signals of positive selection in gene sets involved in the metabolism, regulation and action of these two vitamins in worldwide populations sequenced by Phase I of the 1000 Genomes Project. Comparing allele frequency-spectrum-based summary statistics between these gene sets and matched control genes, we observed a selection signal specific to East Asians for a gene set associated with vitamin D action in bones. The selection signal was mainly driven by three genes CXXC finger protein 1 (CXXC1), low density lipoprotein receptor-related protein 5 (LRP5) and runt-related transcription factor 2 (RUNX2). Examination of population differentiation and haplotypes allowed us to identify several candidate causal regulatory variants in each gene. Four of these candidate variants (one each in CXXC1 and RUNX2 and two in LRP5) had a >70% derived allele frequency in East Asians, but were present at lower (20–60%) frequency in Europeans as well, suggesting that the adaptation might have been part of a common response to climatic and dietary changes as humans expanded out of Africa, with implications for their role in vitamin D-dependent bone mineralization and osteoporosis insurgence. We also observed haplotype sharing between East Asians, Finns and an extinct archaic human (Denisovan) sample at the CXXC1 locus, which is best explained by incomplete lineage sorting. PMID:26719974

  9. High sensitivity to aligner and high rate of false positives in the estimates of positive selection in the 12 Drosophila genomes

    PubMed Central

    Markova-Raina, Penka; Petrov, Dmitri

    2011-01-01

    We investigate the effect of aligner choice on inferences of positive selection using site-specific models of molecular evolution. We find that independently of the choice of aligner, the rate of false positives is unacceptably high. Our study is a whole-genome analysis of all protein-coding genes in 12 Drosophila genomes annotated in either all 12 species (∼6690 genes) or in the six melanogaster group species. We compare six popular aligners: PRANK, T-Coffee, ClustalW, ProbCons, AMAP, and MUSCLE, and find that the aligner choice strongly influences the estimates of positive selection. Differences persist when we use (1) different stringency cutoffs, (2) different selection inference models, (3) alignments with or without gaps, and/or additional masking, (4) per-site versus per-gene statistics, (5) closely related melanogaster group species versus more distant 12 Drosophila genomes. Furthermore, we find that these differences are consequential for downstream analyses such as determination of over/under-represented GO terms associated with positive selection. Visual analysis indicates that most sites inferred as positively selected are, in fact, misaligned at the codon level, resulting in false positive rates of 48%–82%. PRANK, which has been reported to outperform other aligners in simulations, performed best in our empirical study as well. Unfortunately, PRANK still had a high, and unacceptable for most applications, false positives rate of 50%–55%. We identify misannotations and indels, many of which appear to be located in disordered protein regions, as primary culprits for the high misalignment-related error levels and discuss possible workaround approaches to this apparently pervasive problem in genome-wide evolutionary analyses. PMID:21393387

  10. Ongoing Recovery Basic Information Tool (ORBIT)

    NASA Technical Reports Server (NTRS)

    Oberg, Donald

    1993-01-01

    The Federal Drug Free Work Place Program (DFWP) has now matured to the point of being able to return employees to sensitive testing designated positions (TDP) after completion of treatment of their addiction. The known tendency of addicted individuals to suffer multiple relapses prior to their final recovery has resulted in several positive urine tests (relapses) occurring among those Federal employees who have already completed treatment and who have been returned to TDP's. The very real potential for further relapses occurring after additional employees return to TDP's will be a critical factor in the ultimate success of the DFWP and in the public's impression of the program's effectiveness. In response to this concern, NASA has begun development of its Ongoing Recovery Basic Information Tool (ORBIT) instrument. The aim of the NASA ORBIT is to provide Employee Assistance Program (EAP) professionals with an advanced clinical tool which will be helpful in supporting recovery from substance abuse and which will allow more accurate determinations of when clients may be successfully returned to sensitive positions.

  11. Species specific exome probes reveal new insights in positively selected genes in nonhuman primates

    PubMed Central

    Su, Zheng; Zhang, Junjie; Kumar, Chanchal; Molony, Cliona; Lu, Hongchao; Chen, Ronghua; Stone, David J.; Ling, Fei; Liu, Xiao

    2016-01-01

    Nonhuman primates (NHP) are important biomedical animal models for the study of human disease. Of these, the most widely used models in biomedical research currently are from the genus Macaca. However, evolutionary genetic divergence between human and NHP species makes human-based probes inefficient for the capture of genomic regions of NHP for sequencing and study. Here we introduce a new method to resequence the exome of NHP species by a designed capture approach specifically targeted to the NHP, and demonstrate its superior performance on four NHP species or subspecies. Detailed investigation on biomedically relevant genes demonstrated superior capture by the new approach. We identified 28 genes that appeared to be pseudogenized and inactivated in macaque. Finally, we identified 187 genes showing strong evidence for positive selection across all branches of the primate phylogeny including many novel findings. PMID:27659771

  12. Analysis of complexity measures and information planes of selected molecules in position and momentum spaces.

    PubMed

    Esquivel, Rodolfo O; Angulo, Juan Carlos; Antolín, Juan; Dehesa, Jesús S; López-Rosa, Sheila; Flores-Gallegos, Nelson

    2010-07-14

    The Fisher-Shannon and LMC shape complexities and the Shannon-disequilibrium, Fisher-Shannon and Fisher-disequilibrium information planes, which consist of two localization-delocalization factors, are computed in both position and momentum spaces for the one-particle densities of 90 selected molecules of various chemical types, at the CISD/6-311++G(3df,2p) level of theory. We found that while the two measures of complexity show general trends only, the localization-delocalization planes clearly exhibit chemically significant patterns. Several molecular properties (energy, ionization potential, total dipole moment, hardness, electrophilicity) are analyzed and used to interpret and understand the chemical nature of the composite information-theoretic measures above mentioned. Our results show that these measures detect not only randomness or localization but also pattern and organization.

  13. Selective Inactivation of Resistant Gram-Positive Pathogens with a Light-Driven Hybrid Nanomaterial.

    PubMed

    Grüner, Malte; Tuchscherr, Lorena; Löffler, Bettina; Gonnissen, Dominik; Riehemann, Kristina; Staniford, Mark C; Kynast, Ulrich; Strassert, Cristian A

    2015-09-23

    Herein, we present a straightforward strategy to disperse highly insoluble photosensitizers in aqueous environments, without major synthetic efforts and keeping their photosensitizing abilities unaffected. A layered nanoclay was employed to adsorb and to solubilize a highly efficient yet hydrophobic Si(IV) phthalocyaninate in water. The aggregation of the photoactive dye was correlated with its photophysical properties, particularly with the ability to produce highly cytotoxic singlet oxygen. Moreover, the resulting hybrid nanomaterial is able to selectively photoinactivate Gram-positive pathogens, due to local interactions between the bacterial membranes and the negatively charged nanodiscs. Nanotoxicity assays confirmed its innocuousness toward eukaryotic cells, showing that it constitutes a new class of "phototriggered magic bullet" for the inactivation of pathogens in phototherapy, as well as in the development of coatings for self-disinfecting surfaces.

  14. Cross-linked block copolymer templated assembly of nanoparticle arrays with high density and position selectivity

    NASA Astrophysics Data System (ADS)

    Liu, Zhicheng; Chang, Tongxin; Huang, Haiying; Bai, Lu

    2016-10-01

    Patterning ordered nanoparticle arrays is crucial for the fascinating collective properties of nanoparticles. Block copolymer template provides us a platform for the simple and efficient assembly of nanoparticle arrays. In this work, cylinder-forming poly(styrene-block-2-vinylpyridine) thin film was firstly plasma-etched to expose poly(2-vinylpyridine) cylinders. Then the templates were cross-linked by small molecules so as to access gold nanoparticle arrays with both high density and excellent position selectivity. The cross-linking process significantly restrains the unfavorable surface reconstruction of the thin film. It is demonstrated that the quality of the nanoparticle array was affected by the degree of the cross-linking and the immersion time in nanoparticle solution. The highly ordered gold nanoparticle arrays are promising in several fields such as optics and surface enhanced Raman scattering (SERS).

  15. In Brucella: Selective pressure may turn some genes on instead of default off position.

    PubMed

    Wareth, Gamal; Melzer, Falk; Neubauer, Heinrich

    2017-06-01

    Brucellosis is a major zoonosis with worldwide prevalence; more than half a million new human cases are expected every year. The genus Brucella (B) encompasses 12 accepted nomo-species and brucellae were described as Gram negative, aerobic, non-motile and non-haemolytic facultative intracellular bacteria. The Brucella genome contains flagella-specific genes and various hemolysins, but no flagella are formed and nor hemolysis is seen. Selective pressure can cause accumulation of mutations that turn those genes on instead of default off position and provoked the motile and hemolytic phenotypes. The ability of brucellae to change from a non-haemolytic to a haemolytic phenotype might influence their pathogenicity and could provide a substantial insight to explain the correlation of acute brucellosis and hemolytic anemia in humans. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  16. Trans genomic capture and sequencing of primate exomes reveals new targets of positive selection.

    PubMed

    George, Renee D; McVicker, Graham; Diederich, Rachel; Ng, Sarah B; MacKenzie, Alexandra P; Swanson, Willie J; Shendure, Jay; Thomas, James H

    2011-10-01

    Comparison of protein-coding DNA sequences from diverse primates can provide insight into these species' evolutionary history and uncover the molecular basis for their phenotypic differences. Currently, the number of available primate reference genomes limits these genome-wide comparisons. Here we use targeted capture methods designed for human to sequence the protein-coding regions, or exomes, of four non-human primate species (three Old World monkeys and one New World monkey). Despite average sequence divergence of up to 4% from the human sequence probes, we are able to capture ~96% of coding sequences. Using a combination of mapping and assembly techniques, we generated high-quality full-length coding sequences for each species. Both the number of nucleotide differences and the distribution of insertion and deletion (indel) lengths indicate that the quality of the assembled sequences is very high and exceeds that of most reference genomes. Using this expanded set of primate coding sequences, we performed a genome-wide scan for genes experiencing positive selection and identified a novel class of adaptively evolving genes involved in the conversion of epithelial cells in skin, hair, and nails to keratin. Interestingly, the genes we identify under positive selection also exhibit significantly increased allele frequency differences among human populations, suggesting that they play a role in both recent and long-term adaptation. We also identify several genes that have been lost on specific primate lineages, which illustrate the broad utility of this data set for other evolutionary analyses. These results demonstrate the power of second-generation sequencing in comparative genomics and greatly expand the repertoire of available primate coding sequences.

  17. Retention of duplicated long-wavelength opsins in mosquito lineages by positive selection and differential expression.

    PubMed

    Giraldo-Calderón, Gloria I; Zanis, Michael J; Hill, Catherine A

    2017-03-21

    Opsins are light sensitive receptors associated with visual processes. Insects typically possess opsins that are stimulated by ultraviolet, short and long wavelength (LW) radiation. Six putative LW-sensitive opsins predicted in the yellow fever mosquito, Aedes aegypti and malaria mosquito, Anopheles gambiae, and eight in the southern house mosquito, Culex quinquefasciatus, suggest gene expansion in the Family Culicidae (mosquitoes) relative to other insects. Here we report the first detailed molecular and evolutionary analyses of LW opsins in three mosquito vectors, with a goal to understanding the molecular basis of opsin-mediated visual processes that could be exploited for mosquito control. Time of divergence estimates suggest that the mosquito LW opsins originated from 18 or 19 duplication events between 166.9/197.5 to 1.07/0.94 million years ago (MY) and that these likely occurred following the predicted divergence of the lineages Anophelinae and Culicinae 145-226 MY. Fitmodel analyses identified nine amino acid residues in the LW opsins that may be under positive selection. Of these, eight amino acids occur in the N and C termini and are shared among all three species, and one residue in TMIII was unique to culicine species. Alignment of 5' non-coding regions revealed potential Conserved Non-coding Sequences (CNS) and transcription factor binding sites (TFBS) in seven pairs of LW opsin paralogs. Our analyses suggest opsin gene duplication and residues possibly associated with spectral tuning of LW-sensitive photoreceptors. We explore two mechanisms - positive selection and differential expression mediated by regulatory units in CNS - that may have contributed to the retention of LW opsin genes in Culicinae and Anophelinae. We discuss the evolution of mosquito LW opsins in the context of major Earth events and possible adaptation of mosquitoes to LW-dominated photo environments, and implications for mosquito control strategies based on disrupting vision

  18. Positive and negative selection towards tetracycline resistance genes in manure treatment lagoons.

    PubMed

    Barkovskii, A L; Manoylov, K M; Bridges, C

    2012-05-01

    To evaluate the role of manure treatment lagoons of swine operations in the fate of faeces- and feed-borne tetracycline-resistant genes (TRG). Samples of feed, faeces, lagoon liquid and lagoon sediment in farm's vicinity were collected at three swine operations varied on their operational practices and analysed on the presence and frequencies of incidence of sixteen TRG in upstream sources (feed, faeces) and downstream receptacles (lagoon liquid and sediments). The highest frequency of TRG incidence was observed in a farm with extensive antibiotic usage and the lowest in the antibiotic-free farm. The study revealed a decrease in TRG richness and diversity in the downstream habitats of each farm. The observed TRG diverged into two groups, the persistent genes that were detected both upstream and downstream, and the transient genes that were detected in the upstream habitats but became nondetectable in the lagoons. Quantitative PCR analysis revealed that upstream concentrations and abundances (determined as TRG/16S rRNA gene ratios) of transient and persistent TRG were similar; however, the former were attenuated in the lagoons to the levels below the detection limit, whereas the latter were ∼ 100-1000 fold amplified in their (mostly) liquid phases and were also detected in farms' vicinities. Manure lagoons of swine operations imposed both positive and negative selection towards faeces- and feed-borne TRG that, respectively, caused either their proliferation or attenuation in those environments. The study reveals that discharge of antibiotic resistance genes from swine farms to the environment is linked to their positive selection (defined as an impact leading to proliferation of those genes) in manure lagoons. © 2012 The Authors. Journal of Applied Microbiology © 2012 The Society for Applied Microbiology.

  19. Serial position functions following selective hippocampal lesions in monkeys: Effects of delays and interference✩

    PubMed Central

    Bachevalier, Jocelyne; Wright, Anthony A.; Katz, Jeffrey S.

    2013-01-01

    We examined the role of the hippocampus in list-memory processing. Three rhesus monkeys that had extensive experience in this task and had demonstrated full abstract-concept learning and excellent list memory performance (Katz et al., 2002; Wright et al., 2003) received bilateral neurotoxic hippocampal lesions and were re-tested in the serial list memory task. Effects of delays on memory performance were measured in all monkeys, whereas the effects of proactive interference were assessed in only one. Despite a slight change in performance of one of the three animals during re-learning of the same/different task, selective hippocampal damage had little or no effects on list memory accuracy. In addition, the hippocampal damage did not impact serial list position functions (SPFs) but slightly altered the dynamic of the SPF curves. Finally, even more remarkable was that accurate memory performance of one animal remained intact despite the use of small set size of 8 items that created high proactive interference across lists thereby eliminating any use of familiarity judgments to support performance. Together the findings indicate that, with short list items and extensive training in the task (i.e., reference memory), monkeys with selective hippocampal lesions may be able to use alternative memory processes (i.e., working memory) that are mediated by structures other than the hippocampus. PMID:23246643

  20. Augmenting the Genetic Toolbox for Sulfolobus islandicus with a Stringent Positive Selectable Marker for Agmatine Prototrophy

    PubMed Central

    Cooper, Tara E.; Krause, David J.

    2013-01-01

    Sulfolobus species have become the model organisms for studying the unique biology of the crenarchaeal division of the archaeal domain. In particular, Sulfolobus islandicus provides a powerful opportunity to explore natural variation via experimental functional genomics. To support these efforts, we further expanded genetic tools for S. islandicus by developing a stringent positive selection for agmatine prototrophs in strains in which the argD gene, encoding arginine decarboxylase, has been deleted. Strains with deletions in argD were shown to be auxotrophic for agmatine even in nutrient-rich medium, but growth could be restored by either supplementation of exogenous agmatine or reintroduction of a functional copy of the argD gene from S. solfataricus P2 into the ΔargD host. Using this stringent selection, a robust targeted gene knockout system was established via an improved next generation of the MID (marker insertion and unmarked target gene deletion) method. Application of this novel system was validated by targeted knockout of the upsEF genes involved in UV-inducible cell aggregation formation. PMID:23835176

  1. Positive mRNA Translational Control in Germ Cells by Initiation Factor Selectivity

    PubMed Central

    Friday, Andrew J.; Keiper, Brett D.

    2015-01-01

    Ultimately, the production of new proteins in undetermined cells pushes them to new fates. Other proteins hold a stem cell in a mode of self-renewal. In germ cells, these decision-making proteins are produced largely from translational control of preexisting mRNAs. To date, all of the regulation has been attributed to RNA binding proteins (RBPs) that repress mRNAs in many models of germ cell development (Drosophila, mouse, C. elegans, and Xenopus). In this review, we focus on the selective, positive function of translation initiation factors eIF4E and eIF4G, which recruit mRNAs to ribosomes upon derepression. Evidence now shows that the two events are not separate but rather are coordinated through composite complexes of repressors and germ cell isoforms of eIF4 factors. Strikingly, the initiation factor isoforms are themselves mRNA selective. The mRNP complexes of translation factors and RBPs are built on specific populations of mRNAs to prime them for subsequent translation initiation. Simple rearrangement of the partners causes a dormant mRNP to become synthetically active in germ cells when and where they are required to support gametogenesis. PMID:26357652

  2. Discovery, synthesis, and molecular pharmacology of selective positive allosteric modulators of the δ-opioid receptor.

    PubMed

    Burford, Neil T; Livingston, Kathryn E; Canals, Meritxell; Ryan, Molly R; Budenholzer, Lauren M L; Han, Ying; Shang, Yi; Herbst, John J; O'Connell, Jonathan; Banks, Martyn; Zhang, Litao; Filizola, Marta; Bassoni, Daniel L; Wehrman, Tom S; Christopoulos, Arthur; Traynor, John R; Gerritz, Samuel W; Alt, Andrew

    2015-05-28

    Allosteric modulators of G protein-coupled receptors (GPCRs) have a number of potential advantages compared to agonists or antagonists that bind to the orthosteric site of the receptor. These include the potential for receptor selectivity, maintenance of the temporal and spatial fidelity of signaling in vivo, the ceiling effect of the allosteric cooperativity which may prevent overdose issues, and engendering bias by differentially modulating distinct signaling pathways. Here we describe the discovery, synthesis, and molecular pharmacology of δ-opioid receptor-selective positive allosteric modulators (δ PAMs). These δ PAMs increase the affinity and/or efficacy of the orthosteric agonists leu-enkephalin, SNC80 and TAN67, as measured by receptor binding, G protein activation, β-arrestin recruitment, adenylyl cyclase inhibition, and extracellular signal-regulated kinases (ERK) activation. As such, these compounds are useful pharmacological tools to probe the molecular pharmacology of the δ receptor and to explore the therapeutic potential of δ PAMs in diseases such as chronic pain and depression.

  3. Recurrent positive selection and heterogeneous codon usage bias events leading to coexistence of divergent pigeon circoviruses.

    PubMed

    Liao, Pei-Chun; Wang, Kung-Kai; Tsai, Shinn-Shyong; Liu, Hung-Jen; Huang, Bing-Hong; Chuang, Kuo-Pin

    2015-08-01

    The capsid genes from 14 pigeon circovirus (PiCV) sequences, collected from Taiwan between 2009 and 2010, were sequenced and compared with 14 PiCV capsid gene sequences from GenBank. Based on pairwise comparison, PiCV strains from Taiwan shared 73.9-100% nucleotide identity and 72-100% amino acid identity with those of the 14 reported PiCV sequences. Phylogenetic analyses revealed that Taiwanese PiCV isolates can be grouped into two clades: clade 1 comprising isolates from Belgium, Australia, USA, Italy and China, and clade 2 showing close relation to isolates from Germany and France. Recurrent positive selection was detected in clade 1 PiCV lineages, which may contribute to the diversification of predominant PiCV sequences in Taiwan. Further observations suggest that synonymous codon usage variations between PiCV clade 1 and clade 2 may reflect the adaptive divergence on translation efficiency of capsid genes in infectious hosts. Variation in selective pressures acting on the evolutionary divergence and codon usage bias of both clades explains the regional coexistence of virus sequences congeners prevented from competitive exclusion within an island such as Taiwan. Our genotyping results also provide insight into the aetiological agents of PiCV outbreak in Taiwan and we present a comparative analysis of the central coding region of PiCV genome. From the sequence comparison results of 28 PiCVs which differs in regard to the geographical origin and columbid species, we identified conserved regions within the capsid gene that are likely to be suitable for primer selection and vaccine development.

  4. Miiuy Croaker Transferrin Gene and Evidence for Positive Selection Events Reveal Different Evolutionary Patterns

    PubMed Central

    Sun, Yueyan; Zhu, Zhihuang; Wang, Rixin; Sun, Yuena; Xu, Tianjun

    2012-01-01

    Transferrin (TF) is a protein that plays a central role in iron metabolism. This protein is associated with the innate immune system, which is responsible for disease defense responses after bacterial infection. The clear link between TF and the immune defense mechanism has led researchers to consider TF as a candidate gene for disease resistance. In this study, the Miichthys miiuy (miiuy croaker) TF gene (MIMI-TF) was cloned and characterized. The gene structure consisted of a coding region of 2070 nucleotides divided into 17 exons, as well as a non-coding region that included 16 introns and spans 6757 nucleotides. The deduced MIMI-TF protein consisted of 689 amino acids that comprised a signal peptide and two lobes (N- and C-lobes). MIMI-TF expression was significantly up-regulated after infection with Vibrio anguillarum. A series of model tests implemented in the CODEML program showed that TF underwent a complex evolutionary process. Branch-site models revealed that vertebrate TF was vastly different from that of invertebrates, and that the TF of the ancestors of aquatic and terrestrial organisms underwent different selection pressures. The site models detected 10 positively selected sites in extant TF genes. One site was located in the cleft between the N1 and N2 domains and was expected to affect the capability of TF to bind to or release iron indirectly. In addition, eight sites were found near the TF exterior. Two of these sites, which could have evolved from the competition for iron between pathogenic bacteria and TF, were located in potential pathogen-binding domains. Our results could be used to further investigate the function of TF and the selective mechanisms involved. PMID:22957037

  5. Evidence of positive selection towards Zebuine haplotypes in the BoLA region of Brangus cattle.

    PubMed

    Goszczynski, D E; Corbi-Botto, C M; Durand, H M; Rogberg-Muñoz, A; Munilla, S; Peral-Garcia, P; Cantet, R J C; Giovambattista, G

    2017-07-14

    The Brangus breed was developed to combine the superior characteristics of both of its founder breeds, Angus and Brahman. It combines the high adaptability to tropical and subtropical environments, disease resistance, and overall hardiness of Zebu cattle with the reproductive potential and carcass quality of Angus. It is known that the major histocompatibility complex (MHC, also known as bovine leucocyte antigen: BoLA), located on chromosome 23, encodes several genes involved in the adaptive immune response and may be responsible for adaptation to harsh environments. The objective of this work was to evaluate whether the local breed ancestry percentages in the BoLA locus of a Brangus population diverged from the estimated genome-wide proportions and to identify signatures of positive selection in this genomic region. For this, 167 animals (100 Brangus, 45 Angus and 22 Brahman) were genotyped using a high-density single nucleotide polymorphism array. The local ancestry analysis showed that more than half of the haplotypes (55.0%) shared a Brahman origin. This value was significantly different from the global genome-wide proportion estimated by cluster analysis (34.7% Brahman), and the proportion expected by pedigree (37.5% Brahman). The analysis of selection signatures by genetic differentiation (F st ) and extended haplotype homozygosity-based methods (iHS and Rsb) revealed 10 and seven candidate regions, respectively. The analysis of the genes located within these candidate regions showed mainly genes involved in immune response-related pathway, while other genes and pathways were also observed (cell surface signalling pathways, membrane proteins and ion-binding proteins). Our results suggest that the BoLA region of Brangus cattle may have been enriched with Brahman haplotypes as a consequence of selection processes to promote adaptation to subtropical environments.

  6. An Abdominal CT may be Safe in Selected Hypotensive Trauma Patients with Positive FAST Exam

    PubMed Central

    Cook, Mackenzie R.; Holcomb, John B.; Rahbar, Mohammad H.; Alarcon, Louis H.; Bulger, Eileen M.; Brasel, Karen J.; Schreiber, Martin A.

    2016-01-01

    Background Positive Focused Assessment with Sonography in Trauma (FAST) and hypotension often indicates urgent surgery. An abdomen/pelvis CT (apCT) may allow less invasive management but the delay may be associated with adverse outcomes. Methods Patients in the Prospective Observational Multicenter Major Trauma Transfusion study with hypotension and a positive FAST (HF+) who underwent a CT (apCT+) were compared to those who did not. Results Of the 92 HF+ identified, 32(35%) underwent apCT during initial evaluation and apCT was associated with decreased odds of an emergency operation, OR 0.11 95% CI (0.001–0.116) and increased odds of angiographic intervention, OR 14.3 95% CI (1.5–135). There was no significant difference in 30 day mortality or need for dialysis. Conclusion An apCt in HF+ patients is associated with reduced odds of emergency surgery, but not mortality. Select HF+ patients can safely undergo apCT to obtain clinically useful information. PMID:25805456

  7. Selective targeting of cellular nucleus using positively-charged quantum dots.

    PubMed

    Lee, Junghan; Choi, Youngseon; Cho, Yoojin; Song, Rita

    2013-01-01

    Developing highly selective probes for subcellular regions such as nucleus and cytoplamic organelles is of great interest for cellular imaging and high content screening analysis for biology and medicine. Cytoplasmic delivery of QDs has been well-understood, while nuclear delivery of QDs has been a challenge due to the unique structural characteristics of cell nucleus. In this study, we systematically investigated nucleus penetrating properties of small-sized ligand-exchanged QDs with either positive or negative surface charges in the similar size range of hydrodynamic diameter (7-10 nm). We found that the positively-charged QDs efficiently stain the nucleus in fixed HeLa cells as well as label nucleolar compartments in live HeLa cells. In contrast, the negatively charged QDs with the similar size range stain only the cytoplam in either fixed or live cells. The charge-dependent labeling pattern allowed us to simultaneously perform multiplex imaging of nuclues and cytoplasm. This study offers an insight into efficient nuclear delivery of nanoparticles such as QDs of which surface charge and size are critical for intracelllar localization and delivery.

  8. Symmetrically Substituted Xanthone Amphiphiles Combat Gram-Positive Bacterial Resistance with Enhanced Membrane Selectivity.

    PubMed

    Lin, Shuimu; Koh, Jun-Jie; Aung, Thet Tun; Lim, Fanghui; Li, Jianguo; Zou, Hanxun; Wang, Lin; Lakshminarayanan, Rajamani; Verma, Chandra; Wang, Yingjun; Tan, Donald T H; Cao, Derong; Beuerman, Roger W; Ren, Li; Liu, Shouping

    2017-02-23

    This is the first report of the design of a new series of symmetric xanthone derivatives that mimic antimicrobial peptides using a total synthesis approach. This novel design is advantageous because of its low cost, synthetic simplicity and versatility, and easy tuning of amphiphilicity by controlling the incorporated cationic and hydrophobic moieties. Two water-soluble optimized compounds, 6 and 18, showed potent activities against Gram-positive bacteria, including MRSA and VRE (MICs = 0.78-6.25 μg/mL) with a rapid bactericidal effect, low toxicity, and no emergence of drug resistance. Both compounds demonstrated enhanced membrane selectivity that was higher than those of most membrane-active antimicrobials in clinical trials or previous reports. The compounds appear to kill bacteria by disrupting their membranes. Significantly, 6 was effective in vivo using a mouse model of corneal infection. These results provide compelling evidence that these compounds have therapeutic potential as novel antimicrobials for multidrug-resistant Gram-positive infections.

  9. Positive selection in octopus haemocyanin indicates functional links to temperature adaptation.

    PubMed

    Oellermann, Michael; Strugnell, Jan M; Lieb, Bernhard; Mark, Felix C

    2015-07-05

    Octopods have successfully colonised the world's oceans from the tropics to the poles. Yet, successful persistence in these habitats has required adaptations of their advanced physiological apparatus to compensate impaired oxygen supply. Their oxygen transporter haemocyanin plays a major role in cold tolerance and accordingly has undergone functional modifications to sustain oxygen release at sub-zero temperatures. However, it remains unknown how molecular properties evolved to explain the observed functional adaptations. We thus aimed to assess whether natural selection affected molecular and structural properties of haemocyanin that explains temperature adaptation in octopods. Analysis of 239 partial sequences of the haemocyanin functional units (FU) f and g of 28 octopod species of polar, temperate, subtropical and tropical origin revealed natural selection was acting primarily on charge properties of surface residues. Polar octopods contained haemocyanins with higher net surface charge due to decreased glutamic acid content and higher numbers of basic amino acids. Within the analysed partial sequences, positive selection was present at site 2545, positioned between the active copper binding centre and the FU g surface. At this site, methionine was the dominant amino acid in polar octopods and leucine was dominant in tropical octopods. Sites directly involved in oxygen binding or quaternary interactions were highly conserved within the analysed sequence. This study has provided the first insight into molecular and structural mechanisms that have enabled octopods to sustain oxygen supply from polar to tropical conditions. Our findings imply modulation of oxygen binding via charge-charge interaction at the protein surface, which stabilize quaternary interactions among functional units to reduce detrimental effects of high pH on venous oxygen release. Of the observed partial haemocyanin sequence, residue 2545 formed a close link between the FU g surface and the

  10. Development of a screen for ongoing intimate partner violence.

    PubMed

    Weiss, Steve J; Ernst, Amy A; Cham, Elaine; Nick, Todd G

    2003-04-01

    A five-question Ongoing Abuse Screen (OAS) was developed to evaluate ongoing intimate partner violence. Our hypothesis was that the OAS was more accurate and more likely to reflect ongoing intimate partner violence than the AAS when compared to the Index of Spouse Abuse (ISA). The survey included the ISA, the OAS, and the AAS. During the busiest emergency department hours, a sampling of 856 patients completed all aspects of the survey tool. Comparisons were made between the two scales and the ISA. The accuracy, positive predictive value, and positive likelihood ratio were 84%, 58%, and 6.0 for the OAS and 59%, 33%, and 2.0 for the AAS. The OAS was more accurate, had a better positive predictive value, and was three times more likely to detect victims of ongoing intimate partner violence than the AAS. Because the OAS was still not accurate enough, we developed a new screen, based on the ISA, titled the Ongoing Violence Assessment Tool (OVAT).

  11. Conserved positive selection signals in gp41 across multiple subtypes and difference in selection signals detectable in gp41 sequences sampled during acute and chronic HIV-1 subtype C infection

    PubMed Central

    Bandawe, Gama P; Martin, Darren P; Treurnicht, Florette; Mlisana, Koleka; Karim, Salim S Abdool; Williamson, Carolyn

    2008-01-01

    Background The high diversity of HIV variants driving the global AIDS epidemic has caused many to doubt whether an effective vaccine against the virus is possible. However, by identifying the selective forces that are driving the ongoing diversification of HIV and characterising their genetic consequences, it may be possible to design vaccines that pre-empt some of the virus' more common evasion tactics. One component of such vaccines might be the envelope protein, gp41. Besides being targeted by both the humoral and cellular arms of the immune system this protein mediates fusion between viral and target cell membranes and is likely to be a primary determinant of HIV transmissibility. Results Using recombination aware analysis tools we compared site specific signals of selection in gp41 sequences from different HIV-1 M subtypes and circulating recombinant forms and identified twelve sites evolving under positive selection across multiple major HIV-1 lineages. To identify evidence of selection operating during transmission our analysis included two matched datasets sampled from patients with acute or chronic subtype C infections. We identified six gp41 sites apparently evolving under different selection pressures during acute and chronic HIV-1 infections. These sites mostly fell within functional gp41 domains, with one site located within the epitope recognised by the broadly neutralizing antibody, 4E10. Conclusion Whereas these six sites are potentially determinants of fitness and are therefore good candidate targets for subtype-C specific vaccines, the twelve sites evolving under diversifying selection across multiple subtypes might make good candidate targets for broadly protective vaccines. PMID:19025632

  12. Inactive alleles of cytochrome P450 2C19 may be positively selected in human evolution

    PubMed Central

    2014-01-01

    Background Cytochrome P450 CYP2C19 metabolizes a wide range of pharmacologically active substances and a relatively small number of naturally occurring environmental toxins. Poor activity alleles of CYP2C19 are very frequent worldwide, particularly in Asia, raising the possibility that reduced metabolism could be advantageous in some circumstances. The evolutionary selective forces acting on this gene have not previously been investigated. We analyzed CYP2C19 genetic markers from 127 Gambians and on 120 chromosomes from Yoruba, Europeans and Asians (Japanese + Han Chinese) in the Hapmap database. Haplotype breakdown was explored using bifurcation plots and relative extended haplotype homozygosity (REHH). Allele frequency differentiation across populations was estimated using the fixation index (FST) and haplotype diversity with coalescent models. Results Bifurcation plots suggested conservation of alleles conferring slow metabolism (CYP2C19*2 and *3). REHH was high around CYP2C19*2 in Yoruba (REHH 8.3, at 133.3 kb from the core) and to a lesser extent in Europeans (3.5, at 37.7 kb) and Asians (2.8, at −29.7 kb). FST at the CYP2C19 locus was low overall (0.098). CYP2C19*3 was an FST outlier in Asians (0.293), CYP2C19 haplotype diversity < = 0.037, p <0.001. Conclusions We found some evidence that the slow metabolizing allele CYP2C19*2 is subject to positive selective forces worldwide. Similar evidence was also found for CYP2C19*3 which is frequent only in Asia. FST is low at the CYP2C19 locus, suggesting balancing selection overall. The biological factors responsible for these selective pressures are currently unknown. One possible explanation is that early humans were exposed to a ubiquitous novel toxin activated by CYP2C19. The genetic adaptation took place within the last 10,000 years which coincides with the development of systematic agricultural practices. PMID:24690327

  13. Recent positive selection has acted on genes encoding proteins with more interactions within the whole human interactome.

    PubMed

    Luisi, Pierre; Alvarez-Ponce, David; Pybus, Marc; Fares, Mario A; Bertranpetit, Jaume; Laayouni, Hafid

    2015-04-02

    Genes vary in their likelihood to undergo adaptive evolution. The genomic factors that determine adaptability, however, remain poorly understood. Genes function in the context of molecular networks, with some occupying more important positions than others and thus being likely to be under stronger selective pressures. However, how positive selection distributes across the different parts of molecular networks is still not fully understood. Here, we inferred positive selection using comparative genomics and population genetics approaches through the comparison of 10 mammalian and 270 human genomes, respectively. In agreement with previous results, we found that genes with lower network centralities are more likely to evolve under positive selection (as inferred from divergence data). Surprisingly, polymorphism data yield results in the opposite direction than divergence data: Genes with higher centralities are more likely to have been targeted by recent positive selection during recent human evolution. Our results indicate that the relationship between centrality and the impact of adaptive evolution highly depends on the mode of positive selection and/or the evolutionary time-scale. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

  14. Recent Positive Selection Has Acted on Genes Encoding Proteins with More Interactions within the Whole Human Interactome

    PubMed Central

    Pybus, Marc; Fares, Mario A.; Bertranpetit, Jaume; Laayouni, Hafid

    2015-01-01

    Genes vary in their likelihood to undergo adaptive evolution. The genomic factors that determine adaptability, however, remain poorly understood. Genes function in the context of molecular networks, with some occupying more important positions than others and thus being likely to be under stronger selective pressures. However, how positive selection distributes across the different parts of molecular networks is still not fully understood. Here, we inferred positive selection using comparative genomics and population genetics approaches through the comparison of 10 mammalian and 270 human genomes, respectively. In agreement with previous results, we found that genes with lower network centralities are more likely to evolve under positive selection (as inferred from divergence data). Surprisingly, polymorphism data yield results in the opposite direction than divergence data: Genes with higher centralities are more likely to have been targeted by recent positive selection during recent human evolution. Our results indicate that the relationship between centrality and the impact of adaptive evolution highly depends on the mode of positive selection and/or the evolutionary time-scale. PMID:25840415

  15. Identifying signatures of positive selection in pigmentation genes in two South Asian populations.

    PubMed

    Jonnalagadda, Manjari; Bharti, Neeraj; Patil, Yatish; Ozarkar, Shantanu; K, Sunitha Manjari; Joshi, Rajendra; Norton, Heather

    2017-09-10

    Skin pigmentation is a polygenic trait showing wide phenotypic variations among global populations. While numerous pigmentation genes have been identified to be under positive selection among European and East populations, genes contributing to phenotypic variation in skin pigmentation within and among South Asian populations are still poorly understood. The present study uses data from the Phase 3 of the 1000 genomes project focusing on two South Asian populations-GIH (Gujarati Indian from Houston, Texas) and ITU (Indian Telugu from UK), so as to decode the genetic architecture involved in adaptation to ultraviolet radiation in South Asian populations. Statistical tests included were (1) tests to identify deviations of the Site Frequency Spectrum (SFS) from neutral expectations (Tajima's D, Fay and Wu's H and Fu and Li's D* and F*), (2) tests focused on the identification of high-frequency haplotypes with extended linkage disequilibrium (iHS and Rsb), and (3) tests based on genetic differentiation between populations (LSBL). Twenty-two pigmentation genes fall in the top 1% for at least one statistic in the GIH population, 5 of which (LYST, OCA2, SLC24A5, SLC45A2, and TYR) have been previously associated with normal variation in skin, hair, or eye color. In comparison, 17 genes fall in the top 1% for at least one statistic in the ITU population. Twelve loci which are identified as outliers in the ITU scan were also identified in the GIH population. These results suggest that selection may have affected these loci broadly across the region. © 2017 Wiley Periodicals, Inc.

  16. PigVar: a database of pig variations and positive selection signatures

    PubMed Central

    Zhou, Zhong-Yin; Li, Aimin; Otecko, Newton O.; Liu, Yan-Hu; Irwin, David M.; Wang, Lu; Adeola, Adeniyi C.; Zhang, Junying; Xie, Hai-Bing

    2017-01-01

    Abstract Pigs are excellent large-animal models for medical research and a promising organ donor source for transplant patients. Next-generation sequencing technology has yielded a dramatic increase in the volume of genomic data for pigs. However, the limited amount of variation data provided by dbSNP, and non-congruent criteria used for calling variation, present considerable hindrances to the utility of this data. We used a uniform pipeline, based on GATK, to identify non-redundant, high-quality, whole-genome SNPs from 280 pigs and 6 outgroup species. A total of 64.6 million SNPs were identified in 280 pigs and 36.8 million in the outgroups. We then used LUMPY to identify a total of 7 236 813 structural variations (SVs) in 211 pigs. Positively selected loci were identified through five statistical tests of different evolutionary attributes of the SNPs. Combining the non-redundant variations and the evolutionary selective scores, we built the first pig-specific variation database, PigVar (http://www.ibiomedical.net/pigvar/), which is a web-based open-access resource. PigVar collects parameters of the variations including summary lists of the locations of the variations within protein-coding and long intergenic non-coding RNA (lincRNA) genes, whether the SNPs are synonymous or non-synonymous, their ancestral and derived states, geographic sampling locations, as well as breed information. The PigVar database will be kept operational and updated to facilitate medical research using the pig as model and agricultural research including pig breeding. Database URL: http://www.ibiomedical.net/pigvar/

  17. Possible Positive Selection for an Arsenic-Protective Haplotype in Humans

    PubMed Central

    Schlebusch, Carina M.; Lewis, Cecil M.; Vahter, Marie; Engström, Karin; Tito, Raúl Y.; Obregón-Tito, Alexandra J.; Huerta, Doris; Polo, Susan I.; Medina, Ángel C.; Brutsaert, Tom D.; Concha, Gabriela; Jakobsson, Mattias

    2012-01-01

    Background: Arsenic in drinking water causes severe health effects. Indigenous people in the South American Andes have likely lived with arsenic-contaminated drinking water for thousands of years. Inhabitants of San Antonio de los Cobres (SAC) in the Argentinean highlands generally carry an AS3MT (the major arsenic-metabolizing gene) haplotype associated with reduced health risks due to rapid arsenic excretion and lower urinary fraction of the monomethylated metabolite. Objectives: We hypothesized an adaptation to high-arsenic living conditions via a possible positive selection for protective AS3MT variants and compared AS3MT haplotype frequencies among different indigenous groups. Methods: Indigenous groups we evaluated were a) inhabitants of SAC and villages near Salta in northern Argentina (n = 346), b) three Native American populations from the Human Genome Diversity Project (HGDP; n = 25), and c) five Peruvian populations (n = 97). The last two groups have presumably lower historical exposure to arsenic. Results: We found a significantly higher frequency of the protective AS3MT haplotype in the SAC population (68.7%) compared with the HGDP (14.3%, p < 0.001, Fisher exact test) and Peruvian (50.5%, p < 0.001) populations. Genome-wide microsatellite (n = 671) analysis showed no detectable level of population structure between SAC and Peruvian populations (measure of population differentiation FST = 0.006) and low levels of structure between SAC and HGDP populations (FST < 0.055 for all pairs of populations compared). Conclusions: Because population stratification seems unlikely to explain the differences in AS3MT haplotype frequencies, our data raise the possibility that, during a few thousand years, natural selection for tolerance to the environmental stressor arsenic may have increased the frequency of protective variants of AS3MT. Further studies are needed to investigate this hypothesis. PMID:23070617

  18. Positive association between ethanol consumption and anxiety-related behaviors in two selected rat lines.

    PubMed

    Izídio, Geison Souza; Ramos, André

    2007-11-01

    The Floripa H and L rat lines were selectively bred, respectively, for high and low scores of locomotion in the central aversive area of an open field (OF), which is a putative index of experimental anxiety. In the present study, we used these lines to examine the relationship between anxiety-related behaviors and ethanol intake through the use of three animal tests used to investigate anxiety (OF, elevated plus maze, and black/white box) and one oral ethanol consumption procedure. Males and females of the Floripa L line were more anxious-like than their counterparts in the three behavioral tests. No line differences in the tests of taste control solutions (saccharin and quinine) and forced ethanol (10%) were found. However, Floripa L female rats consumed more ethanol than their Floripa H counterparts at concentrations of 6 and 10% in a two-bottle choice protocol. Moreover, Floripa L females showed a higher ratio of ethanol to total fluids consumed, regardless of the concentration offered, than all other subgroups (males of both lines and Floripa H females). Males showed no line differences for ethanol consumption. Taken together, the results of this study confirm that there are important sex differences in both anxiety-related behaviors and ethanol consumption. Accordingly, these data suggest a positive genetic relationship between anxiety-related behaviors and ethanol intake, at concentrations of 6 and 10%, in females but not in males. This supports the use of both sexes in animal experiments involving anxiety- and ethanol-related behaviors. Finally, the results and the existing literature indicate that selectively bred laboratory animals constitute a useful tool in the search for genes influencing both anxiety and ethanol consummatory behavior.

  19. Possible positive selection for an arsenic-protective haplotype in humans.

    PubMed

    Schlebusch, Carina M; Lewis, Cecil M; Vahter, Marie; Engström, Karin; Tito, Raúl Y; Obregón-Tito, Alexandra J; Huerta, Doris; Polo, Susan I; Medina, Ángel C; Brutsaert, Tom D; Concha, Gabriela; Jakobsson, Mattias; Broberg, Karin

    2013-01-01

    Arsenic in drinking water causes severe health effects. Indigenous people in the South American Andes have likely lived with arsenic-contaminated drinking water for thousands of years. Inhabitants of San Antonio de los Cobres (SAC) in the Argentinean highlands generally carry an AS3MT (the major arsenic-metabolizing gene) haplotype associated with reduced health risks due to rapid arsenic excretion and lower urinary fraction of the monomethylated metabolite. We hypothesized an adaptation to high-arsenic living conditions via a possible positive selection for protective AS3MT variants and compared AS3MT haplotype frequencies among different indigenous groups. Indigenous groups we evaluated were a) inhabitants of SAC and villages near Salta in northern Argentina (n = 346), b) three Native American populations from the Human Genome Diversity Project (HGDP; n = 25), and c) five Peruvian populations (n = 97). The last two groups have presumably lower historical exposure to arsenic. We found a significantly higher frequency of the protective AS3MT haplotype in the SAC population (68.7%) compared with the HGDP (14.3%, p < 0.001, Fisher exact test) and Peruvian (50.5%, p < 0.001) populations. Genome-wide microsatellite (n = 671) analysis showed no detectable level of population structure between SAC and Peruvian populations (measure of population differentiation FST = 0.006) and low levels of structure between SAC and HGDP populations (FST < 0.055 for all pairs of populations compared). Because population stratification seems unlikely to explain the differences in AS3MT haplotype frequencies, our data raise the possibility that, during a few thousand years, natural selection for tolerance to the environmental stressor arsenic may have increased the frequency of protective variants of AS3MT. Further studies are needed to investigate this hypothesis.

  20. Ozone-induced dissociation: elucidation of double bond position within mass-selected lipid ions.

    PubMed

    Thomas, Michael C; Mitchell, Todd W; Harman, David G; Deeley, Jane M; Nealon, Jessica R; Blanksby, Stephen J

    2008-01-01

    Ions formed from lipids during electrospray ionization of crude lipid extracts have been mass-selected within a quadrupole linear ion trap mass spectrometer and allowed to react with ozone vapor. Gas-phase ion-molecule reactions between unsaturated lipid ions and ozone are found to yield two primary product ions for each carbon-carbon double bond within the molecule. The mass-to-charge ratios of these chemically induced fragments are diagnostic of the position of unsaturation within the precursor ion. This novel analytical technique, dubbed ozone-induced dissociation (OzID), can be applied both in series and in parallel with conventional collision-induced dissociation (CID) to provide near-complete structural assignment of unknown lipids within complex mixtures without prior fractionation or derivatization. In this study, OzID is applied to a suite of complex lipid extracts from sources including human lens, bovine kidney, and commercial olive oil, thus demonstrating the technique to be applicable to a broad range of lipid classes including both neutral and acidic glycerophospholipids, sphingomyelins, and triacylglycerols. Gas-phase ozonolysis reactions are also observed with different types of precursor ions including [M+H]+, [M+Li]+, [M+Na]+, and [M-H]-: in each case yielding fragmentation data that allow double bond position to be unambiguously assigned. Within the human lens lipid extract, three sphingomyelin regioisomers, namely SM(d18:0/15Z-24:1), SM(d18:0/17Z-24:1), and SM(d18:0/19Z-24:1), and a novel phosphatidylethanolamine alkyl ether, GPEtn(11Z-18:1e/9Z-18:1), are identified using a combination of CID and OzID. These discoveries demonstrate that lipid identification based on CID alone belies the natural structural diversity in lipid biochemistry and illustrate the potential of OzID as a complementary approach within automated, high-throughput lipid analysis protocols.

  1. A Novel Selectable Islet 1 Positive Progenitor Cell Reprogrammed to Expandable and Functional Smooth Muscle Cells.

    PubMed

    Turner, Elizabeth C; Huang, Chien-Ling; Sawhney, Neha; Govindarajan, Kalaimathi; Clover, Anthony J P; Martin, Kenneth; Browne, Tara C; Whelan, Derek; Kumar, Arun H S; Mackrill, John J; Wang, Shaohua; Schmeckpeper, Jeffrey; Stocca, Alessia; Pierce, William G; Leblond, Anne-Laure; Cai, Liquan; O'Sullivan, Donnchadh M; Buneker, Chirlei K; Choi, Janet; MacSharry, John; Ikeda, Yasuhiro; Russell, Stephen J; Caplice, Noel M

    2016-05-01

    Disorders affecting smooth muscle structure/function may require technologies that can generate large scale, differentiated and contractile smooth muscle cells (SMC) suitable for cell therapy. To date no clonal precursor population that provides large numbers of differentiated SMC in culture has been identified in a rodent. Identification of such cells may also enhance insight into progenitor cell fate decisions and the relationship between smooth muscle precursors and disease states that implicate differentiated SMC.  In this study, we used classic clonal expansion techniques to identify novel self-renewing Islet 1 (Isl-1) positive primitive progenitor cells (PPC) within rat bone marrow that exhibited canonical stem cell markers and preferential differentiation towards a smooth muscle-like fate. We subsequently used molecular tagging to select Isl-1 positive clonal populations from expanded and de novo marrow cell populations. We refer to these previously undescribed cells as the PPC given its stem cell marker profile, and robust self-renewal capacity. PPC could be directly converted into induced smooth muscle cells (iSMC) using single transcription factor (Kruppel-like factor 4) knockdown or transactivator (myocardin) overexpression in contrast to three control cells (HEK 293, endothelial cells and mesenchymal stem cells) where such induction was not possible. iSMC exhibited immuno- and cytoskeletal-phenotype, calcium signaling profile and contractile responses similar to bona fide SMC. Passaged iSMC could be expanded to a scale sufficient for large scale tissue replacement.  PPC and reprogramed iSMC so derived may offer future opportunities to investigate molecular, structure/function and cell-based replacement therapy approaches to diverse cardiovascular, respiratory, gastrointestinal, and genitourinary diseases that have as their basis smooth muscle cell functional aberrancy or numerical loss. Stem Cells 2016;34:1354-1368.

  2. Positive selection within sperm-egg adhesion domains of fertilin: an ADAM gene with a potential role in fertilization.

    PubMed

    Civetta, Alberto

    2003-01-01

    Genes with a role in fertilization show a common pattern of rapid evolution. The role played by positive selection versus lack of selective constraints has been more difficult to establish. One problem arises from attempts to detect selection in an overall gene sequence analysis. I have analyzed the pattern of molecular evolution of fertilin, a gene coding for a heterodimeric sperm protein belonging to the ADAM (A disintegrin and A metalloprotease) gene family. A nonsynonymous to synonymous rate ratio (d(N)/d(S)) analysis for different protein domains of fertilin alpha and fertilin beta showed d(N)/d(S) < 1, suggesting that purifying selection has shaped fertilin's evolution. However, an analysis of the distribution of single positively selected codon sites using phylogentic analysis by maximum likelihood (PAML) showed sites within adhesion domains (disintegrin and cysteine-rich) of fertilin beta evolving under positive selection. The region 3' to the EGF-like domain of fertilin alpha, where the transmembrane and cytoplasmic tail regions are supposed to be localized, showed higher d(N) and d(S) than any other fertilin alpha region. However, it was not possible to identify positively selected codon sites due to ambiguous alignments of the carboxy-end region (ClustalX vs. DiAlign2). When this region was excluded from the PAML analysis, most single positively selected codon sites were concentrated within adhesion domains (cysteine-rich and EGF-like). The use of an ancestral sequence prior to a recent duplication event of fertilin alpha among non-Hominidae primates (Macaca, Papio, and Saguinus) revealed that the duplication is partially responsible for masking the detection of positively selected sites within the disintegrin domain. Finally, most ADAM genes with a potential role in sperm maturation and/or fertilization showed significantly higher d(N) estimates than other ADAM genes.

  3. Ongoing dengue epidemic - Angola, June 2013.

    PubMed

    2013-06-21

    On April 1, 2013, the Public Health Directorate of Angola announced that six cases of dengue had been reported to the Ministry of Health of Angola (MHA). As of May 31, a total of 517 suspected dengue cases had been reported and tested for dengue with a rapid diagnostic test (RDT). A total of 313 (60.5%) specimens tested positive for dengue, including one from a patient who died. All suspected cases were reported from Luanda Province, except for two from Malanje Province. Confirmatory diagnostic testing of 49 specimens (43 RDT-positive and six RDT-negative) at the CDC Dengue Branch confirmed dengue virus (DENV) infection in 100% of the RDT-positive specimens and 50% of the RDT-negative specimens. Only DENV-1 was detected by molecular diagnostic testing. Phylogenetic analysis indicated this virus has been circulating in the region since at least 1968, strongly suggesting that dengue is endemic in Angola. Health-care professionals throughout Angola should be aware of the ongoing epidemic, the recommended practices for clinical management of dengue patients, and the need to report cases to MHA. Persons in Angola should seek medical care for acute febrile illness to reduce the risk for developing complications. Laboratory-confirmed dengue also has been reported from seven countries on four continents among persons who had recently traveled to Luanda, including 79 persons from Portugal. Angola is the third of four African countries to report a dengue outbreak in 2013. Persons returning from Africa with acute febrile illness should seek medical care, including testing for DENV infection, and suspected cases should be reported to public health authorities.

  4. Antibacterial properties of biosurfactants against selected Gram-positive and -negative bacteria.

    PubMed

    Díaz De Rienzo, Mayri A; Stevenson, Paul; Marchant, Roger; Banat, Ibrahim M

    2016-01-01

    The antibacterial properties and ability to disrupt biofilms of biosurfactants (rhamnolipids, sophorolipids) and sodium dodecyl sulphate (SDS) in the presence and absence of selected organic acids were investigated. Pseudomonas aeruginosa PAO1 was inhibited by sophorolipids and SDS at concentrations >5% v/v, and the growth of Escherichia coli NCTC 10418 was also inhibited by sophorolipids and SDS at concentrations >5% and 0.1% v/v, respectively. Bacillus subtilis NCTC 10400 was inhibited by rhamnolipids, sophorolipids and SDS at concentrations >0.5% v/v of all three; the same effect was observed with Staphylococcus aureus ATCC 9144. The ability to attach to surfaces and biofilm formation of P. aeruginosa PAO1, E. coli NCTC 10418 and B. subtilis NCTC 10400 was inhibited by sophorolipids (1% v/v) in the presence of caprylic acid (0.8% v/v). In the case of S. aureus ATCC 9144, the best results were obtained using caprylic acid on its own. It was concluded that sophorolipids are promising compounds for the inhibition/disruption of biofilms formed by Gram-positive and Gram-negative microorganisms and this activity can be enhanced by the presence of booster compounds such as caprylic acid.

  5. Differential positive selection of malaria resistance genes in three indigenous populations of Peninsular Malaysia.

    PubMed

    Liu, Xuanyao; Yunus, Yushimah; Lu, Dongsheng; Aghakhanian, Farhang; Saw, Woei-Yuh; Deng, Lian; Ali, Mohammad; Wang, Xu; Nor, Fadzilah Mohd; Ghazali, Fadzilah; Rahman, Thuhairah Abdul; Shaari, Shahrul Azlin; Salleh, Mohd Zaki; Phipps, Maude E; Ong, Rick Twee-Hee; Xu, Shuhua; Teo, Yik-Ying; Hoh, Boon-Peng

    2015-04-01

    The indigenous populations from Peninsular Malaysia, locally known as Orang Asli, continue to adopt an agro-subsistence nomadic lifestyle, residing primarily within natural jungle habitats. Leading a hunter-gatherer lifestyle in a tropical jungle environment, the Orang Asli are routinely exposed to malaria. Here we surveyed the genetic architecture of individuals from four Orang Asli tribes with high-density genotyping across more than 2.5 million polymorphisms. These tribes reside in different geographical locations in Peninsular Malaysia and belong to three main ethno-linguistic groups, where there is minimal interaction between the tribes. We first dissect the genetic diversity and admixture between the tribes and with neighboring urban populations. Later, by implementing five metrics, we investigated the genome-wide signatures for positive natural selection of these Orang Asli, respectively. Finally, we searched for evidence of genomic adaptation to the pressure of malaria infection. We observed that different evolutionary responses might have emerged in the different Orang Asli communities to mitigate malaria infection.

  6. An epitope tagged mammalian/prokaryotic expression vector with positive selection of cloned inserts.

    PubMed

    Schneider, S; Georgiev, O; Buchert, M; Adams, M T; Moelling, K; Hovens, C M

    1997-09-15

    A dual eukaryotic/prokaryotic expression vector has been developed which combines the features of positive selection for cloned inserts along with the production of an epitope-tagged cDNA insert by transient transfection in mammalian cells as well as high level induced expression in E. coli cells harbouring T7 RNA polymerase. This vector, pZilch, has two MCSs flanking a mutant E. coli phenylalanyl-tRNA synthetase gene, pheS, which when expressed in combination with the phenylalanine analog p-CI-Phe, results in termination of host cell protein synthesis. Cloning of inserts using unique sites in the flanking MCS regions results in loss of the pZilch pheS allele and hence permits growth of colonies harbouring recombinants on p-Cl-Phe plates. Additional features of the vector include an optimal Kozak consensus sequence for high level eukaryotic cell expression and an efficient prokaryotic translation initiation site in frame and downstream from the eukaryotic initiation site. Recombinant proteins can be produced with an N-terminal FLAG epitope which can be removed via a specific protease cleavage site. Flanking T7 and SP6 RNA polymerase promoter sites permit in vitro transcription and translation of cloned inserts. A derivative of the vector has also been constructed enabling nuclear accumulation of the tagged proteins via an SV40 nuclear localisation signal upstream of the 5' MCS.

  7. Amerindian-specific regions under positive selection harbour new lipid variants in Latinos

    PubMed Central

    Ko, Arthur; Cantor, Rita M.; Weissglas-Volkov, Daphna; Nikkola, Elina; Reddy, Prasad M. V. Linga; Sinsheimer, Janet S.; Pasaniuc, Bogdan; Brown, Robert; Alvarez, Marcus; Rodriguez, Alejandra; Rodriguez-Guillen, Rosario; Bautista, Ivette C.; Arellano-Campos, Olimpia; Muñoz-Hernández, Linda L.; Salomaa, Veikko; Kaprio, Jaakko; Jula, Antti; Jauhiainen, Matti; Heliövaara, Markku; Raitakari, Olli; Lehtimäki, Terho; Eriksson, Johan G.; Perola, Markus; Lohmueller, Kirk E.; Matikainen, Niina; Taskinen, Marja-Riitta; Rodriguez-Torres, Maribel; Riba, Laura; Tusie-Luna, Teresa; Aguilar-Salinas, Carlos A.; Pajukanta, Päivi

    2014-01-01

    Dyslipidemia and obesity are especially prevalent in populations with Amerindian backgrounds, such as Mexican–Americans, which predispose these populations to cardiovascular disease. Here we design an approach, known as the cross-population allele screen (CPAS), which we conduct prior to a genome-wide association study (GWAS) in 19,273 Europeans and Mexicans, in order to identify Amerindian risk genes in Mexicans. Utilizing CPAS to restrict the GWAS input variants to only those differing in frequency between the two populations, we identify novel Amerindian lipid genes, receptor-related orphan receptor alpha (RORA) and salt-inducible kinase 3 (SIK3), and three loci previously unassociated with dyslipidemia or obesity. We also detect lipoprotein lipase (LPL) and apolipoprotein A5 (APOA5) harbouring specific Amerindian signatures of risk variants and haplotypes. Notably, we observe that SIK3 and one novel lipid locus underwent positive selection in Mexicans. Furthermore, after a high-fat meal, the SIK3 risk variant carriers display high triglyceride levels. These findings suggest that Amerindian-specific genetic architecture leads to a higher incidence of dyslipidemia and obesity in modern Mexicans. PMID:24886709

  8. Positive selection of candidate tumor-suppressor genes by subtractive hybridization

    SciTech Connect

    Lee, S.W.; Tomasetto, C.; Sager, R. )

    1991-04-01

    A positive selection system designed to identify and recover candidate tumor-suppressor genes is described. The system compares mRNA expression of genes from normal and tumor-derived human mammary epithelial cells grown in a special medium that supports similar growth rates of the two cell types. mRNAs uniquely expressed in normal cells are recovered as cDNAs after subtraction with mRNA from tumor cells. Seven different clones, from 0.6 to 4.8 kilobases in transcript size and including both rare and abundant transcripts, were recovered in the first 23 clones analyzed. Among the isolated clones were genes encoding the gap-junction protein connexin 26, two different keratins, and glutathione-S-transferase {pi}, as well as an unknown gene in the S100 family of small calcium-binding proteins. In principle, tumor-suppressor genes include two classes: class I, in which loss of function results from mutation or deletion of DNA and class II, in which loss of function is from a regulatory block to expression. A class II suppressor gene is assumed to be regulated by a different suppressor gene that lost its function by mutation or deletion. Both classes of tumor-suppressor genes may provide valuable proteins with clinical applications in cancer diagnosis or therapy. Class II suppressors may be especially useful because the normal genes are present and their reexpression may be inducible by drugs or other treatments.

  9. Amerindian-specific regions under positive selection harbour new lipid variants in Latinos.

    PubMed

    Ko, Arthur; Cantor, Rita M; Weissglas-Volkov, Daphna; Nikkola, Elina; Reddy, Prasad M V Linga; Sinsheimer, Janet S; Pasaniuc, Bogdan; Brown, Robert; Alvarez, Marcus; Rodriguez, Alejandra; Rodriguez-Guillen, Rosario; Bautista, Ivette C; Arellano-Campos, Olimpia; Muñoz-Hernández, Linda L; Salomaa, Veikko; Kaprio, Jaakko; Jula, Antti; Jauhiainen, Matti; Heliövaara, Markku; Raitakari, Olli; Lehtimäki, Terho; Eriksson, Johan G; Perola, Markus; Lohmueller, Kirk E; Matikainen, Niina; Taskinen, Marja-Riitta; Rodriguez-Torres, Maribel; Riba, Laura; Tusie-Luna, Teresa; Aguilar-Salinas, Carlos A; Pajukanta, Päivi

    2014-06-02

    Dyslipidemia and obesity are especially prevalent in populations with Amerindian backgrounds, such as Mexican-Americans, which predispose these populations to cardiovascular disease. Here we design an approach, known as the cross-population allele screen (CPAS), which we conduct prior to a genome-wide association study (GWAS) in 19,273 Europeans and Mexicans, in order to identify Amerindian risk genes in Mexicans. Utilizing CPAS to restrict the GWAS input variants to only those differing in frequency between the two populations, we identify novel Amerindian lipid genes, receptor-related orphan receptor alpha (RORA) and salt-inducible kinase 3 (SIK3), and three loci previously unassociated with dyslipidemia or obesity. We also detect lipoprotein lipase (LPL) and apolipoprotein A5 (APOA5) harbouring specific Amerindian signatures of risk variants and haplotypes. Notably, we observe that SIK3 and one novel lipid locus underwent positive selection in Mexicans. Furthermore, after a high-fat meal, the SIK3 risk variant carriers display high triglyceride levels. These findings suggest that Amerindian-specific genetic architecture leads to a higher incidence of dyslipidemia and obesity in modern Mexicans.

  10. Transcriptome-based phylogeny of endemic Lake Baikal amphipod species flock: fast speciation accompanied by frequent episodes of positive selection.

    PubMed

    Naumenko, Sergey A; Logacheva, Maria D; Popova, Nina V; Klepikova, Anna V; Penin, Aleksey A; Bazykin, Georgii A; Etingova, Anna E; Mugue, Nikolai S; Kondrashov, Alexey S; Yampolsky, Lev Y

    2017-01-01

    Endemic species flocks inhabiting ancient lakes, oceanic islands and other long-lived isolated habitats are often interpreted as adaptive radiations. Yet molecular evidence for directional selection during species flocks radiation is scarce. Using partial transcriptomes of 64 species of Lake Baikal (Siberia, Russia) endemic amphipods and two nonendemic outgroups, we report a revised phylogeny of this species flock and analyse evidence for positive selection within the endemic lineages. We confirm two independent invasions of amphipods into Baikal and demonstrate that several morphological features of Baikal amphipods, such as body armour and reduction in appendages and sensory organs, evolved in several lineages in parallel. Radiation of Baikal amphipods has been characterized by short phylogenetic branches and frequent episodes of positive selection which tended to be more frequent in the early phase of the second invasion of amphipods into Baikal when the most intensive diversification occurred. Notably, signatures of positive selection are frequent in genes encoding mitochondrial membrane proteins with electron transfer chain and ATP synthesis functionality. In particular, subunits of both the membrane and substrate-level ATP synthases show evidence of positive selection in the plankton species Macrohectopus branickii, possibly indicating adaptation to active plankton lifestyle and to survival under conditions of low temperature and high hydrostatic pressures known to affect membranes functioning. Other functional categories represented among genes likely to be under positive selection include Ca-binding muscle-related proteins, possibly indicating adaptation to Ca-deficient low mineralization Baikal waters. © 2016 John Wiley & Sons Ltd.

  11. Accuracy and Power of Statistical Methods for Detecting Adaptive Evolution in Protein Coding Sequences and for Identifying Positively Selected Sites

    PubMed Central

    Wong, Wendy S. W.; Yang, Ziheng; Goldman, Nick; Nielsen, Rasmus

    2004-01-01

    The parsimony method of Suzuki and Gojobori (1999) and the maximum likelihood method developed from the work of Nielsen and Yang (1998) are two widely used methods for detecting positive selection in homologous protein coding sequences. Both methods consider an excess of nonsynonymous (replacement) substitutions as evidence for positive selection. Previously published simulation studies comparing the performance of the two methods show contradictory results. Here we conduct a more thorough simulation study to cover and extend the parameter space used in previous studies. We also reanalyzed an HLA data set that was previously proposed to cause problems when analyzed using the maximum likelihood method. Our new simulations and a reanalysis of the HLA data demonstrate that the maximum likelihood method has good power and accuracy in detecting positive selection over a wide range of parameter values. Previous studies reporting poor performance of the method appear to be due to numerical problems in the optimization algorithms and did not reflect the true performance of the method. The parsimony method has a very low rate of false positives but very little power for detecting positive selection or identifying positively selected sites. PMID:15514074

  12. The Ongoing and Open-Ended Simulation

    ERIC Educational Resources Information Center

    Cohen, Alexander

    2016-01-01

    This case study explores a novel form of classroom simulation that differs from published examples in two important respects. First, it is ongoing. While most simulations represent a single learning episode embedded within a course, the ongoing simulation is a continuous set of interrelated events and decisions that accompany learning throughout…

  13. Epilepsy Surgery: Current Status and Ongoing Challenges

    PubMed Central

    KAWAI, Kensuke

    2015-01-01

    This article reviews the current status of surgical treatment of epilepsy and introduces the ongoing challenges. Seizure outcome of resective surgery for focal seizures associated with focal lesions is satisfactory. Particularly for mesial temporal lobe epilepsy, surgical treatment should be considered from the earlier stage of the disease. Meanwhile, surgical outcome in nonlesional extratemporal lobe epilepsy is still to be improved using various approaches. Disconnective surgeries reduce surgical complications of extensive resections while achieving equivalent or better seizure outcomes. Multiple subpial transection is still being modified expecting a better outcome by transection to the vertical cortices along the sulci- and multi-directional transection from a single entry point. Hippocampal transection is expected to preserve memory function while interrupting the abnormal epileptic synchronization. Proper selection or combination of subdural and depth electrodes and a wide-band analysis of electroencephalography may improve the accurate localization of epileptogenic region. Patients for whom curative resective surgery is not indicated because of generalized or bilateral multiple nature of their epilepsies, neuromodulation therapies are options of treatment which palliate their seizures. PMID:25925752

  14. Transient inflammation-induced ongoing pain is driven by TRPV1 sensitive afferents

    PubMed Central

    2011-01-01

    Background Tissue injury elicits both hypersensitivity to evoked stimuli and ongoing, stimulus-independent pain. We previously demonstrated that pain relief elicits reward in nerve-injured rats. This approach was used to evaluate the temporal and mechanistic features of inflammation-induced ongoing pain. Results Intraplantar Complete Freund's Adjuvant (CFA) produced thermal hyperalgesia and guarding behavior that was reliably observed within 24 hrs and maintained, albeit diminished, 4 days post-administration. Spinal clonidine produced robust conditioned place preference (CPP) in CFA treated rats 1 day, but not 4 days following CFA administration. However, spinal clonidine blocked CFA-induced thermal hyperalgesia at both post-CFA days 1 and 4, indicating different time-courses of ongoing and evoked pain. Peripheral nerve block by lidocaine administration into the popliteal fossa 1 day following intraplantar CFA produced a robust preference for the lidocaine paired chamber, indicating that injury-induced ongoing pain is driven by afferent fibers innervating the site of injury. Pretreatment with resiniferatoxin (RTX), an ultrapotent capsaicin analogue known to produce long-lasting desensitization of TRPV1 positive afferents, fully blocked CFA-induced thermal hypersensitivity and abolished the CPP elicited by administration of popliteal fossa lidocaine 24 hrs post-CFA. In addition, RTX pretreatment blocked guarding behavior observed 1 day following intraplantar CFA. In contrast, administration of the selective TRPV1 receptor antagonist, AMG9810, at a dose that reversed CFA-induced thermal hyperalgesia failed to reduce CFA-induced ongoing pain or guarding behavior. Conclusions These data demonstrate that inflammation induces both ongoing pain and evoked hypersensitivity that can be differentiated on the basis of time course. Ongoing pain (a) is transient, (b) driven by peripheral input resulting from the injury, (c) dependent on TRPV1 positive fibers and (d) not

  15. Silencing, Positive Selection and Parallel Evolution: Busy History of Primate Cytochromes c

    PubMed Central

    Pierron, Denis; Opazo, Juan C.; Heiske, Margit; Papper, Zack; Uddin, Monica; Chand, Gopi; Wildman, Derek E.; Romero, Roberto; Goodman, Morris; Grossman, Lawrence I.

    2011-01-01

    Cytochrome c (cyt c) participates in two crucial cellular processes, energy production and apoptosis, and unsurprisingly is a highly conserved protein. However, previous studies have reported for the primate lineage (i) loss of the paralogous testis isoform, (ii) an acceleration and then a deceleration of the amino acid replacement rate of the cyt c somatic isoform, and (iii) atypical biochemical behavior of human cyt c. To gain insight into the cause of these major evolutionary events, we have retraced the history of cyt c loci among primates. For testis cyt c, all primate sequences examined carry the same nonsense mutation, which suggests that silencing occurred before the primates diversified. For somatic cyt c, maximum parsimony, maximum likelihood, and Bayesian phylogenetic analyses yielded the same tree topology. The evolutionary analyses show that a fast accumulation of non-synonymous mutations (suggesting positive selection) occurred specifically on the anthropoid lineage root and then continued in parallel on the early catarrhini and platyrrhini stems. Analysis of evolutionary changes using the 3D structure suggests they are focused on the respiratory chain rather than on apoptosis or other cyt c functions. In agreement with previous biochemical studies, our results suggest that silencing of the cyt c testis isoform could be linked with the decrease of primate reproduction rate. Finally, the evolution of cyt c in the two sister anthropoid groups leads us to propose that somatic cyt c evolution may be related both to COX evolution and to the convergent brain and body mass enlargement in these two anthropoid clades. PMID:22028846

  16. Natural positive selection and north–south genetic diversity in East Asia

    PubMed Central

    Suo, Chen; Xu, Haiyan; Khor, Chiea-Chuen; Ong, Rick TH; Sim, Xueling; Chen, Jieming; Tay, Wan-Ting; Sim, Kar-Seng; Zeng, Yi-Xin; Zhang, Xuejun; Liu, Jianjun; Tai, E-Shyong; Wong, Tien-Yin; Chia, Kee-Seng; Teo, Yik-Ying

    2012-01-01

    Recent reports have identified a north–south cline in genetic variation in East and South-East Asia, but these studies have not formally explored the basis of these clinical differences. Understanding the origins of these variations may provide valuable insights in tracking down the functional variants in genomic regions identified by genetic association studies. Here we investigate the genetic basis of these differences with genome-wide data from the HapMap, the Human Genome Diversity Project and the Singapore Genome Variation Project. We implemented four bioinformatic measures to discover genomic regions that are considerably differentiated either between two Han Chinese populations in the north and south of China, or across 22 populations in East and South-East Asia. These measures prioritized genomic stretches with: (i) regional differences in the allelic spectrum for SNPs common to the two Han Chinese populations; (ii) differential evidence of positive selection between the two populations as quantified by integrated haplotype score (iHS) and cross-population extended haplotype homozygosity (XP-EHH); (iii) significant correlation between allele frequencies and geographical latitudes of the 22 populations. We also explored the extent of linkage disequilibrium variations in these regions, which is important in combining genetic association studies from North and South Chinese. Two of the regions that emerged are found in HLA class I and II, suggesting that the HLA imputation panel from the HapMap may not be directly applicable to every Chinese sample. This has important implications to autoimmune studies that plan to impute the classical HLA alleles to fine map the SNP association signals. PMID:21792231

  17. Positive Selection Drives Rapid Evolution of the meq Oncogene of Marek’s Disease Virus

    PubMed Central

    Padhi, Abinash

    2016-01-01

    Marek’s disease (MD), caused by Marek’s disease virus (MDV), a poultry-borne alphaherpesvirus, is a devastating disease of poultry causing an estimated annual loss of one billion dollars to poultry producers, worldwide. Despite decades of control through vaccination, MDV field strains continue to emerge having increased virulence. The evolutionary mechanism driving the emergence of this continuum of strains to increased MDV virulence, however, remains largely enigmatic. Increase in MDV virulence has been associated with specific amino acid changes within the C-terminus domain of Mareks’s EcoRI-Q (meq)-encoded oncoprotein. In this study, we sought to determine whether the meq gene has evolved adaptively and whether past vaccination efforts have had any significant effect on the reduction or increase of MDV diversity over time. Our analysis suggests that meq is estimated to be evolving at a much faster rate than most dsDNA viruses, and is comparable with the evolutionary rate of RNA viruses. Interestingly, most of the polymorphisms in meq gene appear to have evolved under positive selection and the time of divergence at the meq locus coincides with the period during which the poultry industry had undergone transitions in management practices including the introduction and widespread use of live attenuated vaccines. Our study has revealed that the decades-long use of vaccines did not reduce MDV diversity, but rather had a stimulating effect on the emergence of field strains with increased genetic diversity until the early 2000s. During the years 2004–2005, there was an abrupt decline in the genetic diversity of field isolates followed by a recovery from this bottleneck in the year 2010. Collectively, these data suggest that vaccination seems to not have had any effect on MDV eradication, but rather had a stimulating effect on MDV emergence through adaptation. PMID:27662574

  18. Prediction of Genes Related to Positive Selection Using Whole-Genome Resequencing in Three Commercial Pig Breeds.

    PubMed

    Kim, HyoYoung; Caetano-Anolles, Kelsey; Seo, Minseok; Kwon, Young-Jun; Cho, Seoae; Seo, Kangseok; Kim, Heebal

    2015-12-01

    Selective sweep can cause genetic differentiation across populations, which allows for the identification of possible causative regions/genes underlying important traits. The pig has experienced a long history of allele frequency changes through artificial selection in the domestication process. We obtained an average of 329,482,871 sequence reads for 24 pigs from three pig breeds: Yorkshire (n = 5), Landrace (n = 13), and Duroc (n = 6). An average read depth of 11.7 was obtained using whole-genome resequencing on an Illumina HiSeq2000 platform. In this study, cross-population extended haplotype homozygosity and cross-population composite likelihood ratio tests were implemented to detect genes experiencing positive selection for the genome-wide resequencing data generated from three commercial pig breeds. In our results, 26, 7, and 14 genes from Yorkshire, Landrace, and Duroc, respectively were detected by two kinds of statistical tests. Significant evidence for positive selection was identified on genes ST6GALNAC2 and EPHX1 in Yorkshire, PARK2 in Landrace, and BMP6, SLA-DQA1, and PRKG1 in Duroc.These genes are reportedly relevant to lactation, reproduction, meat quality, and growth traits. To understand how these single nucleotide polymorphisms (SNPs) related positive selection affect protein function, we analyzed the effect of non-synonymous SNPs. Three SNPs (rs324509622, rs80931851, and rs80937718) in the SLA-DQA1 gene were significant in the enrichment tests, indicating strong evidence for positive selection in Duroc. Our analyses identified genes under positive selection for lactation, reproduction, and meat-quality and growth traits in Yorkshire, Landrace, and Duroc, respectively.

  19. Evidence for increased levels of positive and negative selection on the X chromosome versus autosomes in humans.

    PubMed

    Veeramah, Krishna R; Gutenkunst, Ryan N; Woerner, August E; Watkins, Joseph C; Hammer, Michael F

    2014-09-01

    Partially recessive variants under positive selection are expected to go to fixation more quickly on the X chromosome as a result of hemizygosity, an effect known as faster-X. Conversely, purifying selection is expected to reduce substitution rates more effectively on the X chromosome. Previous work in humans contrasted divergence on the autosomes and X chromosome, with results tending to support the faster-X effect. However, no study has yet incorporated both divergence and polymorphism to quantify the effects of both purifying and positive selection, which are opposing forces with respect to divergence. In this study, we develop a framework that integrates previously developed theory addressing differential rates of X and autosomal evolution with methods that jointly estimate the level of purifying and positive selection via modeling of the distribution of fitness effects (DFE). We then utilize this framework to estimate the proportion of nonsynonymous substitutions fixed by positive selection (α) using exome sequence data from a West African population. We find that varying the female to male breeding ratio (β) has minimal impact on the DFE for the X chromosome, especially when compared with the effect of varying the dominance coefficient of deleterious alleles (h). Estimates of α range from 46% to 51% and from 4% to 24% for the X chromosome and autosomes, respectively. While dependent on h, the magnitude of the difference between α values estimated for these two systems is highly statistically significant over a range of biologically realistic parameter values, suggesting faster-X has been operating in humans.

  20. A Mixed Approach to Similarity Metric Selection in Affinity Propagation-Based WiFi Fingerprinting Indoor Positioning

    PubMed Central

    Caso, Giuseppe; de Nardis, Luca; di Benedetto, Maria-Gabriella

    2015-01-01

    The weighted k-nearest neighbors (WkNN) algorithm is by far the most popular choice in the design of fingerprinting indoor positioning systems based on WiFi received signal strength (RSS). WkNN estimates the position of a target device by selecting k reference points (RPs) based on the similarity of their fingerprints with the measured RSS values. The position of the target device is then obtained as a weighted sum of the positions of the k RPs. Two-step WkNN positioning algorithms were recently proposed, in which RPs are divided into clusters using the affinity propagation clustering algorithm, and one representative for each cluster is selected. Only cluster representatives are then considered during the position estimation, leading to a significant computational complexity reduction compared to traditional, flat WkNN. Flat and two-step WkNN share the issue of properly selecting the similarity metric so as to guarantee good positioning accuracy: in two-step WkNN, in particular, the metric impacts three different steps in the position estimation, that is cluster formation, cluster selection and RP selection and weighting. So far, however, the only similarity metric considered in the literature was the one proposed in the original formulation of the affinity propagation algorithm. This paper fills this gap by comparing different metrics and, based on this comparison, proposes a novel mixed approach in which different metrics are adopted in the different steps of the position estimation procedure. The analysis is supported by an extensive experimental campaign carried out in a multi-floor 3D indoor positioning testbed. The impact of similarity metrics and their combinations on the structure and size of the resulting clusters, 3D positioning accuracy and computational complexity are investigated. Results show that the adoption of metrics different from the one proposed in the original affinity propagation algorithm and, in particular, the combination of different

  1. A Mixed Approach to Similarity Metric Selection in Affinity Propagation-Based WiFi Fingerprinting Indoor Positioning.

    PubMed

    Caso, Giuseppe; de Nardis, Luca; di Benedetto, Maria-Gabriella

    2015-10-30

    The weighted k-nearest neighbors (WkNN) algorithm is by far the most popular choice in the design of fingerprinting indoor positioning systems based on WiFi received signal strength (RSS). WkNN estimates the position of a target device by selecting k reference points (RPs) based on the similarity of their fingerprints with the measured RSS values. The position of the target device is then obtained as a weighted sum of the positions of the k RPs. Two-step WkNN positioning algorithms were recently proposed, in which RPs are divided into clusters using the affinity propagation clustering algorithm, and one representative for each cluster is selected. Only cluster representatives are then considered during the position estimation, leading to a significant computational complexity reduction compared to traditional, flat WkNN. Flat and two-step WkNN share the issue of properly selecting the similarity metric so as to guarantee good positioning accuracy: in two-step WkNN, in particular, the metric impacts three different steps in the position estimation, that is cluster formation, cluster selection and RP selection and weighting. So far, however, the only similarity metric considered in the literature was the one proposed in the original formulation of the affinity propagation algorithm. This paper fills this gap by comparing different metrics and, based on this comparison, proposes a novel mixed approach in which different metrics are adopted in the different steps of the position estimation procedure. The analysis is supported by an extensive experimental campaign carried out in a multi-floor 3D indoor positioning testbed. The impact of similarity metrics and their combinations on the structure and size of the resulting clusters, 3D positioning accuracy and computational complexity are investigated. Results show that the adoption of metrics different from the one proposed in the original affinity propagation algorithm and, in particular, the combination of different

  2. Distinct quasispecies characteristics and positive selection within the core gene in chronic hepatitis B virus infected child and adult patients.

    PubMed

    Haijun, Deng; Yong, Huang; Ailong, Huang; Quanxin, Long

    2015-05-01

    There are significant differences in clinical characteristics between chronic hepatitis B virus infected (CHB) child and adult patients. Viral quasispecies characteristics are associated with its pathogenic properties. For hepatitis B virus (HBV), its core region is the main immune recognition region for its enriched epitopes. In our study, we discuss the quasispecies characteristics and positive selection within core gene within chronic HBV infected child and adult patients. By analyzing 170 core gene sequences from child CHB patients and 121 core genes sequences from adult CHB patients, quasispecies characteristics were described by sequence complexity, diversity, non-synonymous substitution ratio (dN) and synonymous substitution ratios (dS). In addition, positive selection sites were also determined by bioinformatics tools. Then, all these parameters were compared between child and adult CHB patient groups. Compared with child patients, adult patients with CHB showed distinct quasispecies characteristics within the core region, had a higher sequence complexity and diversity and more positive selection sites, suggesting that the adult CHB patients had a higher immune selection pressure on the HBV core gene. Reduced selection pressure on the HBV core gene in hepatitis B e antigen (HBeAg)-positive CHB patients than HBeAg negative CHB patients were observed in both adult and child patient groups. The majority of the screened positive selection sites lay within human leukocyte antigens (HLA)-restricted epitopes. In conclusion, this study analyzed the quasispecies characteristics discrepancy between child and adult patients with CHB, and revealed the possible reason for the distinct clinical characteristics in the perspective of population genetics.

  3. Changes in selective pressures associated with human population expansion may explain metabolic and immune related pathways enriched for signatures of positive selection.

    PubMed

    Vatsiou, Alexandra I; Bazin, Eric; Gaggiotti, Oscar E

    2016-07-21

    The study of local adaptation processes is a very important research topic in the field of population genomics. There is a particular interest in the study of human populations because they underwent a process of rapid spatial expansion and faced important environmental changes that translated into changes in selective pressures. New mutations may have been selected for in the new environment and previously existing genetic variants may have become detrimental. Immune related genes may have been released from the selective pressure exerted by pathogens in the ancestral environment and new variants may have been positively selected due to pathogens present in the newly colonized habitat. Also, variants that had a selective advantage in past environments may have become deleterious in the modern world due to external stimuli including climatic, dietary and behavioral changes, which could explain the high prevalence of some polygenic diseases such as diabetes and obesity. We performed an enrichment analysis to identify gene sets enriched for signals of positive selection in humans. We used two genome scan methods, XPCLR and iHS to detect selection using a dense coverage of SNP markers combined with two gene set enrichment approaches. We identified immune related gene sets that could be involved in the protection against pathogens especially in the African population. We also identified the glycolysis & gluconeogenesis gene set, related to metabolism, which supports the thrifty genotype hypothesis invoked to explain the current high prevalence of diseases such as diabetes and obesity. Extending our analysis to the gene level, we found signals for 23 candidate genes linked to metabolic syndrome, 13 of which are new candidates for positive selection. Our study provides a list of genes and gene sets associated with immunity and metabolic syndrome that are enriched for signals of positive selection in three human populations (Europeans, Africans and Asians). Our results

  4. Whole-genome analysis revealed the positively selected genes during the differentiation of indica and temperate japonica rice.

    PubMed

    Sun, Xinli; Jia, Qi; Guo, Yuchun; Zheng, Xiujuan; Liang, Kangjing

    2015-01-01

    To investigate the selective pressures acting on the protein-coding genes during the differentiation of indica and japonica, all of the possible orthologous genes between the Nipponbare and 93-11 genomes were identified and compared with each other. Among these genes, 8,530 pairs had identical sequences, and 27,384 pairs shared more than 90% sequence identity. Only 2,678 pairs of genes displaying a Ka/Ks ratio significantly greater than one were revealed, and most of these genes contained only nonsynonymous sites. The genes without synonymous site were further analyzed with the SNP data of 1529 O. sativa and O. rufipogon accessions, and 1068 genes were identified to be under positive selection during the differentiation of indica and temperate japonica. The positively selected genes (PSGs) are unevenly distributed on 12 chromosomes, and the proteins encoded by the PSGs are dominant with binding, transferase and hydrolase activities, and especially enriched in the plant responses to stimuli, biological regulations, and transport processes. Meanwhile, the most PSGs of the known function and/or expression were involved in the regulation of biotic/abiotic stresses. The evidence of pervasive positive selection suggested that many factors drove the differentiation of indica and japonica, which has already started in wild rice but is much lower than in cultivated rice. Lower differentiation and less PSGs revealed between the Or-It and Or-IIIt wild rice groups implied that artificial selection provides greater contribution on the differentiation than natural selection. In addition, the phylogenetic tree constructed with positively selected sites showed that the japonica varieties exhibited more diversity than indica on differentiation, and Or-III of O. rufipogon exhibited more than Or-I.

  5. Whole-genome positive selection and habitat-driven evolution in a shallow and a deep-sea urchin.

    PubMed

    Oliver, Thomas A; Garfield, David A; Manier, Mollie K; Haygood, Ralph; Wray, Gregory A; Palumbi, Stephen R

    2010-01-01

    Comparisons of genomic sequence between divergent species can provide insight into the action of natural selection across many distinct classes of proteins. Here, we examine the extent of positive selection as a function of tissue-specific and stage-specific gene expression in two closely-related sea urchins, the shallow-water Strongylocentrotus purpuratus and the deep-sea Allocentrotus fragilis, which have diverged greatly in their adult but not larval habitats. Genes that are expressed specifically in adult somatic tissue have significantly higher dN/dS ratios than the genome-wide average, whereas those in larvae are indistinguishable from the genome-wide average. Testis-specific genes have the highest dN/dS values, whereas ovary-specific have the lowest. Branch-site models involving the outgroup S. franciscanus indicate greater selection (ω(FG)) along the A. fragilis branch than along the S. purpuratus branch. The A. fragilis branch also shows a higher proportion of genes under positive selection, including those involved in skeletal development, endocytosis, and sulfur metabolism. Both lineages are approximately equal in enrichment for positive selection of genes involved in immunity, development, and cell-cell communication. The branch-site models further suggest that adult-specific genes have experienced greater positive selection than those expressed in larvae and that ovary-specific genes are more conserved (i.e., experienced greater negative selection) than those expressed specifically in adult somatic tissues and testis. Our results chart the patterns of protein change that have occurred after habitat divergence in these two species and show that the developmental or functional context in which a gene acts can play an important role in how divergent species adapt to new environments.

  6. An approach to selecting the optimal sensing coil configuration structure for switched reluctance motor rotor position measurement

    NASA Astrophysics Data System (ADS)

    Cai, Jun; Deng, Zhiquan

    2015-02-01

    Accurate rotor position signal is highly required for controlling the switched reluctance motor (SRM). The use of galvanic isolated sensing coils can provide independent circuit for position estimation without affecting the SRM actuation. However, the cross-coupling between main winding and sensing coil, and the mutual coupling between adjacent phase sensing coils may affect the position estimation performance seriously. In this paper, three sensing coil configurations in a 12/8 structure SRM are analyzed and compared for selecting an optimal configuration that can effectively minimize the bad effects of the cross-coupling factors. The finite element analysis and experimental results are provided for verification.

  7. Thinking about a Limited Future Enhances the Positivity of Younger and Older Adults’ Recall: Support for Socioemotional Selectivity Theory

    PubMed Central

    Barber, Sarah J.; Opitz, Philipp C.; Martins, Bruna; Sakaki, Michiko; Mather, Mara

    2016-01-01

    Compared with younger adults, older adults have a relative preference to attend to and remember positive over negative information. This is known as the “positivity effect,” and researchers have typically evoked socioemotional selectivity theory to explain it. According to socioemotional selectivity theory, as people get older they begin to perceive their time left in life as more limited. These reduced time horizons prompt older adults to prioritize achieving emotional gratification and thus exhibit increased positivity in attention and recall. Although this is the most commonly cited explanation of the positivity effect, there is currently a lack of clear experimental evidence demonstrating a link between time horizons and positivity. The goal of the current research was to address this issue. In two separate experiments, we asked participants to complete a writing activity, which directed them to think of time as being either limited or expansive (Experiments 1 and 2) or did not orient them to think about time in a particular manner (Experiment 2). Participants were then shown a series of emotional pictures, which they subsequently tried to recall. Results from both studies showed that regardless of chronological age, thinking about a limited future enhanced the relative positivity of participants’ recall. Furthermore, the results of Experiment 2 showed that this effect was not driven by changes in mood. Thus, the fact that older adults’ recall is typically more positive than younger adults’ recall may index naturally shifting time horizons and goals with age. PMID:27112461

  8. Detecting Loci under recent positive selection in dairy and beef cattle by combining different genome-wide scan methods

    USDA-ARS?s Scientific Manuscript database

    As the methodologies available for the detection of positive selection from genomic data vary in terms of assumptions and execution, weak correlations are expected among them. However, if there is any given signal that is consistently supported across different tests, it might be a strong evidence o...

  9. Positively Selected Codons in Immune-Exposed Loops of the Vaccine Candidate OMP-P1 of Haemophilus influenzae

    PubMed Central

    van Putten, Jos P. M.

    2007-01-01

    The high levels of variation in surface epitopes can be considered as an evolutionary hallmark of immune selection. New computational tools enable analysis of this variation by identifying codons that exhibit high rates of amino acid changes relative to the synonymous substitution rate. In the outer membrane protein P1 of Haemophilus influenzae, a vaccine candidate for nontypeable strains, we identified four codons with this attribute in domains that did not correspond to known or assumed B- and T-cell epitopes of OMP-P1. These codons flank hypervariable domains and do not appear to be false positives as judged from parsimony and maximum likelihood analyses. Some closely spaced positively selected codons have been previously considered part of a transmembrane domain, which would render this region unsuited for inclusion in a vaccine. Secondary structure analysis, three-dimensional structural database searches, and homology modeling using FadL of E. coli as a structural homologue, however, revealed that all positively selected codons are located in or near extracellular looping domains. The spacing and level of diversity of these positively selected and exposed codons in OMP-P1 suggest that vaccine targets based on these and conserved flanking residues may provide broad coverage in H. influenzae. Electronic Supplementary Material The online version of this article (doi:10.1007/s00239-006-0021-2) contains supplementary material, which is available to authorized users. PMID:17479342

  10. Ventrolateral Striatal Medium Spiny Neurons Positively Regulate Food-Incentive, Goal-Directed Behavior Independently of D1 and D2 Selectivity.

    PubMed

    Natsubori, Akiyo; Tsutsui-Kimura, Iku; Nishida, Hiroshi; Bouchekioua, Youcef; Sekiya, Hiroshi; Uchigashima, Motokazu; Watanabe, Masahiko; de Kerchove d'Exaerde, Alban; Mimura, Masaru; Takata, Norio; Tanaka, Kenji F

    2017-03-08

    The ventral striatum is involved in motivated behavior. Akin to the dorsal striatum, the ventral striatum contains two parallel pathways: the striatomesencephalic pathway consisting of dopamine receptor Type 1-expressing medium spiny neurons (D1-MSNs) and the striatopallidal pathway consisting of D2-MSNs. These two genetically identified pathways are thought to encode opposing functions in motivated behavior. It has also been reported that D1/D2 genetic selectivity is not attributed to the anatomical discrimination of two pathways. We wanted to determine whether D1- and D2-MSNs in the ventral striatum functioned in an opposing manner as previous observations claimed, and whether D1/D2 selectivity corresponded to a functional segregation in motivated behavior of mice. To address this question, we focused on the lateral portion of ventral striatum as a region implicated in food-incentive, goal-directed behavior, and recorded D1 or D2-MSN activity by using a gene-encoded ratiometric Ca(2+) indicator and by constructing a fiberphotometry system, and manipulated their activities via optogenetic inhibition during ongoing behaviors. We observed concurrent event-related compound Ca(2+) elevations in ventrolateral D1- and D2-MSNs, especially at trial start cue-related and first lever press-related times. D1 or D2 selective optogenetic inhibition just after the trial start cue resulted in a reduction of goal-directed behavior, indicating a shared coding of motivated behavior by both populations at this time. Only D1-selective inhibition just after the first lever press resulted in the reduction of behavior, indicating D1-MSN-specific coding at that specific time. Our data did not support opposing encoding by both populations in food-incentive, goal-directed behavior.SIGNIFICANCE STATEMENT An opposing role of dopamine receptor Type 1 or Type 2-expressing medium spiny neurons (D1-MSNs or D2-MSNs) on striatum-mediated behaviors has been widely accepted. However, this idea has

  11. Positive frequency-dependent selection on warning color in Alpine leaf beetles.

    PubMed

    Borer, Matthias; Van Noort, Tom; Rahier, Martine; Naisbit, Russell E

    2010-12-01

    Müller's theory of warning color and mimicry, despite forming a textbook example of frequency-dependent selection, has rarely been demonstrated in the wild. This may be largely due to the practical and statistical difficulties of measuring natural selection on mobile prey species. Here we demonstrate that this selection acts in alpine beetle communities by using tethered beetles exposed to natural predators. Oreina gloriosa leaf beetles (Coleoptera: Chrysomelidae) possess chemical defense in the form of cardenolides, accompanied by what appears to be warning color in bright metallic blues and greens. Individuals that match the locally predominant color morph have increased survival, with odds of week-long survival increased by a factor of 1.67 over those that do not match. This corresponds to selection of 13% against foreign morphs. Such selection, acting in concert with variation in community composition, could be responsible for geographic variation in warning color. However, in the face of this purifying selection, the within-population polymorphism seen in many Oreina species remains paradoxical.

  12. Positive selection and ancient duplications in the evolution of class B floral homeotic genes of orchids and grasses.

    PubMed

    Mondragón-Palomino, Mariana; Hiese, Luisa; Härter, Andrea; Koch, Marcus A; Theissen, Günter

    2009-04-21

    Positive selection is recognized as the prevalence of nonsynonymous over synonymous substitutions in a gene. Models of the functional evolution of duplicated genes consider neofunctionalization as key to the retention of paralogues. For instance, duplicate transcription factors are specifically retained in plant and animal genomes and both positive selection and transcriptional divergence appear to have played a role in their diversification. However, the relative impact of these two factors has not been systematically evaluated. Class B MADS-box genes, comprising DEF-like and GLO-like genes, encode developmental transcription factors essential for establishment of perianth and male organ identity in the flowers of angiosperms. Here, we contrast the role of positive selection and the known divergence in expression patterns of genes encoding class B-like MADS-box transcription factors from monocots, with emphasis on the family Orchidaceae and the order Poales. Although in the monocots these two groups are highly diverse and have a strongly canalized floral morphology, there is no information on the role of positive selection in the evolution of their distinctive flower morphologies. Published research shows that in Poales, class B-like genes are expressed in stamens and in lodicules, the perianth organs whose identity might also be specified by class B-like genes, like the identity of the inner tepals of their lily-like relatives. In orchids, however, the number and pattern of expression of class B-like genes have greatly diverged. The DEF-like genes from Orchidaceae form four well-supported, ancient clades of orthologues. In contrast, orchid GLO-like genes form a single clade of ancient orthologues and recent paralogues. DEF-like genes from orchid clade 2 (OMADS3-like genes) are under less stringent purifying selection than the other orchid DEF-like and GLO-like genes. In comparison with orchids, purifying selection was less stringent in DEF-like and GLO-like genes

  13. Positive selection and ancient duplications in the evolution of class B floral homeotic genes of orchids and grasses

    PubMed Central

    Mondragón-Palomino, Mariana; Hiese, Luisa; Härter, Andrea; Koch, Marcus A; Theißen, Günter

    2009-01-01

    Background Positive selection is recognized as the prevalence of nonsynonymous over synonymous substitutions in a gene. Models of the functional evolution of duplicated genes consider neofunctionalization as key to the retention of paralogues. For instance, duplicate transcription factors are specifically retained in plant and animal genomes and both positive selection and transcriptional divergence appear to have played a role in their diversification. However, the relative impact of these two factors has not been systematically evaluated. Class B MADS-box genes, comprising DEF-like and GLO-like genes, encode developmental transcription factors essential for establishment of perianth and male organ identity in the flowers of angiosperms. Here, we contrast the role of positive selection and the known divergence in expression patterns of genes encoding class B-like MADS-box transcription factors from monocots, with emphasis on the family Orchidaceae and the order Poales. Although in the monocots these two groups are highly diverse and have a strongly canalized floral morphology, there is no information on the role of positive selection in the evolution of their distinctive flower morphologies. Published research shows that in Poales, class B-like genes are expressed in stamens and in lodicules, the perianth organs whose identity might also be specified by class B-like genes, like the identity of the inner tepals of their lily-like relatives. In orchids, however, the number and pattern of expression of class B-like genes have greatly diverged. Results The DEF-like genes from Orchidaceae form four well-supported, ancient clades of orthologues. In contrast, orchid GLO-like genes form a single clade of ancient orthologues and recent paralogues. DEF-like genes from orchid clade 2 (OMADS3-like genes) are under less stringent purifying selection than the other orchid DEF-like and GLO-like genes. In comparison with orchids, purifying selection was less stringent in DEF

  14. Evaluation of a new dipslide with a selective medium for the rapid detection of beta-glucuronidase-positive Escherichia coli.

    PubMed

    Larinkari, U; Rautio, M

    1995-07-01

    A selective medium was incorporated into a new three-media dipslide (Uricult Trio, Orion Diagnostica) to allow rapid identification of Escherichia coli. The medium is supplemented with a recently described chromogenic substrate, hydroxyquinoline-beta-D-glucuronide, for beta-glucuronidase enzyme. The performance of the medium was compared to that of three other beta-glucuronidase detection methods in tests of 602 routine urine samples. Of 324 Escherichia coli strains isolated, 92% grew brown colonies on dipslide, thus being beta-glucuronidase positive. The proportion of beta-glucuronidase-positive Escherichia coli detected by the three methods was 93% for BGA II agar plates (Tammer-Tutka), 91% for PGUA tablets (Rosco) and 84% for Fluorocult Brolacin agar plates (Merck). No false-positive reactions were seen in the case of 209 significant isolates of species other than Escherichia coli grown on the selective medium.

  15. Genetic Signatures of Strong Recent Positive Selection at the Lactase Gene

    PubMed Central

    Bersaglieri, Todd; Sabeti, Pardis C.; Patterson, Nick; Vanderploeg, Trisha; Schaffner, Steve F.; Drake, Jared A.; Rhodes, Matthew; Reich, David E.; Hirschhorn, Joel N.

    2004-01-01

    In most human populations, the ability to digest lactose contained in milk usually disappears in childhood, but in European-derived populations, lactase activity frequently persists into adulthood (Scrimshaw and Murray 1988). It has been suggested (Cavalli-Sforza 1973; Hollox et al. 2001; Enattah et al. 2002; Poulter et al. 2003) that a selective advantage based on additional nutrition from dairy explains these genetically determined population differences (Simoons 1970; Kretchmer 1971; Scrimshaw and Murray 1988; Enattah et al. 2002), but formal population-genetics–based evidence of selection has not yet been provided. To assess the population-genetics evidence for selection, we typed 101 single-nucleotide polymorphisms covering 3.2 Mb around the lactase gene. In northern European–derived populations, two alleles that are tightly associated with lactase persistence (Enattah et al. 2002) uniquely mark a common (∼77%) haplotype that extends largely undisrupted for >1 Mb. We provide two new lines of genetic evidence that this long, common haplotype arose rapidly due to recent selection: (1) by use of the traditional FST measure and a novel test based on pexcess, we demonstrate large frequency differences among populations for the persistence-associated markers and for flanking markers throughout the haplotype, and (2) we show that the haplotype is unusually long, given its high frequency—a hallmark of recent selection. We estimate that strong selection occurred within the past 5,000–10,000 years, consistent with an advantage to lactase persistence in the setting of dairy farming; the signals of selection we observe are among the strongest yet seen for any gene in the genome. PMID:15114531

  16. Cloning, expression of, and evidence of positive selection for, the prolactin receptor gene in Chinese giant salamander (Andrias davidianus).

    PubMed

    Hu, Qiaomu; Meng, Yan; Tian, Haifeng; Chen, Songlin; Xiao, Hanbing

    2015-12-01

    Prolactin receptor (PRLR) is a protein associated with reproduction in mammals and with osmoregulation in fish. In this study, the complete length of Chinese giant salamander Andrias davidianus prolactin receptor (AD-prlr) was cloned. Andrias davidianus prlr expression was high in the kidney, pituitary, and ovary and low in other examined tissues. The AD-prlr levels were higher in ovary than in testis, and increased in ovaries with age from 1 to 6 years. To determine effect of exogenous androgen and aromatase inhibitor on AD-prlr expression, methyltestosterone (MT) and letrozole (LE) were injected, resulting in decreased AD-prlr in both brain and ovary, with MT repressing prlr transcription more rapidly than did LE. The molecular evolution of prlr was assessed, and found to have undergone a complex evolution process. The obranch-site test detected four positively selected sites in ancestral lineages prior to the separation of mammals and birds. Fourteen sites underwent positive selection in ancestral lineages of birds and six were positively selected in amphibians. The site model showed that 16, 7, and 30 sites underwent positive selection in extant mammals, amphibians, and birds, respectively. The positively selected sites in amphibians were located outside the transmembrane domain, with four in the extracellular and three in the intracellular domain, indicating that the transmembrane region might be conserved and essential for protein function. Our findings provide a basis for further studies of AD-prlr function and molecular evolution in Chinese giant salamander. J. Exp. Zool. (Mol. Dev. Evol.) 324B: 707-719, 2015. © 2015 Wiley Periodicals, Inc.

  17. Inference of purifying and positive selection in three subspecies of chimpanzees (Pan troglodytes) from exome sequencing.

    PubMed

    Bataillon, Thomas; Duan, Jinjie; Hvilsom, Christina; Jin, Xin; Li, Yingrui; Skov, Laurits; Glemin, Sylvain; Munch, Kasper; Jiang, Tao; Qian, Yu; Hobolth, Asger; Wang, Jun; Mailund, Thomas; Siegismund, Hans R; Schierup, Mikkel H

    2015-03-30

    We study genome-wide nucleotide diversity in three subspecies of extant chimpanzees using exome capture. After strict filtering, Single Nucleotide Polymorphisms and indels were called and genotyped for greater than 50% of exons at a mean coverage of 35× per individual. Central chimpanzees (Pan troglodytes troglodytes) are the most polymorphic (nucleotide diversity, θw = 0.0023 per site) followed by Eastern (P. t. schweinfurthii) chimpanzees (θw = 0.0016) and Western (P. t. verus) chimpanzees (θw = 0.0008). A demographic scenario of divergence without gene flow fits the patterns of autosomal synonymous nucleotide diversity well except for a signal of recent gene flow from Western into Eastern chimpanzees. The striking contrast in X-linked versus autosomal polymorphism and divergence previously reported in Central chimpanzees is also found in Eastern and Western chimpanzees. We show that the direction of selection statistic exhibits a strong nonmonotonic relationship with the strength of purifying selection S, making it inappropriate for estimating S. We instead use counts in synonymous versus nonsynonymous frequency classes to infer the distribution of S coefficients acting on nonsynonymous mutations in each subspecies. The strength of purifying selection we infer is congruent with the differences in effective sizes of each subspecies: Central chimpanzees are undergoing the strongest purifying selection followed by Eastern and Western chimpanzees. Coding indels show stronger selection against indels changing the reading frame than observed in human populations.

  18. Genome-wide scans to detect positive selection in Large White and Tongcheng pigs.

    PubMed

    Li, Xiuling; Yang, Songbai; Tang, Zhonglin; Li, Kui; Rothschild, Max F; Liu, Bang; Fan, Bin

    2014-06-01

    Due to the direction, intensity, duration and consistency of genetic selection, especially recent artificial selection, the production performance of domestic pigs has been greatly changed. Therefore, we reasoned that there must be footprints or selection signatures that had been left during domestication. In this study, with porcine 60K BeadChip genotyping data from both commercial Large White and local Chinese Tongcheng pigs, we calculated the extended haplotype homozygosity values of the two breeds using the long-range haplotype method to detect selection signatures. We found 34 candidate regions, including 61 known genes, from Large White pigs and 25 regions comprising 57 known genes from Tongcheng pigs. Many selection signatures were found on SSC1, SSC4, SSC7 and SSC14 regions in both populations. According to quantitative trait loci and network pathway analyses, most of the regions and genes were linked to growth, reproduction and immune responses. In addition, the average genetic differentiation coefficient FST was 0.254, which means that there had already been a significant differentiation between the breeds. The findings from this study can contribute to further research on molecular mechanisms of pig evolution and domestication and also provide valuable references for improvement of their breeding and cultivation.

  19. Labeling and Selective Inactivation of Gram-Positive Bacteria Employing Bimodal Photoprobes with Dual Readouts.

    PubMed

    Galstyan, Anzhela; Block, Desiree; Niemann, Silke; Grüner, Malte C; Abbruzzetti, Stefania; Oneto, Michele; Daniliuc, Constantin G; Hermann, Sven; Viappiani, Cristiano; Schäfers, Michael; Löffler, Bettina; Strassert, Cristian A; Faust, Andreas

    2016-04-04

    Carbohydrate-conjugated silicon(IV) phthalocyanines with bimodal photoactivity were developed as probes with both fluorescent labeling and photosensitizing capabilities, and the concomitant fluorescent labeling and photoinduced inactivation of Gram-positive and Gram-negative models was explored. The maltohexaose-conjugated photoprobe provides a dual readout to distinguish between both groups of pathogens, as only the Gram-positive species was inactivated, even though both appeared labeled with near-infrared luminescence. Antibiotic resistance did not hinder the phototoxic effect, as even the methicillin-resistant pathogen Staphylococcus aureus (MRSA) was completely photoinactivated. Time-resolved confocal fluorescence microscopy analysis suggests that the photoprobe sticks onto the outer rim of the microorganisms, explaining the resistance of Gram-negative species on the basis of their membrane constitution. The mannose-conjugated photoprobe yields a different readout because it is able to label and to inactivate only the Gram-positive strain.

  20. Selective Localization of Shanks to VGLUT1-Positive Excitatory Synapses in the Mouse Hippocampus

    PubMed Central

    Heise, Christopher; Schroeder, Jan C.; Schoen, Michael; Halbedl, Sonja; Reim, Dominik; Woelfle, Sarah; Kreutz, Michael R.; Schmeisser, Michael J.; Boeckers, Tobias M.

    2016-01-01

    Members of the Shank family of multidomain proteins (Shank1, Shank2, and Shank3) are core components of the postsynaptic density (PSD) of excitatory synapses. At synaptic sites Shanks serve as scaffolding molecules that cluster neurotransmitter receptors as well as cell adhesion molecules attaching them to the actin cytoskeleton. In this study we investigated the synapse specific localization of Shank1-3 and focused on well-defined synaptic contacts within the hippocampal formation. We found that all three family members are present only at VGLUT1-positive synapses, which is particularly visible at mossy fiber contacts. No costaining was found at VGLUT2-positive contacts indicating that the molecular organization of VGLUT2-associated PSDs diverges from classical VGLUT1-positive excitatory contacts in the hippocampus. In light of SHANK mutations in neuropsychiatric disorders, this study indicates which glutamatergic networks within the hippocampus will be primarily affected by shankopathies. PMID:27199660

  1. Detecting Positive Selection of Korean Native Goat Populations Using Next-Generation Sequencing

    PubMed Central

    Lee, Wonseok; Ahn, Sojin; Taye, Mengistie; Sung, Samsun; Lee, Hyun-Jeong; Cho, Seoae; Kim, Heebal

    2016-01-01

    Goats (Capra hircus) are one of the oldest species of domesticated animals. Native Korean goats are a particularly interesting group, as they are indigenous to the area and were raised in the Korean peninsula almost 2,000 years ago. Although they have a small body size and produce low volumes of milk and meat, they are quite resistant to lumbar paralysis. Our study aimed to reveal the distinct genetic features and patterns of selection in native Korean goats by comparing the genomes of native Korean goat and crossbred goat populations. We sequenced the whole genome of 15 native Korean goats and 11 crossbred goats using next-generation sequencing (Illumina platform) to compare the genomes of the two populations. We found decreased nucleotide diversity in the native Korean goats compared to the crossbred goats. Genetic structural analysis demonstrated that the native Korean goat and crossbred goat populations shared a common ancestry, but were clearly distinct. Finally, to reveal the native Korean goat’s selective sweep region, selective sweep signals were identified in the native Korean goat genome using cross-population extended haplotype homozygosity (XP-EHH) and a cross-population composite likelihood ratio test (XP-CLR). As a result, we were able to identify candidate genes for recent selection, such as the CCR3 gene, which is related to lumbar paralysis resistance. Combined with future studies and recent goat genome information, this study will contribute to a thorough understanding of the native Korean goat genome. PMID:27989103

  2. Detecting Positive Selection of Korean Native Goat Populations Using Next-Generation Sequencing.

    PubMed

    Lee, Wonseok; Ahn, Sojin; Taye, Mengistie; Sung, Samsun; Lee, Hyun-Jeong; Cho, Seoae; Kim, Heebal

    2016-12-01

    Goats (Capra hircus) are one of the oldest species of domesticated animals. Native Korean goats are a particularly interesting group, as they are indigenous to the area and were raised in the Korean peninsula almost 2,000 years ago. Although they have a small body size and produce low volumes of milk and meat, they are quite resistant to lumbar paralysis. Our study aimed to reveal the distinct genetic features and patterns of selection in native Korean goats by comparing the genomes of native Korean goat and crossbred goat populations. We sequenced the whole genome of 15 native Korean goats and 11 crossbred goats using next-generation sequencing (Illumina platform) to compare the genomes of the two populations. We found decreased nucleotide diversity in the native Korean goats compared to the crossbred goats. Genetic structural analysis demonstrated that the native Korean goat and crossbred goat populations shared a common ancestry, but were clearly distinct. Finally, to reveal the native Korean goat's selective sweep region, selective sweep signals were identified in the native Korean goat genome using cross-population extended haplotype homozygosity (XP-EHH) and a cross-population composite likelihood ratio test (XP-CLR). As a result, we were able to identify candidate genes for recent selection, such as the CCR3 gene, which is related to lumbar paralysis resistance. Combined with future studies and recent goat genome information, this study will contribute to a thorough understanding of the native Korean goat genome.

  3. The Evaluation and Selection of a Fifth Ground Antenna Site for the Global Positioning System.

    DTIC Science & Technology

    1987-12-07

    selection. SITE MEASURE OF MERIT LOCAL LAND MASS 1. S60E260 .939635 OCEAN 2. S60E220 .939294 OCEAN 3. S60E300 .939109 SOUTH SHETLAND IS 4. S60E180 .93828...best location with a significant land mass nearby is at 60 degrees south latitude and 300 degrees east longitude, near the South Shetland Islands. 3

  4. Direct selection and phage display of a Gram-positive secretome

    PubMed Central

    Jankovic, Dragana; Collett, Michael A; Lubbers, Mark W; Rakonjac, Jasna

    2007-01-01

    Surface, secreted and transmembrane protein-encoding open reading frames, collectively the secretome, can be identified in bacterial genome sequences using bioinformatics. However, functional analysis of translated secretomes is possible only if many secretome proteins are expressed and purified individually. We have now developed and applied a phage display system for direct selection, identification, expression and purification of bacterial secretome proteins. PMID:18078523

  5. Selecting Children's Picture Books with Positive Native American Fathers and Father Figures.

    ERIC Educational Resources Information Center

    Heller, Craig; Cunningham, Bruce; Heller, Hannah M.

    2003-01-01

    Explores images of Native American fathers and father figures in children's picture books, offering background information about Native American cultures, traditional ways of culture and family, and the past and present role of fathers and father figures. Presents distinctive children's books along with guidelines for selecting and evaluating…

  6. Female promiscuity is positively associated with neutral and selected genetic diversity in passerine birds.

    PubMed

    Gohli, Jostein; Anmarkrud, Jarl A; Johnsen, Arild; Kleven, Oddmund; Borge, Thomas; Lifjeld, Jan T

    2013-05-01

    Passerine birds show large interspecific variation in extrapair paternity rates. There is accumulating evidence that such promiscuous behavior is driven by indirect, genetic benefits to females. Sexual selection theory distinguishes between two types of genetic benefits, additive and nonadditive effects, mediated by preferences for good and compatible genes, respectively. Good genes preferences should imply directional selection and mating skew among males, and thus reduced genetic diversity in the population. In contrast, compatible genes preferences should give balancing selection that retains genetic diversity. Here, we test how well these predictions fit with patterns of variation in genetic diversity and promiscuity levels among passerine birds. We found that more promiscuous species had higher nucleotide diversity at autosomal introns, but not at Z-chromosome introns. We also found that major histocompatibility complex (MHC) class IIB alleles had higher sequence diversity, and therefore should recognize a broader spectrum of pathogens, in more promiscuous species. Our results suggest that female promiscuity targets a multitude of autosomal genes for their nonadditive, compatibility benefits. Also, as immunity genes seem to be of particular importance, we hypothesize that interspecific variation in female promiscuity among passerine birds has arisen in response to the strength of pathogen-mediated selection. © 2013 The Author(s). Evolution © 2013 The Society for the Study of Evolution.

  7. Analysis of C3 suggests three periods of positive selection events and different evolutionary patterns between fish and mammals.

    PubMed

    Meng, Fanxing; Sun, Yuena; Liu, Xuezhu; Wang, Jianxin; Xu, Tianjun; Wang, Rixin

    2012-01-01

    The third complement component (C3) is a central protein of the complement system conserved from fish to mammals. It also showed distinct characteristics in different animal groups. Striking features of the fish complement system were unveiled, including prominent levels of extrahepatic expression and isotypic diversity of the complement components. The evidences of the involvement of complement system in the enhancement of B and T cell responses found in mammals indicated that the complement system also serves as a bridge between the innate and adaptive responses. For the reasons mentioned above, it is interesting to explore the evolutionary process of C3 genes and to investigate whether the huge differences between aquatic and terrestrial environments affected the C3 evolution between fish and mammals. Analysis revealed that these two groups of animals had experienced different evolution patterns. The mammalian C3 genes were under purifying selection pressure while the positive selection pressure was detected in fish C3 genes. Three periods of positive selection events of C3 genes were also detected. Two happened on the ancestral lineages to all vertebrates and mammals, respectively, one happened on early period of fish evolutionary history. Three periods of positive selection events had happened on C3 genes during history and the fish and mammals C3 genes experience different evolutionary patterns for their distinct living environments.

  8. Analysis of C3 Suggests Three Periods of Positive Selection Events and Different Evolutionary Patterns between Fish and Mammals

    PubMed Central

    Meng, Fanxing; Sun, Yuena; Liu, Xuezhu; Wang, Jianxin; Xu, Tianjun; Wang, Rixin

    2012-01-01

    Background The third complement component (C3) is a central protein of the complement system conserved from fish to mammals. It also showed distinct characteristics in different animal groups. Striking features of the fish complement system were unveiled, including prominent levels of extrahepatic expression and isotypic diversity of the complement components. The evidences of the involvement of complement system in the enhancement of B and T cell responses found in mammals indicated that the complement system also serves as a bridge between the innate and adaptive responses. For the reasons mentioned above, it is interesting to explore the evolutionary process of C3 genes and to investigate whether the huge differences between aquatic and terrestrial environments affected the C3 evolution between fish and mammals. Methodology/Principal Findings Analysis revealed that these two groups of animals had experienced different evolution patterns. The mammalian C3 genes were under purifying selection pressure while the positive selection pressure was detected in fish C3 genes. Three periods of positive selection events of C3 genes were also detected. Two happened on the ancestral lineages to all vertebrates and mammals, respectively, one happened on early period of fish evolutionary history. Conclusions/Significance Three periods of positive selection events had happened on C3 genes during history and the fish and mammals C3 genes experience different evolutionary patterns for their distinct living environments. PMID:22624039

  9. ‘Obesity’ is healthy for cetaceans? Evidence from pervasive positive selection in genes related to triacylglycerol metabolism

    PubMed Central

    Wang, Zhengfei; Chen, Zhuo; Xu, Shixia; Ren, Wenhua; Zhou, Kaiya; Yang, Guang

    2015-01-01

    Cetaceans are a group of secondarily adapted marine mammals with an enigmatic history of transition from terrestrial to fully aquatic habitat and subsequent adaptive radiation in waters around the world. Numerous physiological and morphological cetacean characteristics have been acquired in response to this drastic habitat transition; for example, the thickened blubber is one of the most striking changes that increases their buoyancy, supports locomotion, and provides thermal insulation. However, the genetic basis underlying the blubber thickening in cetaceans remains poorly explored. Here, 88 candidate genes associated with triacylglycerol metabolism were investigated in representative cetaceans and other mammals to test whether the thickened blubber matched adaptive evolution of triacylglycerol metabolism-related genes. Positive selection was detected in 41 of the 88 candidate genes, and functional characterization of these genes indicated that these are involved mainly in triacylglycerol synthesis and lipolysis processes. In addition, some essential regulatory genes underwent significant positive selection in cetacean-specific lineages, whereas no selection signal was detected in the counterpart terrestrial mammals. The extensive occurrence of positive selection in triacylglycerol metabolism-related genes is suggestive of their essential role in secondary adaptation to an aquatic life, and further implying that ‘obesity’ might be an indicator of good health for cetaceans. PMID:26381091

  10. Positive selection drives adaptive diversification of the 4-coumarate: CoA ligase (4CL) gene in angiosperms

    PubMed Central

    Sun, Haiyan; Guo, Kai; Feng, Shengqiu; Zou, Weihua; Li, Ying; Fan, Chunfen; Peng, Liangcai

    2015-01-01

    Lignin and flavonoids play a vital role in the adaption of plants to a terrestrial environment. 4-Coumarate: coenzyme A ligase (4CL) is a key enzyme of general phenylpropanoid metabolism which provides the precursors for both lignin and flavonoids biosynthesis. However, very little is known about how such essential enzymatic functions evolve and diversify. Here, we analyze 4CL sequence variation patterns in a phylogenetic framework to further identify the evolutionary forces that lead to functional divergence. The results reveal that lignin-biosynthetic 4CLs are under positive selection. The majority of the positively selected sites are located in the substrate-binding pocket and the catalytic center, indicating that nonsynonymous substitutions might contribute to the functional evolution of 4CLs for lignin biosynthesis. The evolution of 4CLs involved in flavonoid biosynthesis is constrained by purifying selection and maintains the ancestral role of the protein in response to biotic and abiotic factors. Overall, our results demonstrate that protein sequence evolution via positive selection is an important evolutionary force driving adaptive diversification in 4CL proteins in angiosperms. This diversification is associated with adaption to a terrestrial environment. PMID:26380674

  11. Identifying positive selection candidate loci for high-altitude adaptation in Andean populations

    PubMed Central

    2009-01-01

    High-altitude environments (>2,500 m) provide scientists with a natural laboratory to study the physiological and genetic effects of low ambient oxygen tension on human populations. One approach to understanding how life at high altitude has affected human metabolism is to survey genome-wide datasets for signatures of natural selection. In this work, we report on a study to identify selection-nominated candidate genes involved in adaptation to hypoxia in one highland group, Andeans from the South American Altiplano. We analysed dense microarray genotype data using four test statistics that detect departures from neutrality. Using a candidate gene, single nucleotide polymorphism-based approach, we identified genes exhibiting preliminary evidence of recent genetic adaptation in this population. These included genes that are part of the hypoxia-inducible transcription factor (HIF) pathway, a biochemical pathway involved in oxygen homeostasis, as well as three other genomic regions previously not known to be associated with high-altitude phenotypes. In addition to identifying selection-nominated candidate genes, we also tested whether the HIF pathway shows evidence of natural selection. Our results indicate that the genes of this biochemical pathway as a group show no evidence of having evolved in response to hypoxia in Andeans. Results from particular HIF-targeted genes, however, suggest that genes in this pathway could play a role in Andean adaptation to high altitude, even if the pathway as a whole does not show higher relative rates of evolution. These data suggest a genetic role in high-altitude adaptation and provide a basis for genotype/phenotype association studies that are necessary to confirm the role of putative natural selection candidate genes and gene regions in adaptation to altitude. PMID:20038496

  12. Ikaros is required to survive positive selection and to maintain clonal diversity during T-cell development in the thymus

    PubMed Central

    Tinsley, Kevin W.; Hong, Changwan; Luckey, Megan A.; Park, Joo-Young; Kim, Grace Y.; Yoon, Hee-won; Keller, Hilary R.; Sacks, Andrew J.; Feigenbaum, Lionel

    2013-01-01

    The zinc-finger protein Ikaros is a key player in T-cell development and a potent tumor suppressor in thymocytes. To understand the molecular basis of its function, we disabled Ikaros activity in vivo using a dominant negative Ikaros transgene (DN-IkTg). In DN-IkTg mice, T-cell development was severely suppressed, and positively selected thymocytes clonally expanded, resulting in a small thymus with a heavily skewed T-cell receptor (TCR) repertoire. Notably, DN-IkTg induced vigorous proliferation concomitant to downregulation of antiapoptotic factor expression such as Bcl2. Ikaros activity was required during positive selection, and specifically at the CD4+CD8lo intermediate stage of thymocyte differentiation, where it prevented persistent TCR signals from inducing aberrant proliferation and expansion. In particular, DN-IkTg induced the accumulation of CD4 single-positive (SP) thymocytes with a developmentally transitional phenotype, and it imposed a developmental arrest accompanied by massive apoptosis. Thus, we identified an in vivo requirement for Ikaros function, which is to suppress the proliferative potential of persistent TCR signals and to promote the survival and differentiation of positively selected thymocytes. PMID:23908463

  13. A genome-wide signature of positive selection in ancient and recent invasive expansions of the honey bee Apis mellifera.

    PubMed

    Zayed, Amro; Whitfield, Charles W

    2008-03-04

    Apis mellifera originated in Africa and extended its range into Eurasia in two or more ancient expansions. In 1956, honey bees of African origin were introduced into South America, their descendents admixing with previously introduced European bees, giving rise to the highly invasive and economically devastating "Africanized" honey bee. Here we ask whether the honey bee's out-of-Africa expansions, both ancient and recent (invasive), were associated with a genome-wide signature of positive selection, detected by contrasting genetic differentiation estimates (F(ST)) between coding and noncoding SNPs. In native populations, SNPs in protein-coding regions had significantly higher F(ST) estimates than those in noncoding regions, indicating adaptive evolution in the genome driven by positive selection. This signal of selection was associated with the expansion of honey bees from Africa into Western and Northern Europe, perhaps reflecting adaptation to temperate environments. We estimate that positive selection acted on a minimum of 852-1,371 genes or approximately 10% of the bee's coding genome. We also detected positive selection associated with the invasion of African-derived honey bees in the New World. We found that introgression of European-derived alleles into Africanized bees was significantly greater for coding than noncoding regions. Our findings demonstrate that Africanized bees exploited the genetic diversity present from preexisting introductions in an adaptive way. Finally, we found a significant negative correlation between F(ST) estimates and the local GC content surrounding coding SNPs, suggesting that AT-rich genes play an important role in adaptive evolution in the honey bee.

  14. A genome-wide signature of positive selection in ancient and recent invasive expansions of the honey bee Apis mellifera

    PubMed Central

    Zayed, Amro; Whitfield, Charles W.

    2008-01-01

    Apis mellifera originated in Africa and extended its range into Eurasia in two or more ancient expansions. In 1956, honey bees of African origin were introduced into South America, their descendents admixing with previously introduced European bees, giving rise to the highly invasive and economically devastating “Africanized” honey bee. Here we ask whether the honey bee's out-of-Africa expansions, both ancient and recent (invasive), were associated with a genome-wide signature of positive selection, detected by contrasting genetic differentiation estimates (FST) between coding and noncoding SNPs. In native populations, SNPs in protein-coding regions had significantly higher FST estimates than those in noncoding regions, indicating adaptive evolution in the genome driven by positive selection. This signal of selection was associated with the expansion of honey bees from Africa into Western and Northern Europe, perhaps reflecting adaptation to temperate environments. We estimate that positive selection acted on a minimum of 852–1,371 genes or ≈10% of the bee's coding genome. We also detected positive selection associated with the invasion of African-derived honey bees in the New World. We found that introgression of European-derived alleles into Africanized bees was significantly greater for coding than noncoding regions. Our findings demonstrate that Africanized bees exploited the genetic diversity present from preexisting introductions in an adaptive way. Finally, we found a significant negative correlation between FST estimates and the local GC content surrounding coding SNPs, suggesting that AT-rich genes play an important role in adaptive evolution in the honey bee. PMID:18299560

  15. The Efficacy of an Outdoor Adventure Education Curriculum on Selected Aspects of Positive Psychological Development

    ERIC Educational Resources Information Center

    Sheard, Michael; Golby, Jim

    2006-01-01

    To date, little empirical research has been conducted to support the claim that outdoor adventure education (OAE) develops desirable psychological characteristics in participants. This study examined the effects of an OAE foundation degree curriculum on positive psychological development. Fifty-two students (26 OAE students, 26 controls on an…

  16. The thuggacins, novel antibacterial macrolides from Sorangium cellulosum acting against selected Gram-positive bacteria.

    PubMed

    Irschik, Herbert; Reichenbach, Hans; Höfle, Gerhard; Jansen, Rolf

    2007-12-01

    In our screening program we found an activity against some Gram-positive bacteria, including mycobacteria in the culture supernatant of Sorangium cellulosum strain So ce895. The antibiotic responsible for this activity was isolated and named thuggacin. Initial studies towards the mechanism of action showed that thuggacin A inhibits a late step of the respiratory chain of some bacteria.

  17. The Efficacy of an Outdoor Adventure Education Curriculum on Selected Aspects of Positive Psychological Development

    ERIC Educational Resources Information Center

    Sheard, Michael; Golby, Jim

    2006-01-01

    To date, little empirical research has been conducted to support the claim that outdoor adventure education (OAE) develops desirable psychological characteristics in participants. This study examined the effects of an OAE foundation degree curriculum on positive psychological development. Fifty-two students (26 OAE students, 26 controls on an…

  18. Sexual Orientation and Spatial Position Effects on Selective Forms of Object Location Memory

    ERIC Educational Resources Information Center

    Rahman, Qazi; Newland, Cherie; Smyth, Beatrice Mary

    2011-01-01

    Prior research has demonstrated robust sex and sexual orientation-related differences in object location memory in humans. Here we show that this sexual variation may depend on the spatial position of target objects and the task-specific nature of the spatial array. We tested the recovery of object locations in three object arrays (object…

  19. Sexual Orientation and Spatial Position Effects on Selective Forms of Object Location Memory

    ERIC Educational Resources Information Center

    Rahman, Qazi; Newland, Cherie; Smyth, Beatrice Mary

    2011-01-01

    Prior research has demonstrated robust sex and sexual orientation-related differences in object location memory in humans. Here we show that this sexual variation may depend on the spatial position of target objects and the task-specific nature of the spatial array. We tested the recovery of object locations in three object arrays (object…

  20. Television's Impact on Children and the Positive Role of Parents. Selected Papers Number 53.

    ERIC Educational Resources Information Center

    Phillips, Shelley

    Television's impact on children and the positive role of parents in moderating that impact is discussed in terms of: (1) the view that television has a largely negative impact on children; (2) the importance of television literacy; (3) ways in which parents are molding television's impact to their purposes; (4) variation in television's impact…

  1. Positive selection during the evolution of the blood coagulation factors in the context of their disease-causing mutations.

    PubMed

    Rallapalli, Pavithra M; Orengo, Christine A; Studer, Romain A; Perkins, Stephen J

    2014-11-01

    Blood coagulation occurs through a cascade of enzymes and cofactors that produces a fibrin clot, while otherwise maintaining hemostasis. The 11 human coagulation factors (FG, FII-FXIII) have been identified across all vertebrates, suggesting that they emerged with the first vertebrates around 500 Ma. Human FVIII, FIX, and FXI are associated with thousands of disease-causing mutations. Here, we evaluated the strength of selective pressures on the 14 genes coding for the 11 factors during vertebrate evolution, and compared these with human mutations in FVIII, FIX, and FXI. Positive selection was identified for fibrinogen (FG), FIII, FVIII, FIX, and FX in the mammalian Primates and Laurasiatheria and the Sauropsida (reptiles and birds). This showed that the coagulation system in vertebrates was under strong selective pressures, perhaps to adapt against blood-invading pathogens. The comparison of these results with disease-causing mutations reported in FVIII, FIX, and FXI showed that the number of disease-causing mutations, and the probability of positive selection were inversely related to each other. It was concluded that when a site was under positive selection, it was less likely to be associated with disease-causing mutations. In contrast, sites under negative selection were more likely to be associated with disease-causing mutations and be destabilizing. A residue-by-residue comparison of the FVIII, FIX, and FXI sequence alignments confirmed this. This improved understanding of evolutionary changes in FVIII, FIX, and FXI provided greater insight into disease-causing mutations, and better assessments of the codon sites that may be mutated in applications of gene therapy.

  2. Genomic organization and differential signature of positive selection in the alpha and beta globin gene clusters in two cetacean species.

    PubMed

    Nery, Mariana F; Arroyo, José Ignacio; Opazo, Juan C

    2013-01-01

    The hemoglobin of jawed vertebrates is a heterotetramer protein that contains two α- and two β-chains, which are encoded by members of α- and β-globin gene families. Given the hemoglobin role in mediating an adaptive response to chronic hypoxia, it is likely that this molecule may have experienced a selective pressure during the evolution of cetaceans, which have to deal with hypoxia tolerance during prolonged diving. This selective pressure could have generated a complex history of gene turnover in these clusters and/or changes in protein structure themselves. Accordingly, we aimed to characterize the genomic organization of α- and β-globin gene clusters in two cetacean species and to detect a possible role of positive selection on them using a phylogenetic framework. Maximum likelihood and Bayesian phylogeny reconstructions revealed that both cetacean species had retained a similar complement of putatively functional genes. For the α-globin gene cluster, the killer whale presents a complement of genes composed of HBZ, HBK, and two functional copies of HBA and HBQ genes, whereas the dolphin possesses HBZ, HBK, HBA and HBQ genes, and one HBA pseudogene. For the β-globin gene cluster, both species retained a complement of four genes, two early expressed genes-HBE and HBH-and two adult expressed genes-HBD and HBB. Our natural selection analysis detected two positively selected sites in the HBB gene (56 and 62) and four in HBA (15, 21, 49, 120). Interestingly, only the genes that are expressed during the adulthood showed the signature of positive selection.

  3. Positive Selection during the Evolution of the Blood Coagulation Factors in the Context of Their Disease-Causing Mutations

    PubMed Central

    Rallapalli, Pavithra M.; Orengo, Christine A.; Studer, Romain A.; Perkins, Stephen J.

    2014-01-01

    Blood coagulation occurs through a cascade of enzymes and cofactors that produces a fibrin clot, while otherwise maintaining hemostasis. The 11 human coagulation factors (FG, FII–FXIII) have been identified across all vertebrates, suggesting that they emerged with the first vertebrates around 500 Ma. Human FVIII, FIX, and FXI are associated with thousands of disease-causing mutations. Here, we evaluated the strength of selective pressures on the 14 genes coding for the 11 factors during vertebrate evolution, and compared these with human mutations in FVIII, FIX, and FXI. Positive selection was identified for fibrinogen (FG), FIII, FVIII, FIX, and FX in the mammalian Primates and Laurasiatheria and the Sauropsida (reptiles and birds). This showed that the coagulation system in vertebrates was under strong selective pressures, perhaps to adapt against blood-invading pathogens. The comparison of these results with disease-causing mutations reported in FVIII, FIX, and FXI showed that the number of disease-causing mutations, and the probability of positive selection were inversely related to each other. It was concluded that when a site was under positive selection, it was less likely to be associated with disease-causing mutations. In contrast, sites under negative selection were more likely to be associated with disease-causing mutations and be destabilizing. A residue-by-residue comparison of the FVIII, FIX, and FXI sequence alignments confirmed this. This improved understanding of evolutionary changes in FVIII, FIX, and FXI provided greater insight into disease-causing mutations, and better assessments of the codon sites that may be mutated in applications of gene therapy. PMID:25158795

  4. Positive selection in development and growth rate regulation genes involved in species divergence of the genus Radix.

    PubMed

    Feldmeyer, Barbara; Greshake, Bastian; Funke, Elisabeth; Ebersberger, Ingo; Pfenninger, Markus

    2015-08-19

    Life history traits like developmental time, age and size at maturity are directly related to fitness in all organisms and play a major role in adaptive evolution and speciation processes. Comparative genomic or transcriptomic approaches to identify positively selected genes involved in species divergence can help to generate hypotheses on the driving forces behind speciation. Here we use a bottom-up approach to investigate this hypothesis by comparative analysis of orthologous transcripts of four closely related European Radix species. Snails of the genus Radix occupy species specific distribution ranges with distinct climatic niches, indicating a potential for natural selection driven speciation based on ecological niche differentiation. We then inferred phylogenetic relationships among the four Radix species based on whole mt-genomes plus 23 nuclear loci. Three different tests to infer selection and changes in amino acid properties yielded a total of 134 genes with signatures of positive selection. The majority of these genes belonged to the functional gene ontology categories "reproduction" and "genitalia" with an overrepresentation of the functions "development" and "growth rate". We show here that Radix species divergence may be primarily enforced by selection on life history traits such as (larval-) development and growth rate. We thus hypothesise that life history differences may confer advantages under the according climate regimes, e.g., species occupying warmer and dryer habitats might have a fitness advantage with fast developing susceptible life stages, which are more tolerant to habitat desiccation.

  5. Activity of retapamulin (SB-275833), a novel pleuromutilin, against selected resistant gram-positive cocci.

    PubMed

    Jones, Ronald N; Fritsche, Thomas R; Sader, Helio S; Ross, James E

    2006-07-01

    Retapamulin (SB-275833), the first pleuromutilin to be developed for human topical use, was tested against a selected population of staphylococci and beta-hemolytic streptococci. The MIC90 results for retapamulin were 0.12 microg/ml for Staphylococcus aureus and < or = 0.03 microg/ml for Streptococcus pyogenes; no cross-resistance was observed for organism subsets resistant to oxacillin, erythromycin, or mupirocin.

  6. Activity of Retapamulin (SB-275833), a Novel Pleuromutilin, against Selected Resistant Gram-Positive Cocci

    PubMed Central

    Jones, Ronald N.; Fritsche, Thomas R.; Sader, Helio S.; Ross, James E.

    2006-01-01

    Retapamulin (SB-275833), the first pleuromutilin to be developed for human topical use, was tested against a selected population of staphylococci and β-hemolytic streptococci. The MIC90 results for retapamulin were 0.12 μg/ml for Staphylococcus aureus and ≤0.03 μg/ml for Streptococcus pyogenes; no cross-resistance was observed for organism subsets resistant to oxacillin, erythromycin, or mupirocin. PMID:16801451

  7. Simultaneous purifying selection on the ancestral MC1R allele and positive selection on the melanoma-risk allele V60L in south Europeans.

    PubMed

    Martínez-Cadenas, Conrado; López, Saioa; Ribas, Gloria; Flores, Carlos; García, Oscar; Sevilla, Arrate; Smith-Zubiaga, Isabel; Ibarrola-Villaba, Maider; Pino-Yanes, Maria del Mar; Gardeazabal, Jesús; Boyano, Dolores; García de Galdeano, Alicia; Izagirre, Neskuts; de la Rúa, Concepción; Alonso, Santos

    2013-12-01

    In humans, the geographical apportionment of the coding diversity of the pigmentary locus melanocortin-1 receptor (MC1R) is, unusually, higher in Eurasians than in Africans. This atypical observation has been interpreted as the result of purifying selection due to functional constraint on MC1R in high UV-B radiation environments. By analyzing 3,142 human MC1R alleles from different regions of Spain in the context of additional haplotypic information from the 1000 Genomes (1000G) Project data, we show that purifying selection is also strong in southern Europe, but not so in northern Europe. Furthermore, we show that purifying and positive selection act simultaneously on MC1R. Thus, at least in Spain, regions at opposite ends of the incident UV-B radiation distribution show significantly different frequencies for the melanoma-risk allele V60L (a mutation also associated to red hair and fair skin and even blonde hair), with higher frequency of V60L at those regions of lower incident UV-B radiation. Besides, using the 1000G south European data, we show that the V60L haplogroup is also characterized by an extended haplotype homozygosity (EHH) pattern indicative of positive selection. We, thus, provide evidence for an adaptive value of human skin depigmentation in Europe and illustrate how an adaptive process can simultaneously help to maintain a disease-risk allele. In addition, our data support the hypothesis proposed by Jablonski and Chaplin (Human skin pigmentation as an adaptation to UVB radiation. Proc Natl Acad Sci U S A. 2010;107:8962-8968), which posits that habitation of middle latitudes involved the evolution of partially depigmented phenotypes that are still capable of suitable tanning.

  8. Croatian Meteor Network: Ongoing work 2015 - 2016

    NASA Astrophysics Data System (ADS)

    Šegon, D.; Vida, D.; Korlević, K.; Andreić, Ž.

    2016-01-01

    Ongoing work of the Croatian Meteor Network (CMN) between the 2015 and 2016 International Meteor Conferences is presented. The current sky coverage is considered, software updates and updates of orbit catalogues are described. Furthermore, the work done on meteor shower searches, international collaborations as well as new fields of research are discussed. Finally, the educational efforts made by the CMN are described.

  9. Croatian Meteor Network: ongoing work 2014 - 2015

    NASA Astrophysics Data System (ADS)

    Šegon, D.; Andreić, Ž.; Korlević, K.; Vida, D.

    2015-01-01

    Ongoing work mainly between 2014-2015 International Meteor Conferences (IMC) has been presented. Current sky coverage, software updates, orbit catalogues updates, shower search updates, international collaboration as well as new fields of research and educational efforts made by the Croatian Meteor Network are described.

  10. Selective and nonselective transfer: positive and negative priming in a multiple-task environment.

    PubMed

    Leboe, Jason P; Whittlesea, Bruce W A; Milliken, Bruce

    2005-09-01

    Processing of a probe stimulus can be affected either positively or negatively by presenting a related stimulus immediately before it. According to structural accounts, such effects occur because processing of the prime activates or inhibits the mental representation of the probe before it is presented. In contrast, transfer-appropriate processing accounts suggest that success in processing a probe depends on resources made available by earlier experiences of related stimuli. The authors manipulated the similarity between the prime and probe on color, lexical status, and orthographic structure, requiring either lexical decision or color identification on each. The authors observed a complex pattern of positive and negative transfer that cannot easily be explained through activation-inhibition of mental structures. Instead, that pattern provides evidence in favor of transfer-appropriate processing.

  11. Progress in the Development of Effective Vaccines to Prevent Selected Gram Positive Bacterial Infections

    PubMed Central

    Bronze, Michael S.; Dale, James B.

    2010-01-01

    Infections due to virulent gram positive bacteria, such as Staphylococcus aureus, group B streptococci and group A streptococci remain significant causes of morbidity and mortality despite progress in antimicrobial therapy. Despite significant advances in the understanding of the pathogenesis of infection due to these organisms, there are only limited strategies to prevent infection. In this paper, we review efforts to develop safe and effective vaccines that would prevent infections due to these 3 pathogens. PMID:20697258

  12. Selective stabilization of the chorismate mutase transition state by a positively charged hydrogen bond donor.

    PubMed

    Kienhöfer, Alexander; Kast, Peter; Hilvert, Donald

    2003-03-19

    Citrulline was incorporated via chemical semisynthesis at position 90 in the active site of the AroH chorismate mutase from Bacillus subtilis. The wild-type arginine at this position makes hydrogen-bonding interactions with the ether oxygen of chorismate. Replacement of the positively charged guanidinium group with the isosteric but neutral urea has a dramatic effect on the ability of the enzyme to convert chorismate into prephenate. The Arg90Cit variant exhibits a >104-fold decrease in the catalytic rate constant kcat with a 2.7-fold increase in the Michaelis constant Km. In contrast, its affinity for a conformationally constrained inhibitor molecule that effectively mimics the geometry but not the dissociative character of the transition state is only reduced by a factor of approximately 6. These results show that an active site merely complementary to the reactive conformation of chorismate is insufficient for catalysis of the mutase reaction. Instead, electrostatic stabilization of the polarized transition state by provision of a cationic hydrogen bond donor proximal to the oxygen in the breaking C-O bond is essential for high catalytic efficiency.

  13. Peptizer, a tool for assessing false positive peptide identifications and manually validating selected results.

    PubMed

    Helsens, Kenny; Timmerman, Evy; Vandekerckhove, Joël; Gevaert, Kris; Martens, Lennart

    2008-12-01

    False positive peptide identifications are a major concern in the field of peptidecentric, mass spectrometry-driven gel-free proteomics. They occur in regions where the score distributions of true positives and true negatives overlap. Removal of these false positive identifications necessarily involves a trade-off between sensitivity and specificity. Existing postprocessing tools typically rely on a fixed or semifixed set of assumptions in their attempts to optimize both the sensitivity and the specificity of peptide and protein identification using MS/MS spectra. Because of the expanding diversity in available proteomics technologies, however, these postprocessing tools often struggle to adapt to emerging technology-specific peculiarity. Here we present a novel tool named Peptizer that solves this adaptability issue by making use of pluggable assumptions. This research-oriented postprocessing tool also includes a graphical user interface to perform efficient manual validation of suspect identifications for optimal sensitivity recovery. Peptizer is open source software under the Apache2 license and is written in Java.

  14. Position-Related Differences in Selected Morphological Body Characteristics of Top-Level Female Handball Players.

    PubMed

    Bon, Marta; Pori, Primoz; Sibila, Marko

    2015-09-01

    The study aimed to establish the main morphological characteristics of Slovenian junior and senior female national handball team players. Morphological characteristics of various player subgroups (goalkeepers, wings, back players and pivots) were also determined so as to establish whether they had distinct profiles. The subjects were 87 handball players who were members of the Slovenian junior and senior female national teams in the period from 2003 to 2009. A standardised anthropometric protocol was used to assess the subjects' morphological characteristics. The measurements included 23 different anthropometric measures. First, basic statistical characteristics of anthropometric measures were obtained for all subjects together and then for each group separately. Somatotypes were determined using Heath-Carter's method. Endomorphic, mesomorphic and ectomorphic components were calculated by computer on the basis of formulas. In order to determine differences in the body composition and anthropometric data of the subjects playing in different positions, a one-way analysis of variance was employed. The results show that, on average, the wings differed the most from the other player groups in terms of their morphological body characteristics. The wings differed most prominently from the other player groups in terms of their morphological body parameters as they were significantly smaller and had a statistically significantly lower body mass than the other groups. In terms of transversal measures of the skeleton and the circumferences, the wings significantly differed mainly from the pivots and goalkeepers and less from the backs. The goalkeepers were the tallest, with high values of body mass and low values of transversal measures compared to P. Their skin folds were the most pronounced among all the groups on average and their share of subcutaneous fat in total body mass was the highest. Consequently, their endomorphic component of the somatotype was pronounced

  15. Evidence of positive selection at codon sites localized in extracellular domains of mammalian CC motif chemokine receptor proteins

    PubMed Central

    2010-01-01

    Background CC chemokine receptor proteins (CCR1 through CCR10) are seven-transmembrane G-protein coupled receptors whose signaling pathways are known for their important roles coordinating immune system responses through targeted trafficking of white blood cells. In addition, some of these receptors have been identified as fusion proteins for viral pathogens: for example, HIV-1 strains utilize CCR5, CCR2 and CCR3 proteins to obtain cellular entry in humans. The extracellular domains of these receptor proteins are involved in ligand-binding specificity as well as pathogen recognition interactions. In mammals, the majority of chemokine receptor genes are clustered together; in humans, seven of the ten genes are clustered in the 3p21-24 chromosome region. Gene conversion events, or exchange of DNA sequence between genes, have been reported in chemokine receptor paralogs in various mammalian lineages, especially between the cytogenetically closely located pairs CCR2/5 and CCR1/3. Datasets of mammalian orthologs for each gene were analyzed separately to minimize the potential confounding impact of analyzing highly similar sequences resulting from gene conversion events. Molecular evolution approaches and the software package Phylogenetic Analyses by Maximum Likelihood (PAML) were utilized to investigate the signature of selection that has acted on the mammalian CC chemokine receptor (CCR) gene family. The results of neutral vs. adaptive evolution (positive selection) hypothesis testing using Site Models are reported. In general, positive selection is defined by a ratio of nonsynonymous/synonymous nucleotide changes (dN/dS, or ω) >1. Results Of the ten mammalian CC motif chemokine receptor sequence datasets analyzed, only CCR2 and CCR3 contain amino acid codon sites that exhibit evidence of positive selection using site based hypothesis testing in PAML. Nineteen of the twenty codon sites putatively indentified as likely to be under positive selection code for amino acid

  16. Positive selection on the Plasmodium falciparum clag2 gene encoding a component of the erythrocyte-binding rhoptry protein complex

    PubMed Central

    Alexandre, Jean SF; Kaewthamasorn, Morakot; Yahata, Kazuhide; Nakazawa, Shusuke; Kaneko, Osamu

    2011-01-01

    A protein complex of high-molecular-mass proteins (PfRhopH) of the human malaria parasite Plasmodium falciparum induces host protective immunity and therefore is a candidate for vaccine development. Clarification of the level of polymorphism and the evolutionary processes is important both for vaccine design and for a better understanding of the evolution of cell invasion in this parasite. In a previous study on 5 genes encoding RhopH1/Clag proteins, positive diversifying selection was detected in clag8 and clag9 but not in the paralogous clag2, clag3.1 and clag3.2. In this study, to extend the analysis of clag polymorphism, we obtained sequences surrounding the most polymorphic regions of clag2, clag8, and clag9 from parasites collected in Thailand. Using sequence data obtained newly in this study and reported previously, we classified clag2 sequences into 5 groups based on the similarity of the deduced amino acid sequences and number of insertions/deletions. By the sliding window method, an excess of nonsynonymous substitutions over synonymous substitutions was detected in the group 1 and group 2 clag2 and clag8 sequences. Population-based analyses also detected a significant departure from the neutral expectation for group 1 clag2 and clag8. Thus, two independent approaches suggest that clag2 is subject to a positive diversifying selection. The previously suggested positive selection on clag8 was also supported by population-based analyses. However, the positive selection on clag9, which was detected by comparing the 5 sequences, was not detected using the additional 34 sequences obtained in this study. PMID:22028613

  17. Positive Selection in Bone Morphogenetic Protein 15 Targets a Natural Mutation Associated with Primary Ovarian Insufficiency in Human

    PubMed Central

    Meslin, Camille; Monestier, Olivier; Di Pasquale, Elisa; Pascal, Géraldine; Persani, Luca; Fabre, Stéphane

    2013-01-01

    Bone Morphogenetic Protein 15 (BMP15) is a TGFβ-like oocyte-derived growth factor involved in ovarian folliculogenesis as a critical regulator of many granulosa cell processes. Alterations of the BMP15 gene have been found associated with different ovarian phenotypic effects depending on the species, from sterility to increased prolificacy in sheep, slight subfertility in mouse or associated with primary ovarian insufficiency (POI) in women. To investigate the evolving role of BMP15, a phylogenetic analysis of this particular TGFβ family member was performed. A maximum likelihood phylogenetic tree of several TGFβ/BMP family members expressed by the ovary showed that BMP15 has a very strong divergence and a rapid evolution compared to others. Moreover, among 24 mammalian species, we detected signals of positive selection in the hominidae clade corresponding to F146, L189 and Y235 residues in human BMP15. The biological importance of these residues was tested functionally after site directed-mutagenesis in a COV434 cells luciferase assay. By replacing the positively selected amino acid either by alanine or the most represented residue in other studied species, only L189A, Y235A and Y235C mutants showed a significant increase of BMP15 signaling when compared to wild type. Additionally, the Y235C mutant was more potent than wild type in inhibiting progesterone secretion of ovine granulosa cells in primary culture. Interestingly, the Y235C mutation was previously identified in association with POI in women. In conclusion, this study evidences that the BMP15 gene has evolved faster than other members of the TGFß family and was submitted to a positive selection pressure in the hominidae clade. Some residues under positive selection are of great importance for the normal function of the protein and thus for female fertility. Y235 represents a critical residue in the determination of BMP15 biological activity, thus indirectly confirming its role in the onset of POI in

  18. Molecular cloning, characterization and positively selected sites of the glutathione S-transferase family from Locusta migratoria.

    PubMed

    Zhang, Xueyao; Wang, Jianxin; Zhang, Min; Qin, Guohua; Li, Daqi; Zhu, Kun Yan; Ma, Enbo; Zhang, Jianzhen

    2014-01-01

    Glutathione S-transferases (GSTs) are multifunctional enzymes that are involved in the metabolism of endogenous and exogenous compounds and are related to insecticide resistance. The purpose of this study was to provide new information on the molecular characteristics and the positive selection of locust GSTs. Based on the transcriptome database, we sequenced 28 cytosolic GSTs and 4 microsomal GSTs from the migratory locust (Locusta migratoria). We assigned the 28 cytosolic GSTs into 6 classes--sigma, epsilon, delta, theta, omega and zeta, and the 4 microsomal GSTs into 2 subclasses--insect and MGST3. The tissue- and stage-expression patterns of the GSTs differed at the mRNA level. Further, the substrate specificities and kinetic constants of the cytosolic GSTs differed markedly at the protein level. The results of likelihood ratio tests provided strong evidence for positive selection in the delta class. The result of Bayes Empirical Bayes analysis identified 4 amino acid sites in the delta class as positive selection sites. These sites were located on the protein surface. Our findings will facilitate the elucidation of the molecular characteristics and evolutionary aspects of insect GST superfamily.

  19. Strong and widespread action of site-specific positive selection in the snake venom Kunitz/BPTI protein family

    PubMed Central

    Župunski, Vera; Kordiš, Dušan

    2016-01-01

    S1 family of serine peptidases is the largest family of peptidases. They are specifically inhibited by the Kunitz/BPTI inhibitors. Kunitz domain is characterized by the compact 3D structure with the most important inhibitory loops for the inhibition of S1 peptidases. In the present study we analysed the action of site-specific positive selection and its impact on the structurally and functionally important parts of the snake venom Kunitz/BPTI family of proteins. By using numerous models we demonstrated the presence of large numbers of site-specific positively selected sites that can reach between 30–50% of the Kunitz domain. The mapping of the positively selected sites on the 3D model of Kunitz/BPTI inhibitors has shown that these sites are located in the inhibitory loops 1 and 2, but also in the Kunitz scaffold. Amino acid replacements have been found exclusively on the surface, and the vast majority of replacements are causing the change of the charge. The consequence of these replacements is the change in the electrostatic potential on the surface of the Kunitz/BPTI proteins that may play an important role in the precise targeting of these inhibitors into the active site of S1 family of serine peptidases. PMID:27841308

  20. No evidence for strong recent positive selection favoring the 7 repeat allele of VNTR in the DRD4 gene.

    PubMed

    Naka, Izumi; Nishida, Nao; Ohashi, Jun

    2011-01-01

    The human dopamine receptor D4 (DRD4) gene contains a 48-bp variable number of tandem repeat (VNTR) in exon 3, encoding the third intracellular loop of this dopamine receptor. The DRD4 7R allele, which seems to have a single origin, is commonly observed in various human populations and the nucleotide diversity of the DRD4 7R haplotype at the DRD4 locus is reduced compared to the most common DRD4 4R haplotype. Based on these observations, previous studies have hypothesized that positive selection has acted on the DRD4 7R allele. However, the degrees of linkage disequilibrium (LD) of the DRD4 7R allele with single nucleotide polymorphisms (SNPs) outside the DRD4 locus have not been evaluated. In this study, to re-examine the possibility of recent positive selection favoring the DRD4 7R allele, we genotyped HapMap subjects for DRD4 VNTR, and conducted several neutrality tests including long range haplotype test and iHS test based on the extended haplotype homozygosity. Our results indicated that LD of the DRD4 7R allele was not extended compared to SNP alleles with the similar frequency. Thus, we conclude that the DRD4 7R allele has not been subjected to strong recent positive selection.

  1. Molecular Cloning, Characterization and Positively Selected Sites of the Glutathione S-Transferase Family from Locusta migratoria

    PubMed Central

    Zhang, Min; Qin, Guohua; Li, Daqi; Zhu, Kun Yan; Ma, Enbo; Zhang, Jianzhen

    2014-01-01

    Glutathione S-transferases (GSTs) are multifunctional enzymes that are involved in the metabolism of endogenous and exogenous compounds and are related to insecticide resistance. The purpose of this study was to provide new information on the molecular characteristics and the positive selection of locust GSTs. Based on the transcriptome database, we sequenced 28 cytosolic GSTs and 4 microsomal GSTs from the migratory locust (Locusta migratoria). We assigned the 28 cytosolic GSTs into 6 classes—sigma, epsilon, delta, theta, omega and zeta, and the 4 microsomal GSTs into 2 subclasses—insect and MGST3. The tissue- and stage-expression patterns of the GSTs differed at the mRNA level. Further, the substrate specificities and kinetic constants of the cytosolic GSTs differed markedly at the protein level. The results of likelihood ratio tests provided strong evidence for positive selection in the delta class. The result of Bayes Empirical Bayes analysis identified 4 amino acid sites in the delta class as positive selection sites. These sites were located on the protein surface. Our findings will facilitate the elucidation of the molecular characteristics and evolutionary aspects of insect GST superfamily. PMID:25486043

  2. Positive selection of transgenic receptor-bearing thymocytes by Kb antigen is altered by Kb mutations that involve peptide binding.

    PubMed Central

    Sha, W C; Nelson, C A; Newberry, R D; Pullen, J K; Pease, L R; Russell, J H; Loh, D Y

    1990-01-01

    A specific interaction between the class I major histocompatibility complex molecule Kb and thymocytes expressing the antigen receptor from the cytolytic T lymphocyte 2C enhances maturation of T cells of the CD8 lineage in transgenic mice. By analyzing transgenic mice backcrossed to Kbm mutant strains of mice, we have identified five bm mutations of the Kb antigen-encoding gene that alter the positive selection of thymocytes induced by Kb antigen. Compared with Kb, Kbm10 and Kbm1 did not induce significant maturation of 2C T-cell receptor-bearing thymocytes, and Kbm8 antigen positively selected for transgenic thymocytes only weakly. Altering residue 77 of Kb molecule from aspartic acid to serine made Kbm3 and Kbm11 allogeneic targets for the 2C antigen receptor and caused deletion of transgenic thymocytes. This deletion spared T cells that expressed low levels of CD8, a result differing from the total deletion of CD8-bearing T cells seen in mice that expressed the original target alloantigen Ld. This evidence indicates that (i) self-peptides bound to thymic major histocompatibility complex molecules can influence the positive selection of thymocytes and (ii) thymocytes with apparently weak interaction with self-major histocompatibility complex antigens can escape clonal deletion. PMID:2117275

  3. Engagement of the T-cell receptor during positive selection in the thymus down-regulates RAG-1 expression.

    PubMed Central

    Brändle, D; Müller, C; Rülicke, T; Hengartner, H; Pircher, H

    1992-01-01

    We have examined the expression of the recombination activating gene RAG-1 by in situ hybridization to thymi from mice bearing transgenes for the T-cell receptor (TCR) alpha chain, TCR beta chain, or both TCR alpha and beta chains. RAG-1 transcription was found in the thymic cortex of transgenic mice carrying a single TCR alpha- or TCR beta-chain transgene, comparable to normal mice. However, RAG-1 transcription was strikingly reduced in the thymic cortex from transgenic mice carrying both TCR alpha- and beta-chain genes and expressing major histocompatibility complex (MHC) class I (H-2b) molecules necessary for positive selection of the transgenic TCR. In contrast, thymi of transgenic mice also carrying both TCR alpha- and beta-chain genes but expressing MHC molecules (H-2d) that did not positively select the transgenic TCR displayed high levels of RAG-1 transcription. The low thymic RAG-1 expression coincided with high transgenic TCR alpha-chain surface expression and with inhibition of endogenous TCR alpha-chain rearrangement. Our findings suggest that binding of the TCR to self MHC molecules during positive selection down-regulates RAG-1 transcription in cortical thymocytes and thereby prevents further TCR alpha-chain rearrangements. Images PMID:1329099

  4. Positive selection systems for discovery of novel polyester biosynthesis genes based on fatty acid detoxification.

    PubMed Central

    Kranz, R G; Gabbert, K K; Madigan, M T

    1997-01-01

    The photosynthetic bacterium Rhodobacter capsulatus can grow with short- to long-chain fatty acids as the sole carbon source (R. G. Kranz, K. K. Gabbert, T. A. Locke, and M. T. Madigan, Appl. Environ. Microbiol. 63:3003-3009, 1997). Concomitant with growth on fatty acids is the production to high levels of the polyester storage compounds called polyhydroxyalkanoates (PHAs). Here, we describe colony screening and selection systems to analyze the production of PHAs in R. capsulatus. A screen with Nile red dissolved in acetone distinguishes between PHA producers and nonproducers. Unlike the wild type, an R. capsulatus PhaC- strain with the gene encoding PHA synthase deleted is unable to grow on solid media containing high concentrations of certain fatty acids. It is proposed that this deficiency is due to the inability of the PhaC- strain to detoxify the surrounding medium by consumption of fatty acids and their incorporation into PHAs. This fatty acid toxicity phenotype is used in selection for the cloning and characterization of heterologous phaC genes. PMID:9251190

  5. Glycerol monolaurate inhibits the effects of Gram-positive select agents on eukaryotic cells.

    PubMed

    Peterson, Marnie L; Schlievert, Patrick M

    2006-02-21

    Many exotoxins of Gram-positive bacteria, such as superantigens [staphylococcal enterotoxins, toxic shock syndrome toxin-1 (TSST-1), and streptococcal pyrogenic exotoxins] and anthrax toxin are bioterrorism agents that cause diseases by immunostimulation or cytotoxicity. Glycerol monolaurate (GML), a fatty acid monoester found naturally in humans, has been reported to prevent synthesis of Gram-positive bacterial exotoxins. This study explored the ability of GML to inhibit the effects of exotoxins on mammalian cells and prevent rabbit lethality from TSS. GML (>or=10 microg/mL) inhibited superantigen (5 microg/mL) immunoproliferation, as determined by inhibition of (3)H-thymidine incorporation into DNA of human peripheral blood mononuclear cells (1 x 10(6) cells/mL) as well as phospholipase Cgamma1, suggesting inhibition of signal transduction. The compound (20 microg/mL) prevented superantigen (100 microg/mL) induced cytokine secretion by human vaginal epithelial cells (HVECs) as measured by ELISA. GML (250 microg) inhibited rabbit lethality as a result of TSST-1 administered vaginally. GML (10 microg/mL) inhibited HVEC and macrophage cytotoxicity by anthrax toxin, prevented erythrocyte lysis by purified hemolysins (staphylococcal alpha and beta) and culture fluids containing streptococcal and Bacillus anthracis hemolysins, and was nontoxic to mammalian cells (up to 100 microg/mL) and rabbits (250 microg). GML stabilized mammalian cell membranes, because erythrocyte lysis was reduced in the presence of hypotonic aqueous solutions (0-0.05 M saline) or staphylococcal alpha- and beta-hemolysins when erythrocytes were pretreated with GML. GML may be useful in the management of Gram-positive exotoxin illnesses; its action appears to be membrane stabilization with inhibition of signal transduction.

  6. Selection Criteria for Patients With Chronic Ankle Instability in Controlled Research: A Position Statement of the International Ankle Consortium

    PubMed Central

    Gribble, Phillip A.; Delahunt, Eamonn; Bleakley, Christopher M.; Caulfield, Brian; Docherty, Carrie L.; Fong, Daniel Tik-Pui; Fourchet, François; Hertel, Jay; Hiller, Claire E.; Kaminski, Thomas W.; McKeon, Patrick O.; Refshauge, Kathryn M.; van der Wees, Philip; Vicenzino, William; Wikstrom, Erik A.

    2014-01-01

    ABSTRACT While research on chronic ankle instability (CAI) and awareness of its impact on society and health care systems has grown substantially in the last 2 decades, the inconsistency in participant or patient selection criteria across studies presents a potential obstacle to addressing the problem properly. This major gap within the literature limits the ability to generalize this evidence to the target patient population. Therefore, there is a need to provide standards for patient or participant selection criteria in research focused on CAI with justifications using the best available evidence. The International Ankle Consortium provides this position paper to present and discuss an endorsed set of selection criteria for patients with CAI based on the best available evidence to be used in future research and study designs. These recommendations will enhance the validity of research conducted in this clinical population with the end goal of bringing the research evidence to the clinician and patient. PMID:24377963

  7. Plasmodium falciparum genome-wide scans for positive selection, recombination hot spots and resistance to antimalarial drugs

    PubMed Central

    Mu, Jianbing; Myers, Rachel A.; Jiang, Hongying; Liu, Shengfa; Ricklefs, Stacy; Waisberg, Michael; Chotivanich, Kesinee; Wilairata, Polrat; Krudsood, Srivicha; White, Nicholas J.; Udomsangpetch, Rachanee; Cui, Liwang; Ho, May; Ou, Fengzheng; Li, Haibo; Song, Jiangping; Li, Guoqiao; Wang, Xinhua; Seila, Suon; Sokunthea, Sreng; Socheat, Duong; Sturdevant, Daniel E.; Porcella, Stephen F.; Fairhurst, Rick M.; Wellems, Thomas E.; Awadalla, Philip; Su, Xin-zhuan

    2010-01-01

    Antimalarial drugs impose strong pressure on Plasmodium falciparum parasites and leave signatures of selection in the parasite genome 1,2. Search for signals of selection may lead to genes encoding drug or immune targets 3. The lack of high-throughput genotyping methods, inadequate knowledge of parasite population history, and time-consuming adaptations of parasites to in vitro culture have hampered genome-wide association studies (GWAS) of parasite traits. Here we report genotyping of DNA from 189 culture-adapted P. falciparum parasites using a custom-built array with thousands of single nucleotide polymorphisms (SNPs). Population structure, variation in recombination rate, and loci under recent positive selection were detected. Parasite half maximum inhibitory concentrations (IC50) to seven antimalarial drugs were obtained and used in GWAS to identify genes associated with drug responses. The SNP array and genome-wide parameters provide valuable tools and information for new advances in P. falciparum genetics. PMID:20101240

  8. Neanderthal introgression at chromosome 3p21.31 was under positive natural selection in East Asians.

    PubMed

    Ding, Qiliang; Hu, Ya; Xu, Shuhua; Wang, Jiucun; Jin, Li

    2014-03-01

    Studies of the Neanderthal and Denisovan genomes demonstrate archaic hominin introgression in Eurasians. Here, we present evidence of Neanderthal introgression within the chromosome 3p21.31 region, occurring with a high frequency in East Asians (ranging from 49.4% to 66.5%) and at a low frequency in Europeans. We also detected a signal of strong positive selection in this region only in East Asians. Our data indicate that likely candidate targets of selection include rs12488302-T and its associated alleles--among which four are nonsynonymous, including rs35455589-G in HYAL2, a gene related to the cellular response to ultraviolet-B irradiation. Furthermore, suggestive evidence supports latitude-dependent selection, implicating a role of ultraviolet-B. Interestingly, the distribution of rs35455589-G suggests that this allele was lost during the exodus of ancestors of modern Eurasians from Africa and reintroduced to Eurasians from Neanderthals.

  9. Evolution of the pygmy phenotype: evidence of positive selection fro genome-wide scans in African, Asian, and Melanesian pygmies.

    PubMed

    Migliano, Andrea Bamberg; Romero, Irene Gallego; Metspalu, Mait; Leavesley, Matthew; Pagani, Luca; Antao, Tiago; Huang, Da-Wei; Sherman, Brad T; Siddle, Katharine; Scholes, Clarissa; Hudjashov, Georgi; Kaitokai, Elton; Babalu, Avis; Belatti, Maggie; Cagan, Alex; Hopkinshaw, Byrony; Shaw, Colin; Nelis, Mari; Metspalu, Ene; Mägi, Reedik; Lempicki, Richard A; Villems, Richard; Lahr, Marta Mirazon; Kivisild, Toomas

    2013-01-01

    Human pygmy populations inhabit different regions of the world, from Africa to Melanesia. In Asia, short-statured populations are often referred to as "negritos." Their short stature has been interpreted as a consequence of thermoregulatory, nutritional, and/or locomotory adaptations to life in tropical forests. A more recent hypothesis proposes that their stature is the outcome of a life history trade-off in high-mortality environments, where early reproduction is favored and, consequently, early sexual maturation and early growth cessation have coevolved. Some serological evidence of deficiencies in the growth hormone/insulin-like growth factor axis have been previously associated with pygmies' short stature. Using genome-wide single-nucleotide polymorphism genotype data, we first tested whether different negrito groups living in the Philippines and Papua New Guinea are closely related and then investigated genomic signals of recent positive selection in African, Asian, and Papuan pygmy populations. We found that negritos in the Philippines and Papua New Guinea are genetically more similar to their nonpygmy neighbors than to one another and have experienced positive selection at different genes. These results indicate that geographically distant pygmy groups are likely to have evolved their short stature independently. We also found that selection on common height variants is unlikely to explain their short stature and that different genes associated with growth, thyroid function, and sexual development are under selection in different pygmy groups.

  10. Positive selection drives the evolution of a major histocompatibility complex gene in an endangered Mexican salamander species complex.

    PubMed

    Tracy, Karen E; Kiemnec-Tyburczy, Karen M; DeWoody, J Andrew; Parra-Olea, Gabriela; Zamudio, Kelly R

    2015-06-01

    Immune gene evolution can be critical to species survival in the face of infectious disease. In particular, polymorphism in the genes of the major histocompatibility complex (MHC) helps vertebrates combat novel and diverse pathogens by increasing the number of pathogen-derived proteins that can initiate the host's acquired immune response. In this study, we used a combination of presumably adaptive and neutral markers to investigate MHC evolution in populations of five salamander species within the Ambystoma velasci complex, a group consisting of 15 recently diverged species, several of which are endangered. We isolated 31 unique MHC class II β alleles from 75 total individuals from five species in this complex. MHC heterozygosity was significantly lower than expected for all five species, and we found no clear relationship between number of MHC alleles and species range, life history, or level of heterozygosity. We inferred a phylogeny representing the evolutionary history of Ambystoma MHC, with which we found signatures of positive selection on the overall gene, putative peptide-binding residues, and allelic lineages. We identified several instances of trans-species polymorphism, a hallmark of balancing selection observed in other groups of closely related species. In contrast, we did not detect comparable allelic diversity or signatures of selection on neutral loci. Additionally, we identified 17 supertypes among the 44 unique Ambystoma alleles, indicating that these sequences may encode functionally distinct MHC variants. We therefore have strong evidence that positive selection is a major evolutionary force driving patterns of MHC polymorphism in this recently radiated species complex.

  11. Likelihood analysis of the chalcone synthase genes suggests the role of positive selection in morning glories (Ipomoea).

    PubMed

    Yang, Ji; Gu, Hongya; Yang, Ziheng

    2004-01-01

    Chalcone synthase (CHS) is a key enzyme in the biosynthesis of flavonoides, which are important for the pigmentation of flowers and act as attractants to pollinators. Genes encoding CHS constitute a multigene family in which the copy number varies among plant species and functional divergence appears to have occurred repeatedly. In morning glories (Ipomoea), five functional CHS genes (A-E) have been described. Phylogenetic analysis of the Ipomoea CHS gene family revealed that CHS A, B, and C experienced accelerated rates of amino acid substitution relative to CHS D and E. To examine whether the CHS genes of the morning glories underwent adaptive evolution, maximum-likelihood models of codon substitution were used to analyze the functional sequences in the Ipomoea CHS gene family. These models used the nonsynonymous/synonymous rate ratio (omega = d(N)/ d(S)) as an indicator of selective pressure and allowed the ratio to vary among lineages or sites. Likelihood ratio test suggested significant variation in selection pressure among amino acid sites, with a small proportion of them detected to be under positive selection along the branches ancestral to CHS A, B, and C. Positive Darwinian selection appears to have promoted the divergence of subfamily ABC and subfamily DE and is at least partially responsible for a rate increase following gene duplication.

  12. Characterization of 40 full-length MHC class IIA functional alleles in miiuy croaker: Polymorphism and positive selection.

    PubMed

    Xu, Tianjun; Liu, Jiang; Sun, Yueyan; Zhu, Zhihuang; Liu, Tianxing

    2016-02-01

    The major histocompatibility complex is a highly polymorphic gene superfamily in vertebrates that plays an important role in adaptive immune response. In the present study, we identified 40 full-length miiuy croaker MHC class IIA (Mimi-DAA) functional alleles from 26 miiuy croaker individuals and found that the alleles encode 30 amino acid sequences. A high level of polymorphism in Mimi-DAA was detected in miiuy croaker. The rate of non-synonymous substitutions (d(N)) occurred at a significantly higher frequency than that of synonymous substitutions (d(S)) in the peptide-binding region (PBR) and non-PBR. This result suggests that balancing selection maintains polymorphisms at the Mimi-DAA locus. Phylogenetic analysis based on the full-length sequences showed that the Mimi-DAA alleles clustered into three groups. However, the phylogenetic tree constructed using the exon 2 sequences indicated that the Mimi-DAA alleles clustered into two groups. A total of 22 positively selected sites were identified on the Mimi-DAA alleles after testing for positive selection, and five sites were predicted to be associated with the binding of peptide antigen, suggesting that a few selected residues may play a significant role in immune function. Copyright © 2015 Elsevier Ltd. All rights reserved.

  13. Does Positive Selection Drive Transcription Factor Binding Site Turnover? A Test with Drosophila Cis-Regulatory Modules

    PubMed Central

    He, Bin Z.; Holloway, Alisha K.; Maerkl, Sebastian J.; Kreitman, Martin

    2011-01-01

    Transcription factor binding site(s) (TFBS) gain and loss (i.e., turnover) is a well-documented feature of cis-regulatory module (CRM) evolution, yet little attention has been paid to the evolutionary force(s) driving this turnover process. The predominant view, motivated by its widespread occurrence, emphasizes the importance of compensatory mutation and genetic drift. Positive selection, in contrast, although it has been invoked in specific instances of adaptive gene expression evolution, has not been considered as a general alternative to neutral compensatory evolution. In this study we evaluate the two hypotheses by analyzing patterns of single nucleotide polymorphism in the TFBS of well-characterized CRM in two closely related Drosophila species, Drosophila melanogaster and Drosophila simulans. An important feature of the analysis is classification of TFBS mutations according to the direction of their predicted effect on binding affinity, which allows gains and losses to be evaluated independently along the two phylogenetic lineages. The observed patterns of polymorphism and divergence are not compatible with neutral evolution for either class of mutations. Instead, multiple lines of evidence are consistent with contributions of positive selection to TFBS gain and loss as well as purifying selection in its maintenance. In discussion, we propose a model to reconcile the finding of selection driving TFBS turnover with constrained CRM function over long evolutionary time. PMID:21572512

  14. Detecting Loci under Recent Positive Selection in Dairy and Beef Cattle by Combining Different Genome-Wide Scan Methods

    PubMed Central

    Utsunomiya, Yuri Tani; Pérez O’Brien, Ana Maria; Sonstegard, Tad Stewart; Van Tassell, Curtis Paul; do Carmo, Adriana Santana; Mészáros, Gábor; Sölkner, Johann; Garcia, José Fernando

    2013-01-01

    As the methodologies available for the detection of positive selection from genomic data vary in terms of assumptions and execution, weak correlations are expected among them. However, if there is any given signal that is consistently supported across different methodologies, it is strong evidence that the locus has been under past selection. In this paper, a straightforward frequentist approach based on the Stouffer Method to combine P-values across different tests for evidence of recent positive selection in common variations, as well as strategies for extracting biological information from the detected signals, were described and applied to high density single nucleotide polymorphism (SNP) data generated from dairy and beef cattle (taurine and indicine). The ancestral Bovinae allele state of over 440,000 SNP is also reported. Using this combination of methods, highly significant (P<3.17×10−7) population-specific sweeps pointing out to candidate genes and pathways that may be involved in beef and dairy production were identified. The most significant signal was found in the Cornichon homolog 3 gene (CNIH3) in Brown Swiss (P = 3.82×10−12), and may be involved in the regulation of pre-ovulatory luteinizing hormone surge. Other putative pathways under selection are the glucolysis/gluconeogenesis, transcription machinery and chemokine/cytokine activity in Angus; calpain-calpastatin system and ribosome biogenesis in Brown Swiss; and gangliosides deposition in milk fat globules in Gyr. The composite method, combined with the strategies applied to retrieve functional information, may be a useful tool for surveying genome-wide selective sweeps and providing insights in to the source of selection. PMID:23696874

  15. Detecting loci under recent positive selection in dairy and beef cattle by combining different genome-wide scan methods.

    PubMed

    Utsunomiya, Yuri Tani; Pérez O'Brien, Ana Maria; Sonstegard, Tad Stewart; Van Tassell, Curtis Paul; do Carmo, Adriana Santana; Mészáros, Gábor; Sölkner, Johann; Garcia, José Fernando

    2013-01-01

    As the methodologies available for the detection of positive selection from genomic data vary in terms of assumptions and execution, weak correlations are expected among them. However, if there is any given signal that is consistently supported across different methodologies, it is strong evidence that the locus has been under past selection. In this paper, a straightforward frequentist approach based on the Stouffer Method to combine P-values across different tests for evidence of recent positive selection in common variations, as well as strategies for extracting biological information from the detected signals, were described and applied to high density single nucleotide polymorphism (SNP) data generated from dairy and beef cattle (taurine and indicine). The ancestral Bovinae allele state of over 440,000 SNP is also reported. Using this combination of methods, highly significant (P<3.17×10(-7)) population-specific sweeps pointing out to candidate genes and pathways that may be involved in beef and dairy production were identified. The most significant signal was found in the Cornichon homolog 3 gene (CNIH3) in Brown Swiss (P = 3.82×10(-12)), and may be involved in the regulation of pre-ovulatory luteinizing hormone surge. Other putative pathways under selection are the glucolysis/gluconeogenesis, transcription machinery and chemokine/cytokine activity in Angus; calpain-calpastatin system and ribosome biogenesis in Brown Swiss; and gangliosides deposition in milk fat globules in Gyr. The composite method, combined with the strategies applied to retrieve functional information, may be a useful tool for surveying genome-wide selective sweeps and providing insights in to the source of selection.

  16. Molecular population genetics of human CYP3A locus: signatures of positive selection and implications for evolutionary environmental medicine.

    PubMed

    Chen, Xiaoping; Wang, Haijian; Zhou, Gangqiao; Zhang, Xiumei; Dong, Xiaojia; Zhi, Lianteng; Jin, Li; He, Fuchu

    2009-10-01

    The human CYP3A gene cluster codes for cytochrome P450 (CYP) subfamily enzymes that catalyze the metabolism of various exogenous and endogenous chemicals and is an obvious candidate for evolutionary and environmental genomic study. Functional variants in the CYP3A locus may have undergone a selective sweep in response to various environmental conditions. The goal of this study was to profile the allelic structure across the human CYP3A locus and investigate natural selection on that locus. From the CYP3A locus spanning 231 kb, we resequenced 54 genomic DNA fragments (a total of 43,675 bases) spanning four genes (CYP3A4, CYP3A5, CYP3A7, and CYP3A43) and two pseudogenes (CYP3AP1 and CYP3AP2), and randomly selected intergenic regions at the CYP3A locus in Africans (24 individuals), Caucasians (24 individuals), and Chinese (29 individuals). We comprehensively investigated the nucleotide diversity and haplotype structure and examined the possible role of natural selection in shaping the sequence variation throughout the gene cluster. Neutrality tests with Tajima's D, Fu and Li's D* and F*, and Fay and Wu's H indicated possible roles of positive selection on the entire CYP3A locus in non-Africans. Sliding-window analyses of nucleotide diversity and frequency spectrum, as well as haplotype diversity and phylogenetically inferred haplotype structure, revealed that CYP3A4 and CYP3A7 had recently undergone or were undergoing a selective sweep in all three populations, whereas CYP3A43 and CYP3A5 were undergoing a selective sweep in non-Africans and Caucasians, respectively. The refined allelic architecture and selection spectrum for the human CYP3A locus highlight that evolutionary dynamics of molecular adaptation may underlie the phenotypic variation of the xenobiotic disposition system and varied predisposition to complex disorders in which xenobiotics play a role.

  17. Sexual orientation and spatial position effects on selective forms of object location memory.

    PubMed

    Rahman, Qazi; Newland, Cherie; Smyth, Beatrice Mary

    2011-04-01

    Prior research has demonstrated robust sex and sexual orientation-related differences in object location memory in humans. Here we show that this sexual variation may depend on the spatial position of target objects and the task-specific nature of the spatial array. We tested the recovery of object locations in three object arrays (object exchanges, object shifts, and novel objects) relative to veridical center (left compared to right side of the arrays) in a sample of 35 heterosexual men, 35 heterosexual women, and 35 homosexual men. Relative to heterosexual men, heterosexual women showed better location recovery in the right side of the array during object exchanges and homosexual men performed better in the right side during novel objects. However, the difference between heterosexual and homosexual men disappeared after controlling for IQ. Heterosexual women and homosexual men did not differ significantly from each other in location change detection with respect to task or side of array. These data suggest that visual space biases in processing categorical spatial positions may enhance aspects of object location memory in heterosexual women.

  18. PosiGene: automated and easy-to-use pipeline for genome-wide detection of positively selected genes

    PubMed Central

    Bens, Martin

    2017-01-01

    Abstract Many comparative genomics studies aim to find the genetic basis of species-specific phenotypic traits. A prevailing strategy is to search genome-wide for genes that evolved under positive selection based on the non-synonymous to synonymous substitution ratio. However, incongruent results largely due to high false positive rates indicate the need for standardization of quality criteria and software tools. Main challenges are the ortholog and isoform assignment, the high sensitivity of the statistical models to alignment errors and the imperative to parallelize large parts of the software. We developed the software tool PosiGene that (i) detects positively selected genes (PSGs) on genome-scale, (ii) allows analysis of specific evolutionary branches, (iii) can be used in arbitrary species contexts and (iv) offers visualization of the results for further manual validation and biological interpretation. We exemplify PosiGene's performance using simulated and real data. In the simulated data approach, we determined a false positive rate <1%. With real data, we found that 68.4% of the PSGs detected by PosiGene, were shared by at least one previous study that used the same set of species. PosiGene is a user-friendly, reliable tool for reproducible genome-wide identification of PSGs and freely available at https://github.com/gengit/PosiGene. PMID:28334822

  19. How the CCA-Adding Enzyme Selects Adenine over Cytosine at Position 76 of tRNA

    SciTech Connect

    Pan, Baocheng; Xiong, Yong; Steitz, Thomas A.

    2010-11-22

    CCA-adding enzymes [ATP(CTP):tRNA nucleotidyltransferases] add CCA onto the 3{prime} end of transfer RNA (tRNA) precursors without using a nucleic acid template. Although the mechanism by which cytosine (C) is selected at position 75 of tRNA has been established, the mechanism by which adenine (A) is selected at position 76 remains elusive. Here, we report five cocrystal structures of the enzyme complexed with both a tRNA mimic and nucleoside triphosphates under catalytically active conditions. These structures suggest that adenosine 5{prime}-monophosphate is incorporated onto the A76 position of the tRNA via a carboxylate-assisted, one-metal-ion mechanism with aspartate 110 functioning as a general base. The discrimination against incorporation of cytidine 5{prime}-triphosphate (CTP) at position 76 arises from improper placement of the {alpha} phosphate of the incoming CTP, which results from the interaction of C with arginine 224 and prevents the nucleophilic attack by the 3{prime} hydroxyl group of cytidine75.

  20. How the CCA-Adding Enzyme Selects Adenine over Cytosine at Position 76 of tRNA

    SciTech Connect

    B Pan; Y Xiong; T Steitz

    2011-12-31

    CCA-adding enzymes [ATP(CTP):tRNA nucleotidyltransferases] add CCA onto the 3' end of transfer RNA (tRNA) precursors without using a nucleic acid template. Although the mechanism by which cytosine (C) is selected at position 75 of tRNA has been established, the mechanism by which adenine (A) is selected at position 76 remains elusive. Here, we report five cocrystal structures of the enzyme complexed with both a tRNA mimic and nucleoside triphosphates under catalytically active conditions. These structures suggest that adenosine 5'-monophosphate is incorporated onto the A76 position of the tRNA via a carboxylate-assisted, one-metal-ion mechanism with aspartate 110 functioning as a general base. The discrimination against incorporation of cytidine 5'-triphosphate (CTP) at position 76 arises from improper placement of the {alpha} phosphate of the incoming CTP, which results from the interaction of C with arginine 224 and prevents the nucleophilic attack by the 3' hydroxyl group of cytidine75.

  1. James Cook University's rurally orientated medical school selection process: quality graduates and positive workforce outcomes.

    PubMed

    Ray, Robin A; Woolley, Torres; Sen Gupta, Tarun

    2015-01-01

    The regionally based James Cook University (JCU) College of Medicine and Dentistry aims to meet its mission to address the health needs of the region by using a selection policy favouring rural origin applicants and providing students with early and repeated exposure to rural experiences during training. This study seeks to determine if the JCU medical school's policy of preferentially selecting rural and remote background students is associated with differing patterns of undergraduate performance or graduate practice location. Data at application to medical school and during the undergraduate years was retrieved from administrative databases held by the university and the medical school. Postgraduate location data were obtained either from personal contact via email, telephone or Facebook or electronically from the Australian Health Practitioner Regulation Authority website. Practice location was described across Australian Standard Geographical Classification Remoteness Area (ASGC-RA) categories, with 1 being a major city and 5 being a very remote location. The 856 Australian-based students accepted into the JCU medical program between 2000 and 2008 came from all geographical regions across Australia: 20% metropolitan (ASGC-RA 1), 20% inner regional (ASGC-RA 2), 56% outer regional (ASGC-RA 3), and 5% from remote or very remote locations (ASGC-RA 4 and 5). Having a rural or remote hometown at application (ASGC-RA 3-5) was significantly associated with a lower tertiary entrance score (p<0.001), a lower interview score in the medical school selection process (p<0.001), being less likely to be admitted into the Honours program (p=0.001), being an advanced standing student (p=0.025), being awarded a Medical Rural Bonded Scholarship (p=0.005), taking longer to complete the 6-year course (p=<0.009) and having a lower academic achievement across years 1 to 3 (p=0.002, p=0.005 and p=0.025, respectively). Graduates having either a rural or a remote home town at application

  2. Positive selection on NIN, a gene involved in neurogenesis, and primate brain evolution.

    PubMed

    Montgomery, S H; Mundy, N I

    2012-11-01

    A long-held dogma in comparative neurobiology has been that the number of neurons under a given area of cortical surface is constant. As such, the attention of those seeking to understand the genetic basis of brain evolution has focused on genes with functions in the lateral expansion of the developing cerebral cortex. However, new data suggest that cortical cytoarchitecture is not constant across primates, raising the possibility that changes in radial cortical development played a role in primate brain evolution. We present the first analysis of a gene with functions relevant to this dimension of brain evolution. We show that NIN, a gene necessary for maintaining asymmetric, neurogenic divisions of radial glial cells (RGCs), evolved adaptively during anthropoid evolution. We explored how this selection relates to neural phenotypes and find a significant association between selection on NIN and neonatal brain size in catarrhines. Our analyses suggest a relationship with prenatal neurogenesis and identify the human data point as an outlier, possibly explained by postnatal changes in development on the human lineage. A similar pattern is found in platyrrhines, but the highly encephalized genus Cebus departs from the general trend. We further show that the evolution of NIN may be associated with variation in neuron number not explained by increases in surface area, a result consistent with NIN's role in neurogenic divisions of RGCs. Our combined results suggest a role for NIN in the evolution of cortical development. © 2012 The Authors. Genes, Brain and Behavior © 2012 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.

  3. Quantitation of the cell surface level of Ld resulting in positive versus negative selection of the 2C transgenic T cell receptor in vivo.

    PubMed

    Cook, J R; Wormstall, E M; Hornell, T; Russell, J; Connolly, J M; Hansen, T H

    1997-08-01

    The 2C transgenic TCR is positively selected on Kb and is alloreactive for and negatively selected on Ld. To test an avidity model for positive selection, mice were bred to express different levels of surface Ld by varying the number of gene copies encoding beta 2-microglobulin (beta 2m) or Ld heavy chain. Whereas mice expressing 35% Ld (beta 2m+/- Ld+/-) negatively selected the 2C TCR, mice expressing 2% Ld (beta 2m-/- Ld+/-) positively selected the 2C TCR. Furthermore, 2C cytotoxic T lymphocytes selected on 2% Ld showed peptide-specific cytolytic activity against Ld/p2Ca targets. These findings provide clear in vivo evidence that positive selection can occur on very low levels of the same class I antigen capable of negative selection when expressed at higher levels.

  4. Impact of low-energy CT imaging on selection of positive oral contrast media concentration.

    PubMed

    Patino, Manuel; Murcia, Diana J; Iamurri, Andrea Prochowski; Kambadakone, Avinash R; Hahn, Peter F; Sahani, Dushyant V

    2017-05-01

    To determine to what extent low-energy CT imaging affects attenuation of gastrointestinal tract (GIT) opacified with positive oral contrast media (OCM). Second, to establish optimal OCM concentrations for low-energy diagnostic CT exams. One hundred patients (38 men and 62 women; age 62 ± 11 years; BMI 26 ± 5) with positive OCM-enhanced 120-kVp single-energy CT (SECT), and follow-up 100-kVp acquisitions (group A; n = 50), or 40-70-keV reconstructions from rapid kV switching-single-source dual-energy CT (ssDECT) (group B; n = 50) were included. Luminal attenuation from different GIT segments was compared between exams. Standard dose of three OCM and diluted solutions (75%, 50%, and 25% concentrations) were introduced serially in a gastrointestinal phantom and scanned using SECT (120, 100, and 80 kVp) and DECT (80/140 kVp) acquisitions on a ssDECT scanner. Luminal attenuation was obtained on SECT and DECT images (40-70 keV), and compared to 120-kVp scans with standard OCM concentrations. Luminal attenuation was higher on 100-kVp (328 HU) and on 40-60-keV images (410-924 HU) in comparison to 120-kVp scans (298 HU) in groups A and B (p < 0.05). Phantom: There was an inverse correlation between luminal attenuation and X-ray energy, increasing up to 527 HU on low-kVp and 999 HU on low-keV images (p < 0.05). 25% and 50% diluted OCM solutions provided similar or higher attenuation than 120 kVp, at low kVp and keV, respectively. Low-energy CT imaging increases the attenuation of GIT opacified with positive OCM, permitting reduction of 25%-75% OCM concentration.

  5. Ongoing developments in sporadic inclusion body myositis.

    PubMed

    Machado, Pedro M; Ahmed, Mhoriam; Brady, Stefen; Gang, Qiang; Healy, Estelle; Morrow, Jasper M; Wallace, Amanda C; Dewar, Liz; Ramdharry, Gita; Parton, Matthew; Holton, Janice L; Houlden, Henry; Greensmith, Linda; Hanna, Michael G

    2014-12-01

    Sporadic inclusion body myositis (IBM) is an acquired muscle disorder associated with ageing, for which there is no effective treatment. Ongoing developments include: genetic studies that may provide insights regarding the pathogenesis of IBM, improved histopathological markers, the description of a new IBM autoantibody, scrutiny of the diagnostic utility of clinical features and biomarkers, the refinement of diagnostic criteria, the emerging use of MRI as a diagnostic and monitoring tool, and new pathogenic insights that have led to novel therapeutic approaches being trialled for IBM, including treatments with the objective of restoring protein homeostasis and myostatin blockers. The effect of exercise in IBM continues to be investigated. However, despite these ongoing developments, the aetiopathogenesis of IBM remains uncertain. A translational and multidisciplinary collaborative approach is critical to improve the diagnosis, treatment, and care of patients with IBM.

  6. Absence of positive selection on centromeric histones in Tetrahymena suggests unsuppressed centromere: drive in lineages lacking male meiosis.

    PubMed

    Elde, Nels C; Roach, Kevin C; Yao, Meng-Chao; Malik, Harmit S

    2011-06-01

    Centromere-drive is a process where centromeres compete for transmission through asymmetric "female" meiosis for inclusion into the oocyte. In symmetric "male" meiosis, all meiotic products form viable germ cells. Therefore, the primary incentive for centromere-drive, a potential transmission bias, is believed to be missing from male meiosis. In this article, we consider whether male meiosis also bears the primary cost of centromere-drive. Because different taxa carry out different combinations of meiotic programs (symmetric + asymmetric, symmetric only, asymmetric only), it is possible to consider the evolutionary consequences of centromere-drive in the context of these differing systems. Groups with both types of meiosis have large, rapidly evolving centromeric regions, and their centromeric histones (CenH3s) have been shown to evolve under positive selection, suggesting roles as suppressors of centromere-drive. In contrast, taxa with only symmetric male meiosis have shown no evidence of positive selection in their centromeric histones. In this article, we present the first evolutionary analysis of centromeric histones in ciliated protozoans, a group that only undergoes asymmetric "female" meiosis. We find no evidence of positive selection acting on CNA1, the CenH3 of Tetrahymena species. Cytological observations of a panel of Tetrahymena species are consistent with dynamic karyotype evolution in this lineage. Our findings suggest that defects in male meiosis, and not mitosis or female meiosis, are the primary selective force behind centromere-drive suppression. Our study raises the possibility that taxa like ciliates, with only female meiosis, may therefore undergo unsuppressed centromere drive.

  7. Multi-scale textural feature extraction and particle swarm optimization based model selection for false positive reduction in mammography.

    PubMed

    Zyout, Imad; Czajkowska, Joanna; Grzegorzek, Marcin

    2015-12-01

    The high number of false positives and the resulting number of avoidable breast biopsies are the major problems faced by current mammography Computer Aided Detection (CAD) systems. False positive reduction is not only a requirement for mass but also for calcification CAD systems which are currently deployed for clinical use. This paper tackles two problems related to reducing the number of false positives in the detection of all lesions and masses, respectively. Firstly, textural patterns of breast tissue have been analyzed using several multi-scale textural descriptors based on wavelet and gray level co-occurrence matrix. The second problem addressed in this paper is the parameter selection and performance optimization. For this, we adopt a model selection procedure based on Particle Swarm Optimization (PSO) for selecting the most discriminative textural features and for strengthening the generalization capacity of the supervised learning stage based on a Support Vector Machine (SVM) classifier. For evaluating the proposed methods, two sets of suspicious mammogram regions have been used. The first one, obtained from Digital Database for Screening Mammography (DDSM), contains 1494 regions (1000 normal and 494 abnormal samples). The second set of suspicious regions was obtained from database of Mammographic Image Analysis Society (mini-MIAS) and contains 315 (207 normal and 108 abnormal) samples. Results from both datasets demonstrate the efficiency of using PSO based model selection for optimizing both classifier hyper-parameters and parameters, respectively. Furthermore, the obtained results indicate the promising performance of the proposed textural features and more specifically, those based on co-occurrence matrix of wavelet image representation technique.

  8. Genetic determinant of Bacillus pumilus lipase lethality and its application as positive selection cloning vector in Escherichia coli.

    PubMed

    Mabizela-Mokoena, Nobalanda Betty; Limani, Shonisani Wendy; Ncube, Ignatious; Piater, Lizelle Ann; Litthauer, Derek; Nthangeni, Mulalo Bethuel

    2017-09-01

    Positive selection vectors carry genes that upon expression produce proteins that cause host cell deaths. Insertion of foreign DNA fragments within the ORF of the gene disrupts the lethal effect of the expressed protein. This study described the cloning of Family I.4 Bacillus pumilus lipase gene whose expressed protein is toxic and lethal to Escherichia coli JM109 (DE3) cells. The determinant of toxicity was identified through Error-prone PCR to be the nature of amino acid residue resident at position 28 of the mature lipase protein. The presence of Thr/Ser28 within the mature lipases of B. pumilus and B. licheniformis resulted in lethality to E. coli cells. However, the Thr28Ala or Thr28Gly mutations relieved the lethal phenotype of mature Family I.4 Bacillus lipases. The toxic effect of the expressed mature B. pumilus lipase protein was exploited in the development of a positive selection cloning vector. The B. pumilus lipase gene was synthesised to contain 13 unique silent restriction sites within the ORF, and placed under the regulation of T7 promoter of the pET expression system. Insertional inactivation of the gene's toxic protein was achieved by cloning DNA fragments of different sizes within the designed multiple cloning sites. The toxic effect of the lipase protein was disrupted indicating the potential of the gene for application in suicidal positive selection cloning vectors. The results revealed that protein expression and engineering studies aimed at optimal production of mature Family I.4 Bacillus lipases in E. coli should take into consideration the nature of amino acid 28 resident. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. CTEQ5 parton distributions and ongoing studies.

    SciTech Connect

    Kuhlmann, S.

    1999-09-21

    The CTEQ5 parton distributions are described, with emphasis on the changes since CTEQ4. The most significant change is in the quark flavor dependence of the parton distributions. Ongoing studies of large-x parton distributions are discussed. Luminosity estimates are given for HERA in order to improve the present uncertainties of the quark distributions. A discussion of how to improve the gluon uncertainty in the future is presented.

  10. Evidence of Positive Selection for a Glycogen Synthase (GYS1) Mutation in Domestic Horse Populations

    PubMed Central

    2014-01-01

    A dominantly inherited gain-of-function mutation in the glycogen synthase (GYS1) gene, resulting in excess skeletal muscle glycogen, has been identified in more than 30 horse breeds. This mutation is associated with the disease Equine Polysaccharide Storage Myopathy Type 1, yet persists at high frequency in some breeds. Under historical conditions of daily work and limited feed, excess muscle glycogen may have been advantageous, driving the increase in frequency of this allele. Fine-scale DNA sequencing in 80 horses and genotype assays in 279 horses revealed a paucity of haplotypes carrying the mutant allele when compared with the wild-type allele. Additionally, we found increased linkage disequilibrium, measured by relative extended haplotype homozygosity, in haplotypes carrying the mutation compared with haplotypes carrying the wild-type allele. Coalescent simulations of Belgian horse populations demonstrated that the high frequency and extended haplotype associated with the GYS1 mutation were unlikely to have arisen under neutrality or due to population demography. In contrast, in Quarter Horses, elevated relative extended haplotype homozygosity was associated with multiple haplotypes and may be the result of recent population expansion or a popular sire effect. These data suggest that the GYS1 mutation underwent historical selection in the Belgian, but not in the Quarter Horse. PMID:24215078

  11. Reciprocal positive selection for weakness - preventing olaparib resistance by inhibiting BRCA2.

    PubMed

    Rytelewski, Mateusz; Maleki Vareki, Saman; Mangala, Lingegowda S; Romanow, Larissa; Jiang, Dahai; Pradeep, Sunila; Rodriguez-Aguayo, Christian; Lopez-Berestein, Gabriel; Figueredo, Rene; Ferguson, Peter J; Vincent, Mark; Sood, Anil K; Koropatnick, James D

    2016-04-12

    Human tumor heterogeneity promotes therapeutic failure by increasing the likelihood of resistant cell subpopulations. The PARP-1 inhibitor olaparib is approved for use in BRCA-mutated ovarian cancers but BRCA2-reversion mutations lead to functional homologous recombination repair (HRR) and olaparib resistance. To overcome that resistance and expand use of PARP1 inhibition to cancers with functional HRR, we developed an antisense strategy to render the majority of tumor cells in a population BRCA2-deficient. We predicted that this strategy would render HRR-proficient tumor cells sensitive to olaparib and prevent emergence of resistance in a tumor cell population heterogeneous for HRR proficiency. We report that BRCA2 downregulation sensitized multiple human tumor cell lines (but not non-cancer human kidney cells) to olaparib and, combined with olaparib, increased aneuploidy and chromosomal translocations in human tumor cells. In a mixed HRR-proficient and HRR-deficient cell population, olaparib monotherapy allowed outgrowth of HRR-proficient cells resistant to subsequent olaparib treatment. Combined BRCA2 inhibition and olaparib treatment prevented selection of HRR-proficient cells and inhibited proliferation of the entire population. Treatment with BRCA2 siRNA and olaparib decreased ovarian xenograft growth in mice more effectively than either treatment alone. In vivo use of BRCA2 antisense oligonucleotides may be a viable option to expand clinical use of olaparib and prevent resistance.

  12. Reciprocal positive selection for weakness - preventing olaparib resistance by inhibiting BRCA2

    PubMed Central

    Rytelewski, Mateusz; Vareki, Saman Maleki; Mangala, Lingegowda S.; Romanow, Larissa; Jiang, Dahai; Pradeep, Sunila; Rodriguez-Aguayo, Christian; Lopez-Berestein, Gabriel; Figueredo, Rene; Ferguson, Peter J.; Vincent, Mark; Sood, Anil K.; Koropatnick, James D.

    2016-01-01

    Human tumor heterogeneity promotes therapeutic failure by increasing the likelihood of resistant cell subpopulations. The PARP-1 inhibitor olaparib is approved for use in BRCA-mutated ovarian cancers but BRCA2-reversion mutations lead to functional homologous recombination repair (HRR) and olaparib resistance. To overcome that resistance and expand use of PARP1 inhibition to cancers with functional HRR, we developed an antisense strategy to render the majority of tumor cells in a population BRCA2-deficient. We predicted that this strategy would render HRR-proficient tumor cells sensitive to olaparib and prevent emergence of resistance in a tumor cell population heterogeneous for HRR proficiency. We report that BRCA2 downregulation sensitized multiple human tumor cell lines (but not non-cancer human kidney cells) to olaparib and, combined with olaparib, increased aneuploidy and chromosomal translocations in human tumor cells. In a mixed HRR-proficient and HRR-deficient cell population, olaparib monotherapy allowed outgrowth of HRR-proficient cells resistant to subsequent olaparib treatment. Combined BRCA2 inhibition and olaparib treatment prevented selection of HRR-proficient cells and inhibited proliferation of the entire population. Treatment with BRCA2 siRNA and olaparib decreased ovarian xenograft growth in mice more effectively than either treatment alone. In vivo use of BRCA2 antisense oligonucleotides may be a viable option to expand clinical use of olaparib and prevent resistance. PMID:26959114

  13. Positive selection of co-opted mobile genetic elements in a mammalian gene

    PubMed Central

    Franchini, Lucia F.; de Souza, Flavio S.J.; Low, Malcolm J.; Rubinstein, Marcelo

    2012-01-01

    The proopiomelanocortin (Pomc) gene encodes a prepropeptide with essential functions in the response to stress and energy balance, which is expressed in the pituitary and hypothalamus of vertebrate animals. Neuronal expression of Pomc is controlled by two distal enhancers named nPE1 and nPE2. Using transgenic mice, we observed that both enhancers drive identical expression patterns in the mammalian hypothalamus, starting at embryonic day 10.5, when endogenous Pomc expression commences. This overlapping enhancer activity is maintained throughout hypothalamic development and into adulthood. We also found that nPE1 and nPE2 were exapted as neuronal enhancers into the POMC locus after the sequential insertion of two unrelated retroposons. Thus, nPE1 and nPE2 are functional analogs and represent an authentic first example of convergent molecular evolution of cell-specific transcriptional enhancers. In this Commentary we discuss the following questions that remain unanswered: (1) how does transcriptional control of POMC operate in hypothalamic neurons of non-mammalian vertebrates? (2) What evolutionary forces are maintaining two discrete neuronal POMC enhancers under purifying selection for the last ~100 million years in all placental mammals? (3) What is the contribution of MaLRs to genome evolution? PMID:22934245

  14. Positive selection of the TRIM family regulatory region in primate genomes.

    PubMed

    He, Dan-Dan; Lu, Yueer; Gittelman, Rachel; Jin, Yabin; Ling, Fei; Joshua, Akey

    2016-10-12

    Viral selection pressure has acted on restriction factors that play an important role in the innate immune system by inhibiting the replication of viruses during primate evolution. Tripartite motif-containing (TRIM) family members are some of these restriction factors. It is becoming increasingly clear that gene expression differences, rather than protein-coding regions changes, could play a vital role in the anti-retroviral immune mechanism. Increasingly, recent studies have created genome-scale catalogues of DNase I hypersensitive sites (DHSs), which demark potentially functional regulatory DNA. To improve our understanding of the molecular evolution mechanism of antiviral differences between species, we leveraged 14 130 DHSs derived from 145 cell types to characterize the regulatory landscape of the TRIM region. Subsequently, we compared the alignments of the DHSs across six primates and found 375 DHSs that are conserved in non-human primates but exhibit significantly accelerated rates of evolution in the human lineage (haDHSs). Furthermore, we discovered 31 human-specific potential transcription factor motifs within haDHSs, including the KROX and SP1, that both interact with HIV-1 Importantly, the corresponding haDHS was correlated with antiviral factor TRIM23 Thus, our results suggested that some viruses may contribute, through regulatory DNA differences, to organismal evolution by mediating TRIM gene expression to escape immune surveillance.

  15. Selective internalization of self-assembled artificial oil bodies by HER2/neu-positive cells

    NASA Astrophysics Data System (ADS)

    Chiang, Chung-Jen; Lin, Li-Jen; Lin, Che-Chin; Chang, Chih-Hsiang; Chao, Yun-Peng

    2011-01-01

    A novel delivery carrier was developed using artificial oil bodies (AOBs). Plant seed oil bodies (OBs) consist of a triacylglycerol matrix surrounded by a monolayer of phospholipids embedded with the storage protein oleosin (Ole). Ole consists of a central hydrophobic domain with two amphiphatic arms that extrude from the surface of OBs. In this study, a bivalent anti-HER2/neu affibody domain (ZH2) was fused with Ole at the C terminus. After overproduction in Escherichia coli, the fusion protein (Ole-ZH2) was recovered to assemble AOBs. The size of self-assembled AOBs was tailored by varying the oil/Ole-ZH2 ratio and pH to reach a nanoscale. Upon co-incubation with tumor cells, the nanoscale AOBs encapsulated with a hydrophobic fluorescence dye were selectively internalized by HER2/neu-overexpressing cells and displayed biocompatibility with the cells. In addition, the ZH2-mediated endosomal entry of AOBs occurred in a time- and AOB dose-dependent manner. The internalization efficiency was as high as 90%. The internalized AOBs disintegrated at the non-permissive pH (e.g. in acidic endosomes) and the cargo dye was released. Results of in vitro study revealed a sustained and prolonged release profile. Taken together, our findings indicate the potential of AOBs as a delivery carrier.

  16. Identification of 48 full-length MHC-DAB functional alleles in miiuy croaker and evidence for positive selection.

    PubMed

    Liu, Jiang; Sun, Yueyan; Xu, Tianjun

    2016-07-01

    Major histocompatibility complex (MHC) molecules play a vital role in the immune response and are a highly polymorphic gene superfamily in vertebrates. As the molecular marker associated with polymorphism and disease susceptibility/resistance, the polymorphism of MHC genes has been investigated in many tetrapods and teleosts. Most studies were focused on the polymorphism of the second exon, which encodes the peptide-binding region (PBR) in the α1- or β1-domain, but few studies have examined the full-length coding region. To comprehensive investigate the polymorphism of MHC gene, we identified 48 full-length miiuy croaker (Miichthys miiuy) MHC class IIB (Mimi-DAB) functional alleles from 26 miiuy croaker individuals. All of the alleles encode 34 amino acid sequences, and a high level of polymorphism was detected in Mimi-DAB alleles. The rate of non-synonymous substitutions (dN) occurred at a significantly higher frequency than that of synonymous substitutions (dS) in the PBR, and this result suggests that balancing selection maintains polymorphisms at the Mimi-DAB locus. Phylogenetic analysis based on the full-length and exon 2 sequences of Mimi-DAB alleles both showed that the Mimi-DAB alleles were clustered into two major groups. A total of 19 positive selected sites were identified on the Mimi-DAB alleles after testing for positive selection, and 14 sites were predicted to be associated with antigen-binding sites, which suggests that most of selected sites are significant for disease resistance. The polymorphism of Mimi-DAB alleles provides an important resource for analyzing the association between the polymorphism of MHC gene and disease susceptibility/resistance, and for researching the molecular selective breeding of miiuy croaker with enhanced disease resistance. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. Positive heterotropic cooperativity for selective guest binding via electronic communications through a fused zinc porphyrin array.

    PubMed

    Sato, Hiroshi; Tashiro, Kentaro; Shinmori, Hideyuki; Osuka, Atsuhiro; Murata, Yasujiro; Komatsu, Koichi; Aida, Takuzo

    2005-09-28

    Upon binding with C60 and diamines, such as 4,4'-bipyridine (bpy) and N,N,N',N'-tetramethylhexane-1,6-diamine (TMHDA), cyclic host 1 possessing two electronically coupled binding sites displays negative homotropic cooperativity and positive heterotropic cooperativity, and their ternary mixtures preferentially form inclusion complexes with hetero-guest pairs 1 supersetC60*bpy and 1 supersetC60*TMHDA under appropriate conditions. Spectroscopic titration profiles in toluene at 20 degrees C demonstrated that the association constants (Kassoc) of C60 with monodiamine complexes 1 supersetbpy (2.8 x 105 M-1) and 1 supersetTMHDA (1.5 x 105 M-1) are 8.5 and 4.5 times greater than that of C60 with guest-free 1 (3.3 x 104 M-1), respectively. On the other hand, mono-C60 complex 1 supersetC60 was 6.1 times more accessible than guest-free 1 toward TMHDA. Absorption spectroscopy in the absence of 1 indicated no direct interaction between C60 and diamines.

  18. A design of a valid signal selecting and position decoding ASIC for PET using silicon photomultipliers

    NASA Astrophysics Data System (ADS)

    Cho, M.; Lim, K.-t.; Kim, H.; Yeom, J.-y.; Kim, J.; Lee, C.; Choi, H.; Cho, G.

    2017-01-01

    In most cases, a PET system has numerous electrical components and channel circuits and thus it would rather be a bulky product. Also, most existing systems receive analog signals from detectors which make them vulnerable to signal distortions. For these reasons, channel reduction techniques are important. In this work, an ASIC for PET module is being proposed. An ASIC chip for 16 PET detector channels, VSSPDC, has been designed and simulated. The main function of the chip is 16-to-1 channel reduction, i.e., finding the position of only the valid signals, signal timing, and magnitudes in all 16 channels at every recorded event. The ASIC comprises four of 4-channel modules and a 2nd 4-to-1 router. A single channel module comprises a transimpedance amplifier for the silicon photomultipliers, dual comparators with high and low level references, and a logic circuitry. While the high level reference was used to test the validity of the signal, the low level reference was used for the timing. The 1-channel module of the ASIC produced an energy pulse by time-over-threshold method and it also produced a time pulse with a fixed delayed time. Since the ASIC chip outputs only a few digital pulses and does not require an external clock, it has an advantage over noise properties. The cadence simulation showed the good performance of the chip as designed.

  19. PATTERN OF HBsAg POSITIVITY IN SELECTED GROUPS AT KING KHALID GENERAL HOSPITAL - HAIL REGION, KINGDOM OF SAUDI ARABIA

    PubMed Central

    Mahaba, Hisham M.; El-Tayeb, Abd El Kader A.; El-Sekibi, Dahl K; El Gofaei, Ali F.; El-Baz, Hisham S.; Ismail, Nanees A.

    1997-01-01

    Background: Hepatitis B virus (HBV) is endemic in the Kingdom of Saudi Arabia. The acquisition of infection occurs early in life. The availability of safe and efficacious vaccines has led to the feasibility of an effective control of HBV infection. This study compares the pattern of HBsAg positivity among selected groups of patients with similar groups in other regions in the Kingdom of Saudi Arabia. Objectives: This study is conducted to determine the prevalence of HBsAg positive subjects among selected groups of patients attending the main general hospital in the Hail region. Subjects and Methods: This retrospective study included 14029 subjects that were tested for HBsAg at King Khalid General Hospital, during the period from April 1994 to April 1996. Results and Discussion: The overall prevalence of HBsAg positive subjects was 3.5%. The prevalence for Saudis was about 3.2% for Saudis. Pakistanis had the highest prevalence of 11.8%. The prevalence was 3.02% for blood donors, and 2.1 % among pregnant women. No significant difference was found among different age groups. Hail region had a lower prevalence of HBsAg positive cases compared to that estimated by previous studies in the Kingdom, suggesting success in efforts applied by the Ministry of Health (110H) for prevention of Hepatitis B viral infection. Conclusion: We can conclude that the prevalence of HBsAg positive subjects is declining in the Hail region, Kingdom of Saudi Arabia (KSA). This decline suggests the success of preventive efforts such as vaccination of newborns with the HBsAg vaccine. However, screening of pregnant women for HBsAg scents to be necessary. PMID:23008563

  20. Positive selection of a duplicated UV-sensitive visual pigment coincides with wing pigment evolution in Heliconius butterflies

    PubMed Central

    Briscoe, Adriana D.; Bybee, Seth M.; Bernard, Gary D.; Yuan, Furong; Sison-Mangus, Marilou P.; Reed, Robert D.; Warren, Andrew D.; Llorente-Bousquets, Jorge; Chiao, Chuan-Chin

    2010-01-01

    The butterfly Heliconius erato can see from the UV to the red part of the light spectrum with color vision proven from 440 to 640 nm. Its eye is known to contain three visual pigments, rhodopsins, produced by an 11-cis-3-hydroxyretinal chromophore together with long wavelength (LWRh), blue (BRh) and UV (UVRh1) opsins. We now find that H. erato has a second UV opsin mRNA (UVRh2)—a previously undescribed duplication of this gene among Lepidoptera. To investigate its evolutionary origin, we screened eye cDNAs from 14 butterfly species in the subfamily Heliconiinae and found both copies only among Heliconius. Phylogeny-based tests of selection indicate positive selection of UVRh2 following duplication, and some of the positively selected sites correspond to vertebrate visual pigment spectral tuning residues. Epi-microspectrophotometry reveals two UV-absorbing rhodopsins in the H. erato eye with λmax = 355 nm and 398 nm. Along with the additional UV opsin, Heliconius have also evolved 3-hydroxy-DL-kynurenine (3-OHK)-based yellow wing pigments not found in close relatives. Visual models of how butterflies perceive wing color variation indicate this has resulted in an expansion of the number of distinguishable yellow colors on Heliconius wings. Functional diversification of the UV-sensitive visual pigments may help explain why the yellow wing pigments of Heliconius are so colorful in the UV range compared to the yellow pigments of close relatives lacking the UV opsin duplicate. PMID:20133601

  1. Selective GABAA α5 Positive Allosteric Modulators Improve Cognitive Function in Aged Rats with Memory Impairment

    PubMed Central

    Koh, Ming Teng; Rosenzweig-Lipson, Sharon; Gallagher, Michela

    2012-01-01

    A condition of excess activity in the hippocampal formation is observed in the aging brain and in conditions that confer additional risk during aging for Alzheimer’s disease. Compounds that act as positive allosteric modulators at GABAA α5 receptors might be useful in targeting this condition because GABAA α5 receptors mediate tonic inhibition of principal neurons in the affected network. While agents to improve cognitive function in the past focused on inverse agonists, which are negative allosteric modulators at GABAA α5 receptors, research supporting that approach used only young animals and predated current evidence for excessive hippocampal activity in age-related conditions of cognitive impairment. Here, we used two compounds, Compound 44 [6,6-dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one] and Compound 6 [methyl 3,5-diphenylpyridazine-4-carboxylate], with functional activity as potentiators of γ-aminobutyric acid at GABAA α5 receptors, to test their ability to improve hippocampal-dependent memory in aged rats with identified cognitive impairment. Improvement was obtained in aged rats across protocols differing in motivational and performance demands and across varying retention intervals. Significant memory improvement occurred after either intracereboventricular infusion with Compound 44 (100 μg) in a water maze task or systemic administration with Compound 6 (3 mg/kg) in a radial arm maze task. Furthermore, systemic administration improved behavioral performance at dosing shown to provide drug exposure in the brain and in vivo receptor occupancy in the hippocampus. These data suggest a novel approach to improve neural network function in clinical conditions of excess hippocampal activity. PMID:22732440

  2. Positively selected amino acid replacements within the RuBisCO enzyme of oak trees are associated with ecological adaptations.

    PubMed

    Hermida-Carrera, Carmen; Fares, Mario A; Fernández, Ángel; Gil-Pelegrín, Eustaquio; Kapralov, Maxim V; Mir, Arnau; Molins, Arántzazu; Peguero-Pina, José Javier; Rocha, Jairo; Sancho-Knapik, Domingo; Galmés, Jeroni

    2017-01-01

    Phylogenetic analysis by maximum likelihood (PAML) has become the standard approach to study positive selection at the molecular level, but other methods may provide complementary ways to identify amino acid replacements associated with particular conditions. Here, we compare results of the decision tree (DT) model method with ones of PAML using the key photosynthetic enzyme RuBisCO as a model system to study molecular adaptation to particular ecological conditions in oaks (Quercus). We sequenced the chloroplast rbcL gene encoding RuBisCO large subunit in 158 Quercus species, covering about a third of the global genus diversity. It has been hypothesized that RuBisCO has evolved differentially depending on the environmental conditions and leaf traits governing internal gas diffusion patterns. Here, we show, using PAML, that amino acid replacements at the residue positions 95, 145, 251, 262 and 328 of the RuBisCO large subunit have been the subject of positive selection along particular Quercus lineages associated with the leaf traits and climate characteristics. In parallel, the DT model identified amino acid replacements at sites 95, 219, 262 and 328 being associated with the leaf traits and climate characteristics, exhibiting partial overlap with the results obtained using PAML.

  3. Selection of HyspIRI optimal band positions for the earth compositional mapping using HyTES data

    NASA Astrophysics Data System (ADS)

    Ullah, Saleem; Khalid, Noora; Iqbal, Arshad

    2016-07-01

    In near future, NASA/JPL will orbit a new space-borne sensor called HyspIRI (Hyperspectral and Infrared Imager) which will cover the spectral range from 0.4 -14μm. Two instruments will be mounted on HyspIRI platform; one is hyperspectral instrument which can sense earth surface between 0.4-2.5μm with 10 nm intervals and a multispectral TIR sensor will acquire images between 3 to 14μm in 8 (1 in MIR and 7 in TIR) spectral bands. The TIR spectral wavebands will be positioned based on their importance in various applications. This study aimed to find HyspIRI optimal TIR wavebands position for earth compositional mapping. Genetic algorithms coupled with Spectral Angle Mapper (GA-SAM) were used as spectral bands selector. High dimensional HyTES (Hyperspectral Thermal Emission Spectrometer) data comprised of 256 spectral bands of Cuprite and Death Valley regions were used to select meaningful subsets of bands for earth compositional mapping. The GA-SAM was trained for eight mineral classes and the algorithms were run iteratively 40 times. High calibration (> 98 %) and validation (> 96 %) accuracies were achieved with limited numbers (seven) of spectral bands selected by GA-SAM. Knowing the important band positions will help scientist of HyspIRI group to place spectral bands at regions were accuracies of earth compositional mapping can be enhanced.

  4. Inhibition of caspases prevents ototoxic and ongoing hair cell death

    NASA Technical Reports Server (NTRS)

    Matsui, Jonathan I.; Ogilvie, Judith M.; Warchol, Mark E.

    2002-01-01

    Sensory hair cells die after acoustic trauma or ototoxic insults, but the signal transduction pathways that mediate hair cell death are not known. Here we identify several important signaling events that regulate the death of vestibular hair cells. Chick utricles were cultured in media supplemented with the ototoxic antibiotic neomycin and selected pharmacological agents that influence signaling molecules in cell death pathways. Hair cells that were treated with neomycin exhibited classically defined apoptotic morphologies such as condensed nuclei and fragmented DNA. Inhibition of protein synthesis (via treatment with cycloheximide) increased hair cell survival after treatment with neomycin, suggesting that hair cell death requires de novo protein synthesis. Finally, the inhibition of caspases promoted hair cell survival after neomycin treatment. Sensory hair cells in avian vestibular organs also undergo continual cell death and replacement throughout mature life. It is unclear whether the loss of hair cells stimulates the proliferation of supporting cells or whether the production of new cells triggers the death of hair cells. We examined the effects of caspase inhibition on spontaneous hair cell death in the chick utricle. Caspase inhibitors reduced the amount of ongoing hair cell death and ongoing supporting cell proliferation in a dose-dependent manner. In isolated sensory epithelia, however, caspase inhibitors did not affect supporting cell proliferation directly. Our data indicate that ongoing hair cell death stimulates supporting cell proliferation in the mature utricle.

  5. Inhibition of caspases prevents ototoxic and ongoing hair cell death

    NASA Technical Reports Server (NTRS)

    Matsui, Jonathan I.; Ogilvie, Judith M.; Warchol, Mark E.

    2002-01-01

    Sensory hair cells die after acoustic trauma or ototoxic insults, but the signal transduction pathways that mediate hair cell death are not known. Here we identify several important signaling events that regulate the death of vestibular hair cells. Chick utricles were cultured in media supplemented with the ototoxic antibiotic neomycin and selected pharmacological agents that influence signaling molecules in cell death pathways. Hair cells that were treated with neomycin exhibited classically defined apoptotic morphologies such as condensed nuclei and fragmented DNA. Inhibition of protein synthesis (via treatment with cycloheximide) increased hair cell survival after treatment with neomycin, suggesting that hair cell death requires de novo protein synthesis. Finally, the inhibition of caspases promoted hair cell survival after neomycin treatment. Sensory hair cells in avian vestibular organs also undergo continual cell death and replacement throughout mature life. It is unclear whether the loss of hair cells stimulates the proliferation of supporting cells or whether the production of new cells triggers the death of hair cells. We examined the effects of caspase inhibition on spontaneous hair cell death in the chick utricle. Caspase inhibitors reduced the amount of ongoing hair cell death and ongoing supporting cell proliferation in a dose-dependent manner. In isolated sensory epithelia, however, caspase inhibitors did not affect supporting cell proliferation directly. Our data indicate that ongoing hair cell death stimulates supporting cell proliferation in the mature utricle.

  6. Inhibition of caspases prevents ototoxic and ongoing hair cell death.

    PubMed

    Matsui, Jonathan I; Ogilvie, Judith M; Warchol, Mark E

    2002-02-15

    Sensory hair cells die after acoustic trauma or ototoxic insults, but the signal transduction pathways that mediate hair cell death are not known. Here we identify several important signaling events that regulate the death of vestibular hair cells. Chick utricles were cultured in media supplemented with the ototoxic antibiotic neomycin and selected pharmacological agents that influence signaling molecules in cell death pathways. Hair cells that were treated with neomycin exhibited classically defined apoptotic morphologies such as condensed nuclei and fragmented DNA. Inhibition of protein synthesis (via treatment with cycloheximide) increased hair cell survival after treatment with neomycin, suggesting that hair cell death requires de novo protein synthesis. Finally, the inhibition of caspases promoted hair cell survival after neomycin treatment. Sensory hair cells in avian vestibular organs also undergo continual cell death and replacement throughout mature life. It is unclear whether the loss of hair cells stimulates the proliferation of supporting cells or whether the production of new cells triggers the death of hair cells. We examined the effects of caspase inhibition on spontaneous hair cell death in the chick utricle. Caspase inhibitors reduced the amount of ongoing hair cell death and ongoing supporting cell proliferation in a dose-dependent manner. In isolated sensory epithelia, however, caspase inhibitors did not affect supporting cell proliferation directly. Our data indicate that ongoing hair cell death stimulates supporting cell proliferation in the mature utricle.

  7. The multigenic structure of the MHC locus contributes to positive selection efficiency: a role for MHC class II gene-specific restriction.

    PubMed

    Monteiro, Miguel Caetano; Couceiro, Sofia; Penha-Gonçalves, Carlos

    2005-12-01

    The study of T cell positive selection in the thymus has long been focused on the specificity of the MHC-TCR interactions, making use of genetically manipulated mice that display TCR specificities or selecting peptides of limited diversity. However, little is known on the role of the MHC molecules irrespective of the peptide specificity and the implications of MHC multigenic structure in thymic positive selection have not been addressed. Here, we investigated the effect of MHC class II genetic configuration on the positive selection efficiency of naturally generated pre-selection repertoires in the mouse thymus. Analysis of positively selected thymocyte populations in MHC-congenic and -transgenic mice revealed that expression of I-E molecule in the thymic cortex increases positive selection efficiency of CD4 cells by approximately 50%. We show that increments in positive selection attributable to either the I-A and I-E genes are not due to increased MHC class II expression in the thymic cortex and are not affected by the number of MHC alleles. Collectively, our findings imply that MHC class II gene-restricted TCR specificities significantly contribute to positive selection efficiency, introducing the notion that multigenic structure of the MHC locus serves to increase selection of non-overlapping TCR repertoires.

  8. Antipsychotic drug-like effects of the selective M4 muscarinic acetylcholine receptor positive allosteric modulator VU0152100.

    PubMed

    Byun, Nellie E; Grannan, Michael; Bubser, Michael; Barry, Robert L; Thompson, Analisa; Rosanelli, John; Gowrishankar, Raajaram; Kelm, Nathaniel D; Damon, Stephen; Bridges, Thomas M; Melancon, Bruce J; Tarr, James C; Brogan, John T; Avison, Malcolm J; Deutch, Ariel Y; Wess, Jürgen; Wood, Michael R; Lindsley, Craig W; Gore, John C; Conn, P Jeffrey; Jones, Carrie K

    2014-06-01

    Accumulating evidence suggests that selective M4 muscarinic acetylcholine receptor (mAChR) activators may offer a novel strategy for the treatment of psychosis. However, previous efforts to develop selective M4 activators were unsuccessful because of the lack of M4 mAChR subtype specificity and off-target muscarinic adverse effects. We recently developed VU0152100, a highly selective M4 positive allosteric modulator (PAM) that exerts central effects after systemic administration. We now report that VU0152100 dose-dependently reverses amphetamine-induced hyperlocomotion in rats and wild-type mice, but not in M4 KO mice. VU0152100 also blocks amphetamine-induced disruption of the acquisition of contextual fear conditioning and prepulse inhibition of the acoustic startle reflex. These effects were observed at doses that do not produce catalepsy or peripheral adverse effects associated with non-selective mAChR agonists. To further understand the effects of selective potentiation of M4 on region-specific brain activation, VU0152100 alone and in combination with amphetamine were evaluated using pharmacologic magnetic resonance imaging (phMRI). Key neural substrates of M4-mediated modulation of the amphetamine response included the nucleus accumbens (NAS), caudate-putamen (CP), hippocampus, and medial thalamus. Functional connectivity analysis of phMRI data, specifically assessing correlations in activation between regions, revealed several brain networks involved in the M4 modulation of amphetamine-induced brain activation, including the NAS and retrosplenial cortex with motor cortex, hippocampus, and medial thalamus. Using in vivo microdialysis, we found that VU0152100 reversed amphetamine-induced increases in extracellular dopamine levels in NAS and CP. The present data are consistent with an antipsychotic drug-like profile of activity for VU0152100. Taken together, these data support the development of selective M4 PAMs as a new approach to the treatment of psychosis

  9. Antipsychotic Drug-Like Effects of the Selective M4 Muscarinic Acetylcholine Receptor Positive Allosteric Modulator VU0152100

    PubMed Central

    Byun, Nellie E; Grannan, Michael; Bubser, Michael; Barry, Robert L; Thompson, Analisa; Rosanelli, John; Gowrishankar, Raajaram; Kelm, Nathaniel D; Damon, Stephen; Bridges, Thomas M; Melancon, Bruce J; Tarr, James C; Brogan, John T; Avison, Malcolm J; Deutch, Ariel Y; Wess, Jürgen; Wood, Michael R; Lindsley, Craig W; Gore, John C; Conn, P Jeffrey; Jones, Carrie K

    2014-01-01

    Accumulating evidence suggests that selective M4 muscarinic acetylcholine receptor (mAChR) activators may offer a novel strategy for the treatment of psychosis. However, previous efforts to develop selective M4 activators were unsuccessful because of the lack of M4 mAChR subtype specificity and off-target muscarinic adverse effects. We recently developed VU0152100, a highly selective M4 positive allosteric modulator (PAM) that exerts central effects after systemic administration. We now report that VU0152100 dose-dependently reverses amphetamine-induced hyperlocomotion in rats and wild-type mice, but not in M4 KO mice. VU0152100 also blocks amphetamine-induced disruption of the acquisition of contextual fear conditioning and prepulse inhibition of the acoustic startle reflex. These effects were observed at doses that do not produce catalepsy or peripheral adverse effects associated with non-selective mAChR agonists. To further understand the effects of selective potentiation of M4 on region-specific brain activation, VU0152100 alone and in combination with amphetamine were evaluated using pharmacologic magnetic resonance imaging (phMRI). Key neural substrates of M4-mediated modulation of the amphetamine response included the nucleus accumbens (NAS), caudate-putamen (CP), hippocampus, and medial thalamus. Functional connectivity analysis of phMRI data, specifically assessing correlations in activation between regions, revealed several brain networks involved in the M4 modulation of amphetamine-induced brain activation, including the NAS and retrosplenial cortex with motor cortex, hippocampus, and medial thalamus. Using in vivo microdialysis, we found that VU0152100 reversed amphetamine-induced increases in extracellular dopamine levels in NAS and CP. The present data are consistent with an antipsychotic drug-like profile of activity for VU0152100. Taken together, these data support the development of selective M4 PAMs as a new approach to the treatment of psychosis

  10. Genomic resources and their influence on the detection of the signal of positive selection in genome scans.

    PubMed

    Manel, S; Perrier, C; Pratlong, M; Abi-Rached, L; Paganini, J; Pontarotti, P; Aurelle, D

    2016-01-01

    Genome scans represent powerful approaches to investigate the action of natural selection on the genetic variation of natural populations and to better understand local adaptation. This is very useful, for example, in the field of conservation biology and evolutionary biology. Thanks to Next Generation Sequencing, genomic resources are growing exponentially, improving genome scan analyses in non-model species. Thousands of SNPs called using Reduced Representation Sequencing are increasingly used in genome scans. Besides, genome sequences are also becoming increasingly available, allowing better processing of short-read data, offering physical localization of variants, and improving haplotype reconstruction and data imputation. Ultimately, genome sequences are also becoming the raw material for selection inferences. Here, we discuss how the increasing availability of such genomic resources, notably genome sequences, influences the detection of signals of selection. Mainly, increasing data density and having the information of physical linkage data expand genome scans by (i) improving the overall quality of the data, (ii) helping the reconstruction of demographic history for the population studied to decrease false-positive rates and (iii) improving the statistical power of methods to detect the signal of selection. Of particular importance, the availability of a high-quality reference genome can improve the detection of the signal of selection by (i) allowing matching the potential candidate loci to linked coding regions under selection, (ii) rapidly moving the investigation to the gene and function and (iii) ensuring that the highly variable regions of the genomes that include functional genes are also investigated. For all those reasons, using reference genomes in genome scan analyses is highly recommended. © 2015 John Wiley & Sons Ltd.

  11. Positive Darwinian Selection in the Piston That Powers Proton Pumps in Complex I of the Mitochondria of Pacific Salmon

    PubMed Central

    Garvin, Michael R.; Bielawski, Joseph P.; Gharrett, Anthony J.

    2011-01-01

    The mechanism of oxidative phosphorylation is well understood, but evolution of the proteins involved is not. We combined phylogenetic, genomic, and structural biology analyses to examine the evolution of twelve mitochondrial encoded proteins of closely related, yet phenotypically diverse, Pacific salmon. Two separate analyses identified the same seven positively selected sites in ND5. A strong signal was also detected at three sites of ND2. An energetic coupling analysis revealed several structures in the ND5 protein that may have co-evolved with the selected sites. These data implicate Complex I, specifically the piston arm of ND5 where it connects the proton pumps, as important in the evolution of Pacific salmon. Lastly, the lineage to Chinook experienced rapid evolution at the piston arm. PMID:21969854

  12. Sexual selection explains sex-specific growth plasticity and positive allometry for sexual size dimorphism in a reef fish

    PubMed Central

    Walker, Stefan P. W.; McCormick, Mark I.

    2009-01-01

    In 1950, Rensch noted that in clades where males are the larger sex, sexual size dimorphism (SSD) tends to be more pronounced in larger species. This fundamental allometric relationship is now known as ‘Rensch's rule’. While most researchers attribute Rensch's rule to sexual selection for male size, experimental evidence is lacking. Here, we suggest that ultimate hypotheses for Rensch's rule should also apply to groups of individuals and that individual trait plasticity can be used to test those hypotheses experimentally. Specifically, we show that in the sex-changing fish Parapercis cylindrica, larger males have larger harems with larger females, and that SSD increases with harem size. Thus, sexual selection for male body size is the ultimate cause of sexual size allometry. In addition, we experimentally illustrate a positive relationship between polygyny potential and individual growth rate during sex change from female to male. Thus, sexual selection is the ultimate cause of variation in growth rate, and variation in growth rate is the proximate cause of sexual size allometry. Taken together, our results provide compelling evidence in support of the sexual selection hypothesis for Rensch's rule and highlight the potential importance of individual growth modification in the shaping of morphological patterns in Nature. PMID:19553253

  13. Positive selection of Kranz and non-Kranz C4 phosphoenolpyruvate carboxylase amino acids in Suaedoideae (Chenopodiaceae).

    PubMed

    Rosnow, Josh J; Edwards, Gerald E; Roalson, Eric H

    2014-07-01

    In subfamily Suaedoideae, four independent gains of C4 photosynthesis are proposed, which includes two parallel origins of Kranz anatomy (sections Salsina and Schoberia) and two independent origins of single-cell C4 anatomy (Bienertia and Suaeda aralocaspica). Additional phylogenetic support for this hypothesis was generated from sequence data of the C-terminal portion of the phosphoenolpyruvate carboxylase (PEPC) gene used in C4 photosynthesis (ppc-1) in combination with previous sequence data. ppc-1 sequence was generated for 20 species in Suaedoideae and two outgroup Salsola species that included all types of C4 anatomies as well as two types of C3 anatomies. A branch-site test for positively selected codons was performed using the software package PAML. From labelling of the four branches where C4 is hypothesized to have developed (foreground branches), residue 733 (maize numbering) was identified to be under positive selection with a posterior probability >0.99 and residue 868 at the >0.95 interval using Bayes empirical Bayes (BEB). When labelling all the branches within C4 clades, the branch-site test identified 13 codons to be under selection with a posterior probability >0.95 by BEB; this is discussed considering current information on functional residues. The signature C4 substitution of an alanine for a serine at position 780 in the C-terminal end (which is considered a major determinant of affinity for PEP) was only found in four of the C4 species sampled, while eight of the C4 species and all the C3 species have an alanine residue; indicating that this substitution is not a requirement for C4 function.

  14. Positive selection of Kranz and non-Kranz C4 phosphoenolpyruvate carboxylase amino acids in Suaedoideae (Chenopodiaceae)

    PubMed Central

    Rosnow, Josh J.; Edwards, Gerald E.; Roalson, Eric H.

    2014-01-01

    In subfamily Suaedoideae, four independent gains of C4 photosynthesis are proposed, which includes two parallel origins of Kranz anatomy (sections Salsina and Schoberia) and two independent origins of single-cell C4 anatomy (Bienertia and Suaeda aralocaspica). Additional phylogenetic support for this hypothesis was generated from sequence data of the C-terminal portion of the phosphoenolpyruvate carboxylase (PEPC) gene used in C4 photosynthesis (ppc-1) in combination with previous sequence data. ppc-1 sequence was generated for 20 species in Suaedoideae and two outgroup Salsola species that included all types of C4 anatomies as well as two types of C3 anatomies. A branch-site test for positively selected codons was performed using the software package PAML. From labelling of the four branches where C4 is hypothesized to have developed (foreground branches), residue 733 (maize numbering) was identified to be under positive selection with a posterior probability >0.99 and residue 868 at the >0.95 interval using Bayes empirical Bayes (BEB). When labelling all the branches within C4 clades, the branch-site test identified 13 codons to be under selection with a posterior probability >0.95 by BEB; this is discussed considering current information on functional residues. The signature C4 substitution of an alanine for a serine at position 780 in the C-terminal end (which is considered a major determinant of affinity for PEP) was only found in four of the C4 species sampled, while eight of the C4 species and all the C3 species have an alanine residue; indicating that this substitution is not a requirement for C4 function. PMID:24600021

  15. Coevolution of positively selected IZUMO1 and CD9 in rodents: evidence of interaction between gamete fusion proteins?

    PubMed

    Vicens, Alberto; Roldan, Eduardo R S

    2014-05-01

    Proteins involved in sexual reproduction are known to evolve rapidly, often as the result of positive Darwinian selection, although the selective forces driving such adaptive changes are poorly understood. A process of coevolution between proteins in male and female gametes may promote rapid divergence of fertilization proteins. In the mouse, only two proteins have been shown so far to be essential for sperm-egg fusion, IZUMO1 in the sperm cell and CD9 in the egg. The role of these proteins has not been fully elucidated, and it has been suggested that they may act as fusogens, interacting in trans with proteins on the other cell, or regulators of fusogens through cis interactions. Here we analyze the evolution of IZUMO1 and CD9 in a group of rodent species. To assess possible protein interactions between IZUMO1 and CD9, we examined potential coevolution based on analyses of correlated evolutionary rates. We found evidence that both proteins evolve adaptively, with a more intense signal of positive selection in IZUMO1. In addition, our findings suggest that these proteins may have some form of interaction, although they have not been regarded as fusogens interacting directly with each other. The adaptive divergence of IZUMO1 and CD9 could influence reproductive compatibility, and, thus, these proteins may participate in the establishment of specific sperm-egg recognition systems. Further studies are required to uncover the role of IZUMO1 and CD9 during gamete fusion in order to understand the molecular basis of their coevolution, as other selective forces could also lead to general signatures of coevolution. © 2014 by the Society for the Study of Reproduction, Inc.