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Sample records for phenotype

  1. Novel phenotypes of prediabetes?

    PubMed

    Häring, Hans-Ulrich

    2016-09-01

    This article describes phenotypes observed in a prediabetic population (i.e. a population with increased risk for type 2 diabetes) from data collected at the University hospital of Tübingen. We discuss the impact of genetic variation on insulin secretion, in particular the effect on compensatory hypersecretion, and the incretin-resistant phenotype of carriers of the gene variant TCF7L2 is described. Imaging studies used to characterise subphenotypes of fat distribution, metabolically healthy obesity and metabolically unhealthy obesity are described. Also discussed are ectopic fat stores in liver and pancreas that determine the phenotype of metabolically healthy and unhealthy fatty liver and the recently recognised phenotype of fatty pancreas. The metabolic impact of perivascular adipose tissue and pancreatic fat is discussed. The role of hepatokines, particularly that of fetuin-A, in the crosstalk between these organs is described. Finally, the role of brain insulin resistance in the development of the different prediabetes phenotypes is discussed. PMID:27344314

  2. Phenotypic switching in bacteria

    NASA Astrophysics Data System (ADS)

    Merrin, Jack

    Living matter is a non-equilibrium system in which many components work in parallel to perpetuate themselves through a fluctuating environment. Physiological states or functionalities revealed by a particular environment are called phenotypes. Transitions between phenotypes may occur either spontaneously or via interaction with the environment. Even in the same environment, genetically identical bacteria can exhibit different phenotypes of a continuous or discrete nature. In this thesis, we pursued three lines of investigation into discrete phenotypic heterogeneity in bacterial populations: the quantitative characterization of the so-called bacterial persistence, a theoretical model of phenotypic switching based on those measurements, and the design of artificial genetic networks which implement this model. Persistence is the phenotype of a subpopulation of bacteria with a reduced sensitivity to antibiotics. We developed a microfluidic apparatus, which allowed us to monitor the growth rates of individual cells while applying repeated cycles of antibiotic treatments. We were able to identify distinct phenotypes (normal and persistent) and characterize the stochastic transitions between them. We also found that phenotypic heterogeneity was present prior to any environmental cue such as antibiotic exposure. Motivated by the experiments with persisters, we formulated a theoretical model describing the dynamic behavior of several discrete phenotypes in a periodically varying environment. This theoretical framework allowed us to quantitatively predict the fitness of dynamic populations and to compare survival strategies according to environmental time-symmetries. These calculations suggested that persistence is a strategy used by bacterial populations to adapt to fluctuating environments. Knowledge of the phenotypic transition rates for persistence may provide statistical information about the typical environments of bacteria. We also describe a design of artificial

  3. Macrophage phenotypes in atherosclerosis.

    PubMed

    Colin, Sophie; Chinetti-Gbaguidi, Giulia; Staels, Bart

    2014-11-01

    Initiation and progression of atherosclerosis depend on local inflammation and accumulation of lipids in the vascular wall. Although many cells are involved in the development and progression of atherosclerosis, macrophages are fundamental contributors. For nearly a decade, the phenotypic heterogeneity and plasticity of macrophages has been studied. In atherosclerotic lesions, macrophages are submitted to a large variety of micro-environmental signals, such as oxidized lipids and cytokines, which influence the phenotypic polarization and activation of macrophages resulting in a dynamic plasticity. The macrophage phenotype spectrum is characterized, at the extremes, by the classical M1 macrophages induced by T-helper 1 (Th-1) cytokines and by the alternative M2 macrophages induced by Th-2 cytokines. M2 macrophages can be further classified into M2a, M2b, M2c, and M2d subtypes. More recently, additional plaque-specific macrophage phenotypes have been identified, termed as Mox, Mhem, and M4. Understanding the mechanisms and functional consequences of the phenotypic heterogeneity of macrophages will contribute to determine their potential role in lesion development and plaque stability. Furthermore, research on macrophage plasticity could lead to novel therapeutic approaches to counteract cardiovascular diseases such as atherosclerosis. The present review summarizes our current knowledge on macrophage subsets in atherosclerotic plaques and mechanism behind the modulation of the macrophage phenotype. PMID:25319333

  4. Genetic resources for phenotyping

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Phenotyping of structured populations, along with molecular genotyping, will be essential for marker development in peanut. This research is essential for making the peanut genome sequence and genomic tools useful to breeders because it makes the connection between genes, gene markers, genetic maps...

  5. Down Syndrome: Cognitive Phenotype

    ERIC Educational Resources Information Center

    Silverman, Wayne

    2007-01-01

    Down syndrome is the most prevalent cause of intellectual impairment associated with a genetic anomaly, in this case, trisomy of chromosome 21. It affects both physical and cognitive development and produces a characteristic phenotype, although affected individuals vary considerably with respect to severity of specific impairments. Studies…

  6. Bioimaging for quantitative phenotype analysis.

    PubMed

    Chen, Weiyang; Xia, Xian; Huang, Yi; Chen, Xingwei; Han, Jing-Dong J

    2016-06-01

    With the development of bio-imaging techniques, an increasing number of studies apply these techniques to generate a myriad of image data. Its applications range from quantification of cellular, tissue, organismal and behavioral phenotypes of model organisms, to human facial phenotypes. The bio-imaging approaches to automatically detect, quantify, and profile phenotypic changes related to specific biological questions open new doors to studying phenotype-genotype associations and to precisely evaluating molecular changes associated with quantitative phenotypes. Here, we review major applications of bioimage-based quantitative phenotype analysis. Specifically, we describe the biological questions and experimental needs addressable by these analyses, computational techniques and tools that are available in these contexts, and the new perspectives on phenotype-genotype association uncovered by such analyses. PMID:26850283

  7. EHR Big Data Deep Phenotyping

    PubMed Central

    Lenert, L.; Lopez-Campos, G.

    2014-01-01

    Summary Objectives Given the quickening speed of discovery of variant disease drivers from combined patient genotype and phenotype data, the objective is to provide methodology using big data technology to support the definition of deep phenotypes in medical records. Methods As the vast stores of genomic information increase with next generation sequencing, the importance of deep phenotyping increases. The growth of genomic data and adoption of Electronic Health Records (EHR) in medicine provides a unique opportunity to integrate phenotype and genotype data into medical records. The method by which collections of clinical findings and other health related data are leveraged to form meaningful phenotypes is an active area of research. Longitudinal data stored in EHRs provide a wealth of information that can be used to construct phenotypes of patients. We focus on a practical problem around data integration for deep phenotype identification within EHR data. The use of big data approaches are described that enable scalable markup of EHR events that can be used for semantic and temporal similarity analysis to support the identification of phenotype and genotype relationships. Conclusions Stead and colleagues’ 2005 concept of using light standards to increase the productivity of software systems by riding on the wave of hardware/processing power is described as a harbinger for designing future healthcare systems. The big data solution, using flexible markup, provides a route to improved utilization of processing power for organizing patient records in genotype and phenotype research. PMID:25123744

  8. Pseudomonas Aeruginosa Resistance Phenotypes and Phenotypic Highlighting Methods

    PubMed Central

    BĂLĂŞOIU, MARIA; BĂLĂŞOIU, A.T.; MĂNESCU, RODICA; AVRAMESCU, CARMEN; IONETE, OANA

    2014-01-01

    Pseudomonas aeruginosa genus bacteria are well known for their increased drug resistance (phenotypic ang genotypic resistance). The most important resistance mechanisms are: enzyme production, reduction of pore expression, reduction of the external membrane proteins expression, efflux systems, topoisomerase mutations. These mechanisms often accumulate and lead to multidrug ressitance strains emergence. The most frequent acquired resistance mechanisms are betalactamase-type enzyme production (ESBLs, AmpC, carbapenemases), which determine variable phenotypes of betalactamines resistance, phenotypes which are associated with aminoglycosides and quinolones resistance. The nonenzymatic drug resistance mechanisms are caused by efflux systems, pore reduction and penicillin-binding proteins (PBP) modification, which are often associated to other resistance mechanisms. Phenotypic methods used for testing these mechanisms are based on highlighting these phenotypes using Kirby Bauer antibiogram, clinical breakpoints, and “cut off” values recommended by EUCAST 2013 standard, version 3.1. PMID:25729587

  9. Emerging molecular phenotypes of asthma.

    PubMed

    Ray, Anuradha; Oriss, Timothy B; Wenzel, Sally E

    2015-01-15

    Although asthma has long been considered a heterogeneous disease, attempts to define subgroups of asthma have been limited. In recent years, both clinical and statistical approaches have been utilized to better merge clinical characteristics, biology, and genetics. These combined characteristics have been used to define phenotypes of asthma, the observable characteristics of a patient determined by the interaction of genes and environment. Identification of consistent clinical phenotypes has now been reported across studies. Now the addition of various 'omics and identification of specific molecular pathways have moved the concept of clinical phenotypes toward the concept of molecular phenotypes. The importance of these molecular phenotypes is being confirmed through the integration of molecularly targeted biological therapies. Thus the global term asthma is poised to become obsolete, being replaced by terms that more specifically identify the pathology associated with the disease. PMID:25326577

  10. Plant Phenotype Characterization System

    SciTech Connect

    Daniel W McDonald; Ronald B Michaels

    2005-09-09

    This report is the final scientific report for the DOE Inventions and Innovations Project: Plant Phenotype Characterization System, DE-FG36-04GO14334. The period of performance was September 30, 2004 through July 15, 2005. The project objective is to demonstrate the viability of a new scientific instrument concept for the study of plant root systems. The root systems of plants are thought to be important in plant yield and thus important to DOE goals in renewable energy sources. The scientific study and understanding of plant root systems is hampered by the difficulty in observing root activity and the inadequacy of existing root study instrumentation options. We have demonstrated a high throughput, non-invasive, high resolution technique for visualizing plant root systems in-situ. Our approach is based upon low-energy x-ray radiography and the use of containers and substrates (artificial soil) which are virtually transparent to x-rays. The system allows us to germinate and grow plant specimens in our containers and substrates and to generate x-ray images of the developing root system over time. The same plant can be imaged at different times in its development. The system can be used for root studies in plant physiology, plant morphology, plant breeding, plant functional genomics and plant genotype screening.

  11. Citrullinemia: phenotypic variations.

    PubMed

    Whelan, D T; Brusso, T; Spate, M

    1976-06-01

    An 18-month-old female infant was found to have citrullinemia on routine plasma screening by the Scriver Method at 5 days of age. At 10 days of age, plasma citrulline concentration was 0.704mumol/ml (normal, 0.010 to 0.030mumol/ml) and has remained 60 to 80 times higher than normal. Urine citrulline concentration was markedly elevated. Hyperammonemia occurred at 1 month of age. The serum ammonia concentration was 473mug/100 ml (normal, 50 to 250 mug/100 ml) and rose to 770mug/100 ml at 4 months of age. Dietary protein was restricted to 1.6 gm/kg/day. Without further change in protein intake, the serum ammonia concentration decreased to 280mug/100 ml and, since then, it has returned to normal. The addition of three synthetic L-amino acids was required for a short time during dietary therapy. At 10 months of age, the infant was given a normal diet. At 18 months of age, her physical and mental development is normal. Activity of argininosuccinic acid synthetase measured in skin fibroblasts was 0.0037mumol of radioactive carbon dioxide per milligram of protein per hour. To demonstrate heterozygosity, fasting plasma citrulline concentrations were measured in five members of the family. Comparison of findings in this patient with those reported in the literature suggests phenotypical variation of the disease, probably due to genetic heterogeneity. PMID:934749

  12. Phenotypic mapping and clinical ideology

    SciTech Connect

    Lurie, I.W.; Opitz, J.M.

    1995-07-17

    Scientists have been trying to determine whether the main clinical findings in the 4p deletion syndrome are due to a deletion of one small critical segment, or whether deletions of some particular segments of 4p are responsible for different phenotypic manifestations. This is the basic issue for the whole group of autosomal deletion syndromes, as well as for our understanding of mechanisms of the origin of the abnormal phenotype. All circumstances need to be taken into consideration when trying to apply molecular methods for the mapping of phenotypic findings in the 4p deletion or in any other autosomal deletion syndrome. 8 refs.

  13. Capturing phenotypes for precision medicine.

    PubMed

    Robinson, Peter N; Mungall, Christopher J; Haendel, Melissa

    2015-10-01

    Deep phenotyping followed by integrated computational analysis of genotype and phenotype is becoming ever more important for many areas of genomic diagnostics and translational research. The overwhelming majority of clinical descriptions in the medical literature are available only as natural language text, meaning that searching, analysis, and integration of medically relevant information in databases such as PubMed is challenging. The new journal Cold Spring Harbor Molecular Case Studies will require authors to select Human Phenotype Ontology terms for research papers that will be displayed alongside the manuscript, thereby providing a foundation for ontology-based indexing and searching of articles that contain descriptions of phenotypic abnormalities-an important step toward improving the ability of researchers and clinicians to get biomedical information that is critical for clinical care or translational research. PMID:27148566

  14. Finding Our Way through Phenotypes

    PubMed Central

    Deans, Andrew R.; Lewis, Suzanna E.; Huala, Eva; Anzaldo, Salvatore S.; Ashburner, Michael; Balhoff, James P.; Blackburn, David C.; Blake, Judith A.; Burleigh, J. Gordon; Chanet, Bruno; Cooper, Laurel D.; Courtot, Mélanie; Csösz, Sándor; Cui, Hong; Dahdul, Wasila; Das, Sandip; Dececchi, T. Alexander; Dettai, Agnes; Diogo, Rui; Druzinsky, Robert E.; Dumontier, Michel; Franz, Nico M.; Friedrich, Frank; Gkoutos, George V.; Haendel, Melissa; Harmon, Luke J.; Hayamizu, Terry F.; He, Yongqun; Hines, Heather M.; Ibrahim, Nizar; Jackson, Laura M.; Jaiswal, Pankaj; James-Zorn, Christina; Köhler, Sebastian; Lecointre, Guillaume; Lapp, Hilmar; Lawrence, Carolyn J.; Le Novère, Nicolas; Lundberg, John G.; Macklin, James; Mast, Austin R.; Midford, Peter E.; Mikó, István; Mungall, Christopher J.; Oellrich, Anika; Osumi-Sutherland, David; Parkinson, Helen; Ramírez, Martín J.; Richter, Stefan; Robinson, Peter N.; Ruttenberg, Alan; Schulz, Katja S.; Segerdell, Erik; Seltmann, Katja C.; Sharkey, Michael J.; Smith, Aaron D.; Smith, Barry; Specht, Chelsea D.; Squires, R. Burke; Thacker, Robert W.; Thessen, Anne; Fernandez-Triana, Jose; Vihinen, Mauno; Vize, Peter D.; Vogt, Lars; Wall, Christine E.; Walls, Ramona L.; Westerfeld, Monte; Wharton, Robert A.; Wirkner, Christian S.; Woolley, James B.; Yoder, Matthew J.; Zorn, Aaron M.; Mabee, Paula

    2015-01-01

    Despite a large and multifaceted effort to understand the vast landscape of phenotypic data, their current form inhibits productive data analysis. The lack of a community-wide, consensus-based, human- and machine-interpretable language for describing phenotypes and their genomic and environmental contexts is perhaps the most pressing scientific bottleneck to integration across many key fields in biology, including genomics, systems biology, development, medicine, evolution, ecology, and systematics. Here we survey the current phenomics landscape, including data resources and handling, and the progress that has been made to accurately capture relevant data descriptions for phenotypes. We present an example of the kind of integration across domains that computable phenotypes would enable, and we call upon the broader biology community, publishers, and relevant funding agencies to support efforts to surmount today's data barriers and facilitate analytical reproducibility. PMID:25562316

  15. Epigenetics in heart failure phenotypes.

    PubMed

    Berezin, Alexander

    2016-12-01

    Chronic heart failure (HF) is a leading clinical and public problem posing a higher risk of morbidity and mortality in different populations. HF appears to be in both phenotypic forms: HF with reduced left ventricular ejection fraction (HFrEF) and HF with preserved left ventricular ejection fraction (HFpEF). Although both HF phenotypes can be distinguished through clinical features, co-morbidity status, prediction score, and treatment, the clinical outcomes in patients with HFrEF and HFpEF are similar. In this context, investigation of various molecular and cellular mechanisms leading to the development and progression of both HF phenotypes is very important. There is emerging evidence that epigenetic regulation may have a clue in the pathogenesis of HF. This review represents current available evidence regarding the implication of epigenetic modifications in the development of different HF phenotypes and perspectives of epigenetic-based therapies of HF. PMID:27335803

  16. Capturing phenotypes for precision medicine

    PubMed Central

    Robinson, Peter N.; Mungall, Christopher J.; Haendel, Melissa

    2015-01-01

    Deep phenotyping followed by integrated computational analysis of genotype and phenotype is becoming ever more important for many areas of genomic diagnostics and translational research. The overwhelming majority of clinical descriptions in the medical literature are available only as natural language text, meaning that searching, analysis, and integration of medically relevant information in databases such as PubMed is challenging. The new journal Cold Spring Harbor Molecular Case Studies will require authors to select Human Phenotype Ontology terms for research papers that will be displayed alongside the manuscript, thereby providing a foundation for ontology-based indexing and searching of articles that contain descriptions of phenotypic abnormalities—an important step toward improving the ability of researchers and clinicians to get biomedical information that is critical for clinical care or translational research. PMID:27148566

  17. Finding our way through phenotypes.

    PubMed

    Deans, Andrew R; Lewis, Suzanna E; Huala, Eva; Anzaldo, Salvatore S; Ashburner, Michael; Balhoff, James P; Blackburn, David C; Blake, Judith A; Burleigh, J Gordon; Chanet, Bruno; Cooper, Laurel D; Courtot, Mélanie; Csösz, Sándor; Cui, Hong; Dahdul, Wasila; Das, Sandip; Dececchi, T Alexander; Dettai, Agnes; Diogo, Rui; Druzinsky, Robert E; Dumontier, Michel; Franz, Nico M; Friedrich, Frank; Gkoutos, George V; Haendel, Melissa; Harmon, Luke J; Hayamizu, Terry F; He, Yongqun; Hines, Heather M; Ibrahim, Nizar; Jackson, Laura M; Jaiswal, Pankaj; James-Zorn, Christina; Köhler, Sebastian; Lecointre, Guillaume; Lapp, Hilmar; Lawrence, Carolyn J; Le Novère, Nicolas; Lundberg, John G; Macklin, James; Mast, Austin R; Midford, Peter E; Mikó, István; Mungall, Christopher J; Oellrich, Anika; Osumi-Sutherland, David; Parkinson, Helen; Ramírez, Martín J; Richter, Stefan; Robinson, Peter N; Ruttenberg, Alan; Schulz, Katja S; Segerdell, Erik; Seltmann, Katja C; Sharkey, Michael J; Smith, Aaron D; Smith, Barry; Specht, Chelsea D; Squires, R Burke; Thacker, Robert W; Thessen, Anne; Fernandez-Triana, Jose; Vihinen, Mauno; Vize, Peter D; Vogt, Lars; Wall, Christine E; Walls, Ramona L; Westerfeld, Monte; Wharton, Robert A; Wirkner, Christian S; Woolley, James B; Yoder, Matthew J; Zorn, Aaron M; Mabee, Paula

    2015-01-01

    Despite a large and multifaceted effort to understand the vast landscape of phenotypic data, their current form inhibits productive data analysis. The lack of a community-wide, consensus-based, human- and machine-interpretable language for describing phenotypes and their genomic and environmental contexts is perhaps the most pressing scientific bottleneck to integration across many key fields in biology, including genomics, systems biology, development, medicine, evolution, ecology, and systematics. Here we survey the current phenomics landscape, including data resources and handling, and the progress that has been made to accurately capture relevant data descriptions for phenotypes. We present an example of the kind of integration across domains that computable phenotypes would enable, and we call upon the broader biology community, publishers, and relevant funding agencies to support efforts to surmount today's data barriers and facilitate analytical reproducibility. PMID:25562316

  18. Phenotypic MicroRNA Microarrays

    PubMed Central

    Kwon, Yong-Jun; Heo, Jin Yeong; Kim, Hi Chul; Kim, Jin Yeop; Liuzzi, Michel; Soloveva, Veronica

    2013-01-01

    Microarray technology has become a very popular approach in cases where multiple experiments need to be conducted repeatedly or done with a variety of samples. In our lab, we are applying our high density spots microarray approach to microscopy visualization of the effects of transiently introduced siRNA or cDNA on cellular morphology or phenotype. In this publication, we are discussing the possibility of using this micro-scale high throughput process to study the role of microRNAs in the biology of selected cellular models. After reverse-transfection of microRNAs and siRNA, the cellular phenotype generated by microRNAs regulated NF-κB expression comparably to the siRNA. The ability to print microRNA molecules for reverse transfection into cells is opening up the wide horizon for the phenotypic high content screening of microRNA libraries using cellular disease models.

  19. Optofluidic Detection for Cellular Phenotyping

    PubMed Central

    Tung, Yi-Chung; Huang, Nien-Tsu; Oh, Bo-Ram; Patra, Bishnubrata; Pan, Chi-Chun; Qiu, Teng; Paul, K. Chu; Zhang, Wenjun; Kurabayashi, Katsuo

    2012-01-01

    Quantitative analysis of the output of processes and molecular interactions within a single cell is highly critical to the advancement of accurate disease screening and personalized medicine. Optical detection is one of the most broadly adapted measurement methods in biological and clinical assays and serves cellular phenotyping. Recently, microfluidics has obtained increasing attention due to several advantages, such as small sample and reagent volumes, very high throughput, and accurate flow control in the spatial and temporal domains. Optofluidics, which is the attempt to integrate optics with microfluidic, shows great promise to enable on-chip phenotypic measurements with high precision, sensitivity, specificity, and simplicity. This paper reviews the most recent developments of optofluidic technologies for cellular phenotyping optical detection. PMID:22854915

  20. Normocalcaemic pseudohypoparathyroidism with unusual phenotype.

    PubMed

    Gertner, J M; Tomlinson, S; Gonzalez-Macias, J

    1978-04-01

    We describe a boy who presented at 4 years of age with radiological hyperparathyroidism, osteosclerosis, and necrosis of the femoral heads. Plasma biochemistry was normal but the parathyroid hormone (PTH) level was very high. He was deaf and had an unusual facies but did not have the phenotype of Albright's hereditary osteodystrophy. Plasma and urine cyclic AMP reponses to bovine PTH were markedly subnormal. Vitamin D produced sustained hypercalcaemia and a fall in plasma phosphorus. After four hyperplastic parathyroid glands were removed he became hypocalcaemic and plasma phosphorus rose. After operation he remained unresponsive to exogenous PTH; We suggest that he had a form of pseudohypoparathyroidism without the phenotype of Albright's hereditary osteodystrophy and with some residual skeletal and renal responsiveness to PTH. PMID:646442

  1. Phenotypic deconstruction of gene circuitry

    NASA Astrophysics Data System (ADS)

    Lomnitz, Jason G.; Savageau, Michael A.

    2013-06-01

    It remains a challenge to obtain a global perspective on the behavioral repertoire of complex nonlinear gene circuits. In this paper, we describe a method for deconstructing complex systems into nonlinear sub-systems, based on mathematically defined phenotypes, which are then represented within a system design space that allows the repertoire of qualitatively distinct phenotypes of the complex system to be identified, enumerated, and analyzed. This method efficiently characterizes large regions of system design space and quickly generates alternative hypotheses for experimental testing. We describe the motivation and strategy in general terms, illustrate its use with a detailed example involving a two-gene circuit with a rich repertoire of dynamic behavior, and discuss experimental means of navigating the system design space.

  2. Statistical models for trisomic phenotypes

    SciTech Connect

    Lamb, N.E.; Sherman, S.L.; Feingold, E.

    1996-01-01

    Certain genetic disorders are rare in the general population but more common in individuals with specific trisomies, which suggests that the genes involved in the etiology of these disorders may be located on the trisomic chromosome. As with all aneuploid syndromes, however, a considerable degree of variation exists within each phenotype so that any given trait is present only among a subset of the trisomic population. We have previously presented a simple gene-dosage model to explain this phenotypic variation and developed a strategy to map genes for such traits. The mapping strategy does not depend on the simple model but works in theory under any model that predicts that affected individuals have an increased likelihood of disomic homozygosity at the trait locus. This paper explores the robustness of our mapping method by investigating what kinds of models give an expected increase in disomic homozygosity. We describe a number of basic statistical models for trisomic phenotypes. Some of these are logical extensions of standard models for disomic phenotypes, and some are more specific to trisomy. Where possible, we discuss genetic mechanisms applicable to each model. We investigate which models and which parameter values give an expected increase in disomic homozygosity in individuals with the trait. Finally, we determine the sample sizes required to identify the increased disomic homozygosity under each model. Most of the models we explore yield detectable increases in disomic homozygosity for some reasonable range of parameter values, usually corresponding to smaller trait frequencies. It therefore appears that our mapping method should be effective for a wide variety of moderately infrequent traits, even though the exact mode of inheritance is unlikely to be known. 21 refs., 8 figs., 1 tab.

  3. Phenotypic variation in LADD syndrome.

    PubMed Central

    Thompson, E; Pembrey, M; Graham, J M

    1985-01-01

    A mother and son are reported with chronic dacrocystitis, cup shaped ears, hearing loss, abnormal teeth, and poor formation of saliva and tears. They are similar to previously reported cases of lacrimo-auriculo-dento-digital (LADD) syndrome. The variability of expression of this autosomal dominant syndrome is discussed, and it is suggested that poor saliva and tear formation be added to the phenotype. Images PMID:4078868

  4. Wine Expertise Predicts Taste Phenotype

    PubMed Central

    Hayes, John E; Pickering, Gary J

    2011-01-01

    Taste phenotypes have long been studied in relation to alcohol intake, dependence, and family history, with contradictory findings. However, on balance – with appropriate caveats about populations tested, outcomes measured and psychophysical methods used – an association between variation in taste responsiveness and some alcohol behaviors is supported. Recent work suggests super-tasting (operationalized via propylthiouracil (PROP) bitterness) not only associates with heightened response but also with more acute discrimination between stimuli. Here, we explore relationships between food and beverage adventurousness and taste phenotype. A convenience sample of wine drinkers (n=330) were recruited in Ontario and phenotyped for PROP bitterness via filter paper disk. They also filled out a short questionnaire regarding willingness to try new foods, alcoholic beverages and wines as well as level of wine involvement, which was used to classify them as a wine expert (n=110) or wine consumer (n=220). In univariate logisitic models, food adventurousness predicted trying new wines and beverages but not expertise. Likewise, wine expertise predicted willingness to try new wines and beverages but not foods. In separate multivariate logistic models, willingness to try new wines and beverages was predicted by expertise and food adventurousness but not PROP. However, mean PROP bitterness was higher among wine experts than wine consumers, and the conditional distribution functions differed between experts and consumers. In contrast, PROP means and distributions did not differ with food adventurousness. These data suggest individuals may self-select for specific professions based on sensory ability (i.e., an active gene-environment correlation) but phenotype does not explain willingness to try new stimuli. PMID:22888174

  5. [Plasticity of the cellular phenotype].

    PubMed

    Chneiweiss, Hervé

    2011-01-01

    The tragical consequences of the Hiroshima and Nagasaki atomic bombs in 1945 were to lead to the discovery of hematopoietic stem cells and their phenotypic plasticity, in response to environmental factors. These concepts were much later extended to the founding cells of other tissues. In the following collection of articles, the mechanisms underlying this plasticity, at the frontiers of developmental biology and oncology, are illustrated in the case of various cell types of neural origin and of some tumours. PMID:21501574

  6. Adaptive evolution of molecular phenotypes

    NASA Astrophysics Data System (ADS)

    Held, Torsten; Nourmohammad, Armita; Lässig, Michael

    2014-09-01

    Molecular phenotypes link genomic information with organismic functions, fitness, and evolution. Quantitative traits are complex phenotypes that depend on multiple genomic loci. In this paper, we study the adaptive evolution of a quantitative trait under time-dependent selection, which arises from environmental changes or through fitness interactions with other co-evolving phenotypes. We analyze a model of trait evolution under mutations and genetic drift in a single-peak fitness seascape. The fitness peak performs a constrained random walk in the trait amplitude, which determines the time-dependent trait optimum in a given population. We derive analytical expressions for the distribution of the time-dependent trait divergence between populations and of the trait diversity within populations. Based on this solution, we develop a method to infer adaptive evolution of quantitative traits. Specifically, we show that the ratio of the average trait divergence and the diversity is a universal function of evolutionary time, which predicts the stabilizing strength and the driving rate of the fitness seascape. From an information-theoretic point of view, this function measures the macro-evolutionary entropy in a population ensemble, which determines the predictability of the evolutionary process. Our solution also quantifies two key characteristics of adapting populations: the cumulative fitness flux, which measures the total amount of adaptation, and the adaptive load, which is the fitness cost due to a population's lag behind the fitness peak.

  7. Multivariate Analysis of Genotype-Phenotype Association.

    PubMed

    Mitteroecker, Philipp; Cheverud, James M; Pavlicev, Mihaela

    2016-04-01

    With the advent of modern imaging and measurement technology, complex phenotypes are increasingly represented by large numbers of measurements, which may not bear biological meaning one by one. For such multivariate phenotypes, studying the pairwise associations between all measurements and all alleles is highly inefficient and prevents insight into the genetic pattern underlying the observed phenotypes. We present a new method for identifying patterns of allelic variation (genetic latent variables) that are maximally associated-in terms of effect size-with patterns of phenotypic variation (phenotypic latent variables). This multivariate genotype-phenotype mapping (MGP) separates phenotypic features under strong genetic control from less genetically determined features and thus permits an analysis of the multivariate structure of genotype-phenotype association, including its dimensionality and the clustering of genetic and phenotypic variables within this association. Different variants of MGP maximize different measures of genotype-phenotype association: genetic effect, genetic variance, or heritability. In an application to a mouse sample, scored for 353 SNPs and 11 phenotypic traits, the first dimension of genetic and phenotypic latent variables accounted for >70% of genetic variation present in all 11 measurements; 43% of variation in this phenotypic pattern was explained by the corresponding genetic latent variable. The first three dimensions together sufficed to account for almost 90% of genetic variation in the measurements and for all the interpretable genotype-phenotype association. Each dimension can be tested as a whole against the hypothesis of no association, thereby reducing the number of statistical tests from 7766 to 3-the maximal number of meaningful independent tests. Important alleles can be selected based on their effect size (additive or nonadditive effect on the phenotypic latent variable). This low dimensionality of the genotype-phenotype map

  8. Atypical Ligon Lintless-2 Phenotype in Cotton

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The mutant Li2 is reported to be a dominant single gene mutation in cotton, Gossypium hirsutum L. It has normal vegetative phenotypic morphology and the phenotype of the seed cotton is reported to be fuzzy seed with short fibers. The objective of this research was to report on atypical phenotypes ob...

  9. NIH Mouse Metabolic Phenotyping Centers: the power of centralized phenotyping.

    PubMed

    Laughlin, Maren R; Lloyd, K C Kent; Cline, Gary W; Wasserman, David H

    2012-10-01

    The Mouse Metabolic Phenotyping Centers (MMPCs) were founded in 2001 by the National Institutes of Health (NIH) to advance biomedical research by providing the scientific community with standardized, high-quality phenotyping services for mouse models of diabetes, obesity, and their complications. The intent is to allow researchers to take optimum advantage of the many new mouse models produced in labs and in high-throughput public efforts. The six MMPCs are located at universities around the country and perform complex metabolic tests in intact mice and hormone and analyte assays in tissues on a fee-for-service basis. Testing is subsidized by the NIH in order to reduce the barriers for mouse researchers. Although data derived from these tests belong to the researcher submitting mice or tissues, these data are archived after publication in a public database run by the MMPC Coordinating and Bioinformatics Unit. It is hoped that data from experiments performed in many mouse models of metabolic diseases, using standard protocols, will be useful in understanding the nature of these complex disorders. The current areas of expertise include energy balance and body composition, insulin action and secretion, whole-body and tissue carbohydrate and lipid metabolism, cardiovascular and renal function, and metabolic pathway kinetics. In addition to providing services, the MMPC staff provides expertise and advice to researchers, and works to develop and refine test protocols to best meet the community's needs in light of current scientific developments. Test technology is disseminated by publications and through annual courses. PMID:22940748

  10. Cholestatic phenotypes of autoimmune hepatitis.

    PubMed

    Czaja, Albert J

    2014-09-01

    Autoimmune hepatitis can have cholestatic features that are outside the codified diagnostic criteria. These features have uncertain effects on the clinical presentation and progression of disease. Patients with autoimmune hepatitis can have antimitochondrial antibodies and coincidental bile duct injury or loss (2%-13% of patients), focal biliary strictures and dilations based on cholangiography (2%-11%), or histologic changes of bile duct injury or loss in the absence of other features (5%-11%). These findings probably represent atypical manifestations of autoimmune hepatitis or variants of primary biliary cirrhosis or primary sclerosing cholangitis, depending on the predominant findings. Serum levels of alkaline phosphatase and γ-glutamyl transferase, histologic features of bile duct injury, and findings from cholangiography are associated with responsiveness to corticosteroid therapy and individualized alternative treatments. Corticosteroid therapy, in combination with low-dose ursodeoxycholic acid, has been promulgated by international societies, but these recommendations are not based on strong evidence. The frequency, variable outcomes, and uncertainties in diagnosis and management of the cholestatic phenotypes must be addressed by a collaborative investigational network. This network should define the genetic and pathologic features of these disorders, standardize their nomenclature, and establish a treatment algorithm. In this review, the different cholestatic phenotypes of autoimmune hepatitis, mechanisms of pathogenesis, current management strategies and outcomes, and opportunities for improving understanding and therapy are presented. PMID:24013108

  11. Phenotyping bananas for drought resistance

    PubMed Central

    Ravi, Iyyakkutty; Uma, Subbaraya; Vaganan, Muthu Mayil; Mustaffa, Mohamed M.

    2012-01-01

    Drought has emerged as one of the major constraints in banana production. Its effects are pronounced substantially in the tropics and sub-tropics of the world due to climate change. Bananas are quite sensitive to drought; however, genotypes with “B” genome are more tolerant to abiotic stresses than those solely based on “A” genome. In particular, bananas with “ABB” genomes are more tolerant to drought and other abiotic stresses than other genotypes. A good phenotyping plan is a prerequisite for any improvement program for targeted traits. In the present article, known drought tolerant traits of other crop plants are validated in bananas with different genomic backgrounds and presented. Since, banana is recalcitrant to breeding, strategies for making hybrids between different genomic backgrounds are also discussed. Stomatal conductance, cell membrane stability (CMS), leaf emergence rate, rate of leaf senescence, RWC, and bunch yield under soil moisture deficit stress are some of the traits associated with drought tolerance. Among these stress bunch yield under drought should be given top priority for phenotyping. In the light of recently released Musa genome draft sequence, the molecular breeders may have interest in developing molecular markers for drought resistance. PMID:23443573

  12. Phenotypic plasticity in bacterial plasmids.

    PubMed Central

    Turner, Paul E

    2004-01-01

    Plasmid pB15 was previously shown to evolve increased horizontal (infectious) transfer at the expense of reduced vertical (intergenerational) transfer and vice versa, a key trade-off assumed in theories of parasite virulence. Whereas the models predict that susceptible host abundance should determine which mode of transfer is selectively favored, host density failed to mediate the trade-off in pB15. One possibility is that the plasmid's transfer deviates from the assumption that horizontal spread (conjugation) occurs in direct proportion to cell density. I tested this hypothesis using Escherichia coli/pB15 associations in laboratory serial culture. Contrary to most models of plasmid transfer kinetics, my data show that pB15 invades static (nonshaking) bacterial cultures only at intermediate densities. The results can be explained by phenotypic plasticity in traits governing plasmid transfer. As cells become more numerous, the plasmid's conjugative transfer unexpectedly declines, while the trade-off between transmission routes causes vertical transfer to increase. Thus, at intermediate densities the plasmid's horizontal transfer can offset selection against plasmid-bearing cells, but at high densities pB15 conjugates so poorly that it cannot invade. I discuss adaptive vs. nonadaptive causes for the phenotypic plasticity, as well as potential mechanisms that may lead to complex transfer dynamics of plasmids in liquid environments. PMID:15166133

  13. Evolution of phenotypic plasticity in colonizing species.

    PubMed

    Lande, Russell

    2015-05-01

    I elaborate an hypothesis to explain inconsistent empirical findings comparing phenotypic plasticity in colonizing populations or species with plasticity from their native or ancestral range. Quantitative genetic theory on the evolution of plasticity reveals that colonization of a novel environment can cause a transient increase in plasticity: a rapid initial increase in plasticity accelerates evolution of a new optimal phenotype, followed by slow genetic assimilation of the new phenotype and reduction of plasticity. An association of colonization with increased plasticity depends on the difference in the optimal phenotype between ancestral and colonized environments, the difference in mean, variance and predictability of the environment, the cost of plasticity, and the time elapsed since colonization. The relative importance of these parameters depends on whether a phenotypic character develops by one-shot plasticity to a constant adult phenotype or by labile plasticity involving continuous and reversible development throughout adult life. PMID:25558898

  14. Evolving phenotypic networks in silico.

    PubMed

    François, Paul

    2014-11-01

    Evolved gene networks are constrained by natural selection. Their structures and functions are consequently far from being random, as exemplified by the multiple instances of parallel/convergent evolution. One can thus ask if features of actual gene networks can be recovered from evolutionary first principles. I review a method for in silico evolution of small models of gene networks aiming at performing predefined biological functions. I summarize the current implementation of the algorithm, insisting on the construction of a proper "fitness" function. I illustrate the approach on three examples: biochemical adaptation, ligand discrimination and vertebrate segmentation (somitogenesis). While the structure of the evolved networks is variable, dynamics of our evolved networks are usually constrained and present many similar features to actual gene networks, including properties that were not explicitly selected for. In silico evolution can thus be used to predict biological behaviours without a detailed knowledge of the mapping between genotype and phenotype. PMID:24956562

  15. Epithelial phenotype in total sclerocornea

    PubMed Central

    Yeh, Lung-Kun; Chen, Hung-Chi; Chang, Anna Marie; Ho, Yi-Ju; Chang, Shirley H.L.; Yang, Unique

    2014-01-01

    Purpose To understand whether the epithelial phenotype in total sclerocornea is corneal or conjunctival in origin. Methods Four cases of total sclerocornea (male:female = 1:3; mean age = 5.4±4.3; 1–11 years old) who received penetrating keratoplasty (PKP) at our hospital between 2008 and 2011 were included. Corneal buttons obtained during PKP were used for transmission electron microscopy (TEM) as well as immunoconfocal microscopy for cytokeratins 3, 12, and 13, goblet cell mucin MUC5AC, connexin 43, stem cell markers p63 and ABCG2, laminin-5, and fibronectin. Results After a mean follow-up period of 38.8±14.0 (12–54) months, the grafts remained clear in half of the patients. TEM examination revealed a markedly attenuated Bowman’s layer in the scleralized corneas, with irregular and variably thinned collagen lamellar layers, and disorganization and random distribution of collagen fibrils, which were much larger in diameter compared with a normal cornea. Immunoconfocal microscopy showed that keratin 3 was expressed in all four patients, while p63, ABCG2, and MUC5AC were all absent. Cornea-specific keratin 12 was universally expressed in Patients 1 to 3, while mucosa (including conjunctiva)-specific keratin 13 was negative in these patients. Interestingly, keratin 12 and 13 were expressed in Patient 4 in a mutually exclusive manner. Linear expression of laminin-5 in the basement membrane zone and similar expression of fibronectin were observed. Conclusions The epithelia in total sclerocornea are essentially corneal in phenotype, but in the event of massive corneal angiogenesis, invasion by the conjunctival epithelium is possible. PMID:24744607

  16. [Intermediate phenotype studies in psychiatric disorder].

    PubMed

    Hashimoto, Ryota

    2016-02-01

    The concept of intermediate phenotype was proposed by Dr. Weinberger of the National Institute of Mental Health (NIMH). The risk genes for mental disorders define intermediate phenotypes, neurobiological characteristics observed in psychiatric disorders, and intermediate phenotypes increase the risk of mental disorders. The author worked at Dr. Weinberger's laboratory, and after returning home, introduced the concept to Japan, creating a term "Chukanhyogengata" to translate "intermediate phenotype". Intermediate phenotype has been proposed as a tool for the identification of risk genes for mental disorders, spreading the concept as a biomarker for the bridging between genes and behaviors. Intermediate phenotype studies later became one of the main pillars of psychiatric research. As a large number of data and samples are needed for intermediate phenotype research, we built a research resource database that combines the brain phenotype and bioresources. We performed genome-wide association analysis of cognitive decline in schizophrenia and identified the DEGS2 gene using this sample. This research resource database was developed for a multicenter study by COCORO (Cognitive Genetics Collaborative Research Organization). COCORO carried out genome-wide association analysis of the gray matter volume of the superior temporal gyrus and identified genome-wide significant loci. In this paper, we introduce the concept and history of intermediate phenotype study of mental illness and the latest trends. We hope to contribute to the future development of mental illness research through translational research. PMID:27044135

  17. Latent phenotypes pervade gene regulatory circuits

    PubMed Central

    2014-01-01

    Background Latent phenotypes are non-adaptive byproducts of adaptive phenotypes. They exist in biological systems as different as promiscuous enzymes and genome-scale metabolic reaction networks, and can give rise to evolutionary adaptations and innovations. We know little about their prevalence in the gene expression phenotypes of regulatory circuits, important sources of evolutionary innovations. Results Here, we study a space of more than sixteen million three-gene model regulatory circuits, where each circuit is represented by a genotype, and has one or more functions embodied in one or more gene expression phenotypes. We find that the majority of circuits with single functions have latent expression phenotypes. Moreover, the set of circuits with a given spectrum of functions has a repertoire of latent phenotypes that is much larger than that of any one circuit. Most of this latent repertoire can be easily accessed through a series of small genetic changes that preserve a circuit’s main functions. Both circuits and gene expression phenotypes that are robust to genetic change are associated with a greater number of latent phenotypes. Conclusions Our observations suggest that latent phenotypes are pervasive in regulatory circuits, and may thus be an important source of evolutionary adaptations and innovations involving gene regulation. PMID:24884746

  18. Phenotypic heterogeneity of Streptococcus mutans in dentin.

    PubMed

    Rupf, S; Hannig, M; Breitung, K; Schellenberger, W; Eschrich, K; Remmerbach, T; Kneist, S

    2008-12-01

    Information concerning phenotypic heterogeneity of Streptococcus mutans in carious dentin is sparse. Matrix-assisted laser-desorption/ionization-time-of-flight mass-spectrometry (MALDI-TOF-MS) facilitates the phenotypic differentiation of bacteria to the subspecies level. To verify a supposed influence of restorative treatment on the phenotypic heterogeneity of S. mutans, we isolated and compared a total of 222 S. mutans strains from dentin samples of 21 human deciduous molars during caries excavation (T(1)) and 8 wks (T(2)) after removal of the temporary restoration. Phenotypic heterogeneity was determined by MALDI-TOF-MS and hierarchical clustering. Thirty-six distinct S. mutans phenotypes could be identified. Although indistinguishable phenotypes were found in the same teeth at T(1) and T(2), as well as in different teeth of individual participants, the phenotypic heterogeneity increased significantly, from 1.4 phenotypes per S. mutans-positive dentin sample at T(1) to 2.2 phenotypes at T(2). We attribute this to an adaptation of S. mutans to the modified environment under the restoration following caries excavation. PMID:19029088

  19. Power matters in closing the phenotyping gap

    NASA Astrophysics Data System (ADS)

    Meyer, Carola W.; Elvert, Ralf; Scherag, André; Ehrhardt, Nicole; Gailus-Durner, Valerie; Fuchs, Helmut; Schäfer, Helmut; Hrabé de Angelis, Martin; Heldmaier, Gerhard; Klingenspor, Martin

    2007-05-01

    Much of our understanding of physiology and metabolism is derived from investigating mouse mutants and transgenic mice, and open-access platforms for standardized mouse phenotyping such as the German Mouse Clinic (GMC) are currently viewed as one powerful tool for identifying novel gene-function relationships. Phenotyping or phenotypic screening involves the comparison of wild-type control mice with their mutant or transgenic littermates. In our study, we explored the extent to which standardized phenotyping will succeed in detecting biologically relevant phenotypic differences in mice generated and provided by different collaborators. We analyzed quantitative metabolic data (body mass, energy intake, and energy metabolized) collected at the GMC under the current workflow, and used them for statistical power considerations. Our results demonstrate that there is substantial variability in these parameters among lines of wild-type C57BL/6 (B6) mice from different sources. Given this variable background noise in mice that serve as controls, subtle phenotypes in mutant or transgenic littermates may be overlooked. Furthermore, a phenotype observed in one cohort of a mutant line may not be reproducible (to the same extent) in mice coming from a different environment or supplier. In the light of these constraints, we encourage researchers to incorporate information on intrastrain variability into future study planning, or to perform advanced hierarchical analyses. Both will ultimately improve the detectability of novel phenotypes by phenotypic screening.

  20. Daddy issues: paternal effects on phenotype.

    PubMed

    Rando, Oliver J

    2012-11-01

    The once popular and then heretical idea that ancestral environment can affect the phenotype of future generations is coming back into vogue due to advances in the field of epigenetic inheritance. How paternal environmental conditions influence the phenotype of progeny is now a tractable question, and researchers are exploring potential mechanisms underlying such effects. PMID:23141533

  1. Distribution of phenotypes among Bacillus thuringiensis strains

    Technology Transfer Automated Retrieval System (TEKTRAN)

    An extensive collection of Bacillus thuringiensis isolates from around the world were phenotypically profiled using standard biochemical tests. Six phenotypic traits occurred in 20-86% of the isolates and were useful in distinguishing isolates: production of urease (U; 20.5% of isolates), hydrolysis...

  2. Emerging semantics to link phenotype and environment

    PubMed Central

    Bunker, Daniel E.; Buttigieg, Pier Luigi; Cooper, Laurel D.; Dahdul, Wasila M.; Domisch, Sami; Franz, Nico M.; Jaiswal, Pankaj; Lawrence-Dill, Carolyn J.; Midford, Peter E.; Mungall, Christopher J.; Ramírez, Martín J.; Specht, Chelsea D.; Vogt, Lars; Vos, Rutger Aldo; Walls, Ramona L.; White, Jeffrey W.; Zhang, Guanyang; Deans, Andrew R.; Huala, Eva; Lewis, Suzanna E.; Mabee, Paula M.

    2015-01-01

    Understanding the interplay between environmental conditions and phenotypes is a fundamental goal of biology. Unfortunately, data that include observations on phenotype and environment are highly heterogeneous and thus difficult to find and integrate. One approach that is likely to improve the status quo involves the use of ontologies to standardize and link data about phenotypes and environments. Specifying and linking data through ontologies will allow researchers to increase the scope and flexibility of large-scale analyses aided by modern computing methods. Investments in this area would advance diverse fields such as ecology, phylogenetics, and conservation biology. While several biological ontologies are well-developed, using them to link phenotypes and environments is rare because of gaps in ontological coverage and limits to interoperability among ontologies and disciplines. In this manuscript, we present (1) use cases from diverse disciplines to illustrate questions that could be answered more efficiently using a robust linkage between phenotypes and environments, (2) two proof-of-concept analyses that show the value of linking phenotypes to environments in fishes and amphibians, and (3) two proposed example data models for linking phenotypes and environments using the extensible observation ontology (OBOE) and the Biological Collections Ontology (BCO); these provide a starting point for the development of a data model linking phenotypes and environments. PMID:26713234

  3. The Neuroanatomy of the Autistic Phenotype

    ERIC Educational Resources Information Center

    Fahim, Cherine; Meguid, Nagwa A.; Nashaat, Neveen H.; Yoon, Uicheul; Mancini-Marie, Adham; Evans, Alan C.

    2012-01-01

    The autism phenotype is associated with an excess of brain volume due in part to decreased pruning during development. Here we aimed at assessing brain volume early in development to further elucidate previous findings in autism and determine whether this pattern is restricted to idiopathic autism or shared within the autistic phenotype (fragile X…

  4. Emerging semantics to link phenotype and environment

    SciTech Connect

    Thessen, Anne E.; Bunker, Daniel E.; Buttigieg, Pier Luigi; Cooper, Laurel D.; Dahdul, Wasila M.; Domisch, Sami; Franz, Nico M.; Jaiswal, Pankaj; Lawrence-Dill, Carolyn J.; Midford, Peter E.; Mungall, Christopher J.; Ramirez, Martin J.; Specht, Chelsea D.; Vogt, Lars; Vos, Rutger Aldo; Walls, Ramona L.; White, Jeffrey W.; Zhang, Guanyang; Deans, Andrew R.; Huala, Eva; Lewis, Suzanna E.; Mabee, Paula M.

    2015-12-14

    Understanding the interplay between environmental conditions and phenotypes is a fundamental goal of biology. Unfortunately, data that include observations on phenotype and environment are highly heterogeneous and thus difficult to find and integrate. One approach that is likely to improve the status quo involves the use of ontologies to standardize and link data about phenotypes and environments. Specifying and linking data through ontologies will allow researchers to increase the scope and flexibility of large-scale analyses aided by modern computing methods. Investments in this area would advance diverse fields such as ecology, phylogenetics, and conservation biology. While several biological ontologies are well-developed, using them to link phenotypes and environments is rare because of gaps in ontological coverage and limits to interoperability among ontologies and disciplines. Lastly, in this manuscript, we present (1) use cases from diverse disciplines to illustrate questions that could be answered more efficiently using a robust linkage between phenotypes and environments, (2) two proof-of-concept analyses that show the value of linking phenotypes to environments in fishes and amphibians, and (3) two proposed example data models for linking phenotypes and environments using the extensible observation ontology (OBOE) and the Biological Collections Ontology (BCO); these provide a starting point for the development of a data model linking phenotypes and environments.

  5. The Cognitive Phenotype of Spina Bifida Meningomyelocele

    ERIC Educational Resources Information Center

    Dennis, Maureen; Barnes, Marcia A.

    2010-01-01

    A cognitive phenotype is a product of both assets and deficits that specifies what individuals with spina bifida meningomyelocele (SBM) can and cannot do and why they can or cannot do it. In this article, we review the cognitive phenotype of SBM and describe the processing assets and deficits that cut within and across content domains, sensory…

  6. Emerging semantics to link phenotype and environment

    DOE PAGESBeta

    Thessen, Anne E.; Bunker, Daniel E.; Buttigieg, Pier Luigi; Cooper, Laurel D.; Dahdul, Wasila M.; Domisch, Sami; Franz, Nico M.; Jaiswal, Pankaj; Lawrence-Dill, Carolyn J.; Midford, Peter E.; et al

    2015-12-14

    Understanding the interplay between environmental conditions and phenotypes is a fundamental goal of biology. Unfortunately, data that include observations on phenotype and environment are highly heterogeneous and thus difficult to find and integrate. One approach that is likely to improve the status quo involves the use of ontologies to standardize and link data about phenotypes and environments. Specifying and linking data through ontologies will allow researchers to increase the scope and flexibility of large-scale analyses aided by modern computing methods. Investments in this area would advance diverse fields such as ecology, phylogenetics, and conservation biology. While several biological ontologies aremore » well-developed, using them to link phenotypes and environments is rare because of gaps in ontological coverage and limits to interoperability among ontologies and disciplines. Lastly, in this manuscript, we present (1) use cases from diverse disciplines to illustrate questions that could be answered more efficiently using a robust linkage between phenotypes and environments, (2) two proof-of-concept analyses that show the value of linking phenotypes to environments in fishes and amphibians, and (3) two proposed example data models for linking phenotypes and environments using the extensible observation ontology (OBOE) and the Biological Collections Ontology (BCO); these provide a starting point for the development of a data model linking phenotypes and environments.« less

  7. Emerging semantics to link phenotype and environment.

    PubMed

    Thessen, Anne E; Bunker, Daniel E; Buttigieg, Pier Luigi; Cooper, Laurel D; Dahdul, Wasila M; Domisch, Sami; Franz, Nico M; Jaiswal, Pankaj; Lawrence-Dill, Carolyn J; Midford, Peter E; Mungall, Christopher J; Ramírez, Martín J; Specht, Chelsea D; Vogt, Lars; Vos, Rutger Aldo; Walls, Ramona L; White, Jeffrey W; Zhang, Guanyang; Deans, Andrew R; Huala, Eva; Lewis, Suzanna E; Mabee, Paula M

    2015-01-01

    Understanding the interplay between environmental conditions and phenotypes is a fundamental goal of biology. Unfortunately, data that include observations on phenotype and environment are highly heterogeneous and thus difficult to find and integrate. One approach that is likely to improve the status quo involves the use of ontologies to standardize and link data about phenotypes and environments. Specifying and linking data through ontologies will allow researchers to increase the scope and flexibility of large-scale analyses aided by modern computing methods. Investments in this area would advance diverse fields such as ecology, phylogenetics, and conservation biology. While several biological ontologies are well-developed, using them to link phenotypes and environments is rare because of gaps in ontological coverage and limits to interoperability among ontologies and disciplines. In this manuscript, we present (1) use cases from diverse disciplines to illustrate questions that could be answered more efficiently using a robust linkage between phenotypes and environments, (2) two proof-of-concept analyses that show the value of linking phenotypes to environments in fishes and amphibians, and (3) two proposed example data models for linking phenotypes and environments using the extensible observation ontology (OBOE) and the Biological Collections Ontology (BCO); these provide a starting point for the development of a data model linking phenotypes and environments. PMID:26713234

  8. Adjusting phenotypes by noise control.

    PubMed

    Kim, Kyung H; Sauro, Herbert M

    2012-01-01

    Genetically identical cells can show phenotypic variability. This is often caused by stochastic events that originate from randomness in biochemical processes involving in gene expression and other extrinsic cellular processes. From an engineering perspective, there have been efforts focused on theory and experiments to control noise levels by perturbing and replacing gene network components. However, systematic methods for noise control are lacking mainly due to the intractable mathematical structure of noise propagation through reaction networks. Here, we provide a numerical analysis method by quantifying the parametric sensitivity of noise characteristics at the level of the linear noise approximation. Our analysis is readily applicable to various types of noise control and to different types of system; for example, we can orthogonally control the mean and noise levels and can control system dynamics such as noisy oscillations. As an illustration we applied our method to HIV and yeast gene expression systems and metabolic networks. The oscillatory signal control was applied to p53 oscillations from DNA damage. Furthermore, we showed that the efficiency of orthogonal control can be enhanced by applying extrinsic noise and feedback. Our noise control analysis can be applied to any stochastic model belonging to continuous time Markovian systems such as biological and chemical reaction systems, and even computer and social networks. We anticipate the proposed analysis to be a useful tool for designing and controlling synthetic gene networks. PMID:22253584

  9. The Nature of Stable Insomnia Phenotypes

    PubMed Central

    Pillai, Vivek; Roth, Thomas; Drake, Christopher L.

    2015-01-01

    Study Objectives: We examined the 1-y stability of four insomnia symptom profiles: sleep onset insomnia; sleep maintenance insomnia; combined onset and maintenance insomnia; and neither criterion (i.e., insomnia cases that do not meet quantitative thresholds for onset or maintenance problems). Insomnia cases that exhibited the same symptom profile over a 1-y period were considered to be phenotypes, and were compared in terms of clinical and demographic characteristics. Design: Longitudinal. Setting: Urban, community-based. Participants: Nine hundred fifty-four adults with Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition based current insomnia (46.6 ± 12.6 y; 69.4% female). Interventions: None. Measurements and results: At baseline, participants were divided into four symptom profile groups based on quantitative criteria. Follow-up assessment 1 y later revealed that approximately 60% of participants retained the same symptom profile, and were hence judged to be phenotypes. Stability varied significantly by phenotype, such that sleep onset insomnia (SOI) was the least stable (42%), whereas combined insomnia (CI) was the most stable (69%). Baseline symptom groups (cross-sectionally defined) differed significantly across various clinical indices, including daytime impairment, depression, and anxiety. Importantly, however, a comparison of stable phenotypes (longitudinally defined) did not reveal any differences in impairment or comorbid psychopathology. Another interesting finding was that whereas all other insomnia phenotypes showed evidence of an elevated wake drive both at night and during the day, the “neither criterion” phenotype did not; this latter phenotype exhibited significantly higher daytime sleepiness despite subthreshold onset and maintenance difficulties. Conclusions: By adopting a stringent, stability-based definition, this study offers timely and important data on the longitudinal trajectory of specific insomnia phenotypes. With

  10. Phenotype MicroArrays for High-Throughput Phenotypic Testing and Assay of Gene Function

    PubMed Central

    Bochner, Barry R.; Gadzinski, Peter; Panomitros, Eugenia

    2001-01-01

    The bacterium Escherichia coli is used as a model cellular system to test and validate a new technology called Phenotype MicroArrays (PMs). PM technology is a high-throughput technology for simultaneous testing of a large number of cellular phenotypes. It consists of preconfigured well arrays in which each well tests a different cellular phenotype and an automated instrument that continuously monitors and records the response of the cells in all wells of the arrays. For example, nearly 700 phenotypes of E. coli can be assayed by merely pipetting a cell suspension into seven microplate arrays. PMs can be used to directly assay the effects of genetic changes on cells, especially gene knock-outs. Here, we provide data on phenotypic analysis of six strains and show that we can detect expected phenotypes as well as, in some cases, unexpected phenotypes. PMID:11435407

  11. Refined Phenotyping of Modic Changes

    PubMed Central

    Määttä, Juhani H.; Karppinen, Jaro; Paananen, Markus; Bow, Cora; Luk, Keith D.K.; Cheung, Kenneth M.C.; Samartzis, Dino

    2016-01-01

    Abstract Low back pain (LBP) is the world's most disabling condition. Modic changes (MC) are vertebral bone marrow changes adjacent to the endplates as noted on magnetic resonance imaging. The associations of specific MC types and patterns with prolonged, severe LBP and disability remain speculative. This study assessed the relationship of prolonged, severe LBP and back-related disability, with the presence and morphology of lumbar MC in a large cross-sectional population-based study of Southern Chinese. We addressed the topographical and morphological dimensions of MC along with other magnetic resonance imaging phenotypes (eg, disc degeneration and displacement) on the basis of axial T1 and sagittal T2-weighted imaging of L1-S1. Prolonged severe LBP was defined as LBP lasting ≥30 days during the past year, and a visual analog scale severest pain intensity of at least 6/10. An Oswestry Disability Index score of 15% was regarded as significant disability. We also assessed subject demographics, occupation, and lifestyle factors. In total, 1142 subjects (63% females, mean age 53 years) were assessed. Of these, 282 (24.7%) had MC (7.1% type I, 17.6% type II). MC subjects were older (P = 0.003), had more frequent disc displacements (P < 0.001) and greater degree of disc degeneration (P < 0.001) than non-MC subjects. In adjusted models, any MC (odds ratio [OR] 1.48, 95% confidence interval [CI] 1.01–2.18), MC affecting whole anterior-posterior length (OR 1.62, 95% CI 1.04–2.51), and MC affecting 2/3 posterior length (OR 2.79, 95% CI 1.17–6.65) were associated with prolonged severe LBP. Type I MC tended to associate with pain more strongly than type II MC (OR 1.80, 95% CI 0.94–3.44 vs OR 1.36, 95% CI 0.88–2.09, respectively). Any MC (OR 1.47, 95% CI 1.04–2.10), type II MC (OR 1.56, 95% CI 1.06–2.31), MC affecting 2/3 posterior length (OR 2.96, 95% CI 1.27–6.89), and extensive MC (OR 1.95, 95% CI 1.21–3.15) were associated with disability

  12. Phenoscape: Identifying Candidate Genes for Evolutionary Phenotypes.

    PubMed

    Edmunds, Richard C; Su, Baofeng; Balhoff, James P; Eames, B Frank; Dahdul, Wasila M; Lapp, Hilmar; Lundberg, John G; Vision, Todd J; Dunham, Rex A; Mabee, Paula M; Westerfield, Monte

    2016-01-01

    Phenotypes resulting from mutations in genetic model organisms can help reveal candidate genes for evolutionarily important phenotypic changes in related taxa. Although testing candidate gene hypotheses experimentally in nonmodel organisms is typically difficult, ontology-driven information systems can help generate testable hypotheses about developmental processes in experimentally tractable organisms. Here, we tested candidate gene hypotheses suggested by expert use of the Phenoscape Knowledgebase, specifically looking for genes that are candidates responsible for evolutionarily interesting phenotypes in the ostariophysan fishes that bear resemblance to mutant phenotypes in zebrafish. For this, we searched ZFIN for genetic perturbations that result in either loss of basihyal element or loss of scales phenotypes, because these are the ancestral phenotypes observed in catfishes (Siluriformes). We tested the identified candidate genes by examining their endogenous expression patterns in the channel catfish, Ictalurus punctatus. The experimental results were consistent with the hypotheses that these features evolved through disruption in developmental pathways at, or upstream of, brpf1 and eda/edar for the ancestral losses of basihyal element and scales, respectively. These results demonstrate that ontological annotations of the phenotypic effects of genetic alterations in model organisms, when aggregated within a knowledgebase, can be used effectively to generate testable, and useful, hypotheses about evolutionary changes in morphology. PMID:26500251

  13. Phenoscape: Identifying Candidate Genes for Evolutionary Phenotypes

    PubMed Central

    Edmunds, Richard C.; Su, Baofeng; Balhoff, James P.; Eames, B. Frank; Dahdul, Wasila M.; Lapp, Hilmar; Lundberg, John G.; Vision, Todd J.; Dunham, Rex A.; Mabee, Paula M.; Westerfield, Monte

    2016-01-01

    Phenotypes resulting from mutations in genetic model organisms can help reveal candidate genes for evolutionarily important phenotypic changes in related taxa. Although testing candidate gene hypotheses experimentally in nonmodel organisms is typically difficult, ontology-driven information systems can help generate testable hypotheses about developmental processes in experimentally tractable organisms. Here, we tested candidate gene hypotheses suggested by expert use of the Phenoscape Knowledgebase, specifically looking for genes that are candidates responsible for evolutionarily interesting phenotypes in the ostariophysan fishes that bear resemblance to mutant phenotypes in zebrafish. For this, we searched ZFIN for genetic perturbations that result in either loss of basihyal element or loss of scales phenotypes, because these are the ancestral phenotypes observed in catfishes (Siluriformes). We tested the identified candidate genes by examining their endogenous expression patterns in the channel catfish, Ictalurus punctatus. The experimental results were consistent with the hypotheses that these features evolved through disruption in developmental pathways at, or upstream of, brpf1 and eda/edar for the ancestral losses of basihyal element and scales, respectively. These results demonstrate that ontological annotations of the phenotypic effects of genetic alterations in model organisms, when aggregated within a knowledgebase, can be used effectively to generate testable, and useful, hypotheses about evolutionary changes in morphology. PMID:26500251

  14. Evolution of molecular phenotypes under stabilizing selection

    NASA Astrophysics Data System (ADS)

    Nourmohammad, Armita; Schiffels, Stephan; Lässig, Michael

    2013-01-01

    Molecular phenotypes are important links between genomic information and organismic functions, fitness, and evolution. Complex phenotypes, which are also called quantitative traits, often depend on multiple genomic loci. Their evolution builds on genome evolution in a complicated way, which involves selection, genetic drift, mutations and recombination. Here we develop a coarse-grained evolutionary statistics for phenotypes, which decouples from details of the underlying genotypes. We derive approximate evolution equations for the distribution of phenotype values within and across populations. This dynamics covers evolutionary processes at high and low recombination rates, that is, it applies to sexual and asexual populations. In a fitness landscape with a single optimal phenotype value, the phenotypic diversity within populations and the divergence between populations reach evolutionary equilibria, which describe stabilizing selection. We compute the equilibrium distributions of both quantities analytically and we show that the ratio of mean divergence and diversity depends on the strength of selection in a universal way: it is largely independent of the phenotype’s genomic encoding and of the recombination rate. This establishes a new method for the inference of selection on molecular phenotypes beyond the genome level. We discuss the implications of our findings for the predictability of evolutionary processes.

  15. Phenotypes of childhood asthma: are they real?

    PubMed

    Spycher, B D; Silverman, M; Kuehni, C E

    2010-08-01

    It has been suggested that there are several distinct phenotypes of childhood asthma or childhood wheezing. Here, we review the research relating to these phenotypes, with a focus on the methods used to define and validate them. Childhood wheezing disorders manifest themselves in a range of observable (phenotypic) features such as lung function, bronchial responsiveness, atopy and a highly variable time course (prognosis). The underlying causes are not sufficiently understood to define disease entities based on aetiology. Nevertheless, there is a need for a classification that would (i) facilitate research into aetiology and pathophysiology, (ii) allow targeted treatment and preventive measures and (iii) improve the prediction of long-term outcome. Classical attempts to define phenotypes have been one-dimensional, relying on few or single features such as triggers (exclusive viral wheeze vs. multiple trigger wheeze) or time course (early transient wheeze, persistent and late onset wheeze). These definitions are simple but essentially subjective. Recently, a multi-dimensional approach has been adopted. This approach is based on a wide range of features and relies on multivariate methods such as cluster or latent class analysis. Phenotypes identified in this manner are more complex but arguably more objective. Although phenotypes have an undisputed standing in current research on childhood asthma and wheezing, there is confusion about the meaning of the term 'phenotype' causing much circular debate. If phenotypes are meant to represent 'real' underlying disease entities rather than superficial features, there is a need for validation and harmonization of definitions. The multi-dimensional approach allows validation by replication across different populations and may contribute to a more reliable classification of childhood wheezing disorders and to improved precision of research relying on phenotype recognition, particularly in genetics. Ultimately, the underlying

  16. The Cognitive Phenotype Of Spina Bifida Meningomyelocele

    PubMed Central

    Dennis, Maureen; Barnes, Marcia A.

    2010-01-01

    A cognitive phenotype is a product of both assets and deficits that specifies what individuals with spina bifida meningomyelocele (SBM) can and cannot do and why they can or cannot do it. In this paper, we review the cognitive phenotype of SBM and describe the processing assets and deficits that cut within and across content domains, sensory modality, and material, including studies from our laboratory and other investigations. We discuss some implications of the SBM cognitive phenotype for assessment, rehabilitation, and research. PMID:20419769

  17. Metabolic Phenotypes in Pancreatic Cancer

    PubMed Central

    Yu, Min; Zhou, Quanbo; Zhou, Yu; Fu, Zhiqiang; Tan, Langping; Ye, Xiao; Zeng, Bing; Gao, Wenchao; Zhou, Jiajia; Liu, Yimin; Li, Zhihua; Lin, Ye; Lin, Qing; Chen, Rufu

    2015-01-01

    Introduction The aim of present study was to profile the glucose-dependent and glutamine- dependent metabolism in pancreatic cancer. Methods We performed Immunohistochemical staining of GLUT1, CAIX, BNIP3, p62, LC3, GLUD1, and GOT1. Based on the expression of metabolism-related proteins, the metabolic phenotypes of tumors were classified into two categories, including glucose- and glutamine-dependent metabolism. There were Warburg type, reverse Warburg type, mixed type, and null type in glucose-dependent metabolism, and canonical type, non-canonical type, mixed type, null type in glutamine-dependent metabolism. Results Longer overall survival was associated with high expression of BNIP3 in tumor (p = 0.010). Shorter overall survival was associated with high expression of GLUT1 in tumor (P = 0.002) and GOT1 in tumor (p = 0.030). Warburg type of glucose-dependent metabolism had a highest percentage of tumors with nerve infiltration (P = 0.0003), UICC stage (P = 0.0004), and activated autophagic status in tumor (P = 0.0167). Mixed type of glucose-dependent metabolism comprised the highest percentage of tumors with positive marginal status (P<0.0001), lymphatic invasion (P<0.0001), and activated autophagic status in stroma (P = 0.0002). Mixed type and Warburg type had a significant association with shorter overall survival (P = 0.018). Non-canonical type and mixed type of glutamine-dependent metabolism comprised the highest percentage of tumors with vascular invasion (p = 0.0073), highest percentage of activated autophagy in tumors (P = 0.0034). Moreover, these two types of glutamine-dependent metabolism were significantly associated with shorter overall survival (P<0.001). Further analysis suggested that most of tumors were dependent on both glucose- and glutamine-dependent metabolism. After dividing the tumors according to the number of metabolism, we found that the increasing numbers of metabolism subtypes inversely associated with survival outcome. Conclusion

  18. Metabolic phenotype of bladder cancer.

    PubMed

    Massari, Francesco; Ciccarese, Chiara; Santoni, Matteo; Iacovelli, Roberto; Mazzucchelli, Roberta; Piva, Francesco; Scarpelli, Marina; Berardi, Rossana; Tortora, Giampaolo; Lopez-Beltran, Antonio; Cheng, Liang; Montironi, Rodolfo

    2016-04-01

    serine hydroxymethyltransferase-2 (SHMT2), resulting in an increased glycine and purine ring of nucleotides synthesis, thus supporting cells proliferation. A deep understanding of the metabolic phenotype of bladder cancer will provide novel opportunities for targeted therapeutic strategies. PMID:26975021

  19. Phenotypic Assessment and the Discovery of Topiramate.

    PubMed

    Maryanoff, Bruce E

    2016-07-14

    The role of phenotypic assessment in drug discovery is discussed, along with the discovery and development of TOPAMAX (topiramate), a billion-dollar molecule for the treatment of epilepsy and migraine. PMID:27437073

  20. Finding the target after screening the phenotype.

    PubMed

    Hart, Charles P

    2005-04-01

    Although most screening for new drug leads is being directed at known or emerging molecular targets, there has been a renaissance in screening based on changes in cell or organismal phenotypes. Phenotype-based screening is accompanied by the challenge of identifying the molecular target or targets bound by the drug leads and responsible for their pharmacological activity. A variety of technologies and approaches are being explored for target identification after phenotypic screening. Direct approaches employing affinity chromatography, expression cloning and protein microarrays analyze the compound bound to its target. Indirect approaches are based on comparison of the genome-wide activity profile of the compound with databases of the activity profiles of other compounds with known targets or activity profiles following specific genetic changes. This review will use case studies of target identification efforts and highlight the advantages and disadvantages of the various approaches to target identification after phenotypic screening. PMID:15809197

  1. International Mouse Phenotyping Consortium (IMPC) —

    Cancer.gov

    The International Mouse Phenotyping Consortium (IMPC) comprises a group of major mouse genetics research institutions along with national funding organisations formed to address the challenge of developing an encyclopedia of mammalian gene function.

  2. Phenotypic Assessment and the Discovery of Topiramate

    PubMed Central

    2016-01-01

    The role of phenotypic assessment in drug discovery is discussed, along with the discovery and development of TOPAMAX (topiramate), a billion-dollar molecule for the treatment of epilepsy and migraine. PMID:27437073

  3. Acetylator phenotypes in Papua New Guinea

    PubMed Central

    Penketh, R J A; Gibney, S F A; Nurse, G T; Hopkinson, D A

    1983-01-01

    Acetylator phenotypes have been determined in 139 unrelated subjects from the hitherto untested populations of Papua New Guinea, and their relevance to current antituberculous isoniazid chemotherapy is discussed. PMID:6842533

  4. Phenotype Standardization for Statin-Induced Myotoxicity

    PubMed Central

    Alfirevic, A; Neely, D; Armitage, J; Chinoy, H; Cooper, R G; Laaksonen, R; Carr, D F; Bloch, K M; Fahy, J; Hanson, A; Yue, Q-Y; Wadelius, M; Maitland-van Der Zee, A H; Voora, D; Psaty, B M; Palmer, C N A; Pirmohamed, M

    2014-01-01

    Statins are widely used lipid-lowering drugs that are effective in reducing cardiovascular disease risk. Although they are generally well tolerated, they can cause muscle toxicity, which can lead to severe rhabdomyolysis. Research in this area has been hampered to some extent by the lack of standardized nomenclature and phenotypic definitions. We have used numerical and descriptive classifications and developed an algorithm to define statin-related myotoxicity phenotypes, including myalgia, myopathy, rhabdomyolysis, and necrotizing autoimmune myopathy. PMID:24897241

  5. Phenotypic Screens in Antimalarial Drug Discovery.

    PubMed

    Hovlid, Marisa L; Winzeler, Elizabeth A

    2016-09-01

    Phenotypic high-throughput screens are a valuable tool for identifying new chemical compounds with antimalarial activity. Traditionally, these screens have focused solely on the symptomatic asexual blood stage of the parasite life cycle; however, to discover new medicines for malaria treatment and prevention, robust screening technologies against other parasite life-cycle stages are required. This review highlights recent advances and progress toward phenotypic screening methodologies over the past several years, with a focus on exoerythrocytic stage screens. PMID:27247245

  6. Phenotypic Evolution With and Beyond Genome Evolution.

    PubMed

    Félix, M-A

    2016-01-01

    DNA does not make phenotypes on its own. In this volume entitled "Genes and Phenotypic Evolution," the present review draws the attention on the process of phenotype construction-including development of multicellular organisms-and the multiple interactions and feedbacks between DNA, organism, and environment at various levels and timescales in the evolutionary process. First, during the construction of an individual's phenotype, DNA is recruited as a template for building blocks within the cellular context and may in addition be involved in dynamical feedback loops that depend on the environmental and organismal context. Second, in the production of phenotypic variation among individuals, stochastic, environmental, genetic, and parental sources of variation act jointly. While in controlled laboratory settings, various genetic and environmental factors can be tested one at a time or in various combinations, they cannot be separated in natural populations because the environment is not controlled and the genotype can rarely be replicated. Third, along generations, genotype and environment each have specific properties concerning the origin of their variation, the hereditary transmission of this variation, and the evolutionary feedbacks. Natural selection acts as a feedback from phenotype and environment to genotype. This review integrates recent results and concrete examples that illustrate these three points. Although some themes are shared with recent calls and claims to a new conceptual framework in evolutionary biology, the viewpoint presented here only means to add flesh to the standard evolutionary synthesis. PMID:27282029

  7. Geographically multifarious phenotypic divergence during speciation

    PubMed Central

    Gompert, Zachariah; Lucas, Lauren K; Nice, Chris C; Fordyce, James A; Alex Buerkle, C; Forister, Matthew L

    2013-01-01

    Speciation is an important evolutionary process that occurs when barriers to gene flow evolve between previously panmictic populations. Although individual barriers to gene flow have been studied extensively, we know relatively little regarding the number of barriers that isolate species or whether these barriers are polymorphic within species. Herein, we use a series of field and lab experiments to quantify phenotypic divergence and identify possible barriers to gene flow between the butterfly species Lycaeides idas and Lycaeides melissa. We found evidence that L. idas and L. melissa have diverged along multiple phenotypic axes. Specifically, we identified major phenotypic differences in female oviposition preference and diapause initiation, and more moderate divergence in mate preference. Multiple phenotypic differences might operate as barriers to gene flow, as shown by correlations between genetic distance and phenotypic divergence and patterns of phenotypic variation in admixed Lycaeides populations. Although some of these traits differed primarily between species (e.g., diapause initiation), several traits also varied among conspecific populations (e.g., male mate preference and oviposition preference). PMID:23532669

  8. FYPO: the fission yeast phenotype ontology

    PubMed Central

    Harris, Midori A.; Lock, Antonia; Bähler, Jürg; Oliver, Stephen G.; Wood, Valerie

    2013-01-01

    Motivation: To provide consistent computable descriptions of phenotype data, PomBase is developing a formal ontology of phenotypes observed in fission yeast. Results: The fission yeast phenotype ontology (FYPO) is a modular ontology that uses several existing ontologies from the open biological and biomedical ontologies (OBO) collection as building blocks, including the phenotypic quality ontology PATO, the Gene Ontology and Chemical Entities of Biological Interest. Modular ontology development facilitates partially automated effective organization of detailed phenotype descriptions with complex relationships to each other and to underlying biological phenomena. As a result, FYPO supports sophisticated querying, computational analysis and comparison between different experiments and even between species. Availability: FYPO releases are available from the Subversion repository at the PomBase SourceForge project page (https://sourceforge.net/p/pombase/code/HEAD/tree/phenotype_ontology/). The current version of FYPO is also available on the OBO Foundry Web site (http://obofoundry.org/). Contact: mah79@cam.ac.uk or vw253@cam.ac.uk PMID:23658422

  9. Advanced phenotyping and phenotype data analysis for the study of plant growth and development

    PubMed Central

    Rahaman, Md. Matiur; Chen, Dijun; Gillani, Zeeshan; Klukas, Christian; Chen, Ming

    2015-01-01

    Due to an increase in the consumption of food, feed, fuel and to meet global food security needs for the rapidly growing human population, there is a necessity to breed high yielding crops that can adapt to the future climate changes, particularly in developing countries. To solve these global challenges, novel approaches are required to identify quantitative phenotypes and to explain the genetic basis of agriculturally important traits. These advances will facilitate the screening of germplasm with high performance characteristics in resource-limited environments. Recently, plant phenomics has offered and integrated a suite of new technologies, and we are on a path to improve the description of complex plant phenotypes. High-throughput phenotyping platforms have also been developed that capture phenotype data from plants in a non-destructive manner. In this review, we discuss recent developments of high-throughput plant phenotyping infrastructure including imaging techniques and corresponding principles for phenotype data analysis. PMID:26322060

  10. In silico phenotyping via co-training for improved phenotype prediction from genotype

    PubMed Central

    Witteveen, Menno J.; Anttila, Verneri; Terwindt, Gisela M.; van den Maagdenberg, Arn M.J.M.; Borgwardt, Karsten

    2015-01-01

    Motivation: Predicting disease phenotypes from genotypes is a key challenge in medical applications in the postgenomic era. Large training datasets of patients that have been both genotyped and phenotyped are the key requisite when aiming for high prediction accuracy. With current genotyping projects producing genetic data for hundreds of thousands of patients, large-scale phenotyping has become the bottleneck in disease phenotype prediction. Results: Here we present an approach for imputing missing disease phenotypes given the genotype of a patient. Our approach is based on co-training, which predicts the phenotype of unlabeled patients based on a second class of information, e.g. clinical health record information. Augmenting training datasets by this type of in silico phenotyping can lead to significant improvements in prediction accuracy. We demonstrate this on a dataset of patients with two diagnostic types of migraine, termed migraine with aura and migraine without aura, from the International Headache Genetics Consortium. Conclusions: Imputing missing disease phenotypes for patients via co-training leads to larger training datasets and improved prediction accuracy in phenotype prediction. Availability and implementation: The code can be obtained at: http://www.bsse.ethz.ch/mlcb/research/bioinformatics-and-computational-biology/co-training.html Contact: karsten.borgwardt@bsse.ethz.ch or menno.witteveen@bsse.ethz.ch Supplementary information: Supplementary data are available at Bioinformatics online. PMID:26072497

  11. A method for analysis of phenotypic change for phenotypes described by high-dimensional data.

    PubMed

    Collyer, M L; Sekora, D J; Adams, D C

    2015-10-01

    The analysis of phenotypic change is important for several evolutionary biology disciplines, including phenotypic plasticity, evolutionary developmental biology, morphological evolution, physiological evolution, evolutionary ecology and behavioral evolution. It is common for researchers in these disciplines to work with multivariate phenotypic data. When phenotypic variables exceed the number of research subjects--data called 'high-dimensional data'--researchers are confronted with analytical challenges. Parametric tests that require high observation to variable ratios present a paradox for researchers, as eliminating variables potentially reduces effect sizes for comparative analyses, yet test statistics require more observations than variables. This problem is exacerbated with data that describe 'multidimensional' phenotypes, whereby a description of phenotype requires high-dimensional data. For example, landmark-based geometric morphometric data use the Cartesian coordinates of (potentially) many anatomical landmarks to describe organismal shape. Collectively such shape variables describe organism shape, although the analysis of each variable, independently, offers little benefit for addressing biological questions. Here we present a nonparametric method of evaluating effect size that is not constrained by the number of phenotypic variables, and motivate its use with example analyses of phenotypic change using geometric morphometric data. Our examples contrast different characterizations of body shape for a desert fish species, associated with measuring and comparing sexual dimorphism between two populations. We demonstrate that using more phenotypic variables can increase effect sizes, and allow for stronger inferences. PMID:25204302

  12. Phenotype Standardization for Drug Induced Kidney Disease

    PubMed Central

    Mehta, Ravindra L; Awdishu, Linda; Davenport, Andrew; Murray, Patrick; Macedo, Etienne; Cerda, Jorge; Chakaravarthi, Raj; Holden, Arthur; Goldstein, Stuart L.

    2015-01-01

    Drug induced kidney disease is a frequent cause of renal dysfunction; however, there are no standards to identify and characterize the spectrum of these disorders. We convened a panel of international, adult and pediatric, nephrologists and pharmacists to develop standardized phenotypes for drug induced kidney disease as part of the phenotype standardization project initiated by the International Serious Adverse Events Consortium. We propose four phenotypes of drug induced kidney disease based on clinical presentation: acute kidney injury, glomerular, tubular and nephrolithiasis, along with primary and secondary clinical criteria to support the phenotype definition, and a time course based on the KDIGO/AKIN definitions of acute kidney injury, acute kidney disease and chronic kidney disease. Establishing causality in drug induced kidney disease is challenging and requires knowledge of the biological plausibility for the specific drug, mechanism of injury, time course and assessment of competing risk factors. These phenotypes provide a consistent framework for clinicians, investigators, industry and regulatory agencies to evaluate drug nephrotoxicity across various settings. We believe that this is first step to recognizing drug induced kidney disease and developing strategies to prevent and manage this condition. PMID:25853333

  13. Delineating the GRIN1 phenotypic spectrum

    PubMed Central

    Geider, Kirsten; Helbig, Katherine L.; Heyne, Henrike O.; Schütz, Hannah; Hentschel, Julia; Courage, Carolina; Depienne, Christel; Nava, Caroline; Heron, Delphine; Møller, Rikke S.; Hjalgrim, Helle; Lal, Dennis; Neubauer, Bernd A.; Nürnberg, Peter; Thiele, Holger; Kurlemann, Gerhard; Arnold, Georgianne L.; Bhambhani, Vikas; Bartholdi, Deborah; Pedurupillay, Christeen Ramane J.; Misceo, Doriana; Frengen, Eirik; Strømme, Petter; Dlugos, Dennis J.; Doherty, Emily S.; Bijlsma, Emilia K.; Ruivenkamp, Claudia A.; Hoffer, Mariette J.V.; Goldstein, Amy; Rajan, Deepa S.; Narayanan, Vinodh; Ramsey, Keri; Belnap, Newell; Schrauwen, Isabelle; Richholt, Ryan; Koeleman, Bobby P.C.; Sá, Joaquim; Mendonça, Carla; de Kovel, Carolien G.F.; Weckhuysen, Sarah; Hardies, Katia; De Jonghe, Peter; De Meirleir, Linda; Milh, Mathieu; Badens, Catherine; Lebrun, Marine; Busa, Tiffany; Francannet, Christine; Piton, Amélie; Riesch, Erik; Biskup, Saskia; Vogt, Heinrich; Dorn, Thomas; Helbig, Ingo; Michaud, Jacques L.; Laube, Bodo; Syrbe, Steffen

    2016-01-01

    Objective: To determine the phenotypic spectrum caused by mutations in GRIN1 encoding the NMDA receptor subunit GluN1 and to investigate their underlying functional pathophysiology. Methods: We collected molecular and clinical data from several diagnostic and research cohorts. Functional consequences of GRIN1 mutations were investigated in Xenopus laevis oocytes. Results: We identified heterozygous de novo GRIN1 mutations in 14 individuals and reviewed the phenotypes of all 9 previously reported patients. These 23 individuals presented with a distinct phenotype of profound developmental delay, severe intellectual disability with absent speech, muscular hypotonia, hyperkinetic movement disorder, oculogyric crises, cortical blindness, generalized cerebral atrophy, and epilepsy. Mutations cluster within transmembrane segments and result in loss of channel function of varying severity with a dominant-negative effect. In addition, we describe 2 homozygous GRIN1 mutations (1 missense, 1 truncation), each segregating with severe neurodevelopmental phenotypes in consanguineous families. Conclusions: De novo GRIN1 mutations are associated with severe intellectual disability with cortical visual impairment as well as oculomotor and movement disorders being discriminating phenotypic features. Loss of NMDA receptor function appears to be the underlying disease mechanism. The identification of both heterozygous and homozygous mutations blurs the borders of dominant and recessive inheritance of GRIN1-associated disorders. PMID:27164704

  14. Serum Biochemical Phenotypes in the Domestic Dog

    PubMed Central

    Chang, Yu-Mei; Hadox, Erin; Szladovits, Balazs; Garden, Oliver A.

    2016-01-01

    The serum or plasma biochemical profile is essential in the diagnosis and monitoring of systemic disease in veterinary medicine, but current reference intervals typically take no account of breed-specific differences. Breed-specific hematological phenotypes have been documented in the domestic dog, but little has been published on serum biochemical phenotypes in this species. Serum biochemical profiles of dogs in which all measurements fell within the existing reference intervals were retrieved from a large veterinary database. Serum biochemical profiles from 3045 dogs were retrieved, of which 1495 had an accompanying normal glucose concentration. Sixty pure breeds plus a mixed breed control group were represented by at least 10 individuals. All analytes, except for sodium, chloride and glucose, showed variation with age. Total protein, globulin, potassium, chloride, creatinine, cholesterol, total bilirubin, ALT, CK, amylase, and lipase varied between sexes. Neutering status significantly impacted all analytes except albumin, sodium, calcium, urea, and glucose. Principal component analysis of serum biochemical data revealed 36 pure breeds with distinctive phenotypes. Furthermore, comparative analysis identified 23 breeds with significant differences from the mixed breed group in all biochemical analytes except urea and glucose. Eighteen breeds were identified by both principal component and comparative analysis. Tentative reference intervals were generated for breeds with a distinctive phenotype identified by comparative analysis and represented by at least 120 individuals. This is the first large-scale analysis of breed-specific serum biochemical phenotypes in the domestic dog and highlights potential genetic components of biochemical traits in this species. PMID:26919479

  15. The new mutation theory of phenotypic evolution

    PubMed Central

    Nei, Masatoshi

    2007-01-01

    Recent studies of developmental biology have shown that the genes controlling phenotypic characters expressed in the early stage of development are highly conserved and that recent evolutionary changes have occurred primarily in the characters expressed in later stages of development. Even the genes controlling the latter characters are generally conserved, but there is a large component of neutral or nearly neutral genetic variation within and between closely related species. Phenotypic evolution occurs primarily by mutation of genes that interact with one another in the developmental process. The enormous amount of phenotypic diversity among different phyla or classes of organisms is a product of accumulation of novel mutations and their conservation that have facilitated adaptation to different environments. Novel mutations may be incorporated into the genome by natural selection (elimination of preexisting genotypes) or by random processes such as genetic and genomic drift. However, once the mutations are incorporated into the genome, they may generate developmental constraints that will affect the future direction of phenotypic evolution. It appears that the driving force of phenotypic evolution is mutation, and natural selection is of secondary importance. PMID:17640887

  16. Serum Biochemical Phenotypes in the Domestic Dog.

    PubMed

    Chang, Yu-Mei; Hadox, Erin; Szladovits, Balazs; Garden, Oliver A

    2016-01-01

    The serum or plasma biochemical profile is essential in the diagnosis and monitoring of systemic disease in veterinary medicine, but current reference intervals typically take no account of breed-specific differences. Breed-specific hematological phenotypes have been documented in the domestic dog, but little has been published on serum biochemical phenotypes in this species. Serum biochemical profiles of dogs in which all measurements fell within the existing reference intervals were retrieved from a large veterinary database. Serum biochemical profiles from 3045 dogs were retrieved, of which 1495 had an accompanying normal glucose concentration. Sixty pure breeds plus a mixed breed control group were represented by at least 10 individuals. All analytes, except for sodium, chloride and glucose, showed variation with age. Total protein, globulin, potassium, chloride, creatinine, cholesterol, total bilirubin, ALT, CK, amylase, and lipase varied between sexes. Neutering status significantly impacted all analytes except albumin, sodium, calcium, urea, and glucose. Principal component analysis of serum biochemical data revealed 36 pure breeds with distinctive phenotypes. Furthermore, comparative analysis identified 23 breeds with significant differences from the mixed breed group in all biochemical analytes except urea and glucose. Eighteen breeds were identified by both principal component and comparative analysis. Tentative reference intervals were generated for breeds with a distinctive phenotype identified by comparative analysis and represented by at least 120 individuals. This is the first large-scale analysis of breed-specific serum biochemical phenotypes in the domestic dog and highlights potential genetic components of biochemical traits in this species. PMID:26919479

  17. Behavioural phenotypes predict disease susceptibility and infectiousness.

    PubMed

    Araujo, Alessandra; Kirschman, Lucas; Warne, Robin W

    2016-08-01

    Behavioural phenotypes may provide a means for identifying individuals that disproportionally contribute to disease spread and epizootic outbreaks. For example, bolder phenotypes may experience greater exposure and susceptibility to pathogenic infection because of distinct interactions with conspecifics and their environment. We tested the value of behavioural phenotypes in larval amphibians for predicting ranavirus transmission in experimental trials. We found that behavioural phenotypes characterized by latency-to-food and swimming profiles were predictive of disease susceptibility and infectiousness defined as the capacity of an infected host to transmit an infection by contacts. While viral shedding rates were positively associated with transmission, we also found an inverse relationship between contacts and infections. Together these results suggest intrinsic traits that influence behaviour and the quantity of pathogens shed during conspecific interactions may be an important contributor to ranavirus transmission. These results suggest that behavioural phenotypes provide a means to identify individuals more likely to spread disease and thus give insights into disease outbreaks that threaten wildlife and humans. PMID:27555652

  18. Comprehensive Detection of Genes Causing a Phenotype Using Phenotype Sequencing and Pathway Analysis

    PubMed Central

    Harper, Marc; Gronenberg, Luisa; Liao, James; Lee, Christopher

    2014-01-01

    Discovering all the genetic causes of a phenotype is an important goal in functional genomics. We combine an experimental design for detecting independent genetic causes of a phenotype with a high-throughput sequencing analysis that maximizes sensitivity for comprehensively identifying them. Testing this approach on a set of 24 mutant strains generated for a metabolic phenotype with many known genetic causes, we show that this pathway-based phenotype sequencing analysis greatly improves sensitivity of detection compared with previous methods, and reveals a wide range of pathways that can cause this phenotype. We demonstrate our approach on a metabolic re-engineering phenotype, the PEP/OAA metabolic node in E. coli, which is crucial to a substantial number of metabolic pathways and under renewed interest for biofuel research. Out of 2157 mutations in these strains, pathway-phenoseq discriminated just five gene groups (12 genes) as statistically significant causes of the phenotype. Experimentally, these five gene groups, and the next two high-scoring pathway-phenoseq groups, either have a clear connection to the PEP metabolite level or offer an alternative path of producing oxaloacetate (OAA), and thus clearly explain the phenotype. These high-scoring gene groups also show strong evidence of positive selection pressure, compared with strictly neutral selection in the rest of the genome. PMID:24586303

  19. First insights into the genotype–phenotype map of phenotypic stability in rye

    PubMed Central

    Wang, Yu; Mette, Michael Florian; Miedaner, Thomas; Wilde, Peer; Reif, Jochen C.; Zhao, Yusheng

    2015-01-01

    Improving phenotypic stability of crops is pivotal for coping with the detrimental impacts of climate change. The goal of this study was to gain first insights into the genetic architecture of phenotypic stability in cereals. To this end, we determined grain yield, thousand kernel weight, test weight, falling number, and both protein and soluble pentosan content for two large bi-parental rye populations connected through one common parent and grown in multi-environmental field trials involving more than 15 000 yield plots. Based on these extensive phenotypic data, we calculated parameters for static and dynamic phenotypic stability of the different traits and applied linkage mapping using whole-genome molecular marker profiles. While we observed an absence of large-effect quantitative trait loci (QTLs) underlying yield stability, large and stable QTLs were found for phenotypic stability of test weight, soluble pentosan content, and falling number. Applying genome-wide selection, which in contrast to marker-assisted selection also takes into account loci with small-effect sizes, considerably increased the accuracy of prediction of phenotypic stability for all traits by exploiting both genetic relatedness and linkage between single-nucleotide polymorphisms and QTLs. We conclude that breeding for crop phenotypic stability can be improved in related populations using genomic selection approaches established upon extensive phenotypic data. PMID:25873667

  20. Semi-supervised Learning for Phenotyping Tasks

    PubMed Central

    Dligach, Dmitriy; Miller, Timothy; Savova, Guergana K.

    2015-01-01

    Supervised learning is the dominant approach to automatic electronic health records-based phenotyping, but it is expensive due to the cost of manual chart review. Semi-supervised learning takes advantage of both scarce labeled and plentiful unlabeled data. In this work, we study a family of semi-supervised learning algorithms based on Expectation Maximization (EM) in the context of several phenotyping tasks. We first experiment with the basic EM algorithm. When the modeling assumptions are violated, basic EM leads to inaccurate parameter estimation. Augmented EM attenuates this shortcoming by introducing a weighting factor that downweights the unlabeled data. Cross-validation does not always lead to the best setting of the weighting factor and other heuristic methods may be preferred. We show that accurate phenotyping models can be trained with only a few hundred labeled (and a large number of unlabeled) examples, potentially providing substantial savings in the amount of the required manual chart review. PMID:26958183

  1. Application of phenotypic microarrays to environmental microbiology

    SciTech Connect

    Borglin, sharon; Joyner, Dominique; DeAngelis, Kristen; Khudyakov, Jane; D'haeseleer, Patrik; Joachimiak, Marcin; Hazen, Terry C; Fagan, Lisa Anne

    2012-01-01

    Environmental organisms are extremely diverse and only a small fraction has been successfully cultured in the laboratory. Culture in micro wells provides a method for rapid screening of a wide variety of growth conditions and commercially available plates contain a large number of substrates, nutrient sources, and inhibitors, which can provide an assessment of the phenotype of an organism. This review describes applications of phenotype arrays to anaerobic and thermophilic microorganisms, use of the plates in stress response studies, in development of culture media for newly discovered strains, and for assessment of phenotype of environmental communities. Also discussed are considerations and challenges in data interpretation and visualization, including data normalization, statistics, and curve fitting.

  2. Navigating the Phenotype Frontier: The Monarch Initiative.

    PubMed

    McMurry, Julie A; Köhler, Sebastian; Washington, Nicole L; Balhoff, James P; Borromeo, Charles; Brush, Matthew; Carbon, Seth; Conlin, Tom; Dunn, Nathan; Engelstad, Mark; Foster, Erin; Gourdine, Jean-Philippe; Jacobsen, Julius O B; Keith, Daniel; Laraway, Bryan; Xuan, Jeremy Nguyen; Shefchek, Kent; Vasilevsky, Nicole A; Yuan, Zhou; Lewis, Suzanna E; Hochheiser, Harry; Groza, Tudor; Smedley, Damian; Robinson, Peter N; Mungall, Christopher J; Haendel, Melissa A

    2016-08-01

    The principles of genetics apply across the entire tree of life. At the cellular level we share biological mechanisms with species from which we diverged millions, even billions of years ago. We can exploit this common ancestry to learn about health and disease, by analyzing DNA and protein sequences, but also through the observable outcomes of genetic differences, i.e. phenotypes. To solve challenging disease problems we need to unify the heterogeneous data that relates genomics to disease traits. Without a big-picture view of phenotypic data, many questions in genetics are difficult or impossible to answer. The Monarch Initiative (https://monarchinitiative.org) provides tools for genotype-phenotype analysis, genomic diagnostics, and precision medicine across broad areas of disease. PMID:27516611

  3. Plant phenotypic plasticity in a changing climate.

    PubMed

    Nicotra, A B; Atkin, O K; Bonser, S P; Davidson, A M; Finnegan, E J; Mathesius, U; Poot, P; Purugganan, M D; Richards, C L; Valladares, F; van Kleunen, M

    2010-12-01

    Climate change is altering the availability of resources and the conditions that are crucial to plant performance. One way plants will respond to these changes is through environmentally induced shifts in phenotype (phenotypic plasticity). Understanding plastic responses is crucial for predicting and managing the effects of climate change on native species as well as crop plants. Here, we provide a toolbox with definitions of key theoretical elements and a synthesis of the current understanding of the molecular and genetic mechanisms underlying plasticity relevant to climate change. By bringing ecological, evolutionary, physiological and molecular perspectives together, we hope to provide clear directives for future research and stimulate cross-disciplinary dialogue on the relevance of phenotypic plasticity under climate change. PMID:20970368

  4. Regulatory mechanisms link phenotypic plasticity to evolvability.

    PubMed

    van Gestel, Jordi; Weissing, Franz J

    2016-01-01

    Organisms have a remarkable capacity to respond to environmental change. They can either respond directly, by means of phenotypic plasticity, or they can slowly adapt through evolution. Yet, how phenotypic plasticity links to evolutionary adaptability is largely unknown. Current studies of plasticity tend to adopt a phenomenological reaction norm (RN) approach, which neglects the mechanisms underlying plasticity. Focusing on a concrete question - the optimal timing of bacterial sporulation - we here also consider a mechanistic approach, the evolution of a gene regulatory network (GRN) underlying plasticity. Using individual-based simulations, we compare the RN and GRN approach and find a number of striking differences. Most importantly, the GRN model results in a much higher diversity of responsive strategies than the RN model. We show that each of the evolved strategies is pre-adapted to a unique set of unseen environmental conditions. The regulatory mechanisms that control plasticity therefore critically link phenotypic plasticity to the adaptive potential of biological populations. PMID:27087393

  5. Rational elicitation of cold-sensitive phenotypes.

    PubMed

    Baliga, Chetana; Majhi, Sandipan; Mondal, Kajari; Bhattacharjee, Antara; VijayRaghavan, K; Varadarajan, Raghavan

    2016-05-01

    Cold-sensitive phenotypes have helped us understand macromolecular assembly and biological phenomena, yet few attempts have been made to understand the basis of cold sensitivity or to elicit it by design. We report a method for rational design of cold-sensitive phenotypes. The method involves generation of partial loss-of-function mutants, at either buried or functional sites, coupled with selective overexpression strategies. The only essential input is amino acid sequence, although available structural information can be used as well. The method has been used to elicit cold-sensitive mutants of a variety of proteins, both monomeric and dimeric, and in multiple organisms, namely Escherichia coli, Saccharomyces cerevisiae, and Drosophila melanogaster This simple, yet effective technique of inducing cold sensitivity eliminates the need for complex mutations and provides a plausible molecular mechanism for eliciting cold-sensitive phenotypes. PMID:27091994

  6. Target deconvolution techniques in modern phenotypic profiling

    PubMed Central

    Lee, Jiyoun; Bogyo, Matthew

    2013-01-01

    The past decade has seen rapid growth in the use of diverse compound libraries in classical phenotypic screens to identify modulators of a given process. The subsequent process of identifying the molecular targets of active hits, also called ‘target deconvolution’, is an essential step for understanding compound mechanism of action and for using the identified hits as tools for further dissection of a given biological process. Recent advances in ‘omics’ technologies, coupled with in silico approaches and the reduced cost of whole genome sequencing, have greatly improved the workflow of target deconvolution and have contributed to a renaissance of ‘modern’ phenotypic profiling. In this review, we will outline how both new and old techniques are being used in the difficult process of target identification and validation as well as discuss some of the ongoing challenges remaining for phenotypic screening. PMID:23337810

  7. The Phenotype of Spontaneous Preterm Birth: Application of a Clinical Phenotyping Tool

    PubMed Central

    Manuck, Tracy A.; Esplin, M. Sean; Biggio, Joseph; Bukowski, Radek; Parry, Samuel; Zhang, Heping; Varner, Michael W.; Andrews, William; Saade, George; Sadovsky, Yoel; Reddy, Uma M.; Ilekis, John

    2015-01-01

    Objective Spontaneous preterm birth (SPTB) is a complex condition that is likely a final common pathway with multiple possible etiologies. We hypothesized that a comprehensive classification system could appropriately group women with similar STPB etiologies, and provide an explanation, at least in part, for the disparities in SPTB associated with race and gestational age at delivery. Study Design Planned analysis of a multicenter, prospective study of singleton SPTB. Women with SPTB < 34 weeks were included. We defined 9 potential SPTB phenotypes based on clinical data, including infection/inflammation, maternal stress, decidual hemorrhage, uterine distention, cervical insufficiency, placental dysfunction, premature rupture of the membranes, maternal comorbidities, and familial factors. Each woman was evaluated for each phenotype. Delivery gestational age was compared between those with and without each phenotype. Phenotype profiles were also compared between women with very early (20.0–27.9 weeks) SPTB vs. those with early SPTB (28.0–34.0 weeks), and between African-American and Caucasian women. Statistical analysis was by t-test and chi-square as appropriate. Results The phenotyping tool was applied to 1025 women with SPTB who delivered at a mean 30.0 (+/− 3.2) weeks gestation. Of these, 800 (78%) had ≥2 phenotypes. Only 43 (4.2%) had no phenotypes. The 281 women with early SPTB were more likely to have infection/inflammation, decidual hemorrhage, and cervical insufficiency phenotypes (all p≤0.001). African-American women had more maternal stress and cervical insufficiency but less decidual hemorrhage and placental dysfunction compared to Caucasian women (all p<0.05). Gestational age at delivery decreased as the number of phenotypes present increased. Conclusions Precise SPTB phenotyping classifies women with SPTB and identifies specific differences between very early and early SPTB and between African-Americans and Caucasians. PMID:25687564

  8. Phenotypic approaches to drought in cassava: review

    PubMed Central

    Okogbenin, Emmanuel; Setter, Tim L.; Ferguson, Morag; Mutegi, Rose; Ceballos, Hernan; Olasanmi, Bunmi; Fregene, Martin

    2012-01-01

    Cassava is an important crop in Africa, Asia, Latin America, and the Caribbean. Cassava can be produced adequately in drought conditions making it the ideal food security crop in marginal environments. Although cassava can tolerate drought stress, it can be genetically improved to enhance productivity in such environments. Drought adaptation studies in over three decades in cassava have identified relevant mechanisms which have been explored in conventional breeding. Drought is a quantitative trait and its multigenic nature makes it very challenging to effectively manipulate and combine genes in breeding for rapid genetic gain and selection process. Cassava has a long growth cycle of 12–18 months which invariably contributes to a long breeding scheme for the crop. Modern breeding using advances in genomics and improved genotyping, is facilitating the dissection and genetic analysis of complex traits including drought tolerance, thus helping to better elucidate and understand the genetic basis of such traits. A beneficial goal of new innovative breeding strategies is to shorten the breeding cycle using minimized, efficient or fast phenotyping protocols. While high throughput genotyping have been achieved, this is rarely the case for phenotyping for drought adaptation. Some of the storage root phenotyping in cassava are often done very late in the evaluation cycle making selection process very slow. This paper highlights some modified traits suitable for early-growth phase phenotyping that may be used to reduce drought phenotyping cycle in cassava. Such modified traits can significantly complement the high throughput genotyping procedures to fast track breeding of improved drought tolerant varieties. The need for metabolite profiling, improved phenomics to take advantage of next generation sequencing technologies and high throughput phenotyping are basic steps for future direction to improve genetic gain and maximize speed for drought tolerance breeding. PMID

  9. Phenotypic approaches to drought in cassava: review.

    PubMed

    Okogbenin, Emmanuel; Setter, Tim L; Ferguson, Morag; Mutegi, Rose; Ceballos, Hernan; Olasanmi, Bunmi; Fregene, Martin

    2013-01-01

    Cassava is an important crop in Africa, Asia, Latin America, and the Caribbean. Cassava can be produced adequately in drought conditions making it the ideal food security crop in marginal environments. Although cassava can tolerate drought stress, it can be genetically improved to enhance productivity in such environments. Drought adaptation studies in over three decades in cassava have identified relevant mechanisms which have been explored in conventional breeding. Drought is a quantitative trait and its multigenic nature makes it very challenging to effectively manipulate and combine genes in breeding for rapid genetic gain and selection process. Cassava has a long growth cycle of 12-18 months which invariably contributes to a long breeding scheme for the crop. Modern breeding using advances in genomics and improved genotyping, is facilitating the dissection and genetic analysis of complex traits including drought tolerance, thus helping to better elucidate and understand the genetic basis of such traits. A beneficial goal of new innovative breeding strategies is to shorten the breeding cycle using minimized, efficient or fast phenotyping protocols. While high throughput genotyping have been achieved, this is rarely the case for phenotyping for drought adaptation. Some of the storage root phenotyping in cassava are often done very late in the evaluation cycle making selection process very slow. This paper highlights some modified traits suitable for early-growth phase phenotyping that may be used to reduce drought phenotyping cycle in cassava. Such modified traits can significantly complement the high throughput genotyping procedures to fast track breeding of improved drought tolerant varieties. The need for metabolite profiling, improved phenomics to take advantage of next generation sequencing technologies and high throughput phenotyping are basic steps for future direction to improve genetic gain and maximize speed for drought tolerance breeding. PMID

  10. Phenotypically heterogeneous populations in spatially heterogeneous environments

    NASA Astrophysics Data System (ADS)

    Patra, Pintu; Klumpp, Stefan

    2014-03-01

    The spatial expansion of a population in a nonuniform environment may benefit from phenotypic heterogeneity with interconverting subpopulations using different survival strategies. We analyze the crossing of an antibiotic-containing environment by a bacterial population consisting of rapidly growing normal cells and slow-growing, but antibiotic-tolerant persister cells. The dynamics of crossing is characterized by mean first arrival times and is found to be surprisingly complex. It displays three distinct regimes with different scaling behavior that can be understood based on an analytical approximation. Our results suggest that a phenotypically heterogeneous population has a fitness advantage in nonuniform environments and can spread more rapidly than a homogeneous population.

  11. Lung cancer stem cells—characteristics, phenotype

    PubMed Central

    George, Rachel; Sethi, Tariq

    2016-01-01

    Lung cancer remains a major cause of cancer-related deaths worldwide with unfavourable prognosis mainly due to the late stage of disease at presentation. High incidence and disease recurrence rates are a fact despite advances in treatment. Ongoing experimental and clinical observations suggest that the malignant phenotype in lung cancer is sustained by lung cancer stem cells (CSCs) which are putative stem cells situated throughout the airways that have the potential of initiating lung cancer formation. These cells share the common characteristic of increased proliferation and differentiation, long life span and resistance to chemotherapy and radiation therapy. This review summarises the current knowledge on their characteristics and phenotype. PMID:27413709

  12. Discovery of the gray phenotype and white-gray-opaque tristable phenotypic transitions in Candida dubliniensis.

    PubMed

    Yue, Huizhen; Hu, Jian; Guan, Guobo; Tao, Li; Du, Han; Li, Houmin; Huang, Guanghua

    2016-04-01

    Candida dubliniensis is closely related to Candida albicans, a major causative agent of candidiasis, and is primarily associated with oral colonization and infection in human immunodeficiency virus (HIV)-positive patients. Despite the high similarity of genomic and phenotypic features between the 2 species, C. dubliniensis is much less virulent and less prevalent than C. albicans. The ability to change morphological phenotypes is a striking feature of Candida species and is linked to virulence. In this study, we report a novel phenotype, the gray phenotype, in C. dubliniensis. Together with the previously reported white and opaque cell types, the gray phenotype forms a tristable phenotypic switching system in C. dubliniensis that is similar to the white-gray-opaque tristable switching system in C. albicans. Gray cells of C. dubliniensis are similar to their counterparts in C. albicans in terms of several biological aspects including cellular morphology, mating competence, and genetic regulatory mechanisms. However, the gray phenotypes of the 2 species have some distinguishing features. For example, the secreted aspartyl protease (Sap) activity is induced by bovine serum albumin (BSA) in gray cells of C. albicans, but not in gray cells of C. dubliniensis. Taken together, our results demonstrate that the biological features and regulatory mechanisms of white-gray-opaque tristable transitions are largely conserved in the 2 pathogenic Candida species. PMID:26714067

  13. Parasitism and phenotypic change in colonial hosts.

    PubMed

    Hartikainen, Hanna; Fontes, Inês; Okamura, Beth

    2013-09-01

    Changes in host phenotype are often attributed to manipulation that enables parasites to complete trophic transmission cycles. We characterized changes in host phenotype in a colonial host–endoparasite system that lacks trophic transmission (the freshwater bryozoan Fredericella sultana and myxozoan parasite Tetracapsuloides bryosalmonae). We show that parasitism exerts opposing phenotypic effects at the colony and module levels. Thus, overt infection (the development of infectious spores in the host body cavity) was linked to a reduction in colony size and growth rate, while colony modules exhibited a form of gigantism. Larger modules may support larger parasite sacs and increase metabolite availability to the parasite. Host metabolic rates were lower in overtly infected relative to uninfected hosts that were not investing in propagule production. This suggests a role for direct resource competition and active parasite manipulation (castration) in driving the expression of the infected phenotype. The malformed offspring (statoblasts) of infected colonies had greatly reduced hatching success. Coupled with the severe reduction in statoblast production this suggests that vertical transmission is rare in overtly infected modules. We show that although the parasite can occasionally infect statoblasts during overt infections, no infections were detected in the surviving mature offspring, suggesting that during overt infections, horizontal transmission incurs a trade-off with vertical transmission. PMID:23965820

  14. Restoration of normal phenotype in cancer cells

    DOEpatents

    Bissell, Mina J.; Weaver, Valerie M.

    1998-01-01

    A method for reversing expression of malignant phenotype in cancer cells is described. The method comprises applying .beta..sub.1 integrin function-blocking antibody to the cells. The method can be used to assess the progress of cancer therapy. Human breast epithelial cells were shown to be particularly responsive.

  15. Restoration of normal phenotype in cancer cells

    DOEpatents

    Bissell, M.J.; Weaver, V.M.

    1998-12-08

    A method for reversing expression of malignant phenotype in cancer cells is described. The method comprises applying {beta}{sub 1} integrin function-blocking antibody to the cells. The method can be used to assess the progress of cancer therapy. Human breast epithelial cells were shown to be particularly responsive. 14 figs.

  16. Behavioural Phenotypes in Disability Research: Historical Perspectives

    ERIC Educational Resources Information Center

    Goodey, C. F.

    2006-01-01

    Western medicine has a long history of accounting for behaviour by reducing the body to ultimate explanatory entities. In pre-modern medicine these were invisible "animal spirits" circulating the body. In modern medicine, they are "genes". Both raise questions. The psychological phenotype is defined by human consensus, varying according to time…

  17. Phenotypic mutant library: potential for gene discovery

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The rapid development of high throughput and affordable Next- Generation Sequencing (NGS) techniques has renewed interest in gene discovery using forward genetics. The conventional forward genetic approach starts with isolation of mutants with a phenotype of interest, mapping the mutation within a s...

  18. Phenotype as Agent for Epigenetic Inheritance.

    PubMed

    Torday, John S; Miller, William B

    2016-01-01

    The conventional understanding of phenotype is as a derivative of descent with modification through Darwinian random mutation and natural selection. Recent research has revealed Lamarckian inheritance as a major transgenerational mechanism for environmental action on genomes whose extent is determined, in significant part, by germ line cells during meiosis and subsequent stages of embryological development. In consequence, the role of phenotype can productively be reconsidered. The possibility that phenotype is directed towards the effective acquisition of epigenetic marks in consistent reciprocation with the environment during the life cycle of an organism is explored. It is proposed that phenotype is an active agent in niche construction for the active acquisition of epigenetic marks as a dominant evolutionary mechanism rather than a consequence of Darwinian selection towards reproductive success. The reproductive phase of the life cycle can then be appraised as a robust framework in which epigenetic inheritance is entrained to affect growth and development in continued reciprocal responsiveness to environmental stresses. Furthermore, as first principles of physiology determine the limits of epigenetic inheritance, a coherent justification can thereby be provided for the obligate return of all multicellular eukaryotes to the unicellular state. PMID:27399791

  19. Biodiversity of spoilage lactobacilli: phenotypic characterisation.

    PubMed

    Sanders, J W; Oomes, S J C M; Membré, J-M; Wegkamp, A; Wels, M

    2015-02-01

    Preventing food spoilage is a challenge for the food industry, especially when applying mild preservation methods and when avoiding the use of preservatives. Therefore, it is essential to explore the boundaries of preservation by better understanding the causative microbes, their phenotypic behaviour and their genetic makeup. Traditionally in food microbiology, single strains or small sets of selected strains are studied. Here a collection of 120 strains of 6 different spoilage related Lactobacillus species and a multitude of sources was prepared and their growth characteristics determined in 384-well plates by optical density measurements (OD) over 20 days, for 20 carbon source-related phenotypic parameters and 25 preservation-related phenotypic parameters. Growth under all conditions was highly strain specific and there was no correlation of phenotypes at the species level. On average Lactobacillus brevis strains were amongst the most robust whereas Lactobacillus fructivorans strains had a much narrower growth range. The biodiversity data allowed the definition of preservation boundaries on the basis of the number of Lactobacillus strains that reached a threshold OD, which is different from current methods that are based on growth ability or growth rate of a few selected strains. Genetic information on these microbes and a correlation study will improve the mechanistic understanding of preservation resistance and this will support the future development of superior screening and preservation methods. PMID:25481060

  20. PRIMARY CILIARY DYSKINESIA: DIAGNOSTIC AND PHENOTYPIC FEATURES

    EPA Science Inventory

    Primary ciliary dyskinesia (PCD) is a genetic disease characterized by abnormalities in ciliary structure/function. We hypothesized that the major clinical and biologic phenotypic markers of the disease could be evaluated by studying a cohort of subjects suspected of having PCD. ...

  1. Dynamic Environmental Photosynthetic Imaging Reveals Emergent Phenotypes.

    PubMed

    Cruz, Jeffrey A; Savage, Linda J; Zegarac, Robert; Hall, Christopher C; Satoh-Cruz, Mio; Davis, Geoffry A; Kovac, William Kent; Chen, Jin; Kramer, David M

    2016-06-22

    Understanding and improving the productivity and robustness of plant photosynthesis requires high-throughput phenotyping under environmental conditions that are relevant to the field. Here we demonstrate the dynamic environmental photosynthesis imager (DEPI), an experimental platform for integrated, continuous, and high-throughput measurements of photosynthetic parameters during plant growth under reproducible yet dynamic environmental conditions. Using parallel imagers obviates the need to move plants or sensors, reducing artifacts and allowing simultaneous measurement on large numbers of plants. As a result, DEPI can reveal phenotypes that are not evident under standard laboratory conditions but emerge under progressively more dynamic illumination. We show examples in mutants of Arabidopsis of such "emergent phenotypes" that are highly transient and heterogeneous, appearing in different leaves under different conditions and depending in complex ways on both environmental conditions and plant developmental age. These emergent phenotypes appear to be caused by a range of phenomena, suggesting that such previously unseen processes are critical for plant responses to dynamic environments. PMID:27336966

  2. Phenotypic plasticity with instantaneous but delayed switches.

    PubMed

    Utz, Margarete; Jeschke, Jonathan M; Loeschcke, Volker; Gabriel, Wilfried

    2014-01-01

    Phenotypic plasticity is a widespread phenomenon, allowing organisms to better adapt to changing environments. Most empirical and theoretical studies are restricted to irreversible plasticity where the expression of a specific phenotype is mostly determined during development. However, reversible plasticity is not uncommon; here, organisms are able to switch back and forth between phenotypes. We present two optimization models for the fitness of (i) non-plastic, (ii) irreversibly plastic, and (iii) reversibly plastic genotypes in a fluctuating environment. In one model, the fitness values of an organism during different life phases act together multiplicatively (so as to consider traits that are related to survival). The other model additionally considers additive effects (corresponding to traits related to fecundity). Both models yield qualitatively similar results. If the only costs of reversible plasticity are due to temporal maladaptation while switching between phenotypes, reversibility is virtually always advantageous over irreversibility, especially for slow environmental fluctuations. If reversibility implies an overall decreased fitness, then irreversibility is advantageous if the environment fluctuates quickly or if stress events last relatively short. Our results are supported by observations from different types of organisms and have implications for many basic and applied research questions, e.g., on invasive alien species. PMID:24041594

  3. Cognitive Phenotype of Velocardiofacial Syndrome: A Review

    ERIC Educational Resources Information Center

    Furniss, Frederick; Biswas, Asit B.; Gumber, Rohit; Singh, Niraj

    2011-01-01

    The behavioural phenotype of velocardiofacial syndrome (VCFS), one of the most common human multiple anomaly syndromes, includes developmental disabilities, frequently including intellectual disability (ID) and high risk of diagnosis of psychotic disorders including schizophrenia. VCFS may offer a model of the relationship between ID and risk of…

  4. KSHV Induction of Angiogenic and Lymphangiogenic Phenotypes

    PubMed Central

    DiMaio, Terri A.; Lagunoff, Michael

    2012-01-01

    Kaposi’s sarcoma (KS) is a highly vascularized tumor supporting large amounts of neo-angiogenesis. The major cell type in KS tumors is the spindle cell, a cell that expresses markers of lymphatic endothelium. KSHV, the etiologic agent of KS, is found in the spindle cells of all KS tumors. Considering the extreme extent of angiogenesis in KS tumors at all stages it has been proposed that KSHV directly induces angiogenesis in a paracrine fashion. In accordance with this theory, KSHV infection of endothelial cells in culture induces a number of host pathways involved in activation of angiogenesis and a number of KSHV genes themselves can induce pathways involved in angiogenesis. Spindle cells are phenotypically endothelial in nature, and therefore, activation through the induction of angiogenic and/or lymphangiogenic phenotypes by the virus may also be directly involved in spindle cell growth and tumor induction. Accordingly, KSHV infection of endothelial cells induces cell autonomous angiogenic phenotypes to activate host cells. KSHV infection can also reprogram blood endothelial cells to lymphatic endothelium. However, KSHV induces some blood endothelial specific genes upon infection of lymphatic endothelial cells creating a phenotypic intermediate between blood and lymphatic endothelium. Induction of pathways involved in angiogenesis and lymphangiogenesis are likely to be critical for tumor cell growth and spread. Thus, induction of both cell autonomous and non-autonomous changes in angiogenic and lymphangiogenic pathways by KSHV likely plays a key role in the formation of KS tumors. PMID:22479258

  5. The Behavioural Phenotype of Angelman Syndrome

    ERIC Educational Resources Information Center

    Horsler, K.; Oliver, C.

    2006-01-01

    Background: The purpose of this review is to examine the notion of a behavioural phenotype for Angelman syndrome and identify methodological and conceptual influences on the accepted presentation. Methods: Studies examining the behavioural characteristics associated with Angelman syndrome are reviewed and methodology is described. Results:…

  6. Radiofrequency treatment alters cancer cell phenotype

    NASA Astrophysics Data System (ADS)

    Ware, Matthew J.; Tinger, Sophia; Colbert, Kevin L.; Corr, Stuart J.; Rees, Paul; Koshkina, Nadezhda; Curley, Steven; Summers, H. D.; Godin, Biana

    2015-07-01

    The importance of evaluating physical cues in cancer research is gradually being realized. Assessment of cancer cell physical appearance, or phenotype, may provide information on changes in cellular behavior, including migratory or communicative changes. These characteristics are intrinsically different between malignant and non-malignant cells and change in response to therapy or in the progression of the disease. Here, we report that pancreatic cancer cell phenotype was altered in response to a physical method for cancer therapy, a non-invasive radiofrequency (RF) treatment, which is currently being developed for human trials. We provide a battery of tests to explore these phenotype characteristics. Our data show that cell topography, morphology, motility, adhesion and division change as a result of the treatment. These may have consequences for tissue architecture, for diffusion of anti-cancer therapeutics and cancer cell susceptibility within the tumor. Clear phenotypical differences were observed between cancerous and normal cells in both their untreated states and in their response to RF therapy. We also report, for the first time, a transfer of microsized particles through tunneling nanotubes, which were produced by cancer cells in response to RF therapy. Additionally, we provide evidence that various sub-populations of cancer cells heterogeneously respond to RF treatment.

  7. Characterizing the ADHD Phenotype for Genetic Studies

    ERIC Educational Resources Information Center

    Stevenson, Jim; Asherson, Phil; Hay, David; Levy, Florence; Swanson, Jim; Thapar, Anita; Willcutt, Erik

    2005-01-01

    The genetic study of ADHD has made considerable progress. Further developments in the field will be reliant in part on identifying the most appropriate phenotypes for genetic analysis. The use of both categorical and dimensional measures of symptoms related to ADHD has been productive. The use of multiple reporters is a valuable feature of the…

  8. Radiofrequency treatment alters cancer cell phenotype

    PubMed Central

    Ware, Matthew J.; Tinger, Sophia; Colbert, Kevin L.; Corr, Stuart J.; Rees, Paul; Koshkina, Nadezhda; Curley, Steven; Summers, H. D.; Godin, Biana

    2015-01-01

    The importance of evaluating physical cues in cancer research is gradually being realized. Assessment of cancer cell physical appearance, or phenotype, may provide information on changes in cellular behavior, including migratory or communicative changes. These characteristics are intrinsically different between malignant and non-malignant cells and change in response to therapy or in the progression of the disease. Here, we report that pancreatic cancer cell phenotype was altered in response to a physical method for cancer therapy, a non-invasive radiofrequency (RF) treatment, which is currently being developed for human trials. We provide a battery of tests to explore these phenotype characteristics. Our data show that cell topography, morphology, motility, adhesion and division change as a result of the treatment. These may have consequences for tissue architecture, for diffusion of anti-cancer therapeutics and cancer cell susceptibility within the tumor. Clear phenotypical differences were observed between cancerous and normal cells in both their untreated states and in their response to RF therapy. We also report, for the first time, a transfer of microsized particles through tunneling nanotubes, which were produced by cancer cells in response to RF therapy. Additionally, we provide evidence that various sub-populations of cancer cells heterogeneously respond to RF treatment. PMID:26165830

  9. Phenotypic extremes in rare variant study designs.

    PubMed

    Peloso, Gina M; Rader, Daniel J; Gabriel, Stacey; Kathiresan, Sekar; Daly, Mark J; Neale, Benjamin M

    2016-06-01

    Currently, next-generation sequencing studies aim to identify rare and low-frequency variation that may contribute to disease. For a given effect size, as the allele frequency decreases, the power to detect genes or variants of interest also decreases. Although many methods have been proposed for the analysis of such data, study design and analytic issues still persist in data interpretation. In this study we present sequencing data for ABCA1 that has known rare variants associated with high-density lipoprotein cholesterol (HDL-C). We contrast empirical findings from two study designs: a phenotypic extreme sample and a population-based random sample. We found differing strengths of association with HDL-C across the two study designs (P=0.0006 with n=701 phenotypic extremes vs P=0.03 with n=1600 randomly sampled individuals). To explore this apparent difference in evidence for association, we performed a simulation study focused on the impact of phenotypic selection on power. We demonstrate that the power gain for an extreme phenotypic selection study design is much greater in rare variant studies than for studies of common variants. Our study confirms that studying phenotypic extremes is critical in rare variant studies because it boosts power in two ways: the typical increases from extreme sampling and increasing the proportion of relevant functional variants ascertained and thereby tested for association. Furthermore, we show that when combining statistical evidence through meta-analysis from an extreme-selected sample and a second separate population-based random sample, power is lower when a traditional sample size weighting is used compared with weighting by the noncentrality parameter. PMID:26350511

  10. Determining which phenotypes underlie a pleiotropic signal

    PubMed Central

    Majumdar, Arunabha; Haldar, Tanushree; Witte, John S.

    2016-01-01

    Discovering pleiotropic loci is important to understand the biological basis of seemingly distinct phenotypes. Most methods for assessing pleiotropy only test for the overall association between genetic variants and multiple phenotypes. To determine which specific traits are pleiotropic, we evaluate via simulation and application three different strategies. The first is model selection techniques based on the inverse regression of genotype on phenotypes. The second is a subset-based meta-analysis ASSET [Bhattacharjee et al., 2012], which provides an optimal subset of non-null traits. And the third is a modified Benjamini-Hochberg (B-H) procedure of controlling the expected false discovery rate [Benjamini and Hochberg, 1995] in the framework of phenome-wide association study. From our simulations we see that an inverse regression based approach MultiPhen [O’Reilly et al., 2012] is more powerful than ASSET for detecting overall pleiotropic association, except for when all the phenotypes are associated and have genetic effects in the same direction. For determining which specific traits are pleiotropic, the modified B-H procedure performs consistently better than the other two methods. The inverse regression based selection methods perform competitively with the modified B-H procedure only when the phenotypes are weakly correlated. The efficiency of ASSET is observed to lie below and in between the efficiency of the other two methods when the traits are weakly and strongly correlated, respectively. In our application to a large GWAS, we find that the modified B-H procedure also performs well, indicating that this may be an optimal approach for determining the traits underlying a pleiotropic signal. PMID:27238845

  11. Determining Which Phenotypes Underlie a Pleiotropic Signal.

    PubMed

    Majumdar, Arunabha; Haldar, Tanushree; Witte, John S

    2016-07-01

    Discovering pleiotropic loci is important to understand the biological basis of seemingly distinct phenotypes. Most methods for assessing pleiotropy only test for the overall association between genetic variants and multiple phenotypes. To determine which specific traits are pleiotropic, we evaluate via simulation and application three different strategies. The first is model selection techniques based on the inverse regression of genotype on phenotypes. The second is a subset-based meta analysis ASSET [Bhattacharjee et al., ], which provides an optimal subset of nonnull traits. And the third is a modified Benjamini-Hochberg (B-H) procedure of controlling the expected false discovery rate [Benjamini and Hochberg, ] in the framework of phenome-wide association study. From our simulations we see that an inverse regression-based approach MultiPhen [O'Reilly et al., ] is more powerful than ASSET for detecting overall pleiotropic association, except for when all the phenotypes are associated and have genetic effects in the same direction. For determining which specific traits are pleiotropic, the modified B-H procedure performs consistently better than the other two methods. The inverse regression-based selection methods perform competitively with the modified B-H procedure only when the phenotypes are weakly correlated. The efficiency of ASSET is observed to lie below and in between the efficiency of the other two methods when the traits are weakly and strongly correlated, respectively. In our application to a large GWAS, we find that the modified B-H procedure also performs well, indicating that this may be an optimal approach for determining the traits underlying a pleiotropic signal. PMID:27238845

  12. Imputing Phenotypes for Genome-wide Association Studies.

    PubMed

    Hormozdiari, Farhad; Kang, Eun Yong; Bilow, Michael; Ben-David, Eyal; Vulpe, Chris; McLachlan, Stela; Lusis, Aldons J; Han, Buhm; Eskin, Eleazar

    2016-07-01

    Genome-wide association studies (GWASs) have been successful in detecting variants correlated with phenotypes of clinical interest. However, the power to detect these variants depends on the number of individuals whose phenotypes are collected, and for phenotypes that are difficult to collect, the sample size might be insufficient to achieve the desired statistical power. The phenotype of interest is often difficult to collect, whereas surrogate phenotypes or related phenotypes are easier to collect and have already been collected in very large samples. This paper demonstrates how we take advantage of these additional related phenotypes to impute the phenotype of interest or target phenotype and then perform association analysis. Our approach leverages the correlation structure between phenotypes to perform the imputation. The correlation structure can be estimated from a smaller complete dataset for which both the target and related phenotypes have been collected. Under some assumptions, the statistical power can be computed analytically given the correlation structure of the phenotypes used in imputation. In addition, our method can impute the summary statistic of the target phenotype as a weighted linear combination of the summary statistics of related phenotypes. Thus, our method is applicable to datasets for which we have access only to summary statistics and not to the raw genotypes. We illustrate our approach by analyzing associated loci to triglycerides (TGs), body mass index (BMI), and systolic blood pressure (SBP) in the Northern Finland Birth Cohort dataset. PMID:27292110

  13. Belief propagation in genotype-phenotype networks.

    PubMed

    Moharil, Janhavi; May, Paul; Gaile, Daniel P; Blair, Rachael Hageman

    2016-03-01

    Graphical models have proven to be a valuable tool for connecting genotypes and phenotypes. Structural learning of phenotype-genotype networks has received considerable attention in the post-genome era. In recent years, a dozen different methods have emerged for network inference, which leverage natural variation that arises in certain genetic populations. The structure of the network itself can be used to form hypotheses based on the inferred direct and indirect network relationships, but represents a premature endpoint to the graphical analyses. In this work, we extend this endpoint. We examine the unexplored problem of perturbing a given network structure, and quantifying the system-wide effects on the network in a node-wise manner. The perturbation is achieved through the setting of values of phenotype node(s), which may reflect an inhibition or activation, and propagating this information through the entire network. We leverage belief propagation methods in Conditional Gaussian Bayesian Networks (CG-BNs), in order to absorb and propagate phenotypic evidence through the network. We show that the modeling assumptions adopted for genotype-phenotype networks represent an important sub-class of CG-BNs, which possess properties that ensure exact inference in the propagation scheme. The system-wide effects of the perturbation are quantified in a node-wise manner through the comparison of perturbed and unperturbed marginal distributions using a symmetric Kullback-Leibler divergence. Applications to kidney and skin cancer expression quantitative trait loci (eQTL) data from different mus musculus populations are presented. System-wide effects in the network were predicted and visualized across a spectrum of evidence. Sub-pathways and regions of the network responded in concert, suggesting co-regulation and coordination throughout the network in response to phenotypic changes. We demonstrate how these predicted system-wide effects can be examined in connection with

  14. The Human Phenotype Ontology project: linking molecular biology and disease through phenotype data.

    PubMed

    Köhler, Sebastian; Doelken, Sandra C; Mungall, Christopher J; Bauer, Sebastian; Firth, Helen V; Bailleul-Forestier, Isabelle; Black, Graeme C M; Brown, Danielle L; Brudno, Michael; Campbell, Jennifer; FitzPatrick, David R; Eppig, Janan T; Jackson, Andrew P; Freson, Kathleen; Girdea, Marta; Helbig, Ingo; Hurst, Jane A; Jähn, Johanna; Jackson, Laird G; Kelly, Anne M; Ledbetter, David H; Mansour, Sahar; Martin, Christa L; Moss, Celia; Mumford, Andrew; Ouwehand, Willem H; Park, Soo-Mi; Riggs, Erin Rooney; Scott, Richard H; Sisodiya, Sanjay; Van Vooren, Steven; Wapner, Ronald J; Wilkie, Andrew O M; Wright, Caroline F; Vulto-van Silfhout, Anneke T; de Leeuw, Nicole; de Vries, Bert B A; Washingthon, Nicole L; Smith, Cynthia L; Westerfield, Monte; Schofield, Paul; Ruef, Barbara J; Gkoutos, Georgios V; Haendel, Melissa; Smedley, Damian; Lewis, Suzanna E; Robinson, Peter N

    2014-01-01

    The Human Phenotype Ontology (HPO) project, available at http://www.human-phenotype-ontology.org, provides a structured, comprehensive and well-defined set of 10,088 classes (terms) describing human phenotypic abnormalities and 13,326 subclass relations between the HPO classes. In addition we have developed logical definitions for 46% of all HPO classes using terms from ontologies for anatomy, cell types, function, embryology, pathology and other domains. This allows interoperability with several resources, especially those containing phenotype information on model organisms such as mouse and zebrafish. Here we describe the updated HPO database, which provides annotations of 7,278 human hereditary syndromes listed in OMIM, Orphanet and DECIPHER to classes of the HPO. Various meta-attributes such as frequency, references and negations are associated with each annotation. Several large-scale projects worldwide utilize the HPO for describing phenotype information in their datasets. We have therefore generated equivalence mappings to other phenotype vocabularies such as LDDB, Orphanet, MedDRA, UMLS and phenoDB, allowing integration of existing datasets and interoperability with multiple biomedical resources. We have created various ways to access the HPO database content using flat files, a MySQL database, and Web-based tools. All data and documentation on the HPO project can be found online. PMID:24217912

  15. The Human Phenotype Ontology project: linking molecular biology and disease through phenotype data

    PubMed Central

    Köhler, Sebastian; Doelken, Sandra C.; Mungall, Christopher J.; Bauer, Sebastian; Firth, Helen V.; Bailleul-Forestier, Isabelle; Black, Graeme C. M.; Brown, Danielle L.; Brudno, Michael; Campbell, Jennifer; FitzPatrick, David R.; Eppig, Janan T.; Jackson, Andrew P.; Freson, Kathleen; Girdea, Marta; Helbig, Ingo; Hurst, Jane A.; Jähn, Johanna; Jackson, Laird G.; Kelly, Anne M.; Ledbetter, David H.; Mansour, Sahar; Martin, Christa L.; Moss, Celia; Mumford, Andrew; Ouwehand, Willem H.; Park, Soo-Mi; Riggs, Erin Rooney; Scott, Richard H.; Sisodiya, Sanjay; Vooren, Steven Van; Wapner, Ronald J.; Wilkie, Andrew O. M.; Wright, Caroline F.; Vulto-van Silfhout, Anneke T.; de Leeuw, Nicole; de Vries, Bert B. A.; Washingthon, Nicole L.; Smith, Cynthia L.; Westerfield, Monte; Schofield, Paul; Ruef, Barbara J.; Gkoutos, Georgios V.; Haendel, Melissa; Smedley, Damian; Lewis, Suzanna E.; Robinson, Peter N.

    2014-01-01

    The Human Phenotype Ontology (HPO) project, available at http://www.human-phenotype-ontology.org, provides a structured, comprehensive and well-defined set of 10,088 classes (terms) describing human phenotypic abnormalities and 13,326 subclass relations between the HPO classes. In addition we have developed logical definitions for 46% of all HPO classes using terms from ontologies for anatomy, cell types, function, embryology, pathology and other domains. This allows interoperability with several resources, especially those containing phenotype information on model organisms such as mouse and zebrafish. Here we describe the updated HPO database, which provides annotations of 7,278 human hereditary syndromes listed in OMIM, Orphanet and DECIPHER to classes of the HPO. Various meta-attributes such as frequency, references and negations are associated with each annotation. Several large-scale projects worldwide utilize the HPO for describing phenotype information in their datasets. We have therefore generated equivalence mappings to other phenotype vocabularies such as LDDB, Orphanet, MedDRA, UMLS and phenoDB, allowing integration of existing datasets and interoperability with multiple biomedical resources. We have created various ways to access the HPO database content using flat files, a MySQL database, and Web-based tools. All data and documentation on the HPO project can be found online. PMID:24217912

  16. Understanding COPD: A vision on phenotypes, comorbidities and treatment approach.

    PubMed

    Fragoso, E; André, S; Boleo-Tomé, J P; Areias, V; Munhá, J; Cardoso, J

    2016-01-01

    Chronic Obstructive Pulmonary Disease (COPD) phenotypes have become increasingly recognized as important for grouping patients with similar presentation and/or behavior, within the heterogeneity of the disease. The primary aim of identifying phenotypes is to provide patients with the best health care possible, tailoring the therapeutic approach to each patient. However, the identification of specific phenotypes has been hindered by several factors such as which specific attributes are relevant, which discriminant features should be used for assigning patients to specific phenotypes, and how relevant are they to the therapeutic approach, prognostic and clinical outcome. Moreover, the definition of phenotype is still not consensual. Comorbidities, risk factors, modifiable risk factors and disease severity, although not phenotypes, have impact across all COPD phenotypes. Although there are some identified phenotypes that are fairly consensual, many others have been proposed, but currently lack validation. The on-going debate about which instruments and tests should be used in the identification and definition of phenotypes has contributed to this uncertainty. In this paper, the authors review present knowledge regarding COPD phenotyping, discuss the role of phenotypes and comorbidities on the severity of COPD, propose new phenotypes and suggest a phenotype-based pharmacological therapeutic approach. The authors conclude that a patient-tailored treatment approach, which takes into account each patient's specific attributes and specificities, should be pursued. PMID:26827246

  17. Expanding the phenotype of GMPPB mutations.

    PubMed

    Cabrera-Serrano, Macarena; Ghaoui, Roula; Ravenscroft, Gianina; Johnsen, Russell D; Davis, Mark R; Corbett, Alastair; Reddel, Stephen; Sue, Carolyn M; Liang, Christina; Waddell, Leigh B; Kaur, Simranpreet; Lek, Monkol; North, Kathryn N; MacArthur, Daniel G; Lamont, Phillipa J; Clarke, Nigel F; Laing, Nigel G

    2015-04-01

    Dystroglycanopathies are a heterogeneous group of diseases with a broad phenotypic spectrum ranging from severe disorders with congenital muscle weakness, eye and brain structural abnormalities and intellectual delay to adult-onset limb-girdle muscular dystrophies without mental retardation. Most frequently the disease onset is congenital or during childhood. The exception is FKRP mutations, in which adult onset is a common presentation. Here we report eight patients from five non-consanguineous families where next generation sequencing identified mutations in the GMPPB gene. Six patients presented as an adult or adolescent-onset limb-girdle muscular dystrophy, one presented with isolated episodes of rhabdomyolysis, and one as a congenital muscular dystrophy. This report expands the phenotypic spectrum of GMPPB mutations to include limb-girdle muscular dystrophies with adult onset with or without intellectual disability, or isolated rhabdomyolysis. PMID:25681410

  18. Discovering phenotypic causal structure from nonexperimental data.

    PubMed

    Otsuka, J

    2016-06-01

    The evolutionary potential of organisms depends on how their parts are structured into a cohesive whole. A major obstacle for empirical studies of phenotypic organization is that observed associations among characters usually confound different causal pathways such as pleiotropic modules, interphenotypic causal relationships and environmental effects. The present article proposes causal search algorithms as a new tool to distinguish these different modes of phenotypic integration. Without assuming an a priori structure, the algorithms seek a class of causal hypotheses consistent with independence relationships holding in observational data. The technique can be applied to discover causal relationships among a set of measured traits and to distinguish genuine selection from spurious correlations. The former application is illustrated with a biological data set of rat morphological measurements previously analysed by Cheverud et al. (Evolution 1983, 37, 895). PMID:27007864

  19. Advances in Human B Cell Phenotypic Profiling

    PubMed Central

    Kaminski, Denise A.; Wei, Chungwen; Qian, Yu; Rosenberg, Alexander F.; Sanz, Ignacio

    2012-01-01

    To advance our understanding and treatment of disease, research immunologists have been called-upon to place more centralized emphasis on impactful human studies. Such endeavors will inevitably require large-scale study execution and data management regulation (“Big Biology”), necessitating standardized and reliable metrics of immune status and function. A well-known example setting this large-scale effort in-motion is identifying correlations between eventual disease outcome and T lymphocyte phenotype in large HIV-patient cohorts using multiparameter flow cytometry. However, infection, immunodeficiency, and autoimmunity are also characterized by correlative and functional contributions of B lymphocytes, which to-date have received much less attention in the human Big Biology enterprise. Here, we review progress in human B cell phenotyping, analysis, and bioinformatics tools that constitute valuable resources for the B cell research community to effectively join in this effort. PMID:23087687

  20. New genes as drivers of phenotypic evolution

    PubMed Central

    Chen, Sidi; Krinsky, Benjamin H.; Long, Manyuan

    2014-01-01

    During the course of evolution, genomes acquire novel genetic elements as sources of functional and phenotypic diversity, including new genes that originated in recent evolution. In the past few years, substantial progress has been made in understanding the evolution and phenotypic effects of new genes. In particular, an emerging picture is that new genes, despite being present in the genomes of only a subset of species, can rapidly evolve indispensable roles in fundamental biological processes, including development, reproduction, brain function and behaviour. The molecular underpinnings of how new genes can develop these roles are starting to be characterized. These recent discoveries yield fresh insights into our broad understanding of biological diversity at refined resolution. PMID:23949544

  1. The phenotype range of achondrogenesis 1A.

    PubMed

    Grigelioniene, Giedre; Geiberger, Stefan; Papadogiannakis, Nikos; Mäkitie, Outi; Nishimura, Gen; Nordgren, Ann; Conner, Peter

    2013-10-01

    Achondrogenesis 1A (ACG1A; OMIM 200600) is an autosomal recessive perinatally lethal skeletal dysplasia comprising intrauterine growth failure, micromelia, minor facial anomalies, deficient ossification of the skull, absent or extremely defective spinal ossification, short beaded ribs, and short deformed long bones with a stellate appearance. ACG1A is caused by mutations in the TRIP11 gene, resulting in deficiency of the Golgi microtubule associated protein 210. In this study we describe dizygotic twins with a clinical and radiological phenotype of ACG1A who were homozygous for a novel nonsense mutation in the TRIP11 gene. In addition, another patient with a milder manifestation, not readily distinguishable from those of other lethal skeletal dysplasias, was found to be a compound heterozygote for a nonsense mutation and a deletion of the 3' end of the TRIP11 gene. We conclude that mutations of the TRIP11 gene may encompass a wider phenotypic range than previously recognized. PMID:23956106

  2. Phenotypic Signatures Arising from Unbalanced Bacterial Growth

    PubMed Central

    Tan, Cheemeng; Smith, Robert Phillip; Tsai, Ming-Chi; Schwartz, Russell; You, Lingchong

    2014-01-01

    Fluctuations in the growth rate of a bacterial culture during unbalanced growth are generally considered undesirable in quantitative studies of bacterial physiology. Under well-controlled experimental conditions, however, these fluctuations are not random but instead reflect the interplay between intra-cellular networks underlying bacterial growth and the growth environment. Therefore, these fluctuations could be considered quantitative phenotypes of the bacteria under a specific growth condition. Here, we present a method to identify “phenotypic signatures” by time-frequency analysis of unbalanced growth curves measured with high temporal resolution. The signatures are then applied to differentiate amongst different bacterial strains or the same strain under different growth conditions, and to identify the essential architecture of the gene network underlying the observed growth dynamics. Our method has implications for both basic understanding of bacterial physiology and for the classification of bacterial strains. PMID:25101949

  3. Central nervous system phenotypes in craniosynostosis

    PubMed Central

    Aldridge, Kristina; Marsh, Jeffrey L; Govier, Daniel; Richtsmeier, Joan T

    2002-01-01

    Though reduction in the number of cranial elements through loss of a suture is a recognized trend in vertebrate evolution, the premature closure of cranial sutures in humans, craniosynostosis, is considered a pathological condition. Previous research on craniosynostosis has focused primarily on the skeletal phenotype, but the intimate relationship between the developing central nervous system (CNS) and skull is well documented. We investigate the morphology of the CNS in patients with isolated craniosynostosis through an analysis of cortical and subcortical features using 3-D magnetic resonance images (MRI). Results show that a distinct CNS phenotype can be defined for specific diagnostic categories. Many differences in CNS morphology observed in the patient samples may be anticipated based on skeletal morphology, but others are not reflected in the skull. We propose a developmental approach to determining the cause of premature suture fusion, which includes investigation of the craniofacial complex as a system, rather than study of isolated tissues. PMID:12171474

  4. Evolution of environmental cues for phenotypic plasticity.

    PubMed

    Chevin, Luis-Miguel; Lande, Russell

    2015-10-01

    Phenotypically plastic characters may respond to multiple variables in their environment, but the evolutionary consequences of this phenomenon have rarely been addressed theoretically. We model the evolution of linear reaction norms in response to several correlated environmental variables, in a population undergoing stationary environmental fluctuations. At evolutionary equilibrium, the linear combination of environmental variables that acts as a developmental cue for the plastic trait is the multivariate best linear predictor of changes in the optimum. However, the reaction norm with respect to any single environmental variable may exhibit nonintuitive patterns. Apparently maladaptive, or hyperadaptive plasticity can evolve with respect to single environmental variables, and costs of plasticity may increase, rather than reduce, plasticity in response to some variables. We also find conditions for the evolution of an indirect environmental indicator that affects expression of a plastic phenotype, despite not influencing natural selection on it. PMID:26292649

  5. The behavioral phenotype of FMR1 mutations.

    PubMed

    Boyle, Lia; Kaufmann, Walter E

    2010-11-15

    The purpose of this article is to provide an overview of the behavioral phenotype of FMR1 mutations, including fragile X syndrome (FXS) in order to better understand the clinical involvement of individuals affected by mutations in this gene. FXS is associated with a wide range of intellectual and behavioral problems, some relatively mild and others quite severe. FXS is the most common cause of inherited intellectual disability and one of the most prevalent genetic causes of autism spectrum disorder. Learning difficulties, attentional problems, anxiety, aggressive behavior, stereotypies, and mood disorders are also frequent in FXS. Recent studies of children and adults have identified associations between FMR1 premutation and many of the same disorders. We examine the neurobehavioral phenotypes of FXS and FMR1 premutation as they manifest across the lifespan of the individual. PMID:20981777

  6. Histomorphological Phenotyping of the Adult Mouse Brain.

    PubMed

    Mikhaleva, Anna; Kannan, Meghna; Wagner, Christel; Yalcin, Binnaz

    2016-01-01

    This article describes a series of standard operating procedures for morphological phenotyping of the mouse brain using basic histology. Many histological studies of the mouse brain use qualitative approaches based on what the human eye can detect. Consequently, some phenotypic information may be missed. Here we describe a quantitative approach for the assessment of brain morphology that is simple and robust. A total of 78 measurements are made throughout the brain at specific and well-defined regions, including the cortex, the hippocampus, and the cerebellum. Experimental design and timeline considerations, including strain background effects, the importance of sectioning quality, measurement variability, and efforts to correct human errors are discussed. © 2016 by John Wiley & Sons, Inc. PMID:27584555

  7. Causal Phenotype Discovery via Deep Networks

    PubMed Central

    Kale, David C.; Che, Zhengping; Bahadori, Mohammad Taha; Li, Wenzhe; Liu, Yan; Wetzel, Randall

    2015-01-01

    The rapid growth of digital health databases has attracted many researchers interested in using modern computational methods to discover and model patterns of health and illness in a research program known as computational phenotyping. Much of the work in this area has focused on traditional statistical learning paradigms, such as classification, prediction, clustering, pattern mining. In this paper, we propose a related but different paradigm called causal phenotype discovery, which aims to discover latent representations of illness that are causally predictive. We illustrate this idea with a two-stage framework that combines the latent representation learning power of deep neural networks with state-of-the-art tools from causal inference. We apply this framework to two large ICU time series data sets and show that it can learn features that are predictively useful, that capture complex physiologic patterns associated with critical illnesses, and that are potentially more clinically meaningful than manually designed features. PMID:26958203

  8. Phenotyping maize for adaptation to drought

    PubMed Central

    Araus, Jose L.; Serret, María D.; Edmeades, Gregory O.

    2012-01-01

    The need of a better adaptation of crops to drought is an issue of increasing urgency. However, enhancing the tolerance of maize has, therefore, proved to be somewhat elusive in terms of plant breeding. In that context, proper phenotyping remains as one of the main factors limiting breeding advance. Topics covered by this review include the conceptual framework for identifying secondary traits associated with yield response to drought and how to measure these secondary traits in practice. PMID:22934056

  9. Molecular mechanisms of phenotypic plasticity in social insects

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Polyphenism in insects, whereby a single genome expresses different phenotypes in response to environmental cues, is a fascinating biological phenomenon. Social insects are especially intriguing examples of phenotypic plasticity because division of labor results in the development of extreme morphol...

  10. Phenotypic Variability in the Coccolithophore Emiliania huxleyi

    PubMed Central

    Lebrato, Mario; Stoll, Heather M.; Iglesias-Rodriguez, Debora; Müller, Marius N.; Méndez-Vicente, Ana; Oschlies, Andreas

    2016-01-01

    Coccolithophores are a vital part of oceanic phytoplankton assemblages that produce organic matter and calcium carbonate (CaCO3) containing traces of other elements (i.e. Sr and Mg). Their associated carbon export from the euphotic zone to the oceans' interior plays a crucial role in CO2 feedback mechanisms and biogeochemical cycles. The coccolithophore Emiliania huxleyi has been widely studied as a model organism to understand physiological, biogeochemical, and ecological processes in marine sciences. Here, we show the inter-strain variability in physiological and biogeochemical traits in 13 strains of E. huxleyi from various biogeographical provinces obtained from culture collections commonly used in the literature. Our results demonstrate that inter-strain genetic variability has greater potential to induce larger phenotypic differences than the phenotypic plasticity of single strains cultured under a broad range of variable environmental conditions. The range of variation found in physiological parameters and calcite Sr:Ca highlights the need to reconsider phenotypic variability in paleoproxy calibrations and model parameterizations to adequately translate findings from single strain laboratory experiments to the real ocean. PMID:27348427

  11. Regulatory mechanisms link phenotypic plasticity to evolvability

    PubMed Central

    van Gestel, Jordi; Weissing, Franz J.

    2016-01-01

    Organisms have a remarkable capacity to respond to environmental change. They can either respond directly, by means of phenotypic plasticity, or they can slowly adapt through evolution. Yet, how phenotypic plasticity links to evolutionary adaptability is largely unknown. Current studies of plasticity tend to adopt a phenomenological reaction norm (RN) approach, which neglects the mechanisms underlying plasticity. Focusing on a concrete question – the optimal timing of bacterial sporulation – we here also consider a mechanistic approach, the evolution of a gene regulatory network (GRN) underlying plasticity. Using individual-based simulations, we compare the RN and GRN approach and find a number of striking differences. Most importantly, the GRN model results in a much higher diversity of responsive strategies than the RN model. We show that each of the evolved strategies is pre-adapted to a unique set of unseen environmental conditions. The regulatory mechanisms that control plasticity therefore critically link phenotypic plasticity to the adaptive potential of biological populations. PMID:27087393

  12. Modeling the autism spectrum disorder phenotype.

    PubMed

    McCray, Alexa T; Trevvett, Philip; Frost, H Robert

    2014-04-01

    Autism Spectrum Disorder (ASD) is highly heritable, and although there has been active research in an attempt to discover the genetic factors underlying ASD, diagnosis still depends heavily on behavioral assessments. Recently, several large-scale initiatives, including those of the Autism Consortium, have contributed to the collection of extensive information from families affected by ASD. Our goal was to develop an ontology that can be used 1) to provide improved access to the data collected by those who study ASD and other neurodevelopmental disorders, and 2) to assess and compare the characteristics of the instruments that are used in the assessment of ASD. We analyzed two dozen instruments used to assess ASD, studying the nature of the questions asked and items assessed, the method of delivery, and the overall scope of the content. These data together with the extensive literature on ASD contributed to our iterative development of an ASD phenotype ontology. The final ontology comprises 283 concepts distributed across three high-level classes, 'Personal Traits', 'Social Competence', and 'Medical History'. The ontology is fully integrated with the Autism Consortium database, allowing researchers to pose ontology-based questions. The ontology also allows researchers to assess the degree of overlap among a set of candidate instruments according to several objective criteria. The ASD phenotype ontology has promise for use in research settings where extensive phenotypic data have been collected, allowing a concept-based approach to identifying behavioral features of importance and for correlating these with genotypic data. PMID:24163114

  13. Phenotypic Variability in the Coccolithophore Emiliania huxleyi.

    PubMed

    Blanco-Ameijeiras, Sonia; Lebrato, Mario; Stoll, Heather M; Iglesias-Rodriguez, Debora; Müller, Marius N; Méndez-Vicente, Ana; Oschlies, Andreas

    2016-01-01

    Coccolithophores are a vital part of oceanic phytoplankton assemblages that produce organic matter and calcium carbonate (CaCO3) containing traces of other elements (i.e. Sr and Mg). Their associated carbon export from the euphotic zone to the oceans' interior plays a crucial role in CO2 feedback mechanisms and biogeochemical cycles. The coccolithophore Emiliania huxleyi has been widely studied as a model organism to understand physiological, biogeochemical, and ecological processes in marine sciences. Here, we show the inter-strain variability in physiological and biogeochemical traits in 13 strains of E. huxleyi from various biogeographical provinces obtained from culture collections commonly used in the literature. Our results demonstrate that inter-strain genetic variability has greater potential to induce larger phenotypic differences than the phenotypic plasticity of single strains cultured under a broad range of variable environmental conditions. The range of variation found in physiological parameters and calcite Sr:Ca highlights the need to reconsider phenotypic variability in paleoproxy calibrations and model parameterizations to adequately translate findings from single strain laboratory experiments to the real ocean. PMID:27348427

  14. The Evolutionary Potential of Phenotypic Mutations

    PubMed Central

    Yanagida, Hayato; Gispan, Ariel; Kadouri, Noam; Rozen, Shelly; Sharon, Michal; Barkai, Naama; Tawfik, Dan S.

    2015-01-01

    Errors in protein synthesis, so-called phenotypic mutations, are orders-of-magnitude more frequent than genetic mutations. Here, we provide direct evidence that alternative protein forms and phenotypic variability derived from translational errors paved the path to genetic, evolutionary adaptations via gene duplication. We explored the evolutionary origins of Saccharomyces cerevisiae IDP3 - an NADP-dependent isocitrate dehydrogenase mediating fatty acids ß-oxidation in the peroxisome. Following the yeast whole genome duplication, IDP3 diverged from a cytosolic ancestral gene by acquisition of a C-terminal peroxisomal targeting signal. We discovered that the pre-duplicated cytosolic IDPs are partially localized to the peroxisome owing to +1 translational frameshifts that bypass the stop codon and unveil cryptic peroxisomal targeting signals within the 3’-UTR. Exploring putative cryptic signals in all 3’-UTRs of yeast genomes, we found that other enzymes related to NADPH production such as pyruvate carboxylase 1 (PYC1) might be prone to peroxisomal localization via cryptic signals. Using laboratory evolution we found that these translational frameshifts are rapidly imprinted via genetic single base deletions occurring within the very same gene location. Further, as exemplified here, the sequences that promote translational frameshifts are also more prone to genetic deletions. Thus, genotypes conferring higher phenotypic variability not only meet immediate challenges by unveiling cryptic 3’-UTR sequences, but also boost the potential for future genetic adaptations. PMID:26244544

  15. Abaxial Greening Phenotype in Hybrid Aspen

    PubMed Central

    Nowak, Julia S.; Douglas, Carl J.; Cronk, Quentin C.B.

    2013-01-01

    The typical angiosperm leaf, as in Arabidopsis, is bifacial consisting of top (adaxial) and bottom (abaxial) surfaces readily distinguishable by the underlying cell type (palisade and spongy mesophyll, respectively). Species of the genus Populus have leaves that are either conventionally bifacial or isobilateral. Isobilateral leaves have palisade mesophyll on the top and bottom of the leaf, making the two sides virtually indistinguishable at the macroscopic level. In poplars this has been termed the “abaxial greening” phenotype. Previous work has implicated ASYMMETRIC LEAVES1 (AS1) as an essential determinant of palisade mesophyll development. This gene, as well as other genes (84 in all) putatively involved in setting the dorsiventral axis of leaves, were investigated in two Populus species: black cottonwood (Populus trichocarpa) and hybrid aspen (P. tremula x tremuloides), representative of each leaf type (bifacial and isobilateral, respectively). Poplar orthologs of AS1 have significantly higher expression in aspen leaf blade and lower in the petiole, suggestive of a potential role in the isobilateral leaf phenotype consistent with the previously observed phenotypes. Furthermore, an ABERRANT TESTA SHAPE (ATS) ortholog has significantly lower expression in aspen leaf tissue, also suggesting a possible contribution of this gene to abaxial greening. PMID:27137376

  16. Phenotypic Heterogeneity of Monogenic Frontotemporal Dementia

    PubMed Central

    Benussi, Alberto; Padovani, Alessandro; Borroni, Barbara

    2015-01-01

    Frontotemporal dementia (FTD) is a genetically and pathologically heterogeneous disorder characterized by personality changes, language impairment, and deficits of executive functions associated with frontal and temporal lobe degeneration. Different phenotypes have been defined on the basis of presenting clinical symptoms, i.e., the behavioral variant of FTD, the agrammatic variant of primary progressive aphasia, and the semantic variant of PPA. Some patients have an associated movement disorder, either parkinsonism, as in progressive supranuclear palsy and corticobasal syndrome, or motor neuron disease (FTD–MND). A family history of dementia is found in 40% of cases of FTD and about 10% have a clear autosomal-dominant inheritance. Genetic studies have identified several genes associated with monogenic FTD: microtubule-associated protein tau, progranulin, TAR DNA-binding protein 43, valosin-containing protein, charged multivesicular body protein 2B, fused in sarcoma, and the hexanucleotide repeat expansion in intron 1 of the chromosome 9 open reading frame 72. Patients often present with an extensive phenotypic variability, even among different members of the same kindred carrying an identical disease mutation. The objective of the present work is to review and evaluate available literature data in order to highlight recent advances in clinical, biological, and neuroimaging features of monogenic frontotemporal lobar degeneration and try to identify different mechanisms underlying the extreme phenotypic heterogeneity that characterizes this disease. PMID:26388768

  17. Olfactory phenotypic expression unveils human aging

    PubMed Central

    Mazzatenta, Andrea; Cellerino, Alessandro; Origlia, Nicola; Barloscio, Davide; Sartucci, Ferdinando; Giulio, Camillo Di; Domenici, Luciano

    2016-01-01

    The mechanism of the natural aging of olfaction and its declinein the absence of any overt disease conditions remains unclear. Here, we investigated this mechanism through measurement of one of the parameters of olfactory function, the absolute threshold, in a healthy population from childhood to old age. The absolute olfactory threshold data were collected from an Italian observational study with 622 participants aged 5-105 years. A subjective testing procedure of constant stimuli was used, which was also compared to the ‘staircase’ method, with the calculation of the reliability. The n-butanol stimulus was used as an ascending series of nine molar concentrations that were monitored using an electronic nose. The data were analyzed using nonparametric statistics because of the multimodal distribution. We show that the age-related variations in the absolute olfactory threshold are not continuous; instead, there are multiple olfactory phenotypes. Three distinct age-related phenotypes were defined, termed as ‘juvenile’, ‘mature’ and ‘elder’. The frequency of these three phenotypes depends on age. Our data suggest that the sense of smell does not decrease linearly with aging. Our findings provide the basis for further understanding of olfactory loss as an anticipatory sign of aging and neurodegenerative processes. PMID:27027240

  18. Expanding the phenotype of mosaic trisomy 20.

    PubMed

    Willis, Mary J H; Bird, Lynne M; Dell'Aquilla, Marie; Jones, Marilyn C

    2008-02-01

    Mosaic trisomy 20 is one of the more common cytogenetic abnormalities found on amniocentesis or chorionic villus sampling. Studies have shown that outcome is normal in 90-93% of prenatally diagnosed cases. There are however, reports in the literature of children with mosaic trisomy 20 described as having an assortment of dysmorphic features and varying levels of developmental delay. Unfortunately, the literature has not defined a specific phenotype for this entity. Here we report on three patients with mosaic trisomy 20, two of whom were identified prenatally. Over a number of years of follow-up it has become apparent that there are some striking similarities among the three. Comparison between our patients and the literature cases indicates a more consistent phenotype than has previously been suggested. Recurring features include; spinal abnormalities (including spinal stenosis, vertebral fusion, and kyphosis), hypotonia, lifelong constipation, sloped shoulders, and significant learning disabilities despite normal intelligence. These findings may be overlooked on routine history and physical exam or assumed to be standard pediatric problems. It is not our intention to suggest that there is a distinctive face for this entity but to suggest that a subtle phenotype does exist. We have attempted to identify a set of findings for which any child diagnosed with mosaic trisomy 20 should be assessed or followed even in the presence of an apparently normal physical exam at birth. PMID:18203170

  19. Topological Phenotypes in Complex Leaf Venation Networks

    NASA Astrophysics Data System (ADS)

    Ronellenfitsch, Henrik; Lasser, Jana; Daly, Douglas; Katifori, Eleni

    2015-03-01

    The leaves of vascular plants contain highly complex venation networks consisting of recursively nested, hierarchically organized loops. We analyze the topology of the venation of leaves from ca. 200 species belonging to ca. 10 families, defining topological metrics that quantify the hierarchical nestedness of the network cycles. We find that most of the venation variability can be described by a two dimensional phenotypic space, where one dimension consists of a linear combination of geometrical metrics and the other dimension of topological, previously uncharacterized metrics. We show how this new topological dimension in the phenotypic space significantly improves identification of leaves from fragments, by calculating a ``leaf fingerprint'' from the topology and geometry of the higher order veins. Further, we present a simple model suggesting that the topological phenotypic traits can be explained by noise effects and variations in the timing of higher order vein developmental events. This work opens the path to (a) new quantitative identification techniques for leaves which go beyond simple geometric traits such as vein density and (b) topological quantification of other planar or almost planar networks such as arterial vaculature in the neocortex and lung tissue.

  20. Peripheral circadian clocks--a conserved phenotype?

    PubMed

    Weigl, Yuval; Harbour, Valerie L; Robinson, Barry; Dufresne, Line; Amir, Shimon

    2013-05-01

    The circadian system of mammals regulates the timing of occurrence of behavioral and physiological events, thereby optimizing adaptation to their surroundings. This system is composed of a single master pacemaker located in the suprachiasmatic nucleus (SCN) and a population of peripheral clocks. The SCN integrates time information from exogenous sources and, in turn, synchronizes the downstream peripheral clocks. It is assumed that under normal conditions, the circadian phenotype of different peripheral clocks would be conserved with respect to its period and robustness. To study this idea, we measured the daily wheel-running activity (WRA; a marker of the SCN output) in 84 male inbred LEW/Crl rats housed under a 12 h:12 h light-dark cycle. In addition, we assessed the mRNA expression of two clock genes, rPer2 and rBmal1, and one clock-controlled gene, rDbp, in four tissues that have the access to time cues other than those emanating from the SCN: olfactory bulbs (OBs), liver, tail skin, and white blood cells (WBCs). In contrast with the assumption stated above, we found that circadian clocks in peripheral tissues differ in the temporal pattern of the expression of circadian clock genes, in the robustness of the rhythms, and possibly in the number of functional ~24-h-clock cells. Based on the tissue diversity in the robustness of the clock output, the hepatic clock is likely to house the highest number of functional ~24-h-clock cells, and the OBs, the fewest number. Thus, the phenotype of the circadian clock in the periphery is tissue specific and may depend not only on the SCN but also on the sensitivity of the tissue to non-SCN-derived time cues. In the OBs and liver, the circadian clock phenotypes seem to be dominantly shaped by the SCN output. However, in the tail skin and WBC, other time cues participate in the phenotype design. Finally, our study suggests that the basic phenotype of the circadian clock is constructed at the transcript level of the core clock

  1. Detecting virulence and drug resistance mycobacterial phenotypes in vivo

    PubMed Central

    Timmins, Graham

    2015-01-01

    Bacterial phenotypes are predominantly studied in culture because detection of their specific metabolic pathways in the host is challenging. Development of stable isotope breath tests allowing in situ phenotype analyses may endow diagnostics with new modalities based upon direct monitoring of in vivo microbial metabolism and host–pathogen phenotypic interactions. PMID:25800730

  2. Social Cognition, Social Skill, and the Broad Autism Phenotype

    ERIC Educational Resources Information Center

    Sasson, Noah J.; Nowlin, Rachel B.; Pinkham, Amy E.

    2013-01-01

    Social-cognitive deficits differentiate parents with the "broad autism phenotype" from non-broad autism phenotype parents more robustly than other neuropsychological features of autism, suggesting that this domain may be particularly informative for identifying genetic and brain processes associated with the phenotype. The current study…

  3. PhenDisco: phenotype discovery system for the database of genotypes and phenotypes.

    PubMed

    Doan, Son; Lin, Ko-Wei; Conway, Mike; Ohno-Machado, Lucila; Hsieh, Alex; Feupe, Stephanie Feudjio; Garland, Asher; Ross, Mindy K; Jiang, Xiaoqian; Farzaneh, Seena; Walker, Rebecca; Alipanah, Neda; Zhang, Jing; Xu, Hua; Kim, Hyeon-Eui

    2014-01-01

    The database of genotypes and phenotypes (dbGaP) developed by the National Center for Biotechnology Information (NCBI) is a resource that contains information on various genome-wide association studies (GWAS) and is currently available via NCBI's dbGaP Entrez interface. The database is an important resource, providing GWAS data that can be used for new exploratory research or cross-study validation by authorized users. However, finding studies relevant to a particular phenotype of interest is challenging, as phenotype information is presented in a non-standardized way. To address this issue, we developed PhenDisco (phenotype discoverer), a new information retrieval system for dbGaP. PhenDisco consists of two main components: (1) text processing tools that standardize phenotype variables and study metadata, and (2) information retrieval tools that support queries from users and return ranked results. In a preliminary comparison involving 18 search scenarios, PhenDisco showed promising performance for both unranked and ranked search comparisons with dbGaP's search engine Entrez. The system can be accessed at http://pfindr.net. PMID:23989082

  4. Contrasting Association Results between Existing PheWAS Phenotype Definition Methods and Five Validated Electronic Phenotypes

    PubMed Central

    Leader, Joseph B; Pendergrass, Sarah A; Verma, Anurag; Carey, David J; Hartzel, Dustin N; Ritchie, Marylyn D; Kirchner, H. Lester

    2015-01-01

    Phenome-Wide Association Studies (PheWAS) comprehensively investigate the association between genetic variation and a wide array of outcome traits. Electronic health record (EHR) based PheWAS uses various abstractions of International Classification of Diseases, Ninth Revision (ICD-9) codes to identify case/control status for diagnoses that are used as the phenotypic variables. However, there have not been comparisons within a PheWAS between results from high quality derived phenotypes and high-throughput but potentially inaccurate use of ICD-9 codes for case/control definition. For this study we first developed a group of high quality algorithms for five phenotypes. Next we evaluated the association of these “gold standard” phenotypes and 4,636,178 genetic variants with minor allele frequency > 0.01 and compared the results from high-throughput associations at the 3 digit, 5 digit, and PheWAS codes for defining case/control status. We found that certain diseases contained similar patient populations across phenotyping methods but had differences in PheWAS. PMID:26958218

  5. The gray phenotype and tristable phenotypic transitions in the human fungal pathogen Candida tropicalis.

    PubMed

    Zhang, Yulong; Tao, Li; Zhang, Qiuyu; Guan, Guobo; Nobile, Clarissa J; Zheng, Qiushi; Ding, Xuefen; Huang, Guanghua

    2016-08-01

    Phenotypic plasticity, the ability to switch between different morphological types, plays critical roles in environmental adaptation, leading to infections, and allowing for sexual reproduction in pathogenic Candida species. Candida tropicalis, which is both an emerging human fungal pathogen and an environmental fungus, can switch between two heritable cell types termed white and opaque. In this study, we report the discovery of a novel phenotype in C. tropicalis, named the gray phenotype. Similar to Candida albicans and Candida dubliniensis, white, gray, and opaque cell types of C. tropicalis also form a tristable switching system, where gray cells are relatively small and elongated. In C. tropicalis, gray cells exhibit intermediate levels of mating competency and virulence in a mouse systemic infection model compared to the white and opaque cell types, express a set of cell type-enriched genes, and exhibit both common and species-specific biological features. The key regulators of white-opaque transitions, Wor1 and Efg1, are not required for the gray phenotype. A comparative study of the gray phenotypes in C. tropicalis, C. albicans, and C. dubliniensis provides clues to explain the virulence properties and niche preferences of C. tropicalis. PMID:27246518

  6. PhenDisco: phenotype discovery system for the database of genotypes and phenotypes

    PubMed Central

    Doan, Son; Lin, Ko-Wei; Conway, Mike; Ohno-Machado, Lucila; Hsieh, Alex; Feupe, Stephanie Feudjio; Garland, Asher; Ross, Mindy K; Jiang, Xiaoqian; Farzaneh, Seena; Walker, Rebecca; Alipanah, Neda; Zhang, Jing; Xu, Hua; Kim, Hyeon-Eui

    2014-01-01

    The database of genotypes and phenotypes (dbGaP) developed by the National Center for Biotechnology Information (NCBI) is a resource that contains information on various genome-wide association studies (GWAS) and is currently available via NCBI's dbGaP Entrez interface. The database is an important resource, providing GWAS data that can be used for new exploratory research or cross-study validation by authorized users. However, finding studies relevant to a particular phenotype of interest is challenging, as phenotype information is presented in a non-standardized way. To address this issue, we developed PhenDisco (phenotype discoverer), a new information retrieval system for dbGaP. PhenDisco consists of two main components: (1) text processing tools that standardize phenotype variables and study metadata, and (2) information retrieval tools that support queries from users and return ranked results. In a preliminary comparison involving 18 search scenarios, PhenDisco showed promising performance for both unranked and ranked search comparisons with dbGaP's search engine Entrez. The system can be accessed at http://pfindr.net. PMID:23989082

  7. Significance of Lewis phenotyping using saliva and gastric tissue: comparison with the Lewis phenotype inferred from Lewis and secretor genotypes.

    PubMed

    Hong, Yun Ji; Hwang, Sang Mee; Kim, Taek Soo; Song, Eun Young; Park, Kyoung Un; Song, Junghan; Han, Kyou-Sup

    2014-01-01

    Lewis phenotypes using various types of specimen were compared with the Lewis phenotype predicted from Lewis and Secretor genotypes. This is the first logical step in explaining the association between the Lewis expression and Helicobacter pylori. We performed a study of the followings on 209 patients who underwent routine gastroscopy: erythrocyte and saliva Lewis phenotyping, gastric Lewis phenotyping by the tissue array, and the Lewis and Secretor genes genotyping. The results of phenotyping were as follows [Le(a-b-), Le(a+b-), Le(a-b+), and Le(a+b+), respectively, in order]: erythrocyte (12.4%, 25.8%, 61.2%, and 0.5%); saliva (2.4%, 27.3%, 70.3%, and 0.0%); gastric mucosa (8.1%, 6.7%, 45.5%, and 39.7%). The frequency of Le, le (59/508) , le (59/1067) , and le (59) alleles was 74.6%, 21.3%, 3.1%, and 1.0%, respectively, among 418 alleles. The saliva Lewis phenotype was completely consistent with the Lewis phenotype inferred from Lewis and Secretor genotypes, but that of gastric mucosa could not be predicted from genotypes. Lewis phenotyping using erythrocytes is only adequate for transfusion needs. Saliva testing for the Lewis phenotype is a more reliable method for determining the peripheral Lewis phenotype of an individual and the gastric Lewis phenotype must be used for the study on the association between Helicobacter pylori and the Lewis phenotype. PMID:24783214

  8. Invasion strategies in clonal aquatic plants: are phenotypic differences caused by phenotypic plasticity or local adaptation?

    PubMed Central

    Riis, Tenna; Lambertini, Carla; Olesen, Birgit; Clayton, John S.; Brix, Hans; Sorrell, Brian K.

    2010-01-01

    Background and Aims The successful spread of invasive plants in new environments is often linked to multiple introductions and a diverse gene pool that facilitates local adaptation to variable environmental conditions. For clonal plants, however, phenotypic plasticity may be equally important. Here the primary adaptive strategy in three non-native, clonally reproducing macrophytes (Egeria densa, Elodea canadensis and Lagarosiphon major) in New Zealand freshwaters were examined and an attempt was made to link observed differences in plant morphology to local variation in habitat conditions. Methods Field populations with a large phenotypic variety were sampled in a range of lakes and streams with different chemical and physical properties. The phenotypic plasticity of the species before and after cultivation was studied in a common garden growth experiment, and the genetic diversity of these same populations was also quantified. Key Results For all three species, greater variation in plant characteristics was found before they were grown in standardized conditions. Moreover, field populations displayed remarkably little genetic variation and there was little interaction between habitat conditions and plant morphological characteristics. Conclusions The results indicate that at the current stage of spread into New Zealand, the primary adaptive strategy of these three invasive macrophytes is phenotypic plasticity. However, while limited, the possibility that genetic diversity between populations may facilitate ecotypic differentiation in the future cannot be excluded. These results thus indicate that invasive clonal aquatic plants adapt to new introduced areas by phenotypic plasticity. Inorganic carbon, nitrogen and phosphorous were important in controlling plant size of E. canadensis and L. major, but no other relationships between plant characteristics and habitat conditions were apparent. This implies that within-species differences in plant size can be explained

  9. Phenotype Sequencing: Identifying the Genes That Cause a Phenotype Directly from Pooled Sequencing of Independent Mutants

    PubMed Central

    Harper, Marc A.; Chen, Zugen; Toy, Traci; Machado, Iara M. P.; Nelson, Stanley F.; Liao, James C.; Lee, Christopher J.

    2011-01-01

    Random mutagenesis and phenotype screening provide a powerful method for dissecting microbial functions, but their results can be laborious to analyze experimentally. Each mutant strain may contain 50–100 random mutations, necessitating extensive functional experiments to determine which one causes the selected phenotype. To solve this problem, we propose a “Phenotype Sequencing” approach in which genes causing the phenotype can be identified directly from sequencing of multiple independent mutants. We developed a new computational analysis method showing that 1. causal genes can be identified with high probability from even a modest number of mutant genomes; 2. costs can be cut many-fold compared with a conventional genome sequencing approach via an optimized strategy of library-pooling (multiple strains per library) and tag-pooling (multiple tagged libraries per sequencing lane). We have performed extensive validation experiments on a set of E. coli mutants with increased isobutanol biofuel tolerance. We generated a range of sequencing experiments varying from 3 to 32 mutant strains, with pooling on 1 to 3 sequencing lanes. Our statistical analysis of these data (4099 mutations from 32 mutant genomes) successfully identified 3 genes (acrB, marC, acrA) that have been independently validated as causing this experimental phenotype. It must be emphasized that our approach reduces mutant sequencing costs enormously. Whereas a conventional genome sequencing experiment would have cost $7,200 in reagents alone, our Phenotype Sequencing design yielded the same information value for only $1200. In fact, our smallest experiments reliably identified acrB and marC at a cost of only $110–$340. PMID:21364744

  10. Phenotypic variation and modulation in Bordetella bronchiseptica.

    PubMed Central

    Peppler, M S; Schrumpf, M E

    1984-01-01

    Most of the isolates of Bordetella bronchiseptica obtained by this laboratory possessed a characteristic colonial morphology when grown on Bordet- Gengou agar (BGA) at 37 degrees C. The colonies appeared domed (Dom+) with a smooth colonial surface (Scs+) and a clear zone of hemolysis ( Hly +). From these Dom+ Scs+ Hly + BGA colony types arose flat (Dom-), smooth colonial surface (Scs+) and nonhemolytic ( Hly -) variants at frequencies of 10(-2) to 10(-3). Isogenic pairs of Dom+ Scs+ Hly + and Dom- Scs+ Hly - BGA phenotype variants (BGA-PVs) were picked from 11 strains of B. bronchiseptica, and their whole cell lysates were compared with each other by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Characteristic SDS-PAGE profiles were observed for each of the Dom+ Scs+ Hly + and Dom- Scs+ Hly - BGA-PVs with regard to (i) surface-exposed proteins, based on autoradiographs of 125I- Iodogen -labeled organisms, (ii) polypeptide differences, based on gels stained with Coomassie brilliant blue R-250, and (iii) lipopolysaccharide differences based on gels stained with silver after oxidation with periodic acid. SDS-PAGE profiles were then used to monitor the phenotypes expressed by Dom+ Scs+ Hly + and Dom- Scs+ Hly - BGA-PVs transferred and grown on brucella agar, Trypticase soy agar, and nutrient agar. When grown on non-BGA media, the Dom+ Scs+ Hly + BGA-PVs from six of eight strains showed SDS-PAGE profiles identical to those of Dom- Scs+ Hly - BGA-PVs. This phenotypic change was reversible even after 15 subcultures on the non-BGA media, since Dom+ Scs+ Hly + organisms passed back onto BGA expressed both Dom+ Scs+ Hly + colonial morphology and Dom+ Scs+ Hly + SDS-PAGE profiles. The influence of cultural conditions on maintenance of virulence is discussed. Images PMID:6373614

  11. Sample size calculation in metabolic phenotyping studies.

    PubMed

    Billoir, Elise; Navratil, Vincent; Blaise, Benjamin J

    2015-09-01

    The number of samples needed to identify significant effects is a key question in biomedical studies, with consequences on experimental designs, costs and potential discoveries. In metabolic phenotyping studies, sample size determination remains a complex step. This is due particularly to the multiple hypothesis-testing framework and the top-down hypothesis-free approach, with no a priori known metabolic target. Until now, there was no standard procedure available to address this purpose. In this review, we discuss sample size estimation procedures for metabolic phenotyping studies. We release an automated implementation of the Data-driven Sample size Determination (DSD) algorithm for MATLAB and GNU Octave. Original research concerning DSD was published elsewhere. DSD allows the determination of an optimized sample size in metabolic phenotyping studies. The procedure uses analytical data only from a small pilot cohort to generate an expanded data set. The statistical recoupling of variables procedure is used to identify metabolic variables, and their intensity distributions are estimated by Kernel smoothing or log-normal density fitting. Statistically significant metabolic variations are evaluated using the Benjamini-Yekutieli correction and processed for data sets of various sizes. Optimal sample size determination is achieved in a context of biomarker discovery (at least one statistically significant variation) or metabolic exploration (a maximum of statistically significant variations). DSD toolbox is encoded in MATLAB R2008A (Mathworks, Natick, MA) for Kernel and log-normal estimates, and in GNU Octave for log-normal estimates (Kernel density estimates are not robust enough in GNU octave). It is available at http://www.prabi.fr/redmine/projects/dsd/repository, with a tutorial at http://www.prabi.fr/redmine/projects/dsd/wiki. PMID:25600654

  12. Two Clinical Phenotypes in Polycythemia Vera

    PubMed Central

    Spivak, Jerry L.; Considine, Michael; Williams, Donna M.; Talbot, Conover C.; Rogers, Ophelia; Moliterno, Alison R.; Jie, Chunfa; Ochs, Michael F.

    2014-01-01

    BACKGROUND Polycythemia vera is the ultimate phenotypic consequence of the V617F mutation in Janus kinase 2 (encoded by JAK2), but the extent to which this mutation influences the behavior of the involved CD34+ hematopoietic stem cells is unknown. METHODS We analyzed gene expression in CD34+ peripheral-blood cells from 19 patients with polycythemia vera, using oligonucleotide microarray technology after correcting for potential confounding by sex, since the phenotypic features of the disease differ between men and women. RESULTS Men with polycythemia vera had twice as many up-regulated or down-regulated genes as women with polycythemia vera, in a comparison of gene expression in the patients and in healthy persons of the same sex, but there were 102 genes with differential regulation that was concordant in men and women. When these genes were used for class discovery by means of unsupervised hierarchical clustering, the 19 patients could be divided into two groups that did not differ significantly with respect to age, neutrophil JAK2 V617F allele burden, white-cell count, platelet count, or clonal dominance. However, they did differ significantly with respect to disease duration; hemoglobin level; frequency of thromboembolic events, palpable splenomegaly, and splenectomy; chemotherapy exposure; leukemic transformation; and survival. The unsupervised clustering was confirmed by a supervised approach with the use of a top-scoring-pair classifier that segregated the 19 patients into the same two phenotypic groups with 100% accuracy. CONCLUSIONS Removing sex as a potential confounder, we identified an accurate molecular method for classifying patients with polycythemia vera according to disease behavior, independently of their JAK2 V617F allele burden, and identified previously unrecognized molecular pathways in polycythemia vera outside the canonical JAK2 pathway that may be amenable to targeted therapy. PMID:25162887

  13. Modeling the Autism Spectrum Disorder Phenotype

    PubMed Central

    McCray, Alexa T.; Trevvett, Philip; Frost, H. Robert

    2013-01-01

    Background Autism Spectrum Disorder (ASD) is highly heritable, and although there has been active research in an attempt to discover the genetic factors underlying ASD, diagnosis still depends heavily on behavioral assessments. Recently, several large-scale initiatives, including those of the Autism Consortium, have contributed to the collection of extensive information from families affected by ASD. Purpose Our goal was to develop an ontology that can be used 1) to provide improved access to the data collected by those who study ASD and other neurodevelopmental disorders, and 2) to assess and compare the characteristics of the instruments that are used in the assessment of ASD. Materials and Methods We analyzed two dozen instruments used to assess ASD, studying the nature of the questions asked and items assessed, the method of delivery, and the overall scope of the content. These data together with the extensive literature on ASD contributed to our iterative development of an ASD phenotype ontology. Results The final ontology comprises 283 concepts distributed across three high-level classes, ‘Personal Traits’, ‘Social Competence’, and ‘Medical History’. The ontology is fully integrated with the Autism Consortium database, allowing researchers to pose ontology-based questions. The ontology also allows researchers to assess the degree of overlap among a set of candidate instruments according to several objective criteria. Conclusions The ASD phenotype ontology has promise for use in research settings where extensive phenotypic data have been collected, allowing a concept-based approach to identifying behavioral features of importance and for correlating these with genotypic data. PMID:24163114

  14. Gonads and the evolution of hormonal phenotypes.

    PubMed

    Rosvall, Kimberly A; Bergeon Burns, Christine M; Jayaratna, Sonya P; Dossey, Emma K; Ketterson, Ellen D

    2016-08-01

    Hormones are dynamic signaling molecules that influence gene activity and phenotype, and they are thus thought to play a central role in phenotypic evolution. In vertebrates, many fitness-related traits are mediated by the hormone testosterone (T), but the mechanisms by which T levels evolve are unclear. Here, we summarize a series of studies that advance our understanding of these mechanisms by comparing males from two subspecies of dark-eyed junco (Junco hyemalis) that differ in aggression, body size, and ornamentation. We first review our research demonstrating population differences in the time-course of T production, as well as findings that point to the gonad as a major source of this variation. In a common garden, the subspecies do not differ in pituitary output of luteinizing hormone, but males from the more androgenized subspecies have greater gonadal gene expression for specific steroidogenic enzymes, and they may be less sensitive to feedback along the hypothalamo-pituitary-gonadal (HPG) axis. Furthermore, we present new data from a common garden study demonstrating that the populations do not differ in gonadal sensitivity to gonadotropin-inhibitory hormone (i.e., GnIH receptor mRNA abundance), but the more androgenized subspecies expresses less gonadal mRNA for glucocorticoid receptor and mineralocorticoid receptor, suggesting altered cross-talk between the hypothalamo-pituitary-gonadal and -adrenal axes as another mechanism by which these subspecies have diverged in T production. These findings highlight the diversity of mechanisms that may generate functional variation in T and influence hormone-mediated phenotypic evolution. PMID:27252189

  15. Temporal abstraction-based clinical phenotyping with Eureka!

    PubMed

    Post, Andrew R; Kurc, Tahsin; Willard, Richie; Rathod, Himanshu; Mansour, Michel; Pai, Akshatha Kalsanka; Torian, William M; Agravat, Sanjay; Sturm, Suzanne; Saltz, Joel H

    2013-01-01

    Temporal abstraction, a method for specifying and detecting temporal patterns in clinical databases, is very expressive and performs well, but it is difficult for clinical investigators and data analysts to understand. Such patterns are critical in phenotyping patients using their medical records in research and quality improvement. We have previously developed the Analytic Information Warehouse (AIW), which computes such phenotypes using temporal abstraction but requires software engineers to use. We have extended the AIW's web user interface, Eureka! Clinical Analytics, to support specifying phenotypes using an alternative model that we developed with clinical stakeholders. The software converts phenotypes from this model to that of temporal abstraction prior to data processing. The model can represent all phenotypes in a quality improvement project and a growing set of phenotypes in a multi-site research study. Phenotyping that is accessible to investigators and IT personnel may enable its broader adoption. PMID:24551400

  16. Temporal Abstraction-based Clinical Phenotyping with Eureka!

    PubMed Central

    Post, Andrew R.; Kurc, Tahsin; Willard, Richie; Rathod, Himanshu; Mansour, Michel; Pai, Akshatha Kalsanka; Torian, William M.; Agravat, Sanjay; Sturm, Suzanne; Saltz, Joel H.

    2013-01-01

    Temporal abstraction, a method for specifying and detecting temporal patterns in clinical databases, is very expressive and performs well, but it is difficult for clinical investigators and data analysts to understand. Such patterns are critical in phenotyping patients using their medical records in research and quality improvement. We have previously developed the Analytic Information Warehouse (AIW), which computes such phenotypes using temporal abstraction but requires software engineers to use. We have extended the AIW’s web user interface, Eureka! Clinical Analytics, to support specifying phenotypes using an alternative model that we developed with clinical stakeholders. The software converts phenotypes from this model to that of temporal abstraction prior to data processing. The model can represent all phenotypes in a quality improvement project and a growing set of phenotypes in a multi-site research study. Phenotyping that is accessible to investigators and IT personnel may enable its broader adoption. PMID:24551400

  17. Acetylation phenotypes in patients with bladder carcinoma.

    PubMed

    Bicho, M P; Breitenfeld, L; Carvalho, A A; Manso, C F

    1988-01-01

    The present study was done to evaluate the possible association of bladder carcinoma with the slow acetylator phenotype in a portuguese population. 49 patients with bladder carcinoma were compared to a normal control group of 84 individuals. No statistically significant association was detected. But when subdividing the group of slow acetylators it is found that in the subgroup with 12-36% acetylation there is a higher percentage of patients, which is statistically significant. These results are in agreement with two other studies, using populations of similar ethnic origin. PMID:3265609

  18. Fryns syndrome phenotype and trisomy 22

    SciTech Connect

    Ladonne, J.M.; Gaillard, D.; Carre-Pigeon, F.; Gabriel, R.

    1996-01-02

    Trisomy 22 was detected in a 32-week-old fetus born to an overweight mother with hypertension. Severe intrauterine growth retardation was associated with phenotypic manifestations of Fryns Syndrome: Diaphragmatic hernia, facial defects, and nail hypoplasia with short distal fifth phalanges. This is the second report of congenital diaphragmatic hernia in trisomy 22. This case demonstrates the importance of karyotyping malformed fetuses or newborns, even if a nonchromosome syndrome seems identifiable on clinical grounds. To date, at least 10 cases of Fryns syndrome have been reported without chromosome analysis. 32 refs., 2 figs.

  19. Triple X syndrome with rare phenotypic presentation.

    PubMed

    Jagadeesh, Sujatha; Jabeen, Gazala; Bhat, Lathaa; Vasikarla, Madhavi; Suresh, Arvind; Seshadri, Suresh; Lata, S

    2008-06-01

    Triple X syndrome is a rare numerical chromosomal anomaly, occurring as a result of non dysjunction in meiosis I. Most cases have neurodevelopmental defects and functional problems. We report two cases diagnosed in our centre. The first was a fetus with cleft lip and palate, 47, XXX was identified by Fetal Blood Sampling. The second was a child with multisystem anomaly including cleft lip and palate, whose karyotype also revealed 47, XXX. Though isolated cases of associated abnormalities have been reported there have not been consistent phenotypic changes reported with this condition. PMID:18759093

  20. Effects of nanotopography on stem cell phenotypes

    PubMed Central

    Ravichandran, Rajeswari; Liao, Susan; Ng, Clarisse CH; Chan, Casey K; Raghunath, Michael; Ramakrishna, Seeram

    2009-01-01

    Stem cells are unspecialized cells that can self renew indefinitely and differentiate into several somatic cells given the correct environmental cues. In the stem cell niche, stem cell-extracellular matrix (ECM) interactions are crucial for different cellular functions, such as adhesion, proliferation, and differentiation. Recently, in addition to chemical surface modifications, the importance of nanometric scale surface topography and roughness of biomaterials has increasingly becoming recognized as a crucial factor for cell survival and host tissue acceptance in synthetic ECMs. This review describes the influence of nanotopography on stem cell phenotypes. PMID:21607108

  1. Moyamoya angiopathy - Is there a Western phenotype?

    PubMed

    Hever, Pennylouise; Alamri, Alexander; Tolias, Christos

    2015-12-01

    Moyamoya disease (MMD) is a chronic cerebrovascular disease involving progressive bilateral stenosis of the intracranial segments of the internal carotid arteries. It results in the development of a rich, but friable collateral supply, prone to rupture. The disease is well described in Japanese literature and was originally thought to be a predozminantly Eastern disease. However, the recent literature describes a Western phenotype that may present with a different clinical course. This review aims to describe the variations in the epidemiology of the MMD between Eastern and Western populations, the possible reasons for them and highlight their implications for clinical practise and future research. PMID:26473792

  2. Phenotype and function of nasal dendritic cells

    PubMed Central

    Lee, Haekyung; Ruane, Darren; Law, Kenneth; Ho, Yan; Garg, Aakash; Rahman, Adeeb; Esterházy, Daria; Cheong, Cheolho; Goljo, Erden; Sikora, Andrew G.; Mucida, Daniel; Chen, Benjamin; Govindraj, Satish; Breton, Gaëlle; Mehandru, Saurabh

    2015-01-01

    Intranasal vaccination generates immunity across local, regional and distant sites. However, nasal dendritic cells (DC), pivotal for the induction of intranasal vaccine- induced immune responses, have not been studied in detail. Here, using a variety of parameters, we define nasal DCs in mice and humans. Distinct subsets of “classical” DCs, dependent on the transcription factor zbtb46 were identified in the murine nose. The murine nasal DCs were FLT3 ligand-responsive and displayed unique phenotypic and functional characteristics including the ability to present antigen, induce an allogeneic T cell response and migrate in response to LPS or live bacterial pathogens. Importantly, in a cohort of human volunteers, BDCA-1+ DCs were observed to be the dominant nasal DC population at steady state. During chronic inflammation, the frequency of both BDCA-1+ and BDCA-3hi DCs was reduced in the nasal tissue, associating the loss of these immune sentinels with chronic nasal inflammation. The present study is the first detailed description of the phenotypic, ontogenetic and functional properties of nasal DCs and will inform the design of preventative immunization strategies as well as therapeutic modalities against chronic rhinosinusitis. PMID:25669151

  3. Aneuploidy underlies a multicellular phenotypic switch

    PubMed Central

    Tan, Zhihao; Hays, Michelle; Cromie, Gareth A.; Jeffery, Eric W.; Scott, Adrian C.; Ahyong, Vida; Sirr, Amy; Skupin, Alexander; Dudley, Aimée M.

    2013-01-01

    Although microorganisms are traditionally used to investigate unicellular processes, the yeast Saccharomyces cerevisiae has the ability to form colonies with highly complex, multicellular structures. Colonies with the “fluffy” morphology have properties reminiscent of bacterial biofilms and are easily distinguished from the “smooth” colonies typically formed by laboratory strains. We have identified strains that are able to reversibly toggle between the fluffy and smooth colony-forming states. Using a combination of flow cytometry and high-throughput restriction-site associated DNA tag sequencing, we show that this switch is correlated with a change in chromosomal copy number. Furthermore, the gain of a single chromosome is sufficient to switch a strain from the fluffy to the smooth state, and its subsequent loss to revert the strain back to the fluffy state. Because copy number imbalance of six of the 16 S. cerevisiae chromosomes and even a single gene can modulate the switch, our results support the hypothesis that the state switch is produced by dosage-sensitive genes, rather than a general response to altered DNA content. These findings add a complex, multicellular phenotype to the list of molecular and cellular traits known to be altered by aneuploidy and suggest that chromosome missegregation can provide a quick, heritable, and reversible mechanism by which organisms can toggle between phenotypes. PMID:23812752

  4. Aneuploidy underlies a multicellular phenotypic switch.

    PubMed

    Tan, Zhihao; Hays, Michelle; Cromie, Gareth A; Jeffery, Eric W; Scott, Adrian C; Ahyong, Vida; Sirr, Amy; Skupin, Alexander; Dudley, Aimée M

    2013-07-23

    Although microorganisms are traditionally used to investigate unicellular processes, the yeast Saccharomyces cerevisiae has the ability to form colonies with highly complex, multicellular structures. Colonies with the "fluffy" morphology have properties reminiscent of bacterial biofilms and are easily distinguished from the "smooth" colonies typically formed by laboratory strains. We have identified strains that are able to reversibly toggle between the fluffy and smooth colony-forming states. Using a combination of flow cytometry and high-throughput restriction-site associated DNA tag sequencing, we show that this switch is correlated with a change in chromosomal copy number. Furthermore, the gain of a single chromosome is sufficient to switch a strain from the fluffy to the smooth state, and its subsequent loss to revert the strain back to the fluffy state. Because copy number imbalance of six of the 16 S. cerevisiae chromosomes and even a single gene can modulate the switch, our results support the hypothesis that the state switch is produced by dosage-sensitive genes, rather than a general response to altered DNA content. These findings add a complex, multicellular phenotype to the list of molecular and cellular traits known to be altered by aneuploidy and suggest that chromosome missegregation can provide a quick, heritable, and reversible mechanism by which organisms can toggle between phenotypes. PMID:23812752

  5. RIN2 syndrome: Expanding the clinical phenotype.

    PubMed

    Rosato, Simonetta; Syx, Delfien; Ivanovski, Ivan; Pollazzon, Marzia; Santodirocco, Daniela; De Marco, Loredana; Beltrami, Marina; Callewaert, Bert; Garavelli, Livia; Malfait, Fransiska

    2016-09-01

    Biallelic defects in the RIN2 gene, encoding the Ras and Rab interactor 2 protein, are associated with a rare autosomal recessive connective tissue disorder, with only nine patients from four independent families reported to date. The condition was initially termed MACS syndrome (macrocephaly, alopecia, cutis laxa, and scoliosis), based on the clinical features of the first identified family; however, with the expansion of the clinical phenotype in additional families, it was subsequently coined RIN2 syndrome. Hallmark features of this condition include dysmorphic facial features with striking, progressive facial coarsening, sparse hair, normal to enlarged occipitofrontal circumference, soft redundant and/or hyperextensible skin, and scoliosis. Patients with RIN2 syndrome present phenotypic overlap with other conditions, including EDS (especially the dermatosparaxis and kyphoscoliosis subtypes). Here, we describe a 10th patient, the first patient of Caucasian origin and the oldest reported patient so far, who harbors the previously identified homozygous RIN2 mutation c.1878dupC (p. (Ile627Hisfs*7)). Besides the hallmark features, this patient also presents problems not previously associated with RIN2 syndrome, including cervical vertebral fusion, mild hearing loss, and colonic fibrosis. We provide an overview of the clinical findings in all reported patients with RIN2 mutations and summarize some of the possible pathogenic mechanisms that may underlie this condition. © 2016 Wiley Periodicals, Inc. PMID:27277385

  6. Aberrant phenotypes in Kikuchi’s disease

    PubMed Central

    Wei, Xue-Jing; Zhou, Xiao-Ge; Xie, Jian-Lan; Zheng, Xiao-Dan; Zheng, Yuan-Yuan

    2014-01-01

    Initial reports emphasized the immunophenotypic similarities between benign and malignant T cell populations, while some previous studies indicating that aberrant T-cell antigen loss is a good marker for detecting malignant T-cell proliferation. Recently, we found a very interesting and thought-provoking phenomenon: In benign disease-28 of 38 (73.7%) cases of Kikuchi’s disease also showed aberrant phenotypes with loss of pan-T cell antigens, which makes the differential diagnosis between Kikuchi’s disease and T cell lymphoma more challenging. In our study, 38 cases of Kikuchi’s disease and 30 cases of reactive lymphoid hyperplasia (RLH) were studied by EliVision immunohistochemical staining. As well as TCR gene rearrangement using PCR was negative in 10 tested cases of the Kikuchi’s disease. Among these cases, the most common antigen deficiency was CD5 (22 cases), then CD7 (11 cases), CD2 (8 cases) and CD3 (2 cases). Compared with proliferative and xanthomatous types of Kikuchi’s disease, antigens tended to be lost in necrotizing type. Based on follow-up data, a correlation was not found between the occurrence of aberrant phenotypes and prognosis. In RLH, obvious pan-T cell antigen loss was also not found. In conclusion, this is the first study to demonstrate distinct patterns of antigen loss in Kikuchi’s disease, suggesting that T cell antigen loss is not reliable as an auxiliary diagnostic standard for T cell lymphoma. PMID:25337197

  7. Amphibious fishes: evolution and phenotypic plasticity.

    PubMed

    Wright, Patricia A; Turko, Andy J

    2016-08-01

    Amphibious fishes spend part of their life in terrestrial habitats. The ability to tolerate life on land has evolved independently many times, with more than 200 extant species of amphibious fishes spanning 17 orders now reported. Many adaptations for life out of water have been described in the literature, and adaptive phenotypic plasticity may play an equally important role in promoting favourable matches between the terrestrial habitat and behavioural, physiological, biochemical and morphological characteristics. Amphibious fishes living at the interface of two very different environments must respond to issues relating to buoyancy/gravity, hydration/desiccation, low/high O2 availability, low/high CO2 accumulation and high/low NH3 solubility each time they traverse the air-water interface. Here, we review the literature for examples of plastic traits associated with the response to each of these challenges. Because there is evidence that phenotypic plasticity can facilitate the evolution of fixed traits in general, we summarize the types of investigations needed to more fully determine whether plasticity in extant amphibious fishes can provide indications of the strategies used during the evolution of terrestriality in tetrapods. PMID:27489213

  8. Syndactyly: phenotypes, genetics and current classification

    PubMed Central

    Malik, Sajid

    2012-01-01

    Syndactyly is one of the most common hereditary limb malformations depicting the fusion of certain fingers and/or toes. It may occur as an isolated entity or a component of more than 300 syndromic anomalies. Syndactylies exhibit great inter- and intra-familial clinical variability. Even within a subject, phenotype can be unilateral or bilateral and symmetrical or asymmetrical. At least nine non-syndromic syndactylies with additional sub-types have been characterized. Most of the syndactyly types are inherited as autosomal dominant but two autosomal recessive and an X-linked recessive entity have also been described. Whereas the underlying genes/mutations for types II-1, III, IV, V, and VII have been worked out, the etiology and molecular basis of the other syndactyly types remain unknown. In this communication, based on an overview of well-characterized isolated syndactylies, their cardinal phenotypes, inheritance patterns, and clinical and genetic heterogeneities, a ‘current classification scheme' is presented. Despite considerable progress in the understanding of syndactyly at clinical and molecular levels, fundamental questions regarding the disturbed developmental mechanisms leading to fused digits, remain to be answered. PMID:22333904

  9. Shaping adult phenotypes through early life environments.

    PubMed

    Weaver, Ian C G

    2009-12-01

    A major question in the biology of stress and environmental adaptation concerns the neurobiological basis of how neuroendocrine systems governing physiological regulatory mechanisms essential for life (metabolism, immune response, organ function) become harmful. The current view is that a switch from protection to damage occurs when vulnerable phenotypes are exposed to adverse environmental conditions. In accordance with this theory, sequelae of early life social and environmental stressors, such as childhood abuse, neglect, poverty, and poor nutrition, have been associated with the emergence of mental and physical illness (i.e., anxiety, mood disorders, poor impulse control, psychosis, and drug abuse) and an increased risk of common metabolic and cardiovascular diseases later in life. Evidence from animal and human studies investigating the associations between early life experiences (including parent-infant bonding), hypothalamus-pituitary-adrenal axis activity, brain development, and health outcome provide important clues into the neurobiological mechanisms that mediate the contribution of stressful experiences to personality development and the manifestation of illness. This review summarizes our current molecular understanding of how early environment influences brain development in a manner that persists through life and highlights recent evidence from rodent studies suggesting that maternal care in the first week of postnatal life establishes diverse and stable phenotypes in the offspring through epigenetic modification of genes expressed in the brain that shape neuroendocrine and behavioral stress responsivity throughout life. PMID:19960543

  10. Analysis and predictive modeling of asthma phenotypes.

    PubMed

    Brasier, Allan R; Ju, Hyunsu

    2014-01-01

    Molecular classification using robust biochemical measurements provides a level of diagnostic precision that is unattainable using indirect phenotypic measurements. Multidimensional measurements of proteins, genes, or metabolites (analytes) can identify subtle differences in the pathophysiology of patients with asthma in a way that is not otherwise possible using physiological or clinical assessments. We overview a method for relating biochemical analyte measurements to generate predictive models of discrete (categorical) clinical outcomes, a process referred to as "supervised classification." We consider problems inherent in wide (small n and large p) high-dimensional data, including the curse of dimensionality, collinearity and lack of information content. We suggest methods for reducing the data to the most informative features. We describe different approaches for phenotypic modeling, using logistic regression, classification and regression trees, random forest and nonparametric regression spline modeling. We provide guidance on post hoc model evaluation and methods to evaluate model performance using ROC curves and generalized additive models. The application of validated predictive models for outcome prediction will significantly impact the clinical management of asthma. PMID:24162915

  11. Phenotypes and Emerging Endotypes of Chronic Rhinosinusitis.

    PubMed

    Bachert, Claus; Akdis, Cezmi A

    2016-01-01

    Chronic rhinosinusitis can be differentiated into several phenotypes based on clinical criteria; however, these phenotypes do not teach us much about the underlying inflammatory mechanisms. Thus, the use of nasal endoscopy and CT scanning, and eventually taking a swab or a biopsy, may not be sufficient to fully appreciate the individual patient's pathology. Endotyping of chronic rhinosinusitis on the basis of pathomechanisms, functionally and pathologically different from others by the involvement of specific molecules or cells, may in contrast provide us with information on the risk of disease progression or recurrence and on the best available treatment, and also helps us identifying innovative therapeutic targets for treatment. Endotyping may best be structured around T helper cells and their downstream events, such as tissue eosinophilia or neutrophilia; this approach involves the cytokines and chemokines related to specific T helper cell populations, and related markers such as IgE. Endotyping is of specific interest at the time of the arrival of new biologicals, confronting us with the challenge of the selection of eligible patients for treatment and predicting their therapeutic response; defining suitable biomarkers is therefore an urgent task. Failure to appreciate the underlying mechanisms and endotypes of chronic rhinosinusitis may limit progress in the management of the disease at present. PMID:27393777

  12. Phenotypic variability of TRPV4 related neuropathies.

    PubMed

    Evangelista, Teresinha; Bansagi, Boglarka; Pyle, Angela; Griffin, Helen; Douroudis, Konstantinos; Polvikoski, Tuomo; Antoniadi, Thalia; Bushby, Kate; Straub, Volker; Chinnery, Patrick F; Lochmüller, Hanns; Horvath, Rita

    2015-06-01

    Mutations in the transient receptor potential vanilloid 4 (TRPV4) gene have been associated with autosomal dominant skeletal dysplasias and peripheral nervous system syndromes (PNSS). PNSS include Charcot-Marie-Tooth disease (CMT) type 2C, congenital spinal muscular atrophy and arthrogryposis and scapuloperoneal spinal muscular atrophy. We report the clinical, electrophysiological and muscle biopsy findings in two unrelated patients with two novel heterozygous missense mutations in the TRPV4 gene. Whole exome sequencing was carried out on genomic DNA using Illumina Truseq(TM) 62Mb exome capture. Patient 1 harbours a de novo c.805C > T (p.Arg269Cys) mutation. Clinically, this patient shows signs of both scapuloperoneal spinal muscular atrophy and skeletal dysplasia. Patient 2 harbours a novel c.184G > A (p.Asp62Asn) mutation. While the clinical phenotype is compatible with CMT type 2C with the patient's muscle harbours basophilic inclusions. Mutations in the TRPV4 gene have a broad phenotypic variability and disease severity and may share a similar pathogenic mechanism with Heat Shock Protein related neuropathies. PMID:25900305

  13. Heliconia phenotypic diversity based on qualitative descriptors.

    PubMed

    Guimarães, W N R; Martins, L S S; Castro, C E F; Carvalho Filho, J L S; Loges, V

    2014-01-01

    The aim of this study was to characterize Heliconia genotypes phenotypically using 26 qualitative descriptors. The evaluations were conducted in five flowering stems per clump in three replicates of 22 Heliconia genotypes. Data were subjected to multivariate analysis, the Mahalanobis dissimilarity measure was estimated, and the dendrogram was generated using the nearest neighbor method. From the values generated by the dissimilarity matrix and the clusters formed among the Heliconia genotypes studied, the phenotypic characterizations that best differentiated the genotypes were: pseudostem and wax green tone (light or dark green), leaf-wax petiole, the petiole hair, cleft margin at the base of the petiole, midrib underside shade of green, wax midrib underside, color sheet (light or dark green), unequal lamina base, torn limb, inflorescence-wax, position of inflorescence, bract leaf in apex, twisting of the rachis, and type of bloom. These results will be applied in the preparation of a catalog for Heliconia descriptors, in the selection of different genotypes with most promising characteristics for crosses, and for the characterization of new genotypes to be introduced in germplasm collections. PMID:24782170

  14. Gingival Tissue Transcriptomes Identify Distinct Periodontitis Phenotypes

    PubMed Central

    Kebschull, M.; Demmer, R.T.; Grün, B.; Guarnieri, P.; Pavlidis, P.; Papapanou, P.N.

    2014-01-01

    The currently recognized principal forms of periodontitis—chronic and aggressive—lack an unequivocal, pathobiology-based foundation. We explored whether gingival tissue transcriptomes can serve as the basis for an alternative classification of periodontitis. We used cross-sectional whole-genome gene expression data from 241 gingival tissue biopsies obtained from sites with periodontal pathology in 120 systemically healthy nonsmokers with periodontitis, with available data on clinical periodontal status, subgingival microbial profiles, and serum IgG antibodies to periodontal microbiota. Adjusted model-based clustering of transcriptomic data using finite mixtures generated two distinct clusters of patients that did not align with the current classification of chronic and aggressive periodontitis. Differential expression profiles primarily related to cell proliferation in cluster 1 and to lymphocyte activation and unfolded protein responses in cluster 2. Patients in the two clusters did not differ with respect to age but presented with distinct phenotypes (statistically significantly different whole-mouth clinical measures of extent/severity, subgingival microbial burden by several species, and selected serum antibody responses). Patients in cluster 2 showed more extensive/severe disease and were more often male. The findings suggest that distinct gene expression signatures in pathologic gingival tissues translate into phenotypic differences and can provide a basis for a novel classification. PMID:24646639

  15. A vestibular phenotype for Waardenburg syndrome?

    NASA Technical Reports Server (NTRS)

    Black, F. O.; Pesznecker, S. C.; Allen, K.; Gianna, C.

    2001-01-01

    OBJECTIVE: To investigate vestibular abnormalities in subjects with Waardenburg syndrome. STUDY DESIGN: Retrospective record review. SETTING: Tertiary referral neurotology clinic. SUBJECTS: Twenty-two adult white subjects with clinical diagnosis of Waardenburg syndrome (10 type I and 12 type II). INTERVENTIONS: Evaluation for Waardenburg phenotype, history of vestibular and auditory symptoms, tests of vestibular and auditory function. MAIN OUTCOME MEASURES: Results of phenotyping, results of vestibular and auditory symptom review (history), results of vestibular and auditory function testing. RESULTS: Seventeen subjects were women, and 5 were men. Their ages ranged from 21 to 58 years (mean, 38 years). Sixteen of the 22 subjects sought treatment for vertigo, dizziness, or imbalance. For subjects with vestibular symptoms, the results of vestibuloocular tests (calorics, vestibular autorotation, and/or pseudorandom rotation) were abnormal in 77%, and the results of vestibulospinal function tests (computerized dynamic posturography, EquiTest) were abnormal in 57%, but there were no specific patterns of abnormality. Six had objective sensorineural hearing loss. Thirteen had an elevated summating/action potential (>0.40) on electrocochleography. All subjects except those with severe hearing loss (n = 3) had normal auditory brainstem response results. CONCLUSION: Patients with Waardenburg syndrome may experience primarily vestibular symptoms without hearing loss. Electrocochleography and vestibular function tests appear to be the most sensitive measures of otologic abnormalities in such patients.

  16. Phenotypic variability of TRPV4 related neuropathies

    PubMed Central

    Evangelista, Teresinha; Bansagi, Boglarka; Pyle, Angela; Griffin, Helen; Douroudis, Konstantinos; Polvikoski, Tuomo; Antoniadi, Thalia; Bushby, Kate; Straub, Volker; Chinnery, Patrick F.; Lochmüller, Hanns; Horvath, Rita

    2015-01-01

    Mutations in the transient receptor potential vanilloid 4 (TRPV4) gene have been associated with autosomal dominant skeletal dysplasias and peripheral nervous system syndromes (PNSS). PNSS include Charcot–Marie–Tooth disease (CMT) type 2C, congenital spinal muscular atrophy and arthrogryposis and scapuloperoneal spinal muscular atrophy. We report the clinical, electrophysiological and muscle biopsy findings in two unrelated patients with two novel heterozygous missense mutations in the TRPV4 gene. Whole exome sequencing was carried out on genomic DNA using Illumina TruseqTM 62Mb exome capture. Patient 1 harbours a de novo c.805C > T (p.Arg269Cys) mutation. Clinically, this patient shows signs of both scapuloperoneal spinal muscular atrophy and skeletal dysplasia. Patient 2 harbours a novel c.184G > A (p.Asp62Asn) mutation. While the clinical phenotype is compatible with CMT type 2C with the patient's muscle harbours basophilic inclusions. Mutations in the TRPV4 gene have a broad phenotypic variability and disease severity and may share a similar pathogenic mechanism with Heat Shock Protein related neuropathies. PMID:25900305

  17. Topological Phenotypes Constitute a New Dimension in the Phenotypic Space of Leaf Venation Networks

    PubMed Central

    Ronellenfitsch, Henrik; Lasser, Jana; Daly, Douglas C.; Katifori, Eleni

    2015-01-01

    The leaves of angiosperms contain highly complex venation networks consisting of recursively nested, hierarchically organized loops. We describe a new phenotypic trait of reticulate vascular networks based on the topology of the nested loops. This phenotypic trait encodes information orthogonal to widely used geometric phenotypic traits, and thus constitutes a new dimension in the leaf venation phenotypic space. We apply our metric to a database of 186 leaves and leaflets representing 137 species, predominantly from the Burseraceae family, revealing diverse topological network traits even within this single family. We show that topological information significantly improves identification of leaves from fragments by calculating a “leaf venation fingerprint” from topology and geometry. Further, we present a phenomenological model suggesting that the topological traits can be explained by noise effects unique to specimen during development of each leaf which leave their imprint on the final network. This work opens the path to new quantitative identification techniques for leaves which go beyond simple geometric traits such as vein density and is directly applicable to other planar or sub-planar networks such as blood vessels in the brain. PMID:26700471

  18. Social-Cognition and the Broad Autism Phenotype: Identifying Genetically Meaningful Phenotypes

    ERIC Educational Resources Information Center

    Losh, Molly; Piven, Joseph

    2007-01-01

    Background: Strong evidence from twin and family studies suggests that the genetic liability to autism may be expressed through personality and language characteristics qualitatively similar, but more subtly expressed than those defining the full syndrome. This study examined behavioral features of this "broad autism phenotype" (BAP) in relation…

  19. Topological Phenotypes Constitute a New Dimension in the Phenotypic Space of Leaf Venation Networks.

    PubMed

    Ronellenfitsch, Henrik; Lasser, Jana; Daly, Douglas C; Katifori, Eleni

    2015-12-01

    The leaves of angiosperms contain highly complex venation networks consisting of recursively nested, hierarchically organized loops. We describe a new phenotypic trait of reticulate vascular networks based on the topology of the nested loops. This phenotypic trait encodes information orthogonal to widely used geometric phenotypic traits, and thus constitutes a new dimension in the leaf venation phenotypic space. We apply our metric to a database of 186 leaves and leaflets representing 137 species, predominantly from the Burseraceae family, revealing diverse topological network traits even within this single family. We show that topological information significantly improves identification of leaves from fragments by calculating a "leaf venation fingerprint" from topology and geometry. Further, we present a phenomenological model suggesting that the topological traits can be explained by noise effects unique to specimen during development of each leaf which leave their imprint on the final network. This work opens the path to new quantitative identification techniques for leaves which go beyond simple geometric traits such as vein density and is directly applicable to other planar or sub-planar networks such as blood vessels in the brain. PMID:26700471

  20. Root phenotyping: from component trait in the lab to breeding.

    PubMed

    Kuijken, René C P; van Eeuwijk, Fred A; Marcelis, Leo F M; Bouwmeester, Harro J

    2015-09-01

    In the last decade cheaper and faster sequencing methods have resulted in an enormous increase in genomic data. High throughput genotyping, genotyping by sequencing and genomic breeding are becoming a standard in plant breeding. As a result, the collection of phenotypic data is increasingly becoming a limiting factor in plant breeding. Genetic studies on root traits are being hampered by the complexity of these traits and the inaccessibility of the rhizosphere. With an increasing interest in phenotyping, breeders and scientists try to overcome these limitations, resulting in impressive developments in automated phenotyping platforms. Recently, many such platforms have been thoroughly described, yet their efficiency to increase genetic gain often remains undiscussed. This efficiency depends on the heritability of the phenotyped traits as well as the correlation of these traits with agronomically relevant breeding targets. This review provides an overview of the latest developments in root phenotyping and describes the environmental and genetic factors influencing root phenotype and heritability. It also intends to give direction to future phenotyping and breeding strategies for optimizing root system functioning. A quantitative framework to determine the efficiency of phenotyping platforms for genetic gain is described. By increasing heritability, managing effects caused by interactions between genotype and environment and by quantifying the genetic relation between traits phenotyped in platforms and ultimate breeding targets, phenotyping platforms can be utilized to their maximum potential. PMID:26071534

  1. Multidimensional Clinical Phenotyping of an Adult Cystic Fibrosis Patient Population

    PubMed Central

    Conrad, Douglas J.; Bailey, Barbara A.

    2015-01-01

    Background Cystic Fibrosis (CF) is a multi-systemic disease resulting from mutations in the Cystic Fibrosis Transmembrane Regulator (CFTR) gene and has major manifestations in the sino-pulmonary, and gastro-intestinal tracts. Clinical phenotypes were generated using 26 common clinical variables to generate classes that overlapped quantiles of lung function and were based on multiple aspects of CF systemic disease. Methods The variables included age, gender, CFTR mutations, FEV1% predicted, FVC% predicted, height, weight, Brasfield chest xray score, pancreatic sufficiency status and clinical microbiology results. Complete datasets were compiled on 211 subjects. Phenotypes were identified using a proximity matrix generated by the unsupervised Random Forests algorithm and subsequent clustering by the Partitioning around Medoids (PAM) algorithm. The final phenotypic classes were then characterized and compared to a similar dataset obtained three years earlier. Findings Clinical phenotypes were identified using a clustering strategy that generated four and five phenotypes. Each strategy identified 1) a low lung health scores phenotype, 2) a younger, well-nourished, male-dominated class, 3) various high lung health score phenotypes that varied in terms of age, gender and nutritional status. This multidimensional clinical phenotyping strategy identified classes with expected microbiology results and low risk clinical phenotypes with pancreatic sufficiency. Interpretation This study demonstrated regional adult CF clinical phenotypes using non-parametric, continuous, ordinal and categorical data with a minimal amount of subjective data to identify clinically relevant phenotypes. These studies identified the relative stability of the phenotypes, demonstrated specific phenotypes consistent with published findings and identified others needing further study. PMID:25822311

  2. Delineation of C12orf65-related phenotypes: a genotype–phenotype relationship

    PubMed Central

    Spiegel, Ronen; Mandel, Hanna; Saada, Ann; Lerer, Issy; Burger, Ayala; Shaag, Avraham; Shalev, Stavit A; Jabaly-Habib, Haneen; Goldsher, Dorit; Gomori, John M; Lossos, Alex; Elpeleg, Orly; Meiner, Vardiella

    2014-01-01

    C12orf65 participates in the process of mitochondrial translation and has been shown to be associated with a spectrum of phenotypes, including early onset optic atrophy, progressive encephalomyopathy, peripheral neuropathy, and spastic paraparesis.We used whole-genome homozygosity mapping as well as exome sequencing and targeted gene sequencing to identify novel C12orf65 disease-causing mutations in seven affected individuals originating from two consanguineous families. In four family members affected with childhood-onset optic atrophy accompanied by slowly progressive peripheral neuropathy and spastic paraparesis, we identified a homozygous frame shift mutation c.413_417 delAACAA, which predicts a truncated protein lacking the C-terminal portion. In the second family, we studied three affected individuals who presented with early onset optic atrophy, peripheral neuropathy, and spastic gait in addition to moderate intellectual disability. Muscle biopsy in two of the patients revealed decreased activities of the mitochondrial respiratory chain complexes I and IV. In these patients, we identified a homozygous splice mutation, g.21043 T>A (c.282+2 T>A) which leads to skipping of exon 2. Our study broadens the phenotypic spectrum of C12orf65 defects and highlights the triad of optic atrophy, axonal neuropathy and spastic paraparesis as its key clinical features. In addition, a clear genotype–phenotype correlation is anticipated in which deleterious mutations which disrupt the GGQ-containing domain in the first coding exon are expected to result in a more severe phenotype, whereas down-stream C-terminal mutations may result in a more favorable phenotype, typically lacking cognitive impairment. PMID:24424123

  3. Gene Networks Underlying Convergent and Pleiotropic Phenotypes in a Large and Systematically-Phenotyped Cohort with Heterogeneous Developmental Disorders

    PubMed Central

    Vulto-van Silfhout, Anneke; Taylor, Avigail; Steinberg, Julia; Hehir-Kwa, Jayne; Pfundt, Rolph; de Leeuw, Nicole; de Vries, Bert B. A.; Webber, Caleb

    2015-01-01

    Readily-accessible and standardised capture of genotypic variation has revolutionised our understanding of the genetic contribution to disease. Unfortunately, the corresponding systematic capture of patient phenotypic variation needed to fully interpret the impact of genetic variation has lagged far behind. Exploiting deep and systematic phenotyping of a cohort of 197 patients presenting with heterogeneous developmental disorders and whose genomes harbour de novo CNVs, we systematically applied a range of commonly-used functional genomics approaches to identify the underlying molecular perturbations and their phenotypic impact. Grouping patients into 408 non-exclusive patient-phenotype groups, we identified a functional association amongst the genes disrupted in 209 (51%) groups. We find evidence for a significant number of molecular interactions amongst the association-contributing genes, including a single highly-interconnected network disrupted in 20% of patients with intellectual disability, and show using microcephaly how these molecular networks can be used as baits to identify additional members whose genes are variant in other patients with the same phenotype. Exploiting the systematic phenotyping of this cohort, we observe phenotypic concordance amongst patients whose variant genes contribute to the same functional association but note that (i) this relationship shows significant variation across the different approaches used to infer a commonly perturbed molecular pathway, and (ii) that the phenotypic similarities detected amongst patients who share the same inferred pathway perturbation result from these patients sharing many distinct phenotypes, rather than sharing a more specific phenotype, inferring that these pathways are best characterized by their pleiotropic effects. PMID:25781962

  4. Rare phenotypes in domestic animals: unique resources for multiple applications.

    PubMed

    Leroy, G; Besbes, B; Boettcher, P; Hoffmann, I; Capitan, A; Baumung, R

    2016-04-01

    Preservation of specific and inheritable phenotypes of current or potential future importance is one of the main purposes of conservation of animal genetic resources. In this review, we investigate the issues behind the characterisation, utilisation and conservation of rare phenotypes, considering their multiple paths of relevance, variable levels of complexity and mode of inheritance. Accurately assessing the rarity of a given phenotype, especially a complex one, is not a simple task, because it requires the phenotypic and genetic characterisation of a large number of animals and populations and remains dependent of the scale of the study. Once characterised, specific phenotypes may contribute to various purposes (adaptedness, production, biological model, aesthetics, etc.) with adequate introgression programmes, which justifies the consideration of (real or potential) existence of such characteristics in in situ or ex situ conservation strategies. Recent biotechnological developments (genomic and genetic engineering) will undoubtedly bring important changes to the way phenotypes are characterised, introgressed and managed. PMID:26662214

  5. Large-scale objective phenotyping of 3D facial morphology

    PubMed Central

    Hammond, Peter; Suttie, Michael

    2012-01-01

    Abnormal phenotypes have played significant roles in the discovery of gene function, but organized collection of phenotype data has been overshadowed by developments in sequencing technology. In order to study phenotypes systematically, large-scale projects with standardized objective assessment across populations are considered necessary. The report of the 2006 Human Variome Project meeting recommended documentation of phenotypes through electronic means by collaborative groups of computational scientists and clinicians using standard, structured descriptions of disease-specific phenotypes. In this report, we describe progress over the past decade in 3D digital imaging and shape analysis of the face, and future prospects for large-scale facial phenotyping. Illustrative examples are given throughout using a collection of 1107 3D face images of healthy controls and individuals with a range of genetic conditions involving facial dysmorphism. PMID:22434506

  6. Decomposing Phenotype Descriptions for the Human Skeletal Phenome

    PubMed Central

    Groza, Tudor; Hunter, Jane; Zankl, Andreas

    2013-01-01

    Over the course of the last few years there has been a significant amount of research performed on ontology-based formalization of phenotype descriptions. The intrinsic value and knowledge captured within such descriptions can only be expressed by taking advantage of their inner structure that implicitly combines qualities and anatomical entities. We present a meta-model (the Phenotype Fragment Ontology) and a processing pipeline that enable together the automatic decomposition and conceptualization of phenotype descriptions for the human skeletal phenome. We use this approach to showcase the usefulness of the generic concept of phenotype decomposition by performing an experimental study on all skeletal phenotype concepts defined in the Human Phenotype Ontology. PMID:23440304

  7. Phenotyping common beans for adaptation to drought

    PubMed Central

    Beebe, Stephen E.; Rao, Idupulapati M.; Blair, Matthew W.; Acosta-Gallegos, Jorge A.

    2013-01-01

    Common beans (Phaseolus vulgaris L.) originated in the New World and are the grain legume of greatest production for direct human consumption. Common bean production is subject to frequent droughts in highland Mexico, in the Pacific coast of Central America, in northeast Brazil, and in eastern and southern Africa from Ethiopia to South Africa. This article reviews efforts to improve common bean for drought tolerance, referring to genetic diversity for drought response, the physiology of drought tolerance mechanisms, and breeding strategies. Different races of common bean respond differently to drought, with race Durango of highland Mexico being a major source of genes. Sister species of P. vulgaris likewise have unique traits, especially P. acutifolius which is well adapted to dryland conditions. Diverse sources of tolerance may have different mechanisms of plant response, implying the need for different methods of phenotyping to recognize the relevant traits. Practical considerations of field management are discussed including: trial planning; water management; and field preparation. PMID:23507928

  8. Endothelial Plasticity: Shifting Phenotypes through Force Feedback

    PubMed Central

    Krenning, Guido; Barauna, Valerio G.; Krieger, José E.; Harmsen, Martin C.; Moonen, Jan-Renier A. J.

    2016-01-01

    The endothelial lining of the vasculature is exposed to a large variety of biochemical and hemodynamic stimuli with different gradients throughout the vascular network. Adequate adaptation requires endothelial cells to be highly plastic, which is reflected by the remarkable heterogeneity of endothelial cells in tissues and organs. Hemodynamic forces such as fluid shear stress and cyclic strain are strong modulators of the endothelial phenotype and function. Although endothelial plasticity is essential during development and adult physiology, proatherogenic stimuli can induce adverse plasticity which contributes to disease. Endothelial-to-mesenchymal transition (EndMT), the hallmark of endothelial plasticity, was long thought to be restricted to embryonic development but has emerged as a pathologic process in a plethora of diseases. In this perspective we argue how shear stress and cyclic strain can modulate EndMT and discuss how this is reflected in atherosclerosis and pulmonary arterial hypertension. PMID:26904133

  9. Distinguishing Asthma Phenotypes Using Machine Learning Approaches.

    PubMed

    Howard, Rebecca; Rattray, Magnus; Prosperi, Mattia; Custovic, Adnan

    2015-07-01

    Asthma is not a single disease, but an umbrella term for a number of distinct diseases, each of which are caused by a distinct underlying pathophysiological mechanism. These discrete disease entities are often labelled as 'asthma endotypes'. The discovery of different asthma subtypes has moved from subjective approaches in which putative phenotypes are assigned by experts to data-driven ones which incorporate machine learning. This review focuses on the methodological developments of one such machine learning technique-latent class analysis-and how it has contributed to distinguishing asthma and wheezing subtypes in childhood. It also gives a clinical perspective, presenting the findings of studies from the past 5 years that used this approach. The identification of true asthma endotypes may be a crucial step towards understanding their distinct pathophysiological mechanisms, which could ultimately lead to more precise prevention strategies, identification of novel therapeutic targets and the development of effective personalized therapies. PMID:26143394

  10. Identifying biochemical phenotypic differences between cryptic species

    PubMed Central

    Liebeke, Manuel; Bruford, Michael W.; Donnelly, Robert K.; Ebbels, Timothy M. D.; Hao, Jie; Kille, Peter; Lahive, Elma; Madison, Rachael M.; Morgan, A. John; Pinto-Juma, Gabriela A.; Spurgeon, David J.; Svendsen, Claus; Bundy, Jacob G.

    2014-01-01

    Molecular genetic methods can distinguish divergent evolutionary lineages in what previously appeared to be single species, but it is not always clear what functional differences exist between such cryptic species. We used a metabolomic approach to profile biochemical phenotype (metabotype) differences between two putative cryptic species of the earthworm Lumbricus rubellus. There were no straightforward metabolite biomarkers of lineage, i.e. no metabolites that were always at higher concentration in one lineage. Multivariate methods, however, identified a small number of metabolites that together helped distinguish the lineages, including uncommon metabolites such as Nε-trimethyllysine, which is not usually found at high concentrations. This approach could be useful for characterizing functional trait differences, especially as it is applicable to essentially any species group, irrespective of its genome sequencing status. PMID:25252836

  11. ARC syndrome: an expanding range of phenotypes

    PubMed Central

    Eastham, K; McKiernan, P; Milford, D; Ramani, P; Wyllie, J; van't, H; Lynch, S; Morris, A

    2001-01-01

    AIM—To describe the clinical phenotype in infants with ARC syndrome, the association of arthrogryposis, renal tubular acidosis, and cholestasis.
METHODS—The medical records for six patients with ARC syndrome were reviewed, presenting over 10 years to three paediatric referral centres.
RESULTS—All patients had the typical pattern of arthrogryposis. Renal Fanconi syndrome was present in all but one patient, who presented with nephrogenic diabetes insipidus. Although all patients had severe cholestasis, serum γ glutamyltransferase values were normal. Many of our patients showed dysmorphic features or ichthyosis. All had recurrent febrile illnesses, diarrhoea, and failed to thrive. Blood films revealed abnormally large platelets.
CONCLUSIONS—ARC syndrome exhibits notable clinical variability and may not be as rare as previously thought. The association of Fanconi syndrome, ichthyosis, dysmorphism, jaundice, and diarrhoea has previously been reported as a separate syndrome: our observations indicate that it is part of the ARC spectrum.

 PMID:11668108

  12. Do convergent developmental mechanisms underlie convergent phenotypes?

    NASA Technical Reports Server (NTRS)

    Wray, Gregory A.

    2002-01-01

    Convergence is a pervasive evolutionary process, affecting many aspects of phenotype and even genotype. Relatively little is known about convergence in developmental processes, however, nor about the degree to which convergence in development underlies convergence in anatomy. A switch in the ecology of sea urchins from feeding to nonfeeding larvae illustrates how convergence in development can be associated with convergence in anatomy. Comparisons to more distantly related taxa, however, suggest that this association may be limited to relatively close phylogenetic comparisons. Similarities in gene expression during development provide another window into the association between convergence in developmental processes and convergence in anatomy. Several well-studied transcription factors exhibit likely cases of convergent gene expression in distantly related animal phyla. Convergence in regulatory gene expression domains is probably more common than generally acknowledged, and can arise for several different reasons. Copyright 2002 S. Karger AG, Basel.

  13. Phenotypic Correlates of HIV-1 Macrophage Tropism

    PubMed Central

    Arrildt, Kathryn T.; LaBranche, Celia C.; Joseph, Sarah B.; Dukhovlinova, Elena N.; Graham, William D.; Ping, Li-Hua; Schnell, Gretja; Sturdevant, Christa B.; Kincer, Laura P.; Mallewa, Macpherson; Heyderman, Robert S.; Van Rie, Annelies; Cohen, Myron S.; Spudich, Serena; Price, Richard W.; Montefiori, David C.

    2015-01-01

    ABSTRACT HIV-1 is typically CCR5 using (R5) and T cell tropic (T-tropic), targeting memory CD4+ T cells throughout acute and chronic infections. However, viruses can expand into alternative cells types. Macrophage-tropic (M-tropic) HIV-1 variants have evolved to infect macrophages, which have only low levels of surface CD4. Most M-tropic variants have been isolated from the central nervous system during late-stage chronic infection. We used the HIV-1 env genes of well-defined, subject-matched M-tropic and T-tropic viruses to characterize the phenotypic features of the M-tropic Env protein. We found that, compared to T-tropic viruses, M-tropic viruses infect monocyte-derived macrophages (MDMs) on average 28-fold more efficiently, use low-density CD4 more efficiently, have increased sensitivity to soluble CD4 (sCD4), and show trends toward sensitivity to some CD4 binding site antibodies but no difference in sensitivity to antibodies targeting the CD4-bound conformation. M-tropic viruses also displayed a trend toward resistance to neutralization by monoclonal antibodies targeting the V1/V2 region of Env, suggesting subtle changes in Env protein conformation. The paired M- and T-tropic viruses did not differ in autologous serum neutralization, temperature sensitivity, entry kinetics, intrinsic infectivity, or Env protein incorporation. We also examined viruses with modestly increased CD4 usage. These variants have significant sensitivity to sCD4 and may represent evolutionary intermediates. CD4 usage is strongly correlated with infectivity of MDMs over a wide range of CD4 entry phenotypes. These data suggest that emergence of M-tropic HIV-1 includes multiple steps in which a phenotype of increased sensitivity to sCD4 and enhanced CD4 usage accompany subtle changes in Env conformation. IMPORTANCE HIV-1 typically replicates in CD4+ T cells. However, HIV-1 can evolve to infect macrophages, especially within the brain. Understanding how CCR5-using macrophage-tropic viruses

  14. Clinical interpretation of CNVs with cross-species phenotype data

    PubMed Central

    Czeschik, Johanna Christina; Doelken, Sandra C; Hehir-Kwa, Jayne Y; Ibn-Salem, Jonas; Mungall, Christopher J; Smedley, Damian; Haendel, Melissa A; Robinson, Peter N

    2015-01-01

    Background Clinical evaluation of CNVs identified via techniques such as array comparative genome hybridisation (aCGH) involves the inspection of lists of known and unknown duplications and deletions with the goal of distinguishing pathogenic from benign CNVs. A key step in this process is the comparison of the individual's phenotypic abnormalities with those associated with Mendelian disorders of the genes affected by the CNV. However, because often there is not much known about these human genes, an additional source of data that could be used is model organism phenotype data. Currently, almost 6000 genes in mouse and zebrafish are, when knocked out, associated with a phenotype in the model organism, but no disease is known to be caused by mutations in the human ortholog. Yet, searching model organism databases and comparing model organism phenotypes with patient phenotypes for identifying novel disease genes and medical evaluation of CNVs is hindered by the difficulty in integrating phenotype information across species and the lack of appropriate software tools. Methods Here, we present an integrated ranking scheme based on phenotypic matching, degree of overlap with known benign or pathogenic CNVs and the haploinsufficiency score for the prioritisation of CNVs responsible for a patient's clinical findings. Results We show that this scheme leads to significant improvements compared with rankings that do not exploit phenotypic information. We provide a software tool called PhenogramViz, which supports phenotype-driven interpretation of aCGH findings based on multiple data sources, including the integrated cross-species phenotype ontology Uberpheno, in order to visualise gene-to-phenotype relations. Conclusions Integrating and visualising cross-species phenotype information on the affected genes may help in routine diagnostics of CNVs. PMID:25280750

  15. Developing predictive assays: the phenotypic screening "rule of 3".

    PubMed

    Vincent, Fabien; Loria, Paula; Pregel, Marko; Stanton, Robert; Kitching, Linda; Nocka, Karl; Doyonnas, Regis; Steppan, Claire; Gilbert, Adam; Schroeter, Thomas; Peakman, Marie-Claire

    2015-06-24

    Phenotypic drug discovery approaches can positively affect the translation of preclinical findings to patients. However, not all phenotypic assays are created equal. A critical question then follows: What are the characteristics of the optimal assays? We analyze this question and propose three specific criteria related to the disease relevance of the assay-system, stimulus, and end point-to help design the most predictive phenotypic assays. PMID:26109101

  16. Extremely varied phenotypes in granular corneal dystrophy type 2 heterozygotes

    PubMed Central

    Han, Kyung Eun; Choi, Seung-il; Chung, Woo Suk; Jung, Se Hwan; Katsanis, Nicholas; Kim, Tae-im

    2012-01-01

    Purpose To investigate the phenotypic variability of patients bearing the heterozygous R124H mutation in the TGFBI (transforming growth factor-beta-induced) gene that causes granular corneal dystrophy type 2 (GCD2). Methods We describe the phenotypic range of GCD2 heterozygotes for the common R124H mutation in TGFBI; seven with an extremely mild phenotype and six with an extremely severe phenotype. Detailed slit-lamp photographs of these patients were generated. All patients had no history of ocular surgery and were diagnosed as being heterozygous for GCD2 by DNA analysis from peripheral blood. Expression levels of transforming growth factor-beta-induced protein (TGFBIp) were compared among cultured corneal fibroblasts from ten normal donors. Results We report profound differences in the severity of the phenotype across our case series. Two patients with a mild phenotype were diagnosed as unaffected at presentation; however follow-up examinations revealed granular deposits. Importantly, we also observed familial clustering of phenotypic variance; five patients from two families with a mild phenotype showed a similarly mild phenotype within family members. Similarly, six patients from two families with severe phenotypes showed corneal deposits with similar patterns and severity within each distinct family, but distinct patterns between families. TGFBIp expressions from different donor derived cultured corneal fibroblasts were different between one another. Conclusions GCD2 heterozygotes have extremely varied phenotypes between individual patients. However phenotypes were broadly consistent within families, suggesting that the observed variable expressivity might be regulated by other genetic factors that could influence the abundance of TGFBIp or the function of the pathway. From a clinical perspective, our data also highlighted that genetic analysis and meticulous slit-lamp examination in both eyes at multiple time intervals is necessary. PMID:22815629

  17. Phenotype accessibility and noise in random threshold gene regulatory networks.

    PubMed

    Pinho, Ricardo; Garcia, Victor; Feldman, Marcus W

    2014-01-01

    Evolution requires phenotypic variation in a population of organisms for selection to function. Gene regulatory processes involved in organismal development affect the phenotypic diversity of organisms. Since only a fraction of all possible phenotypes are predicted to be accessed by the end of development, organisms may evolve strategies to use environmental cues and noise-like fluctuations to produce additional phenotypic diversity, and hence to enhance the speed of adaptation. We used a generic model of organismal development --gene regulatory networks-- to investigate how different levels of noise on gene expression states (i.e. phenotypes) may affect access to new, unique phenotypes, thereby affecting phenotypic diversity. We studied additional strategies that organisms might adopt to attain larger phenotypic diversity: either by augmenting their genome or the number of gene expression states. This was done for different types of gene regulatory networks that allow for distinct levels of regulatory influence on gene expression or are more likely to give rise to stable phenotypes. We found that if gene expression is binary, increasing noise levels generally decreases phenotype accessibility for all network types studied. If more gene expression states are considered, noise can moderately enhance the speed of discovery if three or four gene expression states are allowed, and if there are enough distinct regulatory networks in the population. These results were independent of the network types analyzed, and were robust to different implementations of noise. Hence, for noise to increase the number of accessible phenotypes in gene regulatory networks, very specific conditions need to be satisfied. If the number of distinct regulatory networks involved in organismal development is large enough, and the acquisition of more genes or fine tuning of their expression states proves costly to the organism, noise can be useful in allowing access to more unique phenotypes

  18. Phenotype Accessibility and Noise in Random Threshold Gene Regulatory Networks

    PubMed Central

    Feldman, Marcus W.

    2015-01-01

    Evolution requires phenotypic variation in a population of organisms for selection to function. Gene regulatory processes involved in organismal development affect the phenotypic diversity of organisms. Since only a fraction of all possible phenotypes are predicted to be accessed by the end of development, organisms may evolve strategies to use environmental cues and noise-like fluctuations to produce additional phenotypic diversity, and hence to enhance the speed of adaptation. We used a generic model of organismal development --gene regulatory networks-- to investigate how different levels of noise on gene expression states (i.e. phenotypes) may affect access to new, unique phenotypes, thereby affecting phenotypic diversity. We studied additional strategies that organisms might adopt to attain larger phenotypic diversity: either by augmenting their genome or the number of gene expression states. This was done for different types of gene regulatory networks that allow for distinct levels of regulatory influence on gene expression or are more likely to give rise to stable phenotypes. We found that if gene expression is binary, increasing noise levels generally decreases phenotype accessibility for all network types studied. If more gene expression states are considered, noise can moderately enhance the speed of discovery if three or four gene expression states are allowed, and if there are enough distinct regulatory networks in the population. These results were independent of the network types analyzed, and were robust to different implementations of noise. Hence, for noise to increase the number of accessible phenotypes in gene regulatory networks, very specific conditions need to be satisfied. If the number of distinct regulatory networks involved in organismal development is large enough, and the acquisition of more genes or fine tuning of their expression states proves costly to the organism, noise can be useful in allowing access to more unique phenotypes

  19. Genetic Regulation of Phenotypic Plasticity and Canalisation in Yeast Growth.

    PubMed

    Yadav, Anupama; Dhole, Kaustubh; Sinha, Himanshu

    2016-01-01

    The ability of a genotype to show diverse phenotypes in different environments is called phenotypic plasticity. Phenotypic plasticity helps populations to evade extinctions in novel environments, facilitates adaptation and fuels evolution. However, most studies focus on understanding the genetic basis of phenotypic regulation in specific environments. As a result, while it's evolutionary relevance is well established, genetic mechanisms regulating phenotypic plasticity and their overlap with the environment specific regulators is not well understood. Saccharomyces cerevisiae is highly sensitive to the environment, which acts as not just external stimulus but also as signalling cue for this unicellular, sessile organism. We used a previously published dataset of a biparental yeast population grown in 34 diverse environments and mapped genetic loci regulating variation in phenotypic plasticity, plasticity QTL, and compared them with environment-specific QTL. Plasticity QTL is one whose one allele exhibits high plasticity whereas the other shows a relatively canalised behaviour. We mapped phenotypic plasticity using two parameters-environmental variance, an environmental order-independent parameter and reaction norm (slope), an environmental order-dependent parameter. Our results show a partial overlap between pleiotropic QTL and plasticity QTL such that while some plasticity QTL are also pleiotropic, others have a significant effect on phenotypic plasticity without being significant in any environment independently. Furthermore, while some plasticity QTL are revealed only in specific environmental orders, we identify large effect plasticity QTL, which are order-independent such that whatever the order of the environments, one allele is always plastic and the other is canalised. Finally, we show that the environments can be divided into two categories based on the phenotypic diversity of the population within them and the two categories have differential regulators of

  20. Phenotypic characteristics of early Wolfram syndrome

    PubMed Central

    2013-01-01

    Background Wolfram Syndrome (WFS:OMIM 222300) is an autosomal recessive, progressive, neurologic and endocrinologic degenerative disorder caused by mutations in the WFS1 gene, encoding the endoplasmic reticulum (ER) protein wolframin, thought to be involved in the regulation of ER stress. This paper reports a cross section of data from the Washington University WFS Research Clinic, a longitudinal study to collect detailed phenotypic data on a group of young subjects in preparation for studies of therapeutic interventions. Methods Eighteen subjects (ages 5.9–25.8, mean 14.2 years) with genetically confirmed WFS were identified through the Washington University International Wolfram Registry. Examinations included: general medical, neurologic, ophthalmologic, audiologic, vestibular, and urologic exams, cognitive testing and neuroimaging. Results Seventeen (94%) had diabetes mellitus with the average age of diabetes onset of 6.3 ± 3.5 years. Diabetes insipidus was diagnosed in 13 (72%) at an average age of 10.6 ± 3.3 years. Seventeen (94%) had optic disc pallor and defects in color vision, 14 (78%) had hearing loss and 13 (72%) had olfactory defects, eight (44%) had impaired vibration sensation. Enuresis was reported by four (22%) and nocturia by three (17%). Of the 11 tested for bladder emptying, five (45%) had elevated post-void residual bladder volume. Conclusions WFS causes multiple endocrine and neurologic deficits detectable on exam, even early in the course of the disease. Defects in olfaction have been underappreciated. The proposed mechanism of these deficits in WFS is ER stress-induced damage to neuronal and hormone-producing cells. This group of subjects with detailed clinical phenotyping provides a pool for testing proposed treatments for ER stress. Longitudinal follow-up is necessary for establishing the natural history and identifying potential biomarkers of progression. PMID:23981289

  1. Glucose metabolic phenotype of pancreatic cancer

    PubMed Central

    Chan, Anthony KC; Bruce, Jason IE; Siriwardena, Ajith K

    2016-01-01

    AIM: To construct a global “metabolic phenotype” of pancreatic ductal adenocarcinoma (PDAC) reflecting tumour-related metabolic enzyme expression. METHODS: A systematic review of the literature was performed using OvidSP and PubMed databases using keywords “pancreatic cancer” and individual glycolytic and mitochondrial oxidative phosphorylation (MOP) enzymes. Both human and animal studies investigating the oncological effect of enzyme expression changes and inhibitors in both an in vitro and in vivo setting were included in the review. Data reporting changes in enzyme expression and the effects on PDAC cells, such as survival and metastatic potential, were extracted to construct a metabolic phenotype. RESULTS: Seven hundred and ten papers were initially retrieved, and were screened to meet the review inclusion criteria. 107 unique articles were identified as reporting data involving glycolytic enzymes, and 28 articles involving MOP enzymes in PDAC. Data extraction followed a pre-defined protocol. There is consistent over-expression of glycolytic enzymes and lactate dehydrogenase in keeping with the Warburg effect to facilitate rapid adenosine-triphosphate production from glycolysis. Certain isoforms of these enzymes were over-expressed specifically in PDAC. Altering expression levels of HK, PGI, FBA, enolase, PK-M2 and LDA-A with metabolic inhibitors have shown a favourable effect on PDAC, thus identifying these as potential therapeutic targets. However, the Warburg effect on MOP enzymes is less clear, with different expression levels at different points in the Krebs cycle resulting in a fundamental change of metabolite levels, suggesting that other essential anabolic pathways are being stimulated. CONCLUSION: Further characterisation of the PDAC metabolic phenotype is necessary as currently there are few clinical studies and no successful clinical trials targeting metabolic enzymes. PMID:27022229

  2. Zinc and the prooxidant heart failure phenotype.

    PubMed

    Efeovbokhan, Nephertiti; Bhattacharya, Syamal K; Ahokas, Robert A; Sun, Yao; Guntaka, Ramareddy V; Gerling, Ivan C; Weber, Karl T

    2014-10-01

    Neurohormonal activation with attendant aldosteronism contributes to the clinical appearance of congestive heart failure (CHF). Aldosteronism is intrinsically coupled to Zn and Ca dyshomeostasis, in which consequent hypozincemia compromises Zn homeostasis and Zn-based antioxidant defenses that contribute to the CHF prooxidant phenotype. Ionized hypocalcemia leads to secondary hyperparathyroidism with parathyroid hormone-mediated Ca overloading of diverse cells, including cardiomyocytes. When mitochondrial Ca overload exceeds a threshold, myocyte necrosis follows. The reciprocal regulation involving cytosolic free [Zn]i as antioxidant and [Ca]i as prooxidant can be uncoupled in favor of Zn-based antioxidant defenses. Increased [Zn]i acts as a multifaceted antioxidant by: (1) inhibiting Ca entry through L-type channels and hence cardioprotectant from the Ca-driven mitochondriocentric signal-transducer effector pathway to nonischemic necrosis, (2) serving as catalytic regulator of Cu/Zn-superoxide dismutase, and (3) activating its cytosolic sensor, metal-responsive transcription factor that regulates the expression of relevant antioxidant defense genes. Albeit present in subnanomolar range, increased cytosolic free [Zn]i enhances antioxidant capacity that confers cardioprotection. It can be achieved exogenously by ZnSO4 supplementation or endogenously using a β3-receptor agonist (eg, nebivolol) that enhances NO generation to release inactive cytosolic Zn bound to metallothionein. By recognizing the pathophysiologic relevance of Zn dyshomeostasis in the prooxidant CHF phenotype and by exploiting the pharmacophysiologic potential of [Zn]i as antioxidant, vulnerable cardiomyocytes under assault from neurohormonal activation can be protected and the myocardium spared from adverse structural remodeling. PMID:25291496

  3. ZINC AND THE PROOXIDANT HEART FAILURE PHENOTYPE

    PubMed Central

    Efeovbokhan, Nephertiti; Bhattacharya, Syamal K.; Ahokas, Robert A.; Sun, Yao; Guntaka, Ramareddy V.; Gerling, Ivan C.; Weber, Karl T.

    2014-01-01

    Neurohormonal activation with attendant aldosteronism contributes to the clinical appearance of congestive heart failure (CHF). Aldosteronism is intrinsically coupled to Zn2+ and Ca2+ dyshomeostasis, in which consequent hypozincemia compromises Zn2+ homeostasis and Zn2+-based antioxidant defenses that contribute to the CHF prooxidant phenotype. Ionized hypocalcemia leads to secondary hyperparathyroidism with parathyroid hormone-mediated Ca2+ overloading of diverse cells, including cardiomyocytes. When mitochondrial Ca2+ overload exceeds a threshold, myocyte necrosis follows. The reciprocal regulation involving cytosolic free [Zn2+]i as antioxidant and [Ca2+]i as prooxidant that can be uncoupled in favor of Zn2+-based antioxidant defenses. Increased [Zn2+]i acts as a multifaceted antioxidant by: i) inhibiting Ca2+ entry via L-type channels and hence cardioprotectant from the Ca2+-driven mitochondriocentric signal-transducer-effector pathway to nonischemic necrosis; ii) serving as catalytic regulator of Cu/Zn-superoxide dismutase; and iii) activating its cytosolic sensor, metal-responsive transcription factor that regulates the expression of relevant antioxidant defense genes. Albeit present in subnanomolar range, increased cytosolic free [Zn2+]i enhances antioxidant capacity that confers cardioprotection. It can be achieved exogenously by ZnSO4 supplementation or endogenously, using a β3 receptor agonist, (e.g., nebivolol) that enhances NO generation to release inactive cytosolic Zn2+ bound to metallothionein. By recognizing the pathophysiologic relevance of Zn2+ dyshomeostasis in the prooxidant CHF phenotype and by exploiting the pharmacophysiologic potential of [Zn2+]i as antioxidant, vulnerable cardiomyocytes under assault from neurohormonal activation can be protected and the myocardium spared from adverse structural remodeling. PMID:25291496

  4. Neuroanatomical Phenotypes In The Reeler Mouse

    PubMed Central

    Badea, Alexandra; Nicholls, Peter J.; Johnson, G. Allan; Wetsel, William C.

    2007-01-01

    The reeler mouse (Reln) has been proposed as a neurodevelopmental model for certain neurological and psychiatric conditions and has been studied by qualitative histochemistry and electron microscopy. Using magnetic resonance microscopy (MRM), we have quantitated for the first time the neuromorphology of Reln mice at a resolution of 21.5 μm. The neuroanatomical phenotypes of heterozygous and homozygous mutant Reln mice were compared to those of wild type (WT) littermates using morphometry and texture analysis. The cortical, hippocampal, and cerebellar phenotypes of the heterozygous and homozygous mutant Reln mice were confirmed, and new features were revealed. The Relnrl/rl mice possessed a smaller brain, and both Relnrl/+ and Relnrl/rl mice had increased ventricles compared to WT controls. Shape differences were found between WT and Relnrl/rl brains, specifically in cerebellum, olfactory bulbs, dorsomedial frontal and parietal cortex, certain regions of temporal and occipital lobes, as well as in the lateral ventricles and ventral hippocampus. These findings suggest that certain brain regions may be more severely impacted by the Reln mutation than others. Gadolinium-based active-staining demonstrated that layers of the hippocampus were disorganized in Relnrl/rl mice and differences in thickness of these layers were identified between WT and Relnrl/rl mice. The intensity distributions characteristic to the dorsal, middle, and ventral hippocampus were altered in the Relnrl/rl, especially in the ventral hippocampus. These differences were quantified using skewness and modeling the intensity distributions with a Gaussian mixture. Our results suggest that structural features of Relnrl/rl brain most closely phenocopy those of patients with Norman-Roberts lissencephaly. PMID:17185001

  5. Phenotype heterogeneity in cancer cell populations

    NASA Astrophysics Data System (ADS)

    Almeida, Luis; Chisholm, Rebecca; Clairambault, Jean; Escargueil, Alexandre; Lorenzi, Tommaso; Lorz, Alexander; Trélat, Emmanuel

    2016-06-01

    Phenotype heterogeneity in cancer cell populations, be it of genetic, epigenetic or stochastic origin, has been identified as a main source of resistance to drug treatments and a major source of therapeutic failures in cancers. The molecular mechanisms of drug resistance are partly understood at the single cell level (e.g., overexpression of ABC transporters or of detoxication enzymes), but poorly predictable in tumours, where they are hypothesised to rely on heterogeneity at the cell population scale, which is thus the right level to describe cancer growth and optimise its control by therapeutic strategies in the clinic. We review a few results from the biological literature on the subject, and from mathematical models that have been published to predict and control evolution towards drug resistance in cancer cell populations. We propose, based on the latter, optimisation strategies of combined treatments to limit emergence of drug resistance to cytotoxic drugs in cancer cell populations, in the monoclonal situation, which limited as it is still retains consistent features of cell population heterogeneity. The polyclonal situation, that may be understood as "bet hedging" of the tumour, thus protecting itself from different sources of drug insults, may lie beyond such strategies and will need further developments. In the monoclonal situation, we have designed an optimised therapeutic strategy relying on a scheduled combination of cytotoxic and cytostatic treatments that can be adapted to different situations of cancer treatments. Finally, we review arguments for biological theoretical frameworks proposed at different time and development scales, the so-called atavistic model (diachronic view relying on Darwinian genotype selection in the coursof billions of years) and the Waddington-like epigenetic landscape endowed with evolutionary quasi-potential (synchronic view relying on Lamarckian phenotype instruction of a given genome by reversible mechanisms), to

  6. Phenotypes in phylogeography: Species’ traits, environmental variation, and vertebrate diversification

    PubMed Central

    Bell, Rayna C.; Mason, Nicholas A.

    2016-01-01

    Almost 30 y ago, the field of intraspecific phylogeography laid the foundation for spatially explicit and genealogically informed studies of population divergence. With new methods and markers, the focus in phylogeography shifted to previously unrecognized geographic genetic variation, thus reducing the attention paid to phenotypic variation in those same diverging lineages. Although phenotypic differences among lineages once provided the main data for studies of evolutionary change, the mechanisms shaping phenotypic differentiation and their integration with intraspecific genetic structure have been underexplored in phylogeographic studies. However, phenotypes are targets of selection and play important roles in species performance, recognition, and diversification. Here, we focus on three questions. First, how can phenotypes elucidate mechanisms underlying concordant or idiosyncratic responses of vertebrate species evolving in shared landscapes? Second, what mechanisms underlie the concordance or discordance of phenotypic and phylogeographic differentiation? Third, how can phylogeography contribute to our understanding of functional phenotypic evolution? We demonstrate that the integration of phenotypic data extends the reach of phylogeography to explain the origin and maintenance of biodiversity. Finally, we stress the importance of natural history collections as sources of high-quality phenotypic data that span temporal and spatial axes. PMID:27432983

  7. Intramolecular phenotypic capacitance in a modular RNA molecule

    PubMed Central

    Hayden, Eric J.; Bendixsen, Devin P.; Wagner, Andreas

    2015-01-01

    Phenotypic capacitance refers to the ability of a genome to accumulate mutations that are conditionally hidden and only reveal phenotype-altering effects after certain environmental or genetic changes. Capacitance has important implications for the evolution of novel forms and functions, but experimentally studied mechanisms behind capacitance are mostly limited to complex, multicomponent systems often involving several interacting protein molecules. Here we demonstrate phenotypic capacitance within a much simpler system, an individual RNA molecule with catalytic activity (ribozyme). This naturally occurring RNA molecule has a modular structure, where a scaffold module acts as an intramolecular chaperone that facilitates folding of a second catalytic module. Previous studies have shown that the scaffold module is not absolutely required for activity, but dramatically decreases the concentration of magnesium ions required for the formation of an active site. Here, we use an experimental perturbation of magnesium ion concentration that disrupts the folding of certain genetic variants of this ribozyme and use in vitro selection followed by deep sequencing to identify genotypes with altered phenotypes (catalytic activity). We identify multiple conditional mutations that alter the wild-type ribozyme phenotype under a stressful environmental condition of low magnesium ion concentration, but preserve the phenotype under more relaxed conditions. This conditional buffering is confined to the scaffold module, but controls the catalytic phenotype, demonstrating how modularity can enable phenotypic capacitance within a single macromolecule. RNA’s ancient role in life suggests that phenotypic capacitance may have influenced evolution since life’s origins. PMID:26401020

  8. The evolution of phenotypic correlations and ‘developmental memory’

    PubMed Central

    Watson, Richard A.; Wagner, Günter P.; Pavlicev, Mihaela; Weinreich, Daniel M.; Mills, Rob

    2014-01-01

    Development introduces structured correlations among traits that may constrain or bias the distribution of phenotypes produced. Moreover, when suitable heritable variation exists, natural selection may alter such constraints and correlations, affecting the phenotypic variation available to subsequent selection. However, exactly how the distribution of phenotypes produced by complex developmental systems can be shaped by past selective environments is poorly understood. Here we investigate the evolution of a network of recurrent non-linear ontogenetic interactions, such as a gene regulation network, in various selective scenarios. We find that evolved networks of this type can exhibit several phenomena that are familiar in cognitive learning systems. These include formation of a distributed associative memory that can ‘store’ and ‘recall’ multiple phenotypes that have been selected in the past, recreate complete adult phenotypic patterns accurately from partial or corrupted embryonic phenotypes, and ‘generalise’ (by exploiting evolved developmental modules) to produce new combinations of phenotypic features. We show that these surprising behaviours follow from an equivalence between the action of natural selection on phenotypic correlations and associative learning, well-understood in the context of neural networks. This helps to explain how development facilitates the evolution of high-fitness phenotypes and how this ability changes over evolutionary time. PMID:24351058

  9. Phenotypes in phylogeography: Species' traits, environmental variation, and vertebrate diversification.

    PubMed

    Zamudio, Kelly R; Bell, Rayna C; Mason, Nicholas A

    2016-07-19

    Almost 30 y ago, the field of intraspecific phylogeography laid the foundation for spatially explicit and genealogically informed studies of population divergence. With new methods and markers, the focus in phylogeography shifted to previously unrecognized geographic genetic variation, thus reducing the attention paid to phenotypic variation in those same diverging lineages. Although phenotypic differences among lineages once provided the main data for studies of evolutionary change, the mechanisms shaping phenotypic differentiation and their integration with intraspecific genetic structure have been underexplored in phylogeographic studies. However, phenotypes are targets of selection and play important roles in species performance, recognition, and diversification. Here, we focus on three questions. First, how can phenotypes elucidate mechanisms underlying concordant or idiosyncratic responses of vertebrate species evolving in shared landscapes? Second, what mechanisms underlie the concordance or discordance of phenotypic and phylogeographic differentiation? Third, how can phylogeography contribute to our understanding of functional phenotypic evolution? We demonstrate that the integration of phenotypic data extends the reach of phylogeography to explain the origin and maintenance of biodiversity. Finally, we stress the importance of natural history collections as sources of high-quality phenotypic data that span temporal and spatial axes. PMID:27432983

  10. The value of translational biomarkers to phenotypic assays

    PubMed Central

    Swinney, David C.

    2014-01-01

    Phenotypic assays are tools essential for drug discovery. Phenotypic assays have different types of endpoints depending on the goals; (1) empirical endpoints for basic research to understand the underlying biology that will lead to identification of translation biomarkers, (2) empirical endpoints to identify undesired effects related to toxicity of drug candidates, and (3) knowledge-based endpoints (biomarkers) for drug discovery which ideally are translational biomarkers that will be used to identify new drug candidates and their corresponding molecular mechanisms of action. The value of phenotypic assays is increased through effective alignment of phenotypic assay endpoints with the objectives of the relevant stage in the drug discovery and development cycle. PMID:25076910

  11. Intramolecular phenotypic capacitance in a modular RNA molecule.

    PubMed

    Hayden, Eric J; Bendixsen, Devin P; Wagner, Andreas

    2015-10-01

    Phenotypic capacitance refers to the ability of a genome to accumulate mutations that are conditionally hidden and only reveal phenotype-altering effects after certain environmental or genetic changes. Capacitance has important implications for the evolution of novel forms and functions, but experimentally studied mechanisms behind capacitance are mostly limited to complex, multicomponent systems often involving several interacting protein molecules. Here we demonstrate phenotypic capacitance within a much simpler system, an individual RNA molecule with catalytic activity (ribozyme). This naturally occurring RNA molecule has a modular structure, where a scaffold module acts as an intramolecular chaperone that facilitates folding of a second catalytic module. Previous studies have shown that the scaffold module is not absolutely required for activity, but dramatically decreases the concentration of magnesium ions required for the formation of an active site. Here, we use an experimental perturbation of magnesium ion concentration that disrupts the folding of certain genetic variants of this ribozyme and use in vitro selection followed by deep sequencing to identify genotypes with altered phenotypes (catalytic activity). We identify multiple conditional mutations that alter the wild-type ribozyme phenotype under a stressful environmental condition of low magnesium ion concentration, but preserve the phenotype under more relaxed conditions. This conditional buffering is confined to the scaffold module, but controls the catalytic phenotype, demonstrating how modularity can enable phenotypic capacitance within a single macromolecule. RNA's ancient role in life suggests that phenotypic capacitance may have influenced evolution since life's origins. PMID:26401020

  12. Automated tools for phenotype extraction from medical records.

    PubMed

    Yetisgen-Yildiz, Meliha; Bejan, Cosmin A; Vanderwende, Lucy; Xia, Fei; Evans, Heather L; Wurfel, Mark M

    2013-01-01

    Clinical research studying critical illness phenotypes relies on the identification of clinical syndromes defined by consensus definitions. Historically, identifying phenotypes has required manual chart review, a time and resource intensive process. The overall research goal of C ritical I llness PH enotype E xt R action (deCIPHER) project is to develop automated approaches based on natural language processing and machine learning that accurately identify phenotypes from EMR. We chose pneumonia as our first critical illness phenotype and conducted preliminary experiments to explore the problem space. In this abstract, we outline the tools we built for processing clinical records, present our preliminary findings for pneumonia extraction, and describe future steps. PMID:24303281

  13. The DDBJ Japanese Genotype-phenotype Archive for genetic and phenotypic human data

    PubMed Central

    Kodama, Yuichi; Mashima, Jun; Kosuge, Takehide; Katayama, Toshiaki; Fujisawa, Takatomo; Kaminuma, Eli; Ogasawara, Osamu; Okubo, Kousaku; Takagi, Toshihisa; Nakamura, Yasukazu

    2015-01-01

    The DNA Data Bank of Japan Center (DDBJ Center; http://www.ddbj.nig.ac.jp) maintains and provides public archival, retrieval and analytical services for biological information. Since October 2013, DDBJ Center has operated the Japanese Genotype-phenotype Archive (JGA) in collaboration with our partner institute, the National Bioscience Database Center (NBDC) of the Japan Science and Technology Agency. DDBJ Center provides the JGA database system which securely stores genotype and phenotype data collected from individuals whose consent agreements authorize data release only for specific research use. NBDC has established guidelines and policies for sharing human-derived data and reviews data submission and usage requests from researchers. In addition to the JGA project, DDBJ Center develops Semantic Web technologies for data integration and sharing in collaboration with the Database Center for Life Science. This paper describes the overview of the JGA project, updates to the DDBJ databases, and services for data retrieval, analysis and integration. PMID:25477381

  14. Simulation of avascular tumor growth by agent-based game model involving phenotype-phenotype interactions.

    PubMed

    Chen, Yong; Wang, Hengtong; Zhang, Jiangang; Chen, Ke; Li, Yumin

    2015-01-01

    All tumors, both benign and metastatic, undergo an avascular growth stage with nutrients supplied by the surrounding tissue. This avascular growth process is much easier to carry out in more qualitative and quantitative experiments starting from tumor spheroids in vitro with reliable reproducibility. Essentially, this tumor progression would be described as a sequence of phenotypes. Using agent-based simulation in a two-dimensional spatial lattice, we constructed a composite growth model in which the phenotypic behavior of tumor cells depends on not only the local nutrient concentration and cell count but also the game among cells. Our simulation results demonstrated that in silico tumors are qualitatively similar to those observed in tumor spheroid experiments. We also found that the payoffs in the game between two living cell phenotypes can influence the growth velocity and surface roughness of tumors at the same time. Finally, this current model is flexible and can be easily extended to discuss other situations, such as environmental heterogeneity and mutation. PMID:26648395

  15. Simulation of avascular tumor growth by agent-based game model involving phenotype-phenotype interactions

    PubMed Central

    Chen, Yong; Wang, Hengtong; Zhang, Jiangang; Chen, Ke; Li, Yumin

    2015-01-01

    All tumors, both benign and metastatic, undergo an avascular growth stage with nutrients supplied by the surrounding tissue. This avascular growth process is much easier to carry out in more qualitative and quantitative experiments starting from tumor spheroids in vitro with reliable reproducibility. Essentially, this tumor progression would be described as a sequence of phenotypes. Using agent-based simulation in a two-dimensional spatial lattice, we constructed a composite growth model in which the phenotypic behavior of tumor cells depends on not only the local nutrient concentration and cell count but also the game among cells. Our simulation results demonstrated that in silico tumors are qualitatively similar to those observed in tumor spheroid experiments. We also found that the payoffs in the game between two living cell phenotypes can influence the growth velocity and surface roughness of tumors at the same time. Finally, this current model is flexible and can be easily extended to discuss other situations, such as environmental heterogeneity and mutation. PMID:26648395

  16. The Genetic Basis of Mendelian Phenotypes: Discoveries, Challenges, and Opportunities

    PubMed Central

    Chong, Jessica X.; Buckingham, Kati J.; Jhangiani, Shalini N.; Boehm, Corinne; Sobreira, Nara; Smith, Joshua D.; Harrell, Tanya M.; McMillin, Margaret J.; Wiszniewski, Wojciech; Gambin, Tomasz; Coban Akdemir, Zeynep H.; Doheny, Kimberly; Scott, Alan F.; Avramopoulos, Dimitri; Chakravarti, Aravinda; Hoover-Fong, Julie; Mathews, Debra; Witmer, P. Dane; Ling, Hua; Hetrick, Kurt; Watkins, Lee; Patterson, Karynne E.; Reinier, Frederic; Blue, Elizabeth; Muzny, Donna; Kircher, Martin; Bilguvar, Kaya; López-Giráldez, Francesc; Sutton, V. Reid; Tabor, Holly K.; Leal, Suzanne M.; Gunel, Murat; Mane, Shrikant; Gibbs, Richard A.; Boerwinkle, Eric; Hamosh, Ada; Shendure, Jay; Lupski, James R.; Lifton, Richard P.; Valle, David; Nickerson, Deborah A.; Bamshad, Michael J.

    2015-01-01

    Discovering the genetic basis of a Mendelian phenotype establishes a causal link between genotype and phenotype, making possible carrier and population screening and direct diagnosis. Such discoveries also contribute to our knowledge of gene function, gene regulation, development, and biological mechanisms that can be used for developing new therapeutics. As of February 2015, 2,937 genes underlying 4,163 Mendelian phenotypes have been discovered, but the genes underlying ∼50% (i.e., 3,152) of all known Mendelian phenotypes are still unknown, and many more Mendelian conditions have yet to be recognized. This is a formidable gap in biomedical knowledge. Accordingly, in December 2011, the NIH established the Centers for Mendelian Genomics (CMGs) to provide the collaborative framework and infrastructure necessary for undertaking large-scale whole-exome sequencing and discovery of the genetic variants responsible for Mendelian phenotypes. In partnership with 529 investigators from 261 institutions in 36 countries, the CMGs assessed 18,863 samples from 8,838 families representing 579 known and 470 novel Mendelian phenotypes as of January 2015. This collaborative effort has identified 956 genes, including 375 not previously associated with human health, that underlie a Mendelian phenotype. These results provide insight into study design and analytical strategies, identify novel mechanisms of disease, and reveal the extensive clinical variability of Mendelian phenotypes. Discovering the gene underlying every Mendelian phenotype will require tackling challenges such as worldwide ascertainment and phenotypic characterization of families affected by Mendelian conditions, improvement in sequencing and analytical techniques, and pervasive sharing of phenotypic and genomic data among researchers, clinicians, and families. PMID:26166479

  17. Familial aggregation of candidate phenotypes for borderline personality disorder.

    PubMed

    Ruocco, Anthony C; Hudson, James I; Zanarini, Mary C; Gunderson, John G

    2015-01-01

    Borderline personality disorder (BPD) and its core Diagnostic and Statistical Manual of Mental Disorders (DSM) factor-analytically derived phenotypes aggregate in families. To potentially inform future conceptualizations of BPD, this study examined the familial aggregation and co-aggregation with BPD of 3 additional candidate phenotypes for BPD psychopathology: anxiousness, aggressiveness, and cognitive dysregulation. Participants included 347 probands (126 with BPD, 128 without BPD, and 93 with major depressive disorder) and 814 parents and siblings of probands. All participants completed diagnostic assessments and scales assessing the candidate phenotypes. The familial aggregation of phenotypes (correlation of level of phenotype between family members), the familial co-aggregation of phenotypes with BPD (correlation of phenotype with BPD between family members), and the within-individual correlation of phenotypes with BPD were assessed. All 3 candidate phenotypes showed high levels of familial aggregation (rs = .14 - .53, ps < .001), the magnitudes of which were comparable with DSM-based core sectors of psychopathology. Anxiousness and cognitive dysregulation showed strong within-individual associations with BPD (rs = .55 and .46, respectively; ps < .001) and substantial familial co-aggregation with BPD (rs = .12 and .13, respectively; ps ≤ .002). In contrast, aggressiveness showed a weak within-individual association with BPD (r = .11, p = .12) and little familial co-aggregation with BPD (r = .05, p = .21). These findings suggest that anxiousness and cognitive dysregulation are promising phenotypes for BPD psychopathology that move beyond factor-analytically based conceptualizations. In contrast, aggressiveness was only weakly related to BPD, suggesting that this phenotype may not represent an essential feature of this disorder. PMID:25046574

  18. Early constraints in sexual dimorphism: survival benefits of feminized phenotypes.

    PubMed

    López-Rull, I; Vergara, P; Martínez-Padilla, J; Fargallo, J A

    2016-02-01

    Sexual dimorphism (SD) has evolved in response to selection pressures that differ between sexes. Since such pressures change across an individual's life, SD may vary within age classes. Yet, little is known about how selection on early phenotypes may drive the final SD observed in adults. In many dimorphic species, juveniles resemble adult females rather than adult males, meaning that out of the selective pressures established by sexual selection feminized phenotypes may be adaptive. If true, fitness benefits of early female-like phenotypes may constrain the expression of male phenotypes in adulthood. Using the common kestrel Falco tinnunculus as a study model, we evaluated the fitness advantages of expressing more feminized phenotypes at youth. Although more similar to adult females than to adult males, common kestrel fledglings are still sexually dimorphic in size and coloration. Integrating morphological and chromatic variables, we analysed the phenotypic divergence between sexes as a measure of how much each individual looks like the sex to which it belongs (phenotypic sexual resemblance, PSR). We then tested the fitness benefits associated with PSR by means of the probability of recruitment in the population. We found a significant interaction between PSR and sex, showing that in both sexes more feminized phenotypes recruited more into the population than less feminized phenotypes. Moreover, males showed lower PSR than females and a higher proportion of incorrect sex classifications. These findings suggest that the mechanisms in males devoted to resembling female phenotypes in youth, due to a trend to increase fitness through more feminized phenotypes, may provide a mechanism to constrain the SD in adulthood. PMID:26494322

  19. Development of the microglial phenotype in culture.

    PubMed

    Szabo, M; Gulya, K

    2013-06-25

    Selected morphological, molecular and functional aspects of various microglial cell populations were characterized in cell cultures established from the forebrains of E18 rat embryos. The mixed primary cortical cultures were maintained for up to 28days using routine culturing techniques when the microglial cells in the culture were not stimulated or immunologically challenged. During culturing, expansion of the microglial cell populations was observed, as evidenced by quantitative assessment of selected monocyte/macrophage/microglial cell-specific markers (human leukocyte antigen (HLA) DP, DQ, DR, CD11b/c and Iba1) via immunocyto- and histochemistry and Western blot analysis. The Iba1 immunoreactivity in Western blots steadily increased about 750-fold, and the number of Iba1-immunoreactive cells rose at least 67-fold between one day in vitro (DIV1) and DIV28. Morphometric analysis on binary (digital) silhouettes of the microglia revealed their evolving morphology during culturing. Microglial cells were mainly ameboid in the early stages of in vitro differentiation, while mixed populations of ameboid and ramified cell morphologies were characteristic of older cultures as the average transformation index (TI) increased from 1.96 (DIV1) to 15.17 (DIV28). Multiple immunofluorescence labeling of selected biomarkers revealed different microglial phenotypes during culturing. For example, while HLA DP, DQ, DR immunoreactivity was present exclusively in ameboid microglia (TI<3) between DIV1 and DIV10, CD11b/c- and Iba1-positive microglial cells were moderately (TI<13) and progressively (TI<81) more ramified, respectively, and always present throughout culturing. Regardless of the age of the cultures, proliferating microglia were Ki67-positive and characterized by low TI values (TI<3). The microglial function was assessed by an in vitro phagocytosis assay. Unstimulated microglia with low TI values were significantly more active in phagocytosing fluorescent microspheres than

  20. Prediction of microbial phenotypes based on comparative genomics

    PubMed Central

    2015-01-01

    The accessibility of almost complete genome sequences of uncultivable microbial species from metagenomes necessitates computational methods predicting microbial phenotypes solely based on genomic data. Here we investigate how comparative genomics can be utilized for the prediction of microbial phenotypes. The PICA framework facilitates application and comparison of different machine learning techniques for phenotypic trait prediction. We have improved and extended PICA's support vector machine plug-in and suggest its applicability to large-scale genome databases and incomplete genome sequences. We have demonstrated the stability of the predictive power for phenotypic traits, not perturbed by the rapid growth of genome databases. A new software tool facilitates the in-depth analysis of phenotype models, which associate expected and unexpected protein functions with particular traits. Most of the traits can be reliably predicted in only 60-70% complete genomes. We have established a new phenotypic model that predicts intracellular microorganisms. Thereby we could demonstrate that also independently evolved phenotypic traits, characterized by genome reduction, can be reliably predicted based on comparative genomics. Our results suggest that the extended PICA framework can be used to automatically annotate phenotypes in near-complete microbial genome sequences, as generated in large numbers in current metagenomics studies. PMID:26451672

  1. A Comprehensive Evaluation of Disease Phenotype Networks for Gene Prioritization

    PubMed Central

    Li, Jianhua; Lin, Xiaoyan; Teng, Yueyang; Qi, Shouliang; Xiao, Dayu; Zhang, Jianying; Kang, Yan

    2016-01-01

    Identification of disease-causing genes is a fundamental challenge for human health studies. The phenotypic similarity among diseases may reflect the interactions at the molecular level, and phenotype comparison can be used to predict disease candidate genes. Online Mendelian Inheritance in Man (OMIM) is a database of human genetic diseases and related genes that has become an authoritative source of disease phenotypes. However, disease phenotypes have been described by free text; thus, standardization of phenotypic descriptions is needed before diseases can be compared. Several disease phenotype networks have been established in OMIM using different standardization methods. Two of these networks are important for phenotypic similarity analysis: the first and most commonly used network (mimMiner) is standardized by medical subject heading, and the other network (resnikHPO) is the first to be standardized by human phenotype ontology. This paper comprehensively evaluates for the first time the accuracy of these two networks in gene prioritization based on protein–protein interactions using large-scale, leave-one-out cross-validation experiments. The results show that both networks can effectively prioritize disease-causing genes, and the approach that relates two diseases using a logistic function improves prioritization performance. Tanimoto, one of four methods for normalizing resnikHPO, generates a symmetric network and it performs similarly to mimMiner. Furthermore, an integration of these two networks outperforms either network alone in gene prioritization, indicating that these two disease networks are complementary. PMID:27415759

  2. Puerto Rican Phenotype: Understanding Its Historical Underpinnings and Psychological Associations

    ERIC Educational Resources Information Center

    Lopez, Irene

    2008-01-01

    The following is a historically informed review of Puerto Rican phenotype. Geared toward educating psychologists, this review discusses how various psychological issues associated with phenotype may have arisen as a result of historical legacies and policies associated with race and racial mixing. It discusses how these policies used various…

  3. Monozygotic twins with trisomy 18: a report of discordant phenotype.

    PubMed Central

    Schlessel, J S; Brown, W T; Lysikiewicz, A; Schiff, R; Zaslav, A L

    1990-01-01

    The predicted incidence of liveborn monozygotic trisomy 18 twins is one per million births. The first case of liveborn monozygotic trisomy 18 twins was reported in 1989 and we report a second case in which striking phenotypic discordance existed. The probability of monozygotic trisomy 18 twinning and the mechanisms for phenotypic discordance in trisomic twins is discussed. Images PMID:2246775

  4. The differential view of genotype–phenotype relationships

    PubMed Central

    Orgogozo, Virginie; Morizot, Baptiste; Martin, Arnaud

    2015-01-01

    An integrative view of diversity and singularity in the living world requires a better understanding of the intricate link between genotypes and phenotypes. Here we re-emphasize the old standpoint that the genotype–phenotype (GP) relationship is best viewed as a connection between two differences, one at the genetic level and one at the phenotypic level. As of today, predominant thinking in biology research is that multiple genes interact with multiple environmental variables (such as abiotic factors, culture, or symbionts) to produce the phenotype. Often, the problem of linking genotypes and phenotypes is framed in terms of genotype and phenotype maps, and such graphical representations implicitly bring us away from the differential view of GP relationships. Here we show that the differential view of GP relationships is a useful explanatory framework in the context of pervasive pleiotropy, epistasis, and environmental effects. In such cases, it is relevant to view GP relationships as differences embedded into differences. Thinking in terms of differences clarifies the comparison between environmental and genetic effects on phenotypes and helps to further understand the connection between genotypes and phenotypes. PMID:26042146

  5. Impage Analysis for Mapping Immeasurable Phenotypes in Maize

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A majority of phenotypic variance in maize has qualitative aspects that are immeasurable by rulers or scalars. Image analysis may improve the phenotypic quantification by increasing the objectivity and granularity of quantification, which in turn may result in an increase in the rate at which the ge...

  6. Phenotypic Transition as a Survival Strategy of Glioma

    PubMed Central

    ICHIKAWA, Tomotsugu; OTANI, Yoshihiro; KUROZUMI, Kazuhiko; DATE, Isao

    2016-01-01

    Malignant glioma is characterized by rapid proliferation, invasion into surrounding central nervous system tissues, and aberrant vascularization. There is increasing evidence that shows gliomas are more complex than previously thought, as each tumor comprises considerable intratumoral heterogeneity with mixtures of genetically and phenotypically distinct subclones. Heterogeneity within and across tumors is recognized as a critical factor that limits therapeutic progress for malignant glioma. Recent genotyping and expression profiling of gliomas has allowed for the creation of classification schemes that assign tumors to subtypes based on similarity to defined expression signatures. Also, malignant gliomas frequently shift their biological features upon recurrence and progression. The ability of glioma cells to resist adverse conditions such as hypoxia and metabolic stress is necessary for sustained tumor growth and strongly influences tumor behaviors. In general, glioma cells are in one of two phenotypic categories: higher proliferative activity with angiogenesis, or higher migratory activity with attenuated proliferative ability. Further, they switch phenotypic categories depending on the situation. To date, a multidimensional approach has been employed to clarify the mechanisms of phenotypic shift of glioma. Various molecular and signaling pathways are involved in phenotypic shifts of glioma, possibly with crosstalk between them. In this review, we discuss molecular and phenotypic heterogeneity of glioma cells and mechanisms of phenotypic shifts in regard to the glioma proliferation, angiogenesis, and invasion. A better understanding of the molecular mechanisms that underlie phenotypic shifts of glioma may provide new insights into targeted therapeutic strategies. PMID:27169497

  7. The Down Syndrome Behavioural Phenotype: Taking a Developmental Approach

    ERIC Educational Resources Information Center

    Fidler, Deborah; Most, David; Philofsky, Amy

    2009-01-01

    Individuals with Down syndrome are predisposed to show a specific behavioural phenotype, or a pattern of strengths and challenges in functioning across different domains of development. It is argued that a developmental approach to researching the Down syndrome behavioural phenotype, including an examination of the dynamic process of the unfolding…

  8. Computable visually observed phenotype ontological framework for plants

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The ability to search for and precisely compare similar phenotypic appearances within and across differenct crop plants has vast potential in plant breeding, and in basic science and genetic research. The difficulty in doing so lies in the fact that many visual phenotypic data, especially visually ...

  9. The nutritional phenotype in the age of metabolomics

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The concept of the nutritional phenotype is proposed as a defined and integrated set of genetic, proteomic, metabolomic, functional, and behavioral factors that, when measured, form the basis for assessment of human nutritional status. The nutritional phenotype integrates the effects of diet on dise...

  10. Quality Control Test for Sequence-Phenotype Assignments

    PubMed Central

    Ortiz, Maria Teresa Lara; Rosario, Pablo Benjamín Leon; Luna-Nevarez, Pablo; Gamez, Alba Savin; Martínez-del Campo, Ana; Del Rio, Gabriel

    2015-01-01

    Relating a gene mutation to a phenotype is a common task in different disciplines such as protein biochemistry. In this endeavour, it is common to find false relationships arising from mutations introduced by cells that may be depurated using a phenotypic assay; yet, such phenotypic assays may introduce additional false relationships arising from experimental errors. Here we introduce the use of high-throughput DNA sequencers and statistical analysis aimed to identify incorrect DNA sequence-phenotype assignments and observed that 10–20% of these false assignments are expected in large screenings aimed to identify critical residues for protein function. We further show that this level of incorrect DNA sequence-phenotype assignments may significantly alter our understanding about the structure-function relationship of proteins. We have made available an implementation of our method at http://bis.ifc.unam.mx/en/software/chispas. PMID:25700273

  11. Quantifying the impact of development on phenotypic variation and evolution.

    PubMed

    Sears, Karen E

    2014-12-01

    A primary goal of evolutionary biology is to identify the factors that shape phenotypic evolution. According to the theory of natural selection, phenotypic evolution occurs through the differential survival and reproduction of individuals whose traits are selectively advantageous relative to other individuals in the population. This implies that evolution by natural selection is contingent upon the distribution and magnitude of phenotypic variation among individuals, which are in turn the products of developmental processes. Development therefore has the potential to affect the trajectory and rate of phenotypic evolution. Recent research in diverse systems (e.g., mammalian teeth, cichlid skulls, butterfly wings, and marsupial limbs) supports the hypothesis that development biases phenotypic variation and evolution, but suggests that these biases might be system-specific. PMID:25393554

  12. A Review of Imaging Techniques for Plant Phenotyping

    PubMed Central

    Li, Lei; Zhang, Qin; Huang, Danfeng

    2014-01-01

    Given the rapid development of plant genomic technologies, a lack of access to plant phenotyping capabilities limits our ability to dissect the genetics of quantitative traits. Effective, high-throughput phenotyping platforms have recently been developed to solve this problem. In high-throughput phenotyping platforms, a variety of imaging methodologies are being used to collect data for quantitative studies of complex traits related to the growth, yield and adaptation to biotic or abiotic stress (disease, insects, drought and salinity). These imaging techniques include visible imaging (machine vision), imaging spectroscopy (multispectral and hyperspectral remote sensing), thermal infrared imaging, fluorescence imaging, 3D imaging and tomographic imaging (MRT, PET and CT). This paper presents a brief review on these imaging techniques and their applications in plant phenotyping. The features used to apply these imaging techniques to plant phenotyping are described and discussed in this review. PMID:25347588

  13. Phenotypic plasticity in two marine snails: constraints superseding life history.

    PubMed

    Hollander, J; Collyer, M L; Adams, D C; Johannesson, K

    2006-11-01

    In organisms encountering predictable environments, fixed development is expected, whereas in organisms that cannot predict their future environment, phenotypic plasticity would be optimal to increase local adaptation. To test this prediction we experimentally compared phenotypic plasticity in two rocky-shore snail species; Littorina saxatilis releasing miniature snails on the shore, and Littorina littorea releasing drifting larvae settling on various shores, expecting L. littorea to show more phenotypic plasticity than L. saxatilis. We compared magnitude and direction of vectors of phenotypic difference in juvenile shell traits after 3 months exposure to different stimuli simulating sheltered and crab-rich shores, or wave-exposed and crab-free shores. Both species showed similar direction and magnitude of vectors of phenotypic difference with minor differences only between ecotypes of the nondispersing species, indicating that plasticity is an evolving trait in L. saxatilis. The lack of a strong plastic response in L. littorea might be explained by limits rather than costs to plasticity. PMID:17040383

  14. Methylator phenotype in colorectal cancer: A prognostic factor or not?

    PubMed

    Gallois, C; Laurent-Puig, P; Taieb, J

    2016-03-01

    Colorectal cancer (CRC) is due to different types of genetic alterations that are translated into different phenotypes. Among them, CpG island methylator phenotype (CIMP+) is the most recently involved in carcinogenesis of some CRC. The malignant transformation in this case is mainly due to the transcriptional inactivation of tumor suppressor genes. CIMP+ are reported to be more frequently found in the elderly and in women. The tumors are more frequently located in the proximal part of the colon, BRAF mutated and are associated with microsatellite instability (MSI) phenotype. All sporadic MSI CRC belong to the methylator phenotype, however some non MSI CRC may also harbor a methylator phenotype. The prognostic value of CIMP is not well known. Most studies show a worse prognosis in CIMP+ CRC, and adjuvant treatments seem to be more efficient. We review here the current knowledge on prognostic and predictive values in CIMP+ CRC. PMID:26702883

  15. Quality control test for sequence-phenotype assignments.

    PubMed

    Ortiz, Maria Teresa Lara; Rosario, Pablo Benjamín Leon; Luna-Nevarez, Pablo; Gamez, Alba Savin; Martínez-del Campo, Ana; Del Rio, Gabriel

    2015-01-01

    Relating a gene mutation to a phenotype is a common task in different disciplines such as protein biochemistry. In this endeavour, it is common to find false relationships arising from mutations introduced by cells that may be depurated using a phenotypic assay; yet, such phenotypic assays may introduce additional false relationships arising from experimental errors. Here we introduce the use of high-throughput DNA sequencers and statistical analysis aimed to identify incorrect DNA sequence-phenotype assignments and observed that 10-20% of these false assignments are expected in large screenings aimed to identify critical residues for protein function. We further show that this level of incorrect DNA sequence-phenotype assignments may significantly alter our understanding about the structure-function relationship of proteins. We have made available an implementation of our method at http://bis.ifc.unam.mx/en/software/chispas. PMID:25700273

  16. A review of imaging techniques for plant phenotyping.

    PubMed

    Li, Lei; Zhang, Qin; Huang, Danfeng

    2014-01-01

    Given the rapid development of plant genomic technologies, a lack of access to plant phenotyping capabilities limits our ability to dissect the genetics of quantitative traits. Effective, high-throughput phenotyping platforms have recently been developed to solve this problem. In high-throughput phenotyping platforms, a variety of imaging methodologies are being used to collect data for quantitative studies of complex traits related to the growth, yield and adaptation to biotic or abiotic stress (disease, insects, drought and salinity). These imaging techniques include visible imaging (machine vision), imaging spectroscopy (multispectral and hyperspectral remote sensing), thermal infrared imaging, fluorescence imaging, 3D imaging and tomographic imaging (MRT, PET and CT). This paper presents a brief review on these imaging techniques and their applications in plant phenotyping. The features used to apply these imaging techniques to plant phenotyping are described and discussed in this review. PMID:25347588

  17. Targeted silver nanoparticles for ratiometric cell phenotyping.

    PubMed

    Willmore, Anne-Mari A; Simón-Gracia, Lorena; Toome, Kadri; Paiste, Päärn; Kotamraju, Venkata Ramana; Mölder, Tarmo; Sugahara, Kazuki N; Ruoslahti, Erkki; Braun, Gary B; Teesalu, Tambet

    2016-04-28

    Affinity targeting is used to deliver nanoparticles to cells and tissues. For efficient targeting, it is critical to consider the expression and accessibility of the relevant receptors in the target cells. Here, we describe isotopically barcoded silver nanoparticles (AgNPs) as a tool for auditing affinity ligand receptors in cells. Tumor penetrating peptide RPARPAR (receptor: NRP-1) and tumor homing peptide GKRK (receptor: p32) were used as affinity ligands on the AgNPs. The binding and uptake of the peptide-functionalized AgNPs by cultured PPC-1 prostate cancer and M21 melanoma cells was dependent on the cell surface expression of the cognate peptide receptors. Barcoded peptide-functionalized AgNPs were synthesized from silver and palladium isotopes. The cells were incubated with a cocktail of the barcoded nanoparticles [RPARPAR (R), GKRK (K), and control], and cellular binding and internalization of each type of nanoparticle was assessed by inductively coupled plasma mass spectrometry. The results of isotopic analysis were in agreement with data obtained using optical methods. Using ratiometric measurements, we were able to classify the PPC-1 cell line as mainly NRP-1-positive, with 75 ± 5% R-AgNP uptake, and the M21 cell line as only p32-positive, with 89 ± 9% K-AgNP uptake. The isotopically barcoded multiplexed AgNPs are useful as an in vitro ratiometric phenotyping tool and have potential uses in functional evaluation of the expression of accessible homing peptide receptors in vivo. PMID:26646247

  18. Ameloblastoma Phenotypes Reflected in Distinct Transcriptome Profiles

    PubMed Central

    Hu, Shijia; Parker, Joel; Divaris, Kimon; Padilla, Ricardo; Murrah, Valerie; Wright, John Timothy

    2016-01-01

    Ameloblastoma is a locally invasive benign neoplasm derived from odontogenic epithelium and presents with diverse phenotypes yet to be characterized molecularly. High recurrence rates of 50–80% with conservative treatment in some sub-types warrants radical surgical resections resulting in high morbidity. The objective of the study was to characterize the transcriptome of ameloblastoma and identify relevant genes and molecular pathways using normal odontogenic tissue (human “dentome”) for comparison. Laser capture microdissection was used to obtain neoplastic epithelial tissue from 17 tumors which were examined using the Agilent 44 k whole genome microarray. Ameloblastoma separated into 2 distinct molecular clusters that were associated with pre-secretory ameloblast and odontoblast. Within the pre-secretory cluster, 9/10 of samples were of the follicular type while 6/7 of the samples in the odontoblast cluster were of the plexiform type (p < 0.05). Common pathways altered in both clusters included cell-cycle regulation, inflammatory and MAPkinase pathways, specifically known cancer-driving genes such as TP53 and members of the MAPkinase pathways. The pre-secretory ameloblast cluster exhibited higher activation of inflammatory pathways while the odontoblast cluster showed greater disturbances in transcription regulators. Our results are suggestive of underlying inter-tumor molecular heterogeneity of ameloblastoma sub-types and have implications for the use of tailored treatment. PMID:27491308

  19. Physiological Phenotype and Vulnerability in Parkinson's Disease

    PubMed Central

    Surmeier, D. James; Guzman, Jaime N.; Sanchez, Javier; Schumacker, Paul T.

    2012-01-01

    This review will focus on the principles underlying the hypothesis that neuronal physiological phenotype—how a neuron generates and regulates action potentials—makes a significant contribution to its vulnerability in Parkinson's disease (PD) and aging. A cornerstone of this hypothesis is that the maintenance of ionic gradients underlying excitability can pose a significant energetic burden for neurons, particularly those that have sustained residence times at depolarized membrane potentials, broad action potentials, prominent Ca2+ entry, and modest intrinsic Ca2+ buffering capacity. This energetic burden is shouldered in neurons primarily by mitochondria, the sites of cellular respiration. Mitochondrial respiration increases the production of damaging superoxide and other reactive oxygen species (ROS) that have widely been postulated to contribute to cellular aging and PD. Many of the genetic mutations and toxins associated with PD compromise mitochondrial function, providing a mechanistic linkage between known risk factors and cellular physiology that could explain the pattern of pathology in PD. Because much of the mitochondrial burden created by this at-risk phenotype is created by Ca2+ entry through L-type voltage-dependent channels for which there are antagonists approved for human use, a neuroprotective strategy to reduce this burden is feasible. PMID:22762023

  20. Discovery of rare variants for complex phenotypes.

    PubMed

    Kosmicki, Jack A; Churchhouse, Claire L; Rivas, Manuel A; Neale, Benjamin M

    2016-06-01

    With the rise of sequencing technologies, it is now feasible to assess the role rare variants play in the genetic contribution to complex trait variation. While some of the earlier targeted sequencing studies successfully identified rare variants of large effect, unbiased gene discovery using exome sequencing has experienced limited success for complex traits. Nevertheless, rare variant association studies have demonstrated that rare variants do contribute to phenotypic variability, but sample sizes will likely have to be even larger than those of common variant association studies to be powered for the detection of genes and loci. Large-scale sequencing efforts of tens of thousands of individuals, such as the UK10K Project and aggregation efforts such as the Exome Aggregation Consortium, have made great strides in advancing our knowledge of the landscape of rare variation, but there remain many considerations when studying rare variation in the context of complex traits. We discuss these considerations in this review, presenting a broad range of topics at a high level as an introduction to rare variant analysis in complex traits including the issues of power, study design, sample ascertainment, de novo variation, and statistical testing approaches. Ultimately, as sequencing costs continue to decline, larger sequencing studies will yield clearer insights into the biological consequence of rare mutations and may reveal which genes play a role in the etiology of complex traits. PMID:27221085

  1. Malignant histiocytosis. A phenotypic and genotypic investigation.

    PubMed Central

    Cattoretti, G.; Villa, A.; Vezzoni, P.; Giardini, R.; Lombardi, L.; Rilke, F.

    1990-01-01

    Ten cases of malignant histiocytosis (MH) were evaluated for clinical and histopathologic features, phenotype, and rearrangement of T cell receptor (TCR) beta, gamma, and alpha and immunoglobulin (Ig) genes (7/10). All cases were HLA-DR+ and CD30-positive. Four cases had molecular evidence of T cell lineage such as TCR beta, gamma, and alpha rearrangements, and one additional case synthesized the cytoplasmic TCR beta chain. The remaining five cases did not show unequivocal T, B, natural killer (NK) cell, or macrophagic origin, and three of them had germline TCR and Ig genes. Ultrastructural analysis was not helpful for the definition of the cell lineage. Most myelomonocytic markers (MAC387, CD13, CD14, CD64, CD68) were either negative on the MH cells or were expressed on cells with rearranged TCR gene. Precursor (CD34, CD7) and NK (CD16, CD56, and CD57) cell markers were not found. The lineage of a number of cases of MH remains unresolved. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 PMID:2349962

  2. Phenotypic quality influences fertility in Gombe chimpanzees

    PubMed Central

    Jones, James Holland; Wilson, Michael L.; Murray, Carson; Pusey, Anne

    2011-01-01

    Summary Fertility is an important fitness component, but is difficult to measure in slowly reproducing, long-lived animals such as chimpanzees (Pan troglodytes).We measured fertility and the effect of measured covariates on fertility in a 43-year sample of birth intervals of chimpanzees from the Gombe National Park, Tanzania using Cox proportional hazards regression with individual-level random effects.The birth hazard declined with mothers’ age at a rate of 0·84 per year following age at first reproduction. This value is somewhat stronger than previous estimates.Loss of the infant that opened the birth interval increased the birth hazard 134-fold.Birth intervals following the first complete birth interval were shorter than this first interval, while sex of the previous infant had no significant effect.Maternal dominance rank was significant at the P < 0·1 level when coded as high/middle/low but was highly significant when we simply considered high rank vs. others.Individual heterogeneity had a substantial impact on birth interval duration. We interpret this individual effect as a measure of phenotypic quality, controlling for the measured covariates such as dominance rank. This interpretation is supported by the correlation of individual heterogeneity scores with similar independent measures of body mass. PMID:20412347

  3. Ameloblastoma Phenotypes Reflected in Distinct Transcriptome Profiles.

    PubMed

    Hu, Shijia; Parker, Joel; Divaris, Kimon; Padilla, Ricardo; Murrah, Valerie; Wright, John Timothy

    2016-01-01

    Ameloblastoma is a locally invasive benign neoplasm derived from odontogenic epithelium and presents with diverse phenotypes yet to be characterized molecularly. High recurrence rates of 50-80% with conservative treatment in some sub-types warrants radical surgical resections resulting in high morbidity. The objective of the study was to characterize the transcriptome of ameloblastoma and identify relevant genes and molecular pathways using normal odontogenic tissue (human "dentome") for comparison. Laser capture microdissection was used to obtain neoplastic epithelial tissue from 17 tumors which were examined using the Agilent 44 k whole genome microarray. Ameloblastoma separated into 2 distinct molecular clusters that were associated with pre-secretory ameloblast and odontoblast. Within the pre-secretory cluster, 9/10 of samples were of the follicular type while 6/7 of the samples in the odontoblast cluster were of the plexiform type (p < 0.05). Common pathways altered in both clusters included cell-cycle regulation, inflammatory and MAPkinase pathways, specifically known cancer-driving genes such as TP53 and members of the MAPkinase pathways. The pre-secretory ameloblast cluster exhibited higher activation of inflammatory pathways while the odontoblast cluster showed greater disturbances in transcription regulators. Our results are suggestive of underlying inter-tumor molecular heterogeneity of ameloblastoma sub-types and have implications for the use of tailored treatment. PMID:27491308

  4. Polygenic dissection of the bipolar phenotype

    PubMed Central

    Hamshere, M. L.; O’Donovan, M. C.; Jones, I. R.; Jones, L.; Kirov, G.; Green, E. K.; Moskvina, V.; Grozeva, D.; Bass, N.; McQuillin, A.; Gurling, H.; St Clair, D.; Young, A. H.; Ferrier, I. N.; Farmer, A.; McGuffin, P.; Sklar, P.; Purcell, S.; Holmans, P. A.; Owen, M. J.; Craddock, N.

    2011-01-01

    Background Recent data provide strong support for a substantial common polygenic contribution (i.e. many alleles each of small effect) to genetic susceptibility for schizophrenia and overlapping susceptibility for bipolar disorder. Aims To test hypotheses about the relationship between schizophrenia and psychotic types of bipolar disorder. Method Using a polygenic score analysis to test whether schizophrenia polygenic risk alleles, en masse, significantly discriminate between individuals with bipolar disorder with and without psychotic features. The primary sample included 1829 participants with bipolar disorder and the replication sample comprised 506 people with bipolar disorder. Results The subset of participants with Research Diagnostic Criteria schizoaffective bipolar disorder (n = 277) were significantly discriminated from the remaining participants with bipolar disorder (n = 1552) in both the primary (P = 0.00059) and the replication data-sets (P = 0.0070). In contrast, those with psychotic bipolar disorder as a whole were not significantly different from those with non-psychotic bipolar disorder in either data-set. Conclusions Genetic susceptibility influences at least two major domains of psychopathological variation in the schizophrenia–bipolar disorder clinical spectrum: one that relates to expression of a ‘bipolar disorder-like’ phenotype and one that is associated with expression of ‘schizophrenia-like’ psychotic symptoms. PMID:21972277

  5. Racial Differences in CT Phenotypes in COPD

    PubMed Central

    Hansel, Nadia N.; Washko, George R.; Foreman, Marilyn G.; Han, MeiLan K.; Hoffman, Eric A.; DeMeo, Dawn L.; Barr, R. Graham; Van Beek, Edwin J.R.; Kazerooni, Ella A.; Wise, Robert A.; Brown, Robert H.; Black-Shinn, Jennifer; Hokanson, John E.; Hanania, Nicola A.; Make, Barry; Silverman, Edwin K.; Crapo, James D.; Dransfield, Mark T.

    2015-01-01

    Background Whether African Americans (AA) are more susceptible to COPD than non-Hispanic Whites (NHW) and whether racial differences in disease phenotype exist is controversial. The objective is to determine racial differences in the extent of emphysema and airway remodeling in COPD. Methods First, 2,500 subjects enrolled in the COPDGene study were used to evaluate racial differences in quantitative CT (QCT) parameters of % emphysema, air trapping and airway wall thickness. Independent variables studied included race, age, gender, education, BMI, pack-years, smoking status, age at smoking initiation, asthma, previous work in dusty job, CT scanner and center of recruitment. Results Of the 1,063 subjects with GOLD Stage II-IV COPD, 200 self-reported as AA. AAs had a lower mean % emphysema (13.1 % vs. 16.1%, p = 0.005) than NHW and proportionately less emphysema in the lower lung zones. After adjustment for covariates, there was no statistical difference by race in air trapping or airway wall thickness. Measured QCT parameters were more predictive of poor functional status in NHWs compared to AAs. Conclusions AAs have less emphysema than NHWs but the same degree of airway disease. Additional factors not easily assessed by current QCT techniques may account for the poor functional status in AAs. PMID:23413893

  6. Epigenetic Inheritance of a Cocaine Resistance Phenotype

    PubMed Central

    Vassoler, Fair M.; White, Samantha L.; Schmidt, Heath D.; Sadri-Vakili, Ghazaleh; Pierce, R. Christopher

    2012-01-01

    A heritable phenotype resulting from the self-administration of cocaine in rats was delineated. We observed delayed acquisition and reduced maintenance of cocaine self-administration in male, but not female, offspring of sires that self-administered cocaine. Brain-derived neurotrophic factor (BDNF) mRNA and protein were increased in the medial prefrontal cortex (mPFC) and there was an increased association of acetylated histone H3 with BDNF promoters only in the male offspring of cocaine-experienced sires. Administration of a BDNF receptor antagonist (the TrkB receptor antagonist ANA-12) reversed the diminished cocaine self-administration in male cocaine-sired rats. In addition, the association of acetylated histone H3 with BDNF promoters was increased in the sperm of sires that self-administered cocaine. Collectively, these findings indicate that voluntary paternal ingestion of cocaine results in epigenetic reprograming of the germline resulting in profound effects on mPFC gene expression and resistance to cocaine reinforcement in male offspring. PMID:23242310

  7. Olmsted syndrome: exploration of the immunological phenotype

    PubMed Central

    2013-01-01

    Background Olmsted syndrome is a rare congenital skin disorder presenting with periorifical hyperkeratotic lesions and mutilating palmoplantar keratoderma, which is often associated with infections of the keratotic area. A recent study identified de novo mutations causing constitutive activation of TRPV3 as a cause of the keratotic manifestations of Olmsted syndrome. Methods Genetic, clinical and immunological profiling was performed on a case study patient with the clinical diagnosis of Olmsted syndrome. Results The patient was found to harbour a previously undescribed 1718G-C transversion in TRPV3, causing a G573A point mutation. In depth clinical and immunological analysis found multiple indicators of immune dysregulation, including frequent dermal infections, inflammatory infiltrate in the affected skin, hyper IgE production and elevated follicular T cells and eosinophils in the peripheral blood. Conclusions These results provide the first comprehensive assessment of the immunological features of Olmsted syndrome. The systemic phenotype of hyper IgE and persistent eosinophilia suggest a primary or secondary role of immunological processes in the pathogenesis of Olmsted syndrome, and have important clinical consequences with regard to the treatment of Olmsted syndrome patients. PMID:23692804

  8. Percolation on fitness landscapes: effects of correlation, phenotype, and incompatibilities

    PubMed Central

    Gravner, Janko; Pitman, Damien; Gavrilets, Sergey

    2009-01-01

    We study how correlations in the random fitness assignment may affect the structure of fitness landscapes, in three classes of fitness models. The first is a phenotype space in which individuals are characterized by a large number n of continuously varying traits. In a simple model of random fitness assignment, viable phenotypes are likely to form a giant connected cluster percolating throughout the phenotype space provided the viability probability is larger than 1/2n. The second model explicitly describes genotype-to-phenotype and phenotype-to-fitness maps, allows for neutrality at both phenotype and fitness levels, and results in a fitness landscape with tunable correlation length. Here, phenotypic neutrality and correlation between fitnesses can reduce the percolation threshold, and correlations at the point of phase transition between local and global are most conducive to the formation of the giant cluster. In the third class of models, particular combinations of alleles or values of phenotypic characters are “incompatible” in the sense that the resulting genotypes or phenotypes have zero fitness. This setting can be viewed as a generalization of the canonical Bateson-Dobzhansky-Muller model of speciation and is related to K- SAT problems, prominent in computer science. We analyze the conditions for the existence of viable genotypes, their number, as well as the structure and the number of connected clusters of viable genotypes. We show that analysis based on expected values can easily lead to wrong conclusions, especially when fitness correlations are strong. We focus on pairwise incompatibilities between diallelic loci, but we also address multiple alleles, complex incompatibilities, and continuous phenotype spaces. In the case of diallelic loci, the number of clusters is stochastically bounded and each cluster contains a very large sub-cube. Finally, we demonstrate that the discrete NK model shares some signature properties of models with high

  9. Novel SCN9A Mutations Underlying Extreme Pain Phenotypes: Unexpected Electrophysiological and Clinical Phenotype Correlations

    PubMed Central

    Emery, Edward C.; Habib, Abdella M.; Cox, James J.; Nicholas, Adeline K.; Gribble, Fiona M.

    2015-01-01

    The importance of NaV1.7 (encoded by SCN9A) in the regulation of pain sensing is exemplified by the heterogeneity of clinical phenotypes associated with its mutation. Gain-of-function mutations are typically pain-causing and have been associated with inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD). IEM is usually caused by enhanced NaV1.7 channel activation, whereas mutations that alter steady-state fast inactivation often lead to PEPD. In contrast, nonfunctional mutations in SCN9A are known to underlie congenital insensitivity to pain (CIP). Although well documented, the correlation between SCN9A genotypes and clinical phenotypes is still unclear. Here we report three families with novel SCN9A mutations. In a multiaffected dominant family with IEM, we found the heterozygous change L245 V. Electrophysiological characterization showed that this mutation did not affect channel activation but instead resulted in incomplete fast inactivation and a small hyperpolarizing shift in steady-state slow inactivation, characteristics more commonly associated with PEPD. In two compound heterozygous CIP patients, we found mutations that still retained functionality of the channels, with two C-terminal mutations (W1775R and L1831X) exhibiting a depolarizing shift in channel activation. Two mutations (A1236E and L1831X) resulted in a hyperpolarizing shift in steady-state fast inactivation. To our knowledge, these are the first descriptions of mutations with some retained channel function causing CIP. This study emphasizes the complex genotype–phenotype correlations that exist for SCN9A and highlights the C-terminal cytoplasmic region of NaV1.7 as a critical region for channel function, potentially facilitating analgesic drug development studies. PMID:25995458

  10. The Autism Simplex Collection: an international, expertly phenotyped autism sample for genetic and phenotypic analyses

    PubMed Central

    2014-01-01

    Background There is an urgent need for expanding and enhancing autism spectrum disorder (ASD) samples, in order to better understand causes of ASD. Methods In a unique public-private partnership, 13 sites with extensive experience in both the assessment and diagnosis of ASD embarked on an ambitious, 2-year program to collect samples for genetic and phenotypic research and begin analyses on these samples. The program was called The Autism Simplex Collection (TASC). TASC sample collection began in 2008 and was completed in 2010, and included nine sites from North America and four sites from Western Europe, as well as a centralized Data Coordinating Center. Results Over 1,700 trios are part of this collection, with DNA from transformed cells now available through the National Institute of Mental Health (NIMH). Autism Diagnostic Interview-Revised (ADI-R) and Autism Diagnostic Observation Schedule-Generic (ADOS-G) measures are available for all probands, as are standardized IQ measures, Vineland Adaptive Behavioral Scales (VABS), the Social Responsiveness Scale (SRS), Peabody Picture Vocabulary Test (PPVT), and physical measures (height, weight, and head circumference). At almost every site, additional phenotypic measures were collected, including the Broad Autism Phenotype Questionnaire (BAPQ) and Repetitive Behavior Scale-Revised (RBS-R), as well as the non-word repetition scale, Communication Checklist (Children’s or Adult), and Aberrant Behavior Checklist (ABC). Moreover, for nearly 1,000 trios, the Autism Genome Project Consortium (AGP) has carried out Illumina 1 M SNP genotyping and called copy number variation (CNV) in the samples, with data being made available through the National Institutes of Health (NIH). Whole exome sequencing (WES) has been carried out in over 500 probands, together with ancestry matched controls, and this data is also available through the NIH. Additional WES is being carried out by the Autism Sequencing Consortium (ASC), where the

  11. Targeted silver nanoparticles for ratiometric cell phenotyping

    NASA Astrophysics Data System (ADS)

    Willmore, Anne-Mari A.; Simón-Gracia, Lorena; Toome, Kadri; Paiste, Päärn; Kotamraju, Venkata Ramana; Mölder, Tarmo; Sugahara, Kazuki N.; Ruoslahti, Erkki; Braun, Gary B.; Teesalu, Tambet

    2016-04-01

    Affinity targeting is used to deliver nanoparticles to cells and tissues. For efficient targeting, it is critical to consider the expression and accessibility of the relevant receptors in the target cells. Here, we describe isotopically barcoded silver nanoparticles (AgNPs) as a tool for auditing affinity ligand receptors in cells. Tumor penetrating peptide RPARPAR (receptor: NRP-1) and tumor homing peptide GKRK (receptor: p32) were used as affinity ligands on the AgNPs. The binding and uptake of the peptide-functionalized AgNPs by cultured PPC-1 prostate cancer and M21 melanoma cells was dependent on the cell surface expression of the cognate peptide receptors. Barcoded peptide-functionalized AgNPs were synthesized from silver and palladium isotopes. The cells were incubated with a cocktail of the barcoded nanoparticles [RPARPAR (R), GKRK (K), and control], and cellular binding and internalization of each type of nanoparticle was assessed by inductively coupled plasma mass spectrometry. The results of isotopic analysis were in agreement with data obtained using optical methods. Using ratiometric measurements, we were able to classify the PPC-1 cell line as mainly NRP-1-positive, with 75 +/- 5% R-AgNP uptake, and the M21 cell line as only p32-positive, with 89 +/- 9% K-AgNP uptake. The isotopically barcoded multiplexed AgNPs are useful as an in vitro ratiometric phenotyping tool and have potential uses in functional evaluation of the expression of accessible homing peptide receptors in vivo.Affinity targeting is used to deliver nanoparticles to cells and tissues. For efficient targeting, it is critical to consider the expression and accessibility of the relevant receptors in the target cells. Here, we describe isotopically barcoded silver nanoparticles (AgNPs) as a tool for auditing affinity ligand receptors in cells. Tumor penetrating peptide RPARPAR (receptor: NRP-1) and tumor homing peptide GKRK (receptor: p32) were used as affinity ligands on the AgNPs. The

  12. Integration of Metabolomic and Proteomic Phenotypes

    PubMed Central

    Wienkoop, Stefanie; Morgenthal, Katja; Wolschin, Florian; Scholz, Matthias; Selbig, Joachim; Weckwerth, Wolfram

    2008-01-01

    Statistical mining and integration of complex molecular data including metabolites, proteins, and transcripts is one of the critical goals of systems biology (Ideker, T., Galitski, T., and Hood, L. (2001) A new approach to decoding life: systems biology. Annu. Rev. Genomics Hum. Genet. 2, 343–372). A number of studies have demonstrated the parallel analysis of metabolites and large scale transcript expression. Protein analysis has been ignored in these studies, although a clear correlation between transcript and protein levels is shown only in rare cases, necessitating that actual protein levels have to be determined for protein function analysis. Here, we present an approach to investigate the combined covariance structure of metabolite and protein dynamics in a systemic response to abiotic temperature stress in Arabidopsis thaliana wild-type and a corresponding starch-deficient mutant (phosphoglucomutase-deficient). Independent component analysis revealed phenotype classification resolving genotype-dependent response effects to temperature treatment and genotype-independent general temperature compensation mechanisms. An observation is the stress-induced increase of raffinose-family-oligosaccharide levels in the absence of transitory starch storage/mobilization in temperature-treated phosphoglucomutase plants indicating that sucrose synthesis and storage in these mutant plants is sufficient to bypass the typical starch storage/mobilization pathways under abiotic stress. Eventually, sample pattern recognition and correlation network topology analysis allowed for the detection of specific metabolite-protein co-regulation and assignment of a circadian output regulated RNA-binding protein to these processes. The whole concept of high-dimensional profiling data integration from many replicates, subsequent multivariate statistics for dimensionality reduction, and covariance structure analysis is proposed to be a major strategy for revealing central responses of the

  13. [Phenotype characterization of environmental Cryptococcus neoformans isolates].

    PubMed

    Huérfano, Sandra; Cepero, Maria Caridad; Castañeda, Elizabeth

    2003-09-01

    Cryptococcosis is caused by the three varieties of C. neoformans with physiological and virulence differences, some of which have been studied to determine biological aspects of this microorganism. The phenotypical aspects of environmental isolates from varieties grubii and gattii were evaluated to establish differences associated with their life cycle and virulence. To this end, 28 and 31 strains of C. neoformans serotypes A (var. grubii) and C (var. gattii) were studied. The microscopic and macroscopic morphology on Sabouraud agar and soils, growth rate at 37 degrees C, production of 22 extracellular enzymes, haploid fructification, mating type, killer toxin sensitivity patterns and virulence in BALB/c mice were evaluated. No differences were observed between the two varieties regarding microscopic and macroscopic morphology or growth at 37 degrees C (p > 0.05). However, a decrease in the cellular and capsular sizes of yeast in soil, as compared to Sabouraud, was observed (p < 0.05). Additionally, higher enzimatic activity of proteases, phospholipases, phenoloxidase and beta-glucosidase was observed in var. grubii isolates as compared to var. gattii (p < 0.05). In both varieties, structures related with haploid fruitification were observed and all isolates were mating type alpha. Killer toxin sensitivity patterns of the isolates of var. grubii were I and II; in contrast, in var. gattii, seven different patterns were found: I, V, IX-XIII. In the animal model we found that 12 of 22 (54.5%) isolates of var. grubii caused the death of the mice during the observation period, while none of the 14 var. gattii isolates caused it. The decrease in capsular and cellular sizes of the yeast in soil and the frequency of mating type alpha with structures related to haploid fructification suggest an important mechanism of production of infectious particles in nature. Additionally, greater enzimatic activity of var. grubii can be associated with the virulence in the animal model

  14. Quantification of Orofacial Phenotypes in Xenopus

    PubMed Central

    Kennedy, Allyson E.; Dickinson, Amanda J.

    2014-01-01

    Xenopus has become an important tool for dissecting the mechanisms governing craniofacial development and defects. A method to quantify orofacial development will allow for more rigorous analysis of orofacial phenotypes upon abrogation with substances that can genetically or molecularly manipulate gene expression or protein function. Using two dimensional images of the embryonic heads, traditional size dimensions-such as orofacial width, height and area- are measured. In addition, a roundness measure of the embryonic mouth opening is used to describe the shape of the mouth. Geometric morphometrics of these two dimensional images is also performed to provide a more sophisticated view of changes in the shape of the orofacial region. Landmarks are assigned to specific points in the orofacial region and coordinates are created. A principle component analysis is used to reduce landmark coordinates to principle components that then discriminate the treatment groups. These results are displayed as a scatter plot in which individuals with similar orofacial shapes cluster together. It is also useful to perform a discriminant function analysis, which statistically compares the positions of the landmarks between two treatment groups. This analysis is displayed on a transformation grid where changes in landmark position are viewed as vectors. A grid is superimposed on these vectors so that a warping pattern is displayed to show where significant landmark positions have changed. Shape changes in the discriminant function analysis are based on a statistical measure, and therefore can be evaluated by a p-value. This analysis is simple and accessible, requiring only a stereoscope and freeware software, and thus will be a valuable research and teaching resource. PMID:25407252

  15. Postnatal glucocorticoid exposure alters the adult phenotype.

    PubMed

    He, Jing; Varma, Amit; Weissfeld, Lisa A; Devaskar, Sherin U

    2004-07-01

    We examined the effect of six doses of dexamethasone (Dex) administered daily (2-7 days of age) to postnatal rats on body weight gain, food and water intake, peripheral hormonal/metabolic milieu, and hypothalamic neuropeptides that regulate food intake. We observed a Dex-induced acute (3 days of age) suppression of endogenous corticosterone and an increase in circulating leptin concentrations that were associated with a decrease in body weight in males and females. Followup during the suckling, postsuckling, and adult stages (7-120 days of age) revealed hypoleptinemia in males and females, and hypoinsulinemia, a relative increase in the glucose-to-insulin ratio, and a larger increase in skeletal muscle glucose transporter (GLUT 4) concentrations predominantly in the males, reflective of a catabolic state associated with a persistent decrease in body weight gain. The increase in the glucose-to-insulin ratio and hyperglycemia was associated with an increase in water intake. In addition, the changes in the hormonal/metabolic milieu were associated with an increase in hypothalamic neuropeptide Y content in males and females during the suckling phase, which persisted only in the 120-day-old female with a transient postnatal decline in alpha-melanocyte-stimulating hormone and corticotropin-releasing factor. This increase in neuropeptide Y (NPY) during the suckling phase in males and females was associated with a subsequent increase in adult food intake that outweighed the demands of body weight gain. In contrast to the adult hypothalamic findings, cerebral ventricular dilatation was more prominent in adult males. We conclude that postnatal Dex treatment causes permanent sex-specific changes in the adult phenotype, setting the stage for future development of diabetes (increased glucose:insulin ratio), obesity (increased NPY and food intake), and neurological impairment (loss of cerebral volume). PMID:15001431

  16. Mapping Pathological Phenotypes in Reelin Mutant Mice

    PubMed Central

    Michetti, Caterina; Romano, Emilia; Altabella, Luisa; Caruso, Angela; Castelluccio, Paolo; Bedse, Gaurav; Gaetani, Silvana; Canese, Rossella; Laviola, Giovanni; Scattoni, Maria Luisa

    2014-01-01

    Autism Spectrum Disorders (ASD) are neurodevelopmental disorders with multifactorial origin characterized by social communication deficits and the presence of repetitive behaviors/interests. Several studies showed an association between the reelin gene mutation and increased risk of ASD and a reduced reelin expression in some brain regions of ASD subjects, suggesting a role for reelin deficiency in ASD etiology. Reelin is a large extracellular matrix glycoprotein playing important roles during development of the central nervous system. To deeply investigate the role of reelin dysfunction as vulnerability factor in ASD, we assessed the behavioral, neurochemical, and brain morphological features of reeler male mice. We recently reported a genotype-dependent deviation in the ultrasonic vocal repertoire and a general delay in motor development of reeler pups. We now report that adult male heterozygous (Het) reeler mice did not show social behavior and communication deficits during male–female social interactions. Wildtype and Het mice showed a typical light/dark locomotor activity profile, with a peak during the central interval of the dark phase. However, when faced with a mild stressful stimulus (a saline injection) only Het mice showed an over response to stress. In addition to the behavioral studies, we conducted high performance liquid chromatography and magnetic resonance imaging and spectroscopy to investigate whether reelin mutation influences brain monoamine and metabolites levels in regions involved in ASD. Low levels of dopamine in cortex and high levels of glutamate and taurine in hippocampus were detected in Het mice, in line with clinical data collected on ASD children. Altogether, our data detected subtle but relevant neurochemical abnormalities in reeler mice supporting this mutant line, particularly male subjects, as a valid experimental model to estimate the contribution played by reelin deficiency in the global ASD neurobehavioral phenotype. PMID

  17. Disease insights through cross-species phenotype comparisons.

    PubMed

    Haendel, Melissa A; Vasilevsky, Nicole; Brush, Matthew; Hochheiser, Harry S; Jacobsen, Julius; Oellrich, Anika; Mungall, Christopher J; Washington, Nicole; Köhler, Sebastian; Lewis, Suzanna E; Robinson, Peter N; Smedley, Damian

    2015-10-01

    New sequencing technologies have ushered in a new era for diagnosis and discovery of new causative mutations for rare diseases. However, the sheer numbers of candidate variants that require interpretation in an exome or genomic analysis are still a challenging prospect. A powerful approach is the comparison of the patient's set of phenotypes (phenotypic profile) to known phenotypic profiles caused by mutations in orthologous genes associated with these variants. The most abundant source of relevant data for this task is available through the efforts of the Mouse Genome Informatics group and the International Mouse Phenotyping Consortium. In this review, we highlight the challenges in comparing human clinical phenotypes with mouse phenotypes and some of the solutions that have been developed by members of the Monarch Initiative. These tools allow the identification of mouse models for known disease-gene associations that may otherwise have been overlooked as well as candidate genes may be prioritized for novel associations. The culmination of these efforts is the Exomiser software package that allows clinical researchers to analyse patient exomes in the context of variant frequency and predicted pathogenicity as well the phenotypic similarity of the patient to any given candidate orthologous gene. PMID:26092691

  18. Network motifs that stabilize the hybrid epithelial/mesenchymal phenotype

    NASA Astrophysics Data System (ADS)

    Jolly, Mohit Kumar; Jia, Dongya; Tripathi, Satyendra; Hanash, Samir; Mani, Sendurai; Ben-Jacob, Eshel; Levine, Herbert

    Epithelial to Mesenchymal Transition (EMT) and its reverse - MET - are hallmarks of cancer metastasis. While transitioning between E and M phenotypes, cells can also attain a hybrid epithelial/mesenchymal (E/M) phenotype that enables collective cell migration as a cluster of Circulating Tumor Cells (CTCs). These clusters can form 50-times more tumors than individually migrating CTCs, underlining their importance in metastasis. However, this hybrid E/M phenotype has been hypothesized to be only a transient one that is attained en route EMT. Here, via mathematically modeling, we identify certain `phenotypic stability factors' that couple with the core three-way decision-making circuit (miR-200/ZEB) and can maintain or stabilize the hybrid E/M phenotype. Further, we show experimentally that this phenotype can be maintained stably at a single-cell level, and knockdown of these factors impairs collective cell migration. We also show that these factors enable the association of hybrid E/M with high stemness or tumor-initiating potential. Finally, based on these factors, we deduce specific network motifs that can maintain the E/M phenotype. Our framework can be used to elucidate the effect of other players in regulating cellular plasticity during metastasis. This work was supported by NSF PHY-1427654 (Center for Theoretical Biological Physics) and the CPRIT Scholar in Cancer Research of the State of Texas at Rice University.

  19. A Framework for Comparing Phenotype Annotations of Orthologous Genes

    PubMed Central

    Bodenreider, Olivier; Burgun, Anita

    2015-01-01

    Objectives Animal models are a key resource for the investigation of human diseases. In contrast to functional annotation, phenotype annotation is less standard, and comparing phenotypes across species remains challenging. The objective of this paper is to propose a framework for comparing phenotype annotations of orthologous genes based on the Medical Subject Headings (MeSH) indexing of biomedical articles in which these genes are discussed. Methods 17,769 pairs of orthologous genes (mouse and human) are downloaded from the Mouse Genome Informatics (MGI) system and linked to biomedical articles through Entrez Gene. MeSH index terms corresponding to diseases are extracted from Medline. Results 11,111 pairs of genes exhibited at least one phenotype annotation for each gene in the pair. Among these, 81% have at least one phenotype annotation in common, 80% have at least one annotation specific to the human gene and 84% have at least one annotation specific to the mouse gene. Four disease categories represent 54% of all phenotype annotations. Conclusions This framework supports the curation of phenotype annotation and the generation of research hypotheses based on comparative studies. PMID:20841896

  20. Phenotypic convergence along a gradient of predation risk.

    PubMed

    Dennis, S R; Carter, Mauricio J; Hentley, W T; Beckerman, A P

    2011-06-01

    A long-standing question in ecology is whether phenotypic plasticity, rather than selection per se, is responsible for phenotypic variation among populations. Plasticity can increase or decrease variation, but most previous studies have been limited to single populations, single traits and a small number of environments assessed using univariate reaction norms. Here, examining two genetically distinct populations of Daphnia pulex with different predation histories, we quantified predator-induced plasticity among 11 traits along a fine-scale gradient of predation risk by a predator (Chaoborus) common to both populations. We test the hypothesis that plasticity can be responsible for convergence in phenotypes among different populations by experimentally characterizing multivariate reaction norms with phenotypic trajectory analysis (PTA). Univariate analyses showed that all genotypes increased age and size at maturity, and invested in defensive spikes (neckteeth), but failed to quantitatively describe whole-organism response. In contrast, PTA quantified and qualified the phenotypic strategy the organism mobilized against the selection pressure. We demonstrate, at the whole-organism level, that the two populations occupy different areas of phenotypic space in the absence of predation but converge in phenotypic space as predation threat increases. PMID:21084350

  1. DISCOVERING PATIENT PHENOTYPES USING GENERALIZED LOW RANK MODELS.

    PubMed

    Schuler, Alejandro; Liu, Vincent; Wan, Joe; Callahan, Alison; Udell, Madeleine; Stark, David E; Shah, Nigam H

    2016-01-01

    The practice of medicine is predicated on discovering commonalities or distinguishing characteristics among patients to inform corresponding treatment. Given a patient grouping (hereafter referred to as a phenotype), clinicians can implement a treatment pathway accounting for the underlying cause of disease in that phenotype. Traditionally, phenotypes have been discovered by intuition, experience in practice, and advancements in basic science, but these approaches are often heuristic, labor intensive, and can take decades to produce actionable knowledge. Although our understanding of disease has progressed substantially in the past century, there are still important domains in which our phenotypes are murky, such as in behavioral health or in hospital settings. To accelerate phenotype discovery, researchers have used machine learning to find patterns in electronic health records, but have often been thwarted by missing data, sparsity, and data heterogeneity. In this study, we use a flexible framework called Generalized Low Rank Modeling (GLRM) to overcome these barriers and discover phenotypes in two sources of patient data. First, we analyze data from the 2010 Healthcare Cost and Utilization Project National Inpatient Sample (NIS), which contains upwards of 8 million hospitalization records consisting of administrative codes and demographic information. Second, we analyze a small (N=1746), local dataset documenting the clinical progression of autism spectrum disorder patients using granular features from the electronic health record, including text from physician notes. We demonstrate that low rank modeling successfully captures known and putative phenotypes in these vastly different datasets. PMID:26776181

  2. Apomixis Allows the Transgenerational Fixation of Phenotypes in Hybrid Plants.

    PubMed

    Sailer, Christian; Schmid, Bernhard; Grossniklaus, Ueli

    2016-02-01

    The introduction of apomixis-asexual reproduction through seeds-into crop plants is considered the holy grail of agriculture, as it would provide a mechanism to maintain agriculturally important phenotypes [1, 2]. Apomicts produce clonal offspring, such that apomixis could be used to transgenerationally fix any genotype, including that of F1 hybrids, which are used in agriculture due to their superior vigor and yield [3-9]. However, traits (phenotypes) do not only result from a complex combination of genetic and environmental variation but can also be influenced by epigenetic variation, which can be transgenerationally heritable in plants [10-15]. Hence, it is far from clear whether genetic fixation by apomixis suffices to fix the agriculturally relevant phenotypes of F1 hybrids, in particular because hybridization was recently shown to induce epigenetic changes [16, 17]. Here, we show that the phenotypes of Hieracium pilosella hybrids can be fixed across generations by apomixis. Using a natural apomict, we created 11 hybrid genotypes (lines). In these and a parental line, we analyzed 20 phenotypic traits that are related to plant growth and reproduction. Of the 20 traits, 18 (90%) were stably inherited over two apomictic generations, grown at the same time in a randomized design, in 11 of the 12 lines. Although one hybrid line showed phenotypic instability, our results provide a fundamental proof of principle, demonstrating that apomixis can indeed be used in plant breeding and seed production to fix complex, quantitative phenotypes across generations. PMID:26832437

  3. Association Tests of Multiple Phenotypes: ATeMP.

    PubMed

    Guo, Xiaobo; Li, Yixi; Ding, Xiaohu; He, Mingguang; Wang, Xueqin; Zhang, Heping

    2015-01-01

    Joint analysis of multiple phenotypes has gained growing attention in genome-wide association studies (GWASs), especially for the analysis of multiple intermediate phenotypes which measure the same underlying complex human disorder. One of the multivariate methods, MultiPhen (O' Reilly et al. 2012), employs the proportional odds model to regress a genotype on multiple phenotypes, hence ignoring the phenotypic distributions. Despite the flexibilities of MultiPhen, the properties and performance of MultiPhen are not well understood, especially when the phenotypic distributions are non-normal. In fact, it is well known in the statistical literature that the estimation is attenuated when the explanatory variables contain measurement errors. In this study, we first established an equivalence relationship between MultiPhen and the generalized Kendall tau association test, shedding light on why MultiPhen can perform well for joint association analysis of multiple phenotypes. Through the equivalence, we show that MultiPhen may lose power when the phenotypes are non-normal. To maintain the power, we propose two solutions (ATeMP-rn and ATeMP-or) to improve MultiPhen, and demonstrate their effectiveness through extensive simulation studies and a real case study from the Guangzhou Twin Eye Study. PMID:26479245

  4. Phenotypic plasticity in prostate cancer: role of intrinsically disordered proteins

    PubMed Central

    Mooney, Steven M; Jolly, Mohit Kumar; Levine, Herbert; Kulkarni, Prakash

    2016-01-01

    A striking characteristic of cancer cells is their remarkable phenotypic plasticity, which is the ability to switch states or phenotypes in response to environmental fluctuations. Phenotypic changes such as a partial or complete epithelial to mesenchymal transition (EMT) that play important roles in their survival and proliferation, and development of resistance to therapeutic treatments, are widely believed to arise due to somatic mutations in the genome. However, there is a growing concern that such a deterministic view is not entirely consistent with multiple lines of evidence, which indicate that stochasticity may also play an important role in driving phenotypic plasticity. Here, we discuss how stochasticity in protein interaction networks (PINs) may play a key role in determining phenotypic plasticity in prostate cancer (PCa). Specifically, we point out that the key players driving transitions among different phenotypes (epithelial, mesenchymal, and hybrid epithelial/mesenchymal), including ZEB1, SNAI1, OVOL1, and OVOL2, are intrinsically disordered proteins (IDPs) and discuss how plasticity at the molecular level may contribute to stochasticity in phenotypic switching by rewiring PINs. We conclude by suggesting that targeting IDPs implicated in EMT in PCa may be a new strategy to gain additional insights and develop novel treatments for this disease, which is the most common form of cancer in adult men. PMID:27427552

  5. Phenotypic modulation of macrophages in response to plaque lipids

    PubMed Central

    Adamson, Samantha; Leitinger, Norbert

    2014-01-01

    Purpose of review The accumulation of macrophages in the vascular wall is a hallmark of atherosclerosis. The biological properties of atherosclerotic plaque macrophages determine lesion size, composition and stability. In atherosclerotic plaques, macrophages encounter a microenvironment that is comprised of a variety of lipid oxidation products, each of which has diverse biological effects. In this review, we summarize recent advances in our understanding of the effects of plaque lipids on macrophage phenotypic polarization. Recent findings Atherosclerotic lesions in mice and in humans contain various macrophage phenotypes, which play different roles in mediating inflammation, the clearance of dead cells, and possibly resolution. Macrophages alter their phenotype and biological function in response to plaque lipids through the upregulation of specific sets of genes. Interaction of oxidized lipids with pattern recognition receptors and activation of the inflammasome by cholesterol crystals drive macrophages towards an inflammatory M1 phenotype. A new phenotype, Mox, develops when oxidized phospholipids activate stress response genes via Nrf2. Other lipid mediators such as nitrosylated-fatty acids and omega-3 fatty acid-derived products polarize plaque macrophages towards anti-inflammatory and proresolving phenotypes. Summary A deeper understanding of how lipids that accumulate in atherosclerotic plaques affect macrophage phenotype and function and thus atherosclerotic lesion development and stability will help to devise novel strategies for intervention. PMID:21841486

  6. Phenotypic plasticity in prostate cancer: role of intrinsically disordered proteins.

    PubMed

    Mooney, Steven M; Jolly, Mohit Kumar; Levine, Herbert; Kulkarni, Prakash

    2016-01-01

    A striking characteristic of cancer cells is their remarkable phenotypic plasticity, which is the ability to switch states or phenotypes in response to environmental fluctuations. Phenotypic changes such as a partial or complete epithelial to mesenchymal transition (EMT) that play important roles in their survival and proliferation, and development of resistance to therapeutic treatments, are widely believed to arise due to somatic mutations in the genome. However, there is a growing concern that such a deterministic view is not entirely consistent with multiple lines of evidence, which indicate that stochasticity may also play an important role in driving phenotypic plasticity. Here, we discuss how stochasticity in protein interaction networks (PINs) may play a key role in determining phenotypic plasticity in prostate cancer (PCa). Specifically, we point out that the key players driving transitions among different phenotypes (epithelial, mesenchymal, and hybrid epithelial/mesenchymal), including ZEB1, SNAI1, OVOL1, and OVOL2, are intrinsically disordered proteins (IDPs) and discuss how plasticity at the molecular level may contribute to stochasticity in phenotypic switching by rewiring PINs. We conclude by suggesting that targeting IDPs implicated in EMT in PCa may be a new strategy to gain additional insights and develop novel treatments for this disease, which is the most common form of cancer in adult men. PMID:27427552

  7. DISCOVERING PATIENT PHENOTYPES USING GENERALIZED LOW RANK MODELS

    PubMed Central

    SCHULER, ALEJANDRO; LIU, VINCENT; WAN, JOE; CALLAHAN, ALISON; UDELL, MADELEINE; STARK, DAVID E.; SHAH, NIGAM H.

    2016-01-01

    The practice of medicine is predicated on discovering commonalities or distinguishing characteristics among patients to inform corresponding treatment. Given a patient grouping (hereafter referred to as a phenotype), clinicians can implement a treatment pathway accounting for the underlying cause of disease in that phenotype. Traditionally, phenotypes have been discovered by intuition, experience in practice, and advancements in basic science, but these approaches are often heuristic, labor intensive, and can take decades to produce actionable knowledge. Although our understanding of disease has progressed substantially in the past century, there are still important domains in which our phenotypes are murky, such as in behavioral health or in hospital settings. To accelerate phenotype discovery, researchers have used machine learning to find patterns in electronic health records, but have often been thwarted by missing data, sparsity, and data heterogeneity. In this study, we use a flexible framework called Generalized Low Rank Modeling (GLRM) to overcome these barriers and discover phenotypes in two sources of patient data. First, we analyze data from the 2010 Healthcare Cost and Utilization Project National Inpatient Sample (NIS), which contains upwards of 8 million hospitalization records consisting of administrative codes and demographic information. Second, we analyze a small (N=1746), local dataset documenting the clinical progression of autism spectrum disorder patients using granular features from the electronic health record, including text from physician notes. We demonstrate that low rank modeling successfully captures known and putative phenotypes in these vastly different datasets. PMID:26776181

  8. Implications of the Hybrid Epithelial/Mesenchymal Phenotype in Metastasis

    PubMed Central

    Jolly, Mohit Kumar; Boareto, Marcelo; Huang, Bin; Jia, Dongya; Lu, Mingyang; Ben-Jacob, Eshel; Onuchic, José N.; Levine, Herbert

    2015-01-01

    Transitions between epithelial and mesenchymal phenotypes – the epithelial to ­mesenchymal transition (EMT) and its reverse the mesenchymal to epithelial transition (MET) – are hallmarks of cancer metastasis. While transitioning between the epithelial and mesenchymal phenotypes, cells can also attain a hybrid epithelial/mesenchymal (E/M) (i.e., partial or intermediate EMT) phenotype. Cells in this phenotype have mixed epithelial (e.g., adhesion) and mesenchymal (e.g., migration) properties, thereby allowing them to move collectively as clusters. If these clusters reach the bloodstream intact, they can give rise to clusters of circulating tumor cells (CTCs), as have often been seen experimentally. Here, we review the operating principles of the core regulatory network for EMT/MET that acts as a “three-way” switch giving rise to three distinct phenotypes – E, M and hybrid E/M – and present a theoretical framework that can elucidate the role of many other players in regulating epithelial plasticity. Furthermore, we highlight recent studies on partial EMT and its association with drug resistance and tumor-initiating potential; and discuss how cell–cell communication between cells in a partial EMT phenotype can enable the formation of clusters of CTCs. These clusters can be more apoptosis-resistant and have more tumor-initiating potential than singly moving CTCs with a wholly mesenchymal (complete EMT) phenotype. Also, more such clusters can be formed under inflammatory conditions that are often generated by various therapies. Finally, we discuss the multiple advantages that the partial EMT or hybrid E/M phenotype have as compared to a complete EMT phenotype and argue that these collectively migrating cells are the primary “bad actors” of metastasis. PMID:26258068

  9. Physiological phenotyping of pediatric chronic obstructive airway diseases.

    PubMed

    Nyilas, Sylvia; Singer, Florian; Kumar, Nitin; Yammine, Sophie; Meier-Girard, Delphine; Koerner-Rettberg, Cordula; Casaulta, Carmen; Frey, Urs; Latzin, Philipp

    2016-07-01

    Inert tracer gas washout (IGW) measurements detect increased ventilation inhomogeneity (VI) in chronic lung diseases. Their suitability for different diseases, such as cystic fibrosis (CF) and primary ciliary dyskinesia (PCD), has already been shown. However, it is still unclear if physiological phenotypes based on different IGW variables can be defined independently of underlying disease. Eighty school-age children, 20 with CF, 20 with PCD, 20 former preterm children, and 20 healthy children, performed nitrogen multiple-breath washout, double-tracer gas (DTG) single-breath washout, and spirometry. Our primary outcome was the definition of physiological phenotypes based on IGW variables. We applied principal component analysis, hierarchical Ward's clustering, and enrichment analysis to compare clinical characteristics between the clusters. IGW variables used for clustering were lung clearance index (LCI) and convection-dependent [conductive ventilation heterogeneity index (Scond)] and diffusion-convection-dependent variables [acinar ventilation heterogeneity index (Sacin) and carbon dioxide and DTG phase III slopes]. Three main phenotypes were identified. Phenotype I (n = 38) showed normal values in all IGW outcome variables. Phenotype II (n = 21) was characterized by pronounced global and convection-dependent VI while diffusion-dependent VI was normal. Phenotype III (n = 21) was characterized by increased global and diffusion- and convection-dependent VI. Enrichment analysis revealed an overrepresentation of healthy children and former preterm children in phenotype I and of CF and PCD in phenotypes II and III. Patients in phenotype III showed the highest proportion and frequency of exacerbations and hospitalization in the year prior to the measurement. IGW techniques allow identification of clinically meaningful, disease-independent physiological clusters. Their predictive value of future disease outcomes remains to be determined. PMID:27231309

  10. Multidimensionality of behavioural phenotypes in Atlantic cod, Gadus morhua.

    PubMed

    Meager, Justin J; Fernö, Anders; Skjæraasen, Jon Egil; Järvi, Torbjörn; Rodewald, Petra; Sverdrup, Gisle; Winberg, Svante; Mayer, Ian

    2012-06-25

    Much of the inter-individual variation observed in animal behaviour is now attributed to the existence of behavioural phenotypes or animal personalities. Such phenotypes may be fundamental to fisheries and aquaculture, yet there have been few detailed studies of this phenomenon in exploited marine animals. We investigated the behavioural and neuroendocrine responses of Atlantic cod (Gadus morhua L.), to situations reflecting critical ecological challenges: predator attacks and territorial challenges. Both hatchery-reared and wild fish were tested and behavioural profiles were compared with baseline conditions. We then used an objective, multivariate approach, rather than assigning individuals along one-dimensional behavioural axes, to examine whether distinct behavioural phenotypes were present. Our results indicate that two distinct behavioural phenotypes were evident in fish from each background. In hatchery-reared fish, phenotypes displayed divergent locomotor activity, sheltering, brain monoamine concentrations and responses to competitive challenges. In wild fish, phenotypes were distinguished primarily by locomotor activity, sheltering and responsiveness to predator stimuli. Hatcheries presumably represent a more stressful social environment, and social behaviour and neuroendocrine responses were important in discerning behavioural phenotypes in hatchery fish, whereas antipredator responses were important in discerning phenotypes in wild fish that have previously encountered predators. In both fish types, behavioural and physiological traits that classified individuals into phenotypes were not the same as those that were correlated across situations. These results highlight the multidimensionality of animal personalities, and that the processes that regulate one suite of behavioural traits may be very different to the processes that regulate other behaviours. PMID:22465310

  11. Alternative Sampling Strategies for Cytochrome P450 Phenotyping.

    PubMed

    De Kesel, Pieter M M; Lambert, Willy E; Stove, Christophe P

    2016-02-01

    Interindividual variability in the expression and function of drug metabolizing cytochrome P (CYP) 450 enzymes, determined by a combination of genetic, non-genetic and environmental parameters, is a major source of variable drug response. Phenotyping by administration of a selective enzyme substrate, followed by the determination of a specific phenotyping metric, is an appropriate approach to assess the in vivo activity of CYP450 enzymes as it takes into account all influencing factors. A phenotyping protocol should be as simple and convenient as possible. Typically, phenotyping metrics are determined in traditional matrices, such as blood, plasma or urine. Several sampling strategies have been proposed as an alternative for these traditional sampling techniques. In this review, we provide a comprehensive overview of available methods using dried blood spots (DBS), hair, oral fluid, exhaled breath and sweat for in vivo CYP450 phenotyping. We discuss the relation between phenotyping metrics measured in these samples and those in conventional matrices, along with the advantages and limitations of the alternative sampling techniques. Reliable phenotyping procedures for several clinically relevant CYP450 enzymes, including CYP1A2, CYP2C19 and CYP2D6, are currently available for oral fluid, breath or DBS, while additional studies are needed for other CYP450 isoforms, such as CYP3A4. The role of hair analysis for this purpose remains to be established. Being non- or minimally invasive, these sampling strategies provide convenient and patient-friendly alternatives for classical phenotyping procedures, which may contribute to the implementation of CYP450 phenotyping in clinical practice. PMID:26239501

  12. Multiparameter Phenotyping of Human PBMCs Using Mass Cytometry.

    PubMed

    Leipold, Michael D; Newell, Evan W; Maecker, Holden T

    2015-01-01

    The standard for single-cell analysis of phenotype and function in recent decades has been fluorescence flow cytometry. Mass cytometry is a newer technology that uses heavy metal ions, rather than fluorochromes, as labels for probes such as antibodies. The binding of these ion-labeled probes to cells is quantitated by mass spectrometry. This greatly increases the number of phenotypic and functional markers that can be probed simultaneously. Here, we review topics that must be considered when adapting existing flow cytometry panels to mass cytometry analysis. We present a protocol and representative panels for surface phenotyping and intracellular cytokine staining (ICS) assays. PMID:26420710

  13. Phenotypic Models of Evolution and Development: Geometry as Destiny

    PubMed Central

    Francois, Paul; Siggia, Eric D.

    2012-01-01

    Quantitative models of development that consider all relevant genes typically are difficult to fit to embryonic data alone and have many redundant parameters. Computational evolution supplies models of phenotype with relatively few variables and parameters that allows the patterning dynamics to be reduced to a geometrical picture for how the state of a cell moves. The clock and wavefront model, that defines the phenotype of somitogenesis, can be represented as a sequence of two discrete dynamical transitions (bifurcations). The expression-time to space map for Hox genes and the posterior dominance rule are phenotypes that naturally follow from computational evolution without considering the genetics of Hox regulation. PMID:23026724

  14. Peripheral blood lymphocyte phenotype and function in multiple sclerosis.

    PubMed Central

    Hughes, P J; Compston, D A

    1988-01-01

    T suppressor cell function and phenotype are abnormal in patients with multiple sclerosis, especially during the chronic progressive phase but the sub-populations defined by mitogen stimulation and serological methods may not be identical. In this study, involving 45 patients with multiple sclerosis and 33 controls, there was no correlation between T suppressor function and CD8 cell phenotype in patients with multiple sclerosis or in controls. These phenotypic and functional studies cannot therefore be used interchangeably in the assessment of patients with multiple sclerosis since they provide different information about lymphocyte subpopulations. PMID:2976082

  15. On-time clinical phenotype prediction based on narrative reports

    PubMed Central

    Bejan, Cosmin A.; Vanderwende, Lucy; Evans, Heather L.; Wurfel, Mark M.; Yetisgen-Yildiz, Meliha

    2013-01-01

    In this paper we describe a natural language processing system which is able to predict whether or not a patient exhibits a specific phenotype using the information extracted from the narrative reports associated with the patient. Furthermore, the phenotypic annotations from our report dataset were performed at the report level which allows us to perform the prediction of the clinical phenotype at any point in time during the patient hospitalization period. Our experiments indicate that an important factor in achieving better results for this problem is to determine how much information to extract from the patient reports in the time interval between the patient admission time and the current prediction time. PMID:24551325

  16. Mouse embryonic fibroblasts exhibit extensive developmental and phenotypic diversity

    PubMed Central

    Singhal, Prabhat K.; Sassi, Slim; Lan, Lan; Au, Patrick; Halvorsen, Stefan C.; Fukumura, Dai; Jain, Rakesh K.; Seed, Brian

    2016-01-01

    Analysis of embryonic fibroblasts from GFP reporter mice indicates that the fibroblast cell type harbors a large collection of developmentally and phenotypically heterogeneous subtypes. Some of these cells exhibit multipotency, whereas others do not. Multiparameter flow cytometry analysis shows that a large number of distinct populations of fibroblast-like cells can be found in cultures initiated from different embryonic organs, and cells sorted according to their surface phenotype typically retain their characteristics on continued propagation in culture. Similarly, surface phenotypes of individual cloned fibroblast-like cells exhibit significant variation. The fibroblast cell class appears to contain a very large number of denumerable subtypes. PMID:26699463

  17. A functional perspective on phenotypic heterogeneity in microorganisms.

    PubMed

    Ackermann, Martin

    2015-08-01

    Most microbial communities consist of a genetically diverse assembly of different organisms, and the level of genetic diversity plays an important part in community properties and functions. However, biological diversity also arises at a lower level of biological organization, between genetically identical cells that reside in the same microenvironment. In this Review, I outline the molecular mechanisms responsible for phenotypic heterogeneity and discuss how phenotypic heterogeneity allows genotypes to persist in fluctuating environments. I also describe how it promotes interactions between phenotypic subpopulations in clonal groups, providing microbial groups with new functionality. PMID:26145732

  18. A Modular Architecture for Electronic Health Record-Driven Phenotyping

    PubMed Central

    Rasmussen, Luke V.; Kiefer, Richard C.; Mo, Huan; Speltz, Peter; Thompson, William K.; Jiang, Guoqian; Pacheco, Jennifer A.; Xu, Jie; Zhu, Qian; Denny, Joshua C.; Montague, Enid; Pathak, Jyotishman

    2015-01-01

    Increasing interest in and experience with electronic health record (EHR)-driven phenotyping has yielded multiple challenges that are at present only partially addressed. Many solutions require the adoption of a single software platform, often with an additional cost of mapping existing patient and phenotypic data to multiple representations. We propose a set of guiding design principles and a modular software architecture to bridge the gap to a standardized phenotype representation, dissemination and execution. Ongoing development leveraging this proposed architecture has shown its ability to address existing limitations. PMID:26306258

  19. Epigenetic heredity: RNA-mediated modes of phenotypic variation.

    PubMed

    Rassoulzadegan, Minoo; Cuzin, François

    2015-04-01

    In addition to the Mendelian mutations, several instances of heritable phenotypic variation have been reported. We have observed, in mice, a role for sperm RNAs in the induction of such stable phenotypic variation. When experimentally transferred by RNA microinjection into fertilized mouse eggs, the noncoding RNAs homologous in sequence to the target locus are efficient inducers of variation at the transcriptional level. Transmission of the phenotypic variation to progeny is highly efficient and independent of gender. Here, we have summarized these finding and how they relate to other reports of epigenetic variation. PMID:25726734

  20. Multiparameter Phenotyping of Human PBMCs Using Mass Cytometry

    PubMed Central

    Leipold, Michael D.; Newell, Evan W.; Maecker, Holden T.

    2016-01-01

    The standard for single-cell analysis of phenotype and function in recent decades has been fluorescence flow cytometry. Mass cytometry is a newer technology that uses heavy metal ions, rather than fluorochromes, as labels for probes such as antibodies. The binding of these ion-labeled probes to cells is quantitated by mass spectrometry. This greatly increases the number of phenotypic and functional markers that can be probed simultaneously. Here, we review topics that must be considered when adapting existing flow cytometry panels to mass cytometry analysis. We present a protocol and representative panels for surface phenotyping and intracellular cytokine staining (ICS) assays. PMID:26420710

  1. Mouse embryonic fibroblasts exhibit extensive developmental and phenotypic diversity.

    PubMed

    Singhal, Prabhat K; Sassi, Slim; Lan, Lan; Au, Patrick; Halvorsen, Stefan C; Fukumura, Dai; Jain, Rakesh K; Seed, Brian

    2016-01-01

    Analysis of embryonic fibroblasts from GFP reporter mice indicates that the fibroblast cell type harbors a large collection of developmentally and phenotypically heterogeneous subtypes. Some of these cells exhibit multipotency, whereas others do not. Multiparameter flow cytometry analysis shows that a large number of distinct populations of fibroblast-like cells can be found in cultures initiated from different embryonic organs, and cells sorted according to their surface phenotype typically retain their characteristics on continued propagation in culture. Similarly, surface phenotypes of individual cloned fibroblast-like cells exhibit significant variation. The fibroblast cell class appears to contain a very large number of denumerable subtypes. PMID:26699463

  2. Precision Medicine for Continuing Phenotype Expansion of Human Genetic Diseases

    PubMed Central

    Yu, Hui; Zhang, Victor Wei

    2015-01-01

    Determining the exact genetic causes for a patient and providing definite molecular diagnoses are core elements of precision medicine. Individualized patient care is often limited by our current knowledge of disease etiologies and commonly used phenotypic-based diagnostic approach. The broad and incompletely understood phenotypic spectrum of a disease and various underlying genetic heterogeneity also present extra challenges to our clinical practice. With the rapid adaptation of new sequence technology in clinical setting for diagnostic purpose, phenotypic expansions of disease spectrum are becoming increasingly common. Understanding the underlying molecular mechanisms will help us to integrate genomic information into the workup of individualized patient care and make better clinical decisions. PMID:26137492

  3. Intraspecific phenotypic variation among alewife populations drives parallel phenotypic shifts in bluegill

    PubMed Central

    Huss, Magnus; Howeth, Jennifer G.; Osterman, Julia I.; Post, David M.

    2014-01-01

    Evolutionary diversification within consumer species may generate selection on local ecological communities, affecting prey community structure. However, the extent to which this niche construction can propagate across food webs and shape trait variation in competing species is unknown. Here, we tested whether niche construction by different life-history variants of the planktivorous fish alewife (Alosa pseudoharengus) can drive phenotypic divergence and resource use in the competing species bluegill (Lepomis macrochirus). Using a combination of common garden experiments and a comparative field study, we found that bluegill from landlocked alewife lakes grew relatively better when fed small than large zooplankton, had gill rakers better adapted for feeding on small-bodied prey and selected smaller zooplankton compared with bluegill from lakes with anadromous or no alewife. Observed shifts in bluegill foraging traits in lakes with landlocked alewife parallel those in alewife, suggesting interspecific competition leading to parallel phenotypic changes rather than to divergence (which is commonly predicted). Our findings suggest that species may be locally adapted to prey communities structured by different life-history variants of a competing dominant species. PMID:24920478

  4. The Chronic Bronchitic Phenotype of COPD

    PubMed Central

    Han, MeiLan K.; Vance, Gwendolyn B.; Make, Barry J.; Newell, John D.; Hokanson, John E.; Hersh, Craig P.; Stinson, Douglas; Silverman, Edwin K.; Criner, Gerard J.

    2011-01-01

    Background: Chronic bronchitis (CB) in patients with COPD is associated with an accelerated lung function decline and an increased risk of respiratory infections. Despite its clinical significance, the chronic bronchitic phenotype in COPD remains poorly defined. Methods: We analyzed data from subjects enrolled in the Genetic Epidemiology of COPD (COPDGene) Study. A total of 1,061 subjects with GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage II to IV were divided into two groups: CB (CB+) if subjects noted chronic cough and phlegm production for ≥ 3 mo/y for 2 consecutive years, and no CB (CB−) if they did not. Results: There were 290 and 771 subjects in the CB+ and CB− groups, respectively. Despite similar lung function, the CB+ group was younger (62.8 ± 8.4 vs 64.6 ± 8.4 years, P = .002), smoked more (57 ± 30 vs 52 ± 25 pack-years, P = .006), and had more current smokers (48% vs 27%, P < .0001). A greater percentage of the CB+ group reported nasal and ocular symptoms, wheezing, and nocturnal awakenings secondary to cough and dyspnea. History of exacerbations was higher in the CB+ group (1.21 ± 1.62 vs 0.63 ± 1.12 per patient, P < .027), and more patients in the CB+ group reported a history of severe exacerbations (26.6% vs 20.0%, P = .024). There was no difference in percent emphysema or percent gas trapping, but the CB+ group had a higher mean percent segmental airway wall area (63.2% ± 2.9% vs 62.6% ± 3.1%, P = .013). Conclusions: CB in patients with COPD is associated with worse respiratory symptoms and higher risk of exacerbations. This group may need more directed therapy targeting chronic mucus production and smoking cessation not only to improve symptoms but also to reduce risk, improve quality of life, and improve outcomes. Trial registry: ClinicalTrials.gov; No.: NCT00608764; URL: www.clinicaltrials.gov PMID:21474571

  5. Relaxed selection is a precursor to the evolution of phenotypic plasticity

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Phenotypic plasticity represents one of the most important ways that organisms adaptively respond to environmental variation. Alternate phenotypes produced through phenotypic plasiticity generally arise through conditional gene expression, which is predicted to result in relaxed selective constrain...

  6. Phenotypes of prediabetes and stratification of cardiometabolic risk.

    PubMed

    Stefan, Norbert; Fritsche, Andreas; Schick, Fritz; Häring, Hans-Ulrich

    2016-09-01

    Prediabetes is associated with increased risks of type 2 diabetes, cardiovascular disease, dementia, and cancer, and its prevalence is increasing worldwide. Lifestyle and pharmacological interventions in people with prediabetes can prevent the development of diabetes and possibly cardiovascular disease. However, prediabetes is a highly heterogeneous metabolic state, both with respect to its pathogenesis and prediction of disease. Improved understanding of these features and precise phenotyping of prediabetes could help to improve stratification of disease risk. In this Personal View, we focus on the extreme metabolic phenotypes of metabolically healthy obesity and metabolically unhealthy normal weight, insulin secretion failure, insulin resistance, visceral obesity, and non-alcoholic fatty liver disease. We present new analyses aimed at improving characterisation of phenotypes in lean, overweight, and obese people with prediabetes. We discuss evidence from lifestyle intervention studies to explore whether these phenotypes can also be used for individualised prediction and prevention of cardiometabolic diseases. PMID:27185609

  7. Prioritizing sequence polymorphisms for potential association with phenotype

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The millions of SNP, insertions and deletions revealed by next generation sequencing (NGS), are certain to include polymorphisms responsible for phenotypic variation. Distinguishing causal from benign variants may allow genomic predictions that are robust across populations. While variants underly...

  8. Functional interplay between the cell cycle and cell phenotypes.

    PubMed

    Chen, Wei-Chiang; Wu, Pei-Hsun; Phillip, Jude M; Khatau, Shyam B; Choi, Jae Min; Dallas, Matthew R; Konstantopoulos, Konstantinos; Sun, Sean X; Lee, Jerry S H; Hodzic, Didier; Wirtz, Denis

    2013-03-01

    Cell cycle distribution of adherent cells is typically assessed using flow cytometry, which precludes the measurements of many cell properties and their cycle phase in the same environment. Here we develop and validate a microscopy system to quantitatively analyze the cell-cycle phase of thousands of adherent cells and their associated cell properties simultaneously. This assay demonstrates that population-averaged cell phenotypes can be written as a linear combination of cell-cycle fractions and phase-dependent phenotypes. By perturbing the cell cycle through inhibition of cell-cycle regulators or changing nuclear morphology by depletion of structural proteins, our results reveal that cell cycle regulators and structural proteins can significantly interfere with each other's prima facie functions. This study introduces a high-throughput method to simultaneously measure the cell cycle and phenotypes at single-cell resolution, which reveals a complex functional interplay between the cell cycle and cell phenotypes. PMID:23319145

  9. Molecular mechanisms of phenotypic plasticity in social insects.

    PubMed

    Corona, Miguel; Libbrecht, Romain; Wheeler, Diana E

    2016-02-01

    Polyphenism in insects, whereby a single genome expresses different phenotypes in response to environmental cues, is a fascinating biological phenomenon. Social insects are especially intriguing examples of phenotypic plasticity because division of labor results in the development of extreme morphological phenotypes, such as the queen and worker castes. Although sociality evolved independently in ants, bees, wasps and termites, similar genetic pathways regulate phenotypic plasticity in these different groups of social insects. The insulin/insulin-like growth signaling (IIS) plays a key role in this process. Recent research reveals that IIS interacts with other pathways including target of rapamycin (TOR), epidermal growth factor receptor (Egfr), juvenile hormone (JH) and vitellogenin (Vg) to regulate caste differentiation. PMID:27436553

  10. Cornelia de Lange Syndrome: Evolution of the Phenotype

    ERIC Educational Resources Information Center

    Passarge, Eberhard; And Others

    1971-01-01

    The medical case history of a 2-year-old girl who developed, during the second year of life, the classical phenotype (typical appearance) indicative of the deLange syndrome, with both mental and physical impairment. (KW)

  11. Evolution of cooperation in a multidimensional phenotype space.

    PubMed

    Kroumi, Dhaker; Lessard, Sabin

    2015-06-01

    The emergence of cooperation in populations of selfish individuals is a fascinating topic that has inspired much theoretical work. An important model to study cooperation is the phenotypic model, where individuals are characterized by phenotypic properties that are visible to others. The phenotype of an individual can be represented for instance by a vector x = (x1,…,xn), where x1,…,xn are integers. The population can be well mixed in the sense that everyone is equally likely to interact with everyone else, but the behavioral strategies of the individuals can depend on their distance in the phenotype space. A cooperator can choose to help other individuals exhibiting the same phenotype and defects otherwise. Cooperation is said to be favored by selection if it is more abundant than defection in the stationary state. This means that the average frequency of cooperators in the stationary state strictly exceeds 1/2. Antal et al. (2009c) found conditions that ensure that cooperation is more abundant than defection in a one-dimensional (i.e. n = 1) and an infinite-dimensional (i.e. n = ∞) phenotype space in the case of the Prisoner's Dilemma under weak selection. However, reality lies between these two limit cases. In this paper, we derive the corresponding condition in the case of a phenotype space of any finite dimension. This is done by applying a perturbation method to study a mutation-selection equilibrium under weak selection. This condition is obtained in the limit of a large population size by using the ancestral process. The best scenario for cooperation to be more likely to evolve is found to be a high population-scaled phenotype mutation rate, a low population-scaled strategy mutation rate and a high phenotype space dimension. The biological intuition is that a high population-scaled phenotype mutation rate reduces the quantity of interactions between cooperators and defectors, while a high population-scaled strategy mutation rate introduces newly

  12. Cardiac Sodium Channel Mutations: Why so Many Phenotypes?

    PubMed

    Liu, M; Yang, K-C; Dudley, S C

    2016-01-01

    The cardiac Na(+) channel (Nav1.5) conducts a depolarizing inward Na(+) current that is responsible for the generation of the upstroke Phase 0 of the action potential. In heart tissue, changes in Na(+) currents can affect conduction velocity and impulse propagation. The cardiac Nav1.5 is also involved in determination of the action potential duration, since some channels may reopen during the plateau phase, generating a persistent or late inward current. Mutations of cardiac Nav1.5 can induce gain or loss of channel function because of an increased late current or a decrease of peak current, respectively. Gain-of-function mutations cause Long QT syndrome type 3 and possibly atrial fibrillation, while loss-of-function channel mutations are associated with a wider variety of phenotypes, such as Brugada syndrome, cardiac conduction disease, dilated cardiomyopathy, and sick sinus node syndrome. The penetrance and phenotypes resulting from Nav1.5 mutations also vary with age, gender, body temperature, circadian rhythm, and between regions of the heart. This phenotypic variability makes it difficult to correlate genotype-phenotype. We propose that mutations are only one contributor to the phenotype and additional modifications on Nav1.5 lead to the phenotypic variability. Possible modifiers include other genetic variations and alterations in the life cycle of Nav1.5 such as gene transcription, RNA processing, translation, posttranslational modifications, trafficking, complex assembly, and degradation. In this chapter, we summarize potential modifiers of cardiac Nav1.5 that could help explain the clinically observed phenotypic variability. Consideration of these modifiers could help improve genotype-phenotype correlations and lead to new therapeutic strategies. PMID:27586294

  13. Social parasitism and the molecular basis of phenotypic evolution.

    PubMed

    Cini, Alessandro; Patalano, Solenn; Segonds-Pichon, Anne; Busby, George B J; Cervo, Rita; Sumner, Seirian

    2015-01-01

    Contrasting phenotypes arise from similar genomes through a combination of losses, gains, co-option and modifications of inherited genomic material. Understanding the molecular basis of this phenotypic diversity is a fundamental challenge in modern evolutionary biology. Comparisons of the genes and their expression patterns underlying traits in closely related species offer an unrivaled opportunity to evaluate the extent to which genomic material is reorganized to produce novel traits. Advances in molecular methods now allow us to dissect the molecular machinery underlying phenotypic diversity in almost any organism, from single-celled entities to the most complex vertebrates. Here we discuss how comparisons of social parasites and their free-living hosts may provide unique insights into the molecular basis of phenotypic evolution. Social parasites evolve from a eusocial ancestor and are specialized to exploit the socially acquired resources of their closely-related eusocial host. Molecular comparisons of such species pairs can reveal how genomic material is re-organized in the loss of ancestral traits (i.e., of free-living traits in the parasites) and the gain of new ones (i.e., specialist traits required for a parasitic lifestyle). We define hypotheses on the molecular basis of phenotypes in the evolution of social parasitism and discuss their wider application in our understanding of the molecular basis of phenotypic diversity within the theoretical framework of phenotypic plasticity and shifting reaction norms. Currently there are no data available to test these hypotheses, and so we also provide some proof of concept data using the paper wasp social parasite/host system (Polistes sulcifer-Polistes dominula). This conceptual framework and first empirical data provide a spring-board for directing future genomic analyses on exploiting social parasites as a route to understanding the evolution of phenotypic specialization. PMID:25741361

  14. Social parasitism and the molecular basis of phenotypic evolution

    PubMed Central

    Cini, Alessandro; Patalano, Solenn; Segonds-Pichon, Anne; Busby, George B. J.; Cervo, Rita; Sumner, Seirian

    2015-01-01

    Contrasting phenotypes arise from similar genomes through a combination of losses, gains, co-option and modifications of inherited genomic material. Understanding the molecular basis of this phenotypic diversity is a fundamental challenge in modern evolutionary biology. Comparisons of the genes and their expression patterns underlying traits in closely related species offer an unrivaled opportunity to evaluate the extent to which genomic material is reorganized to produce novel traits. Advances in molecular methods now allow us to dissect the molecular machinery underlying phenotypic diversity in almost any organism, from single-celled entities to the most complex vertebrates. Here we discuss how comparisons of social parasites and their free-living hosts may provide unique insights into the molecular basis of phenotypic evolution. Social parasites evolve from a eusocial ancestor and are specialized to exploit the socially acquired resources of their closely-related eusocial host. Molecular comparisons of such species pairs can reveal how genomic material is re-organized in the loss of ancestral traits (i.e., of free-living traits in the parasites) and the gain of new ones (i.e., specialist traits required for a parasitic lifestyle). We define hypotheses on the molecular basis of phenotypes in the evolution of social parasitism and discuss their wider application in our understanding of the molecular basis of phenotypic diversity within the theoretical framework of phenotypic plasticity and shifting reaction norms. Currently there are no data available to test these hypotheses, and so we also provide some proof of concept data using the paper wasp social parasite/host system (Polistes sulcifer—Polistes dominula). This conceptual framework and first empirical data provide a spring-board for directing future genomic analyses on exploiting social parasites as a route to understanding the evolution of phenotypic specialization. PMID:25741361

  15. Cellular imaging: a key phenotypic screening strategy for predictive toxicology

    PubMed Central

    Xu, Jinghai J.

    2015-01-01

    Incorporating phenotypic screening as a key strategy enhances predictivity and translatability of drug discovery efforts. Cellular imaging serves as a “phenotypic anchor” to identify important toxicologic pathology that encompasses an array of underlying mechanisms, thus provides an effective means to reduce drug development failures due to insufficient safety. This mini-review highlights the latest advances in hepatotoxicity, cardiotoxicity, and genetic toxicity tests that utilized cellular imaging as a screening strategy, and recommends path forward for further improvement. PMID:26441648

  16. 3D Laser Triangulation for Plant Phenotyping in Challenging Environments

    PubMed Central

    Kjaer, Katrine Heinsvig; Ottosen, Carl-Otto

    2015-01-01

    To increase the understanding of how the plant phenotype is formed by genotype and environmental interactions, simple and robust high-throughput plant phenotyping methods should be developed and considered. This would not only broaden the application range of phenotyping in the plant research community, but also increase the ability for researchers to study plants in their natural environments. By studying plants in their natural environment in high temporal resolution, more knowledge on how multiple stresses interact in defining the plant phenotype could lead to a better understanding of the interaction between plant responses and epigenetic regulation. In the present paper, we evaluate a commercial 3D NIR-laser scanner (PlantEye, Phenospex B.V., Herleen, The Netherlands) to track daily changes in plant growth with high precision in challenging environments. Firstly, we demonstrate that the NIR laser beam of the scanner does not affect plant photosynthetic performance. Secondly, we demonstrate that it is possible to estimate phenotypic variation amongst the growth pattern of ten genotypes of Brassica napus L. (rapeseed), using a simple linear correlation between scanned parameters and destructive growth measurements. Our results demonstrate the high potential of 3D laser triangulation for simple measurements of phenotypic variation in challenging environments and in a high temporal resolution. PMID:26066990

  17. Cardiac sodium channel mutations: why so many phenotypes?

    PubMed Central

    Liu, Man; Yang, Kai-Chien; Dudley, Samuel C.

    2016-01-01

    Mutations of the cardiac sodium channel (Nav1.5) can induce gain or loss of channel function. Gain-of-function mutations can cause long QT syndrome type 3 and possibly atrial fibrillation, whereas loss-of-function mutations are associated with a variety of phenotypes, such as Brugada syndrome, cardiac conduction disease, sick sinus syndrome, and possibly dilated cardiomyopathy. The phenotypes produced by Nav1.5 mutations vary according to the direct effect of the mutation on channel biophysics, but also with age, sex, body temperature, and between regions of the heart. This phenotypic variability makes genotype–phenotype correlations difficult. In this Perspectives article, we propose that phenotypic variability not ascribed to mutation-dependent changes in channel function might be the result of additional modifiers of channel behaviour, such as other genetic variation and alterations in transcription, RNA processing, translation, post-translational modifications, and protein degradation. Consideration of these modifiers might help to improve genotype–phenotype correlations and lead to new therapeutic strategies. PMID:24958080

  18. Clinical phenotypes of COPD: identification, definition and implications for guidelines.

    PubMed

    Miravitlles, Marc; Calle, Myriam; Soler-Cataluña, Juan José

    2012-03-01

    The term phenotype in the field of COPD is defined as "a single or combination of disease attributes that describe differences between individuals with COPD as they relate to clinically meaningful outcomes". Among all phenotypes described, there are three that are associated with prognosis and especially are associated with a different response to currently available therapies. There phenotypes are: the exacerbator, the overlap COPD-asthma and the emphysema-hyperinflation. The exacerbator is characterised by the presence of, at least, two exacerbations the previous year, and on top of long-acting bronchodilators, may require the use of antiinflammatory drugs. The overlap phenotype presents symptoms of increased variability of airflow and incompletely reversible airflow obstruction. Due to the underlying inflammatory profile, it uses to have a good therapeutic response to inhaled corticosteroids in addition to bronchodilators. Lastly, the emphysema phenotype presents a poor therapeutic response to the existing antiinflammatory drugs and long-acting bronchodilators together with rehabilitation are the treatments of choice. Identifying the peculiarities of the different phenotypes of COPD will allow us to implement a more personalised treatment, in which the characteristics of the patients, together with their severity will be key to choose the best treatment option. PMID:22196477

  19. Discordant phenotype in siblings with X-linked agammaglobulinemia

    SciTech Connect

    Bykowsky, M.J.; Veksler, K.S.; Sullivan, K.E.

    1996-03-01

    X-linked agammaglobulinemia (XLA) is a congenital humoral immunodeficiency caused by a defect in a B-cell-specific signaling molecule, Btk. There has been little concordance of phenotype with genotype in this disorder, and defects in Btk cause immunodeficiencies that range from mild impairment to complete inability to produce antibodies. The factors modifying the phenotype of XLA are not understood. The current study is the first description of two male siblings with identical T{sup 134}{yields}C mutations in the translation initiation ATG of Btk who have different clinical phenotypes as well as different laboratory phenotypes. The proband lacks immunoglobulins and B cells and has recurrent infections, while the elder, affected brother has normal levels of IgG and IgM and very few infections. Both have undetectable levels of Btk kinase activity in circulating mononuclear cells. Complete sequencing of Btk gene transcripts in both brothers revealed no additional mutations to account for the discordant phenotypes. This description provides unequivocal evidence that the phenotype of XLA is influenced by factors additional to the Btk gene. 39 refs., 3 figs., 3 tabs.

  20. Identifying genetically driven clinical phenotypes using linear mixed models.

    PubMed

    Mosley, Jonathan D; Witte, John S; Larkin, Emma K; Bastarache, Lisa; Shaffer, Christian M; Karnes, Jason H; Stein, C Michael; Phillips, Elizabeth; Hebbring, Scott J; Brilliant, Murray H; Mayer, John; Ye, Zhan; Roden, Dan M; Denny, Joshua C

    2016-01-01

    We hypothesized that generalized linear mixed models (GLMMs), which estimate the additive genetic variance underlying phenotype variability, would facilitate rapid characterization of clinical phenotypes from an electronic health record. We evaluated 1,288 phenotypes in 29,349 subjects of European ancestry with single-nucleotide polymorphism (SNP) genotyping on the Illumina Exome Beadchip. We show that genetic liability estimates are primarily driven by SNPs identified by prior genome-wide association studies and SNPs within the human leukocyte antigen (HLA) region. We identify 44 (false discovery rate q<0.05) phenotypes associated with HLA SNP variation and show that hypothyroidism is genetically correlated with Type I diabetes (rG=0.31, s.e. 0.12, P=0.003). We also report novel SNP associations for hypothyroidism near HLA-DQA1/HLA-DQB1 at rs6906021 (combined odds ratio (OR)=1.2 (95% confidence interval (CI): 1.1-1.2), P=9.8 × 10(-11)) and for polymyalgia rheumatica near C6orf10 at rs6910071 (OR=1.5 (95% CI: 1.3-1.6), P=1.3 × 10(-10)). Phenome-wide application of GLMMs identifies phenotypes with important genetic drivers, and focusing on these phenotypes can identify novel genetic associations. PMID:27109359

  1. Diagnosis, assessment, and phenotyping of COPD: beyond FEV1

    PubMed Central

    Lange, Peter; Halpin, David M; O’Donnell, Denis E; MacNee, William

    2016-01-01

    COPD is now widely recognized as a complex heterogeneous syndrome, having both pulmonary and extrapulmonary features. In clinical practice, the diagnosis of COPD is based on the presence of chronic airflow limitation, as assessed by post-bronchodilator spirometry. The severity of the airflow limitation, as measured by percent predicted FEV1, provides important information to the physician to enable optimization of management. However, in order to accurately assess the complexity of COPD, there need to be other measures made beyond FEV1. At present, there is a lack of reliable and simple blood biomarkers to confirm and further assess the diagnosis of COPD. However, it is possible to identify patients who display different phenotypic characteristics of COPD that relate to clinically relevant outcomes. Currently, validated phenotypes of COPD include alpha-1 antitrypsin deficiency, and “frequent exacerbators”. Recently, a definition and assessment of a new phenotype comprising patients with overlapping features of asthma and COPD has been suggested and is known as “asthma COPD overlap syndrome”. Several other phenotypes have been proposed, but require validation against clinical outcomes. Defining phenotypes requires the assessment of multiple factors indicating disease severity, its impact, and its activity. Recognition and validation of COPD phenotypes has an important role to play in the selection of evidence-based targeted therapy in the future management of COPD, but regardless of the diagnostic terms, patients with COPD should be assessed and treated according to their individual treatable characteristics. PMID:26937185

  2. An Automated Field Phenotyping Pipeline for Application in Grapevine Research

    PubMed Central

    Kicherer, Anna; Herzog, Katja; Pflanz, Michael; Wieland, Markus; Rüger, Philipp; Kecke, Steffen; Kuhlmann, Heiner; Töpfer, Reinhard

    2015-01-01

    Due to its perennial nature and size, the acquisition of phenotypic data in grapevine research is almost exclusively restricted to the field and done by visual estimation. This kind of evaluation procedure is limited by time, cost and the subjectivity of records. As a consequence, objectivity, automation and more precision of phenotypic data evaluation are needed to increase the number of samples, manage grapevine repositories, enable genetic research of new phenotypic traits and, therefore, increase the efficiency in plant research. In the present study, an automated field phenotyping pipeline was setup and applied in a plot of genetic resources. The application of the PHENObot allows image acquisition from at least 250 individual grapevines per hour directly in the field without user interaction. Data management is handled by a database (IMAGEdata). The automatic image analysis tool BIVcolor (Berries in Vineyards-color) permitted the collection of precise phenotypic data of two important fruit traits, berry size and color, within a large set of plants. The application of the PHENObot represents an automated tool for high-throughput sampling of image data in the field. The automated analysis of these images facilitates the generation of objective and precise phenotypic data on a larger scale. PMID:25730485

  3. An automated field phenotyping pipeline for application in grapevine research.

    PubMed

    Kicherer, Anna; Herzog, Katja; Pflanz, Michael; Wieland, Markus; Rüger, Philipp; Kecke, Steffen; Kuhlmann, Heiner; Töpfer, Reinhard

    2015-01-01

    Due to its perennial nature and size, the acquisition of phenotypic data in grapevine research is almost exclusively restricted to the field and done by visual estimation. This kind of evaluation procedure is limited by time, cost and the subjectivity of records. As a consequence, objectivity, automation and more precision of phenotypic data evaluation are needed to increase the number of samples, manage grapevine repositories, enable genetic research of new phenotypic traits and, therefore, increase the efficiency in plant research. In the present study, an automated field phenotyping pipeline was setup and applied in a plot of genetic resources. The application of the PHENObot allows image acquisition from at least 250 individual grapevines per hour directly in the field without user interaction. Data management is handled by a database (IMAGEdata). The automatic image analysis tool BIVcolor (Berries in Vineyards-color) permitted the collection of precise phenotypic data of two important fruit traits, berry size and color, within a large set of plants. The application of the PHENObot represents an automated tool for high-throughput sampling of image data in the field. The automated analysis of these images facilitates the generation of objective and precise phenotypic data on a larger scale. PMID:25730485

  4. Application of Phenotype Microarray technology to soil microbiology

    NASA Astrophysics Data System (ADS)

    Mocali, Stefano

    2016-04-01

    It is well established that soil microorganisms are extremely diverse and only a small fraction has been successfully cultured in the laboratory. Furthermore, addressing the functionality of genomes is one of the most important and challenging tasks of today's biology. In particular the ability to link genotypes to corresponding phenotypes is of interest in the reconstruction and biotechnological manipulation of metabolic pathways. High-throughput culture in micro wells provides a method for rapid screening of a wide variety of growth conditions and commercially available plates contain a large number of substrates, nutrient sources, and inhibitors, which can provide an assessment of the phenotype of an organism. Thus, over the last years, Phenotype Microarray (PM) technology has been used to address many specific issues related to the metabolic functionality of microorganisms. However, computational tools that could directly link PM data with the gene(s) of interest followed by the extraction of information on gene-phenotype correlation are still missing. Here potential applications of phenotype arrays to soil microorganisms, use of the plates in stress response studies and for assessment of phenotype of environmental communities are described. Considerations and challenges in data interpretation and visualization, including data normalization, statistics, and curve fitting are also discussed. In particular, here we present DuctApe, a suite that allows the analysis of both genomic sequences and PM data, to find metabolic differences among PM experiments and to correlate them with KEGG pathways and gene presence/absence patterns.

  5. Probing phenotypic growth in expanding Bacillus subtilis biofilms.

    PubMed

    Wang, Xiaoling; Koehler, Stephan A; Wilking, James N; Sinha, Naveen N; Cabeen, Matthew T; Srinivasan, Siddarth; Seminara, Agnese; Rubinstein, Shmuel; Sun, Qingping; Brenner, Michael P; Weitz, David A

    2016-05-01

    We develop an optical imaging technique for spatially and temporally tracking biofilm growth and the distribution of the main phenotypes of a Bacillus subtilis strain with a triple-fluorescent reporter for motility, matrix production, and sporulation. We develop a calibration procedure for determining the biofilm thickness from the transmission images, which is based on Beer-Lambert's law and involves cross-sectioning of biofilms. To obtain the phenotype distribution, we assume a linear relationship between the number of cells and their fluorescence and determine the best combination of calibration coefficients that matches the total number of cells for all three phenotypes and with the total number of cells from the transmission images. Based on this analysis, we resolve the composition of the biofilm in terms of motile, matrix-producing, sporulating cells and low-fluorescent materials which includes matrix and cells that are dead or have low fluorescent gene expression. We take advantage of the circular growth to make kymograph plots of all three phenotypes and the dominant phenotype in terms of radial distance and time. To visualize the nonlocal character of biofilm growth, we also make kymographs using the local colonization time. Our technique is suitable for real-time, noninvasive, quantitative studies of the growth and phenotype distribution of biofilms which are either exposed to different conditions such as biocides, nutrient depletion, dehydration, or waste accumulation. PMID:27003268

  6. Switching behaviour of two-phenotype bacteria in varying environment

    NASA Astrophysics Data System (ADS)

    Friedman, G.; Gurevich, P.; McCarthy, S.; Rachinskii, D.

    2015-02-01

    An increasing interest in multi-phenotype species has stimulated both experimental and mathematical research. One example is bacteria which have two phenotypes and can make transitions from one phenotype to the other in response to variations in environmental conditions. We model a population of such bacteria subjected to a stochastic environmental input, which fluctuates between two conditions preferred by the phenotypes. Our interest in this model is how the average growth rate of the total population is affected by alterations to the environmental thresholds at which the transitions between phenotypes are allowed. Under certain conditions, we find that the bacteria achieve a maximum growth rate by adjusting their behavior to act in a similar manner to a non-ideal relay. In this scenario, memory helps to increase fitness. We then extend the model to include multiple competing species with different thresholds and examine the limit of distribution of population among these species and phenotypes as time increases. For this purpose, we formulate a reaction-diffusion model which involves non-ideal relays describing the evolution of the state of different species; and, a Preisach operator with time-dependent density function to account for the integral effect of the species on the environment. Formation of patterns and multiple stationary limits are shown numerically in the multi-species model.

  7. Monotonicity is a key feature of genotype-phenotype maps

    PubMed Central

    Gjuvsland, Arne B.; Wang, Yunpeng; Plahte, Erik; Omholt, Stig W.

    2013-01-01

    It was recently shown that monotone gene action, i.e., order-preservation between allele content and corresponding genotypic values in the mapping from genotypes to phenotypes, is a prerequisite for achieving a predictable parent-offspring relationship across the whole allele frequency spectrum. Here we test the consequential prediction that the design principles underlying gene regulatory networks are likely to generate highly monotone genotype-phenotype maps. To this end we present two measures of the monotonicity of a genotype-phenotype map, one based on allele substitution effects, and the other based on isotonic regression. We apply these measures to genotype-phenotype maps emerging from simulations of 1881 different 3-gene regulatory networks. We confirm that in general, genotype-phenotype maps are indeed highly monotonic across network types. However, regulatory motifs involving incoherent feedforward or positive feedback, as well as pleiotropy in the mapping between genotypes and gene regulatory parameters, are clearly predisposed for generating non-monotonicity. We present analytical results confirming these deep connections between molecular regulatory architecture and monotonicity properties of the genotype-phenotype map. These connections seem to be beyond reach by the classical distinction between additive and non-additive gene action. PMID:24223579

  8. Identifying genetically driven clinical phenotypes using linear mixed models

    PubMed Central

    Mosley, Jonathan D.; Witte, John S.; Larkin, Emma K.; Bastarache, Lisa; Shaffer, Christian M.; Karnes, Jason H.; Stein, C. Michael; Phillips, Elizabeth; Hebbring, Scott J.; Brilliant, Murray H.; Mayer, John; Ye, Zhan; Roden, Dan M.; Denny, Joshua C.

    2016-01-01

    We hypothesized that generalized linear mixed models (GLMMs), which estimate the additive genetic variance underlying phenotype variability, would facilitate rapid characterization of clinical phenotypes from an electronic health record. We evaluated 1,288 phenotypes in 29,349 subjects of European ancestry with single-nucleotide polymorphism (SNP) genotyping on the Illumina Exome Beadchip. We show that genetic liability estimates are primarily driven by SNPs identified by prior genome-wide association studies and SNPs within the human leukocyte antigen (HLA) region. We identify 44 (false discovery rate q<0.05) phenotypes associated with HLA SNP variation and show that hypothyroidism is genetically correlated with Type I diabetes (rG=0.31, s.e. 0.12, P=0.003). We also report novel SNP associations for hypothyroidism near HLA-DQA1/HLA-DQB1 at rs6906021 (combined odds ratio (OR)=1.2 (95% confidence interval (CI): 1.1–1.2), P=9.8 × 10−11) and for polymyalgia rheumatica near C6orf10 at rs6910071 (OR=1.5 (95% CI: 1.3–1.6), P=1.3 × 10−10). Phenome-wide application of GLMMs identifies phenotypes with important genetic drivers, and focusing on these phenotypes can identify novel genetic associations. PMID:27109359

  9. Stress-Driven Selection of Novel Phenotypes

    NASA Technical Reports Server (NTRS)

    Fox, George E.; Stepaov, Victor G.; Liu, Yamei

    2011-01-01

    A process has been developed that can confer novel properties, such as metal resistance, to a host bacterium. This same process can also be used to produce RNAs and peptides that have novel properties, such as the ability to bind particular compounds. It is inherent in the method that the peptide or RNA will behave as expected in the target organism. Plasmid-born mini-gene libraries coding for either a population of combinatorial peptides or stable, artificial RNAs carrying random inserts are produced. These libraries, which have no bias towards any biological function, are used to transform the organism of interest and to serve as an initial source of genetic variation for stress-driven evolution. The transformed bacteria are propagated under selective pressure in order to obtain variants with the desired properties. The process is highly distinct from in vitro methods because the variants are selected in the context of the cell while it is experiencing stress. Hence, the selected peptide or RNA will, by definition, work as expected in the target cell as the cell adapts to its presence during the selection process. Once the novel gene, which produces the sought phenotype, is obtained, it can be transferred to the main genome to increase the genetic stability in the organism. Alternatively, the cell line can be used to produce novel RNAs or peptides with selectable properties in large quantity for separate purposes. The system allows for easy, large-scale purification of the RNAs or peptide products. The process has been reduced to practice by imposing sub-inhibitory concentrations of NiCl2 on cells of the bacterium Escherichia coli that were transformed separately with the peptide library and RNA library. The evolved resistant clones were isolated, and sequences of the selected mini-gene variants were established. Clones resistant to NiCl2 were found to carry identical plasmid variants with a functional mini-gene that specifically conferred significant nickel

  10. Phenotypes of apolipoprotein B and apolipoprotein E after liver transplantation.

    PubMed Central

    Linton, M F; Gish, R; Hubl, S T; Bütler, E; Esquivel, C; Bry, W I; Boyles, J K; Wardell, M R; Young, S G

    1991-01-01

    Apolipoprotein (apo) E and the two B apolipoproteins, apoB48 and apoB100, are important proteins in human lipoprotein metabolism. Commonly occurring polymorphisms in the genes for apoE and apoB result in amino acid substitutions that produce readily detectable phenotypic differences in these proteins. We studied changes in apoE and apoB phenotypes before and after liver transplantation to gain new insights into apolipoprotein physiology. In all 29 patients that we studied, the postoperative serum apoE phenotype of the recipient, as assessed by isoelectric focusing, converted virtually completely to that of the donor, providing evidence that greater than 90% of the apoE in the plasma is synthesized by the liver. In contrast, the cerebrospinal fluid apoE phenotype did not change to the donor's phenotype after liver transplantation, indicating that most of the apoE in CSF cannot be derived from the plasma pool and therefore must be synthesized locally. The apoB100 phenotype (assessed with immunoassays using monoclonal antibody MB19, an antibody that detects a two-allele polymorphism in apoB) invariably converted to the phenotype of the donor. In four normolipidemic patients, we determined the MB19 phenotype of both the apoB100 and apoB48 in the "chylomicron fraction" isolated from plasma 3 h after a fat-rich meal. Interestingly, the apoB100 in the chylomicron fraction invariably had the phenotype of the donor, indicating that the vast majority of the large, triglyceride-rich apoB100-containing lipoproteins that appear in the plasma after a fat-rich meal are actually VLDL of hepatic origin. The MB19 phenotype of the apoB48 in the plasma chylomicron fraction did not change after liver transplantation, indicating that almost all of the apoB48 in plasma chylomicrons is derived from the intestine. These results were consistent with our immunocytochemical studies on intestinal biopsy specimens of organ donors; using apoB-specific monoclonal antibodies, we found evidence for

  11. Genotype–phenotype associations: substitution models to detect evolutionary associations between phenotypic variables and genotypic evolutionary rate

    PubMed Central

    O'Connor, Timothy D.; Mundy, Nicholas I.

    2009-01-01

    Motivation: Mapping between genotype and phenotype is one of the primary goals of evolutionary genetics but one that has received little attention at the interspecies level. Recent developments in phylogenetics and statistical modelling have typically been used to examine molecular and phenotypic evolution separately. We have used this background to develop phylogenetic substitution models to test for associations between evolutionary rate of genotype and phenotype. We do this by creating hybrid rate matrices between genotype and phenotype. Results: Simulation results show our models to be accurate in detecting genotype–phenotype associations and robust for various factors that typically affect maximum likelihood methods, such as number of taxa, level of relevant signal, proportion of sites affected and length of evolutionary divergence. Further, simulations show that our method is robust to homogeneity assumptions. We apply the models to datasets of male reproductive system genes in relation to mating systems of primates. We show that evolution of semenogelin II is significantly associated with mating systems whereas two negative control genes (cytochrome b and peptidase inhibitor 3) show no significant association. This provides the first hybrid substitution model of which we are aware to directly test the association between genotype and phenotype using a phylogenetic framework. Availability: Perl and HYPHY scripts are available upon request from the authors. Contact: to252@cam.ac.uk Supplementary information: Supplementary data are available at Bioinformatics online. PMID:19478022

  12. The phenotypic difference discards sib-pair QTL linkage information

    SciTech Connect

    Wright, F.A. |

    1997-03-01

    Kruglyak and Lander provide an important synthesis of methods for (IBD) sib-pair linkage mapping, with an emphasis on the use of complete multipoint inheritance information for each sib pair. These procedures are implemented in the computer program MAPMAKER/SIBS, which performs interval mapping for dichotomous and quantitative traits. The authors present three methods for mapping quantitative trait loci (QTLs): a variant of the commonly used Haseman-Elston regression approach, a maximum-likelihood procedure involving variance components, and a rank-based nonparametric procedure. These approaches and related work use the magnitude of the difference in the sibling phenotype values for each sib pair as the observation for analysis. Linkage is detected if siblings sharing more alleles IBD have similar phenotypes (i.e., a small difference in the phenotype values), while siblings sharing fewer alleles IBD have less similar phenotypes. Such techniques have been used to detect linkage for a number of quantitative traits. However, the exclusive reliance on the phenotypic differences may be due in large part to historical inertia. A likelihood argument is presented here to show that, under certain classical assumptions, the phenotypic differences do not contain the full likelihood information for QTL mapping. Furthermore, considerable gains in power to detect linkage can be achieved with an expanded likelihood model. The development here is related to previous work, which incorporates the full set of phenotypic data using likelihood and robust quasi-likelihood methods. The purpose of this letter is not to endorse a particular approach but to spur research in alternative and perhaps more powerful linkage tests. 17 refs.

  13. Behavioral idiosyncrasy reveals genetic control of phenotypic variability

    PubMed Central

    Ayroles, Julien F.; Buchanan, Sean M.; O’Leary, Chelsea; Skutt-Kakaria, Kyobi; Grenier, Jennifer K.; Clark, Andrew G.; Hartl, Daniel L.; de Bivort, Benjamin L.

    2015-01-01

    Quantitative genetics has primarily focused on describing genetic effects on trait means and largely ignored the effect of alternative alleles on trait variability, potentially missing an important axis of genetic variation contributing to phenotypic differences among individuals. To study the genetic effects on individual-to-individual phenotypic variability (or intragenotypic variability), we used Drosophila inbred lines and measured the spontaneous locomotor behavior of flies walking individually in Y-shaped mazes, focusing on variability in locomotor handedness, an assay optimized to measure variability. We discovered that some lines had consistently high levels of intragenotypic variability among individuals, whereas lines with low variability behaved as although they tossed a coin at each left/right turn decision. We demonstrate that the degree of variability is itself heritable. Using a genome-wide association study (GWAS) for the degree of intragenotypic variability as the phenotype across lines, we identified several genes expressed in the brain that affect variability in handedness without affecting the mean. One of these genes, Ten-a, implicates a neuropil in the central complex of the fly brain as influencing the magnitude of behavioral variability, a brain region involved in sensory integration and locomotor coordination. We validated these results using genetic deficiencies, null alleles, and inducible RNAi transgenes. Our study reveals the constellation of phenotypes that can arise from a single genotype and shows that different genetic backgrounds differ dramatically in their propensity for phenotypic variabililty. Because traditional mean-focused GWASs ignore the contribution of variability to overall phenotypic variation, current methods may miss important links between genotype and phenotype. PMID:25953335

  14. Phenotype standardization for drug-induced kidney disease.

    PubMed

    Mehta, Ravindra L; Awdishu, Linda; Davenport, Andrew; Murray, Patrick T; Macedo, Etienne; Cerda, Jorge; Chakaravarthi, Raj; Holden, Arthur L; Goldstein, Stuart L

    2015-08-01

    Drug-induced kidney disease is a frequent cause of renal dysfunction; however, there are no standards to identify and characterize the spectrum of these disorders. We convened a panel of international, adult and pediatric, nephrologists and pharmacists to develop standardized phenotypes for drug-induced kidney disease as part of the phenotype standardization project initiated by the International Serious Adverse Events Consortium. We propose four phenotypes of drug-induced kidney disease based on clinical presentation: acute kidney injury, glomerular, tubular, and nephrolithiasis, along with the primary and secondary clinical criteria to support the phenotype definition, and a time course based on the KDIGO/AKIN definitions of acute kidney injury, acute kidney disease, and chronic kidney disease. Establishing causality in drug-induced kidney disease is challenging and requires knowledge of the biological plausibility for the specific drug, mechanism of injury, time course, and assessment of competing risk factors. These phenotypes provide a consistent framework for clinicians, investigators, industry, and regulatory agencies to evaluate drug nephrotoxicity across various settings. We believe that this is the first step to recognizing drug-induced kidney disease and developing strategies to prevent and manage this condition. PMID:25853333

  15. Open biomedical pluralism: formalising knowledge about breast cancer phenotypes

    PubMed Central

    2012-01-01

    We demonstrate a heterogeneity of representation types for breast cancer phenotypes and stress that the characterisation of a tumour phenotype often includes parameters that go beyond the representation of a corresponding empirically observed tumour, thus reflecting significant functional features of the phenotypes as well as epistemic interests that drive the modes of representation. Accordingly, the represented features of cancer phenotypes function as epistemic vehicles aiding various classifications, explanations, and predictions. In order to clarify how the plurality of epistemic motivations can be integrated on a formal level, we give a distinction between six categories of human agents as individuals and groups focused around particular epistemic interests. We analyse the corresponding impact of these groups and individuals on representation types, mapping and reasoning scenarios. Respecting the plurality of representations, related formalisms, expressivities and aims, as they are found across diverse scientific communities, we argue for a pluralistic ontology integration. Moreover, we discuss and illustrate to what extent such a pluralistic integration is supported by the distributed ontology language DOL, a meta-language for heterogeneous ontology representation that is currently under standardisation as ISO WD 17347 within the OntoIOp (Ontology Integration and Interoperability) activity of ISO/TC 37/SC 3. We particularly illustrate how DOL supports representations of parthood on various levels of logical expressivity, mapping of terms, merging of ontologies, as well as non-monotonic extensions based on circumscription allowing a transparent formal modelling of the normal/abnormal distinction in phenotypes. PMID:23046572

  16. Emergence of phenotype switching through continuous and discontinuous evolutionary transitions.

    PubMed

    Patra, Pintu; Klumpp, Stefan

    2015-07-01

    Bacterial persistence (phenotypic tolerance to antibiotics) provides a prime example of bet-hedging, where normally growing cells generate slow-growing but antibiotic-tolerant persister cells to survive through periods of exposure to antibiotics. The population dynamics of persistence is explained by a phenotype switching mechanism that allows individual cells to switch between these different cellular states with different environmental sensitivities. Here, we perform a theoretical study based on an exact solution for the case of a periodic variation of the environment to address how phenotype switching emerges and under what conditions switching is or is not beneficial for long-time growth. Specifically we report a bifurcation through which a fitness maximum and minimum emerge above a threshold in the duration of exposure to the antibiotic. Only above this threshold, the optimal phenotype switching rates are adjusted to the time scales of the environment, as emphasized by previous theoretical studies, while below the threshold a non-switching population is fitter than a switching one. The bifurcation can be of different type, depending on how the phenotype switching rates are allowed to vary. If the switching rates for both directions of the switch are coupled, the transition is discontinuous and results in evolutionary hysteresis, which we confirm with a stochastic simulation. If the switching rates vary individually, a continuous transition is obtained and no hysteresis is found. We discuss how both scenarios can be linked to changes in the underlying molecular networks. PMID:26020274

  17. Mutations and phenotype in isolated glycerol kinase deficiency.

    PubMed Central

    Walker, A. P.; Muscatelli, F.; Stafford, A. N.; Chelly, J.; Dahl, N.; Blomquist, H. K.; Delanghe, J.; Willems, P. J.; Steinmann, B.; Monaco, A. P.

    1996-01-01

    We demonstrate that isolated glycerol kinase (GK) deficiency in three families results from mutation of the Xp21 GK gene. GK mutations were detected in four patients with widely differing phenotypes. Patient 1 had a splice-site mutation causing premature termination. His general health was good despite absent GK activity, indicating that isolated GK deficiency can be silent. Patient 2 had GK deficiency and a severe phenotype involving psychomotor retardation and growth delay, bone dysplasia, and seizures, similar to the severe phenotype of one of the first described cases of GK deficiency. His younger brother, patient 3, also had GK deficiency, but so far his development has been normal. GK exon 17 was deleted in both brothers, implicating additional factors in causation of the severe phenotype of patient 2. Patient 4 had both GK deficiency with mental retardation and a GK missense mutation (D440V). Possible explanations for the phenotypic variation of these four patients include ascertainment bias; metabolic or environmental stress as a precipitating factor in revealing GK-related changes, as has previously been described in juvenile GK deficiency; and interactions with functional polymorphisms in other genes that alter the effect of GK deficiency on normal development. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:8651297

  18. Mixed Phenotypic Acute Leukemia Presenting as Mediastinal Mass-2 Cases.

    PubMed

    Vardhan, Rig; Kotwal, Jyoti; Ganguli, Prosenjit; Ahmed, Rehan; Sharma, Ajay; Singh, Jasjit

    2016-06-01

    Mixed phenotype acute leukemia symbolizes a very small subset of acute leukemia that simply cannot be allocated as lymphoid or myeloid lineage. The 2008 World Health Organisation classification established stringent standard for diagnosis of mixed phenotype acute leukemia, accentuating myeloperoxidase for myeloid lineage, cytoplasmic CD3 for T lineage and CD19 with other B markers for B lineage obligation. Mixed phenotype leukemia is rare and 3-5 % of acute leukmias of all age groups, is associated with poor outcome with overall survival of 18 months. We wish to present two cases of mixed phenotypic acute leukemia who presented with mediastinal masses, were suspected to be T cell lymphoma/leukemia clinically and radiologically. In one case, tissue diagnosis was given as lymphoma for which treatment was given. These cases show that patients diagnosed as lymphoma on histopathology can be cases of mixed phenotype acute leukemia and varying specific treatment protocols and follow up are required. Awareness of these entities will help in proper diagnosis and treatment. PMID:27408360

  19. Strategy revealing phenotypic differences among synthetic oscillator designs.

    PubMed

    Lomnitz, Jason G; Savageau, Michael A

    2014-09-19

    Considerable progress has been made in identifying and characterizing the component parts of genetic oscillators, which play central roles in all organisms. Nonlinear interaction among components is sufficiently complex that mathematical models are required to elucidate their elusive integrated behavior. Although natural and synthetic oscillators exhibit common architectures, there are numerous differences that are poorly understood. Utilizing synthetic biology to uncover basic principles of simpler circuits is a way to advance understanding of natural circadian clocks and rhythms. Following this strategy, we address the following questions: What are the implications of different architectures and molecular modes of transcriptional control for the phenotypic repertoire of genetic oscillators? Are there designs that are more realizable or robust? We compare synthetic oscillators involving one of three architectures and various combinations of the two modes of transcriptional control using a methodology that provides three innovations: a rigorous definition of phenotype, a procedure for deconstructing complex systems into qualitatively distinct phenotypes, and a graphical representation for illuminating the relationship between genotype, environment, and the qualitatively distinct phenotypes of a system. These methods provide a global perspective on the behavioral repertoire, facilitate comparisons of alternatives, and assist the rational design of synthetic gene circuitry. In particular, the results of their application here reveal distinctive phenotypes for several designs that have been studied experimentally as well as a best design among the alternatives that has yet to be constructed and tested. PMID:25019938

  20. Endocrine regulation of predator-induced phenotypic plasticity.

    PubMed

    Dennis, Stuart R; LeBlanc, Gerald A; Beckerman, Andrew P

    2014-11-01

    Elucidating the developmental and genetic control of phenotypic plasticity remains a central agenda in evolutionary ecology. Here, we investigate the physiological regulation of phenotypic plasticity induced by another organism, specifically predator-induced phenotypic plasticity in the model ecological and evolutionary organism Daphnia pulex. Our research centres on using molecular tools to test among alternative mechanisms of developmental control tied to hormone titres, receptors and their timing in the life cycle. First, we synthesize detail about predator-induced defenses and the physiological regulation of arthropod somatic growth and morphology, leading to a clear prediction that morphological defences are regulated by juvenile hormone and life-history plasticity by ecdysone and juvenile hormone. We then show how a small network of genes can differentiate phenotype expression between the two primary developmental control pathways in arthropods: juvenoid and ecdysteroid hormone signalling. Then, by applying an experimental gradient of predation risk, we show dose-dependent gene expression linking predator-induced plasticity to the juvenoid hormone pathway. Our data support three conclusions: (1) the juvenoid signalling pathway regulates predator-induced phenotypic plasticity; (2) the hormone titre (ligand), rather than receptor, regulates predator-induced developmental plasticity; (3) evolution has favoured the harnessing of a major, highly conserved endocrine pathway in arthropod development to regulate the response to cues about changing environments (risk) from another organism (predator). PMID:25284611

  1. Emergence of phenotype switching through continuous and discontinuous evolutionary transitions

    NASA Astrophysics Data System (ADS)

    Patra, Pintu; Klumpp, Stefan

    2015-07-01

    Bacterial persistence (phenotypic tolerance to antibiotics) provides a prime example of bet-hedging, where normally growing cells generate slow-growing but antibiotic-tolerant persister cells to survive through periods of exposure to antibiotics. The population dynamics of persistence is explained by a phenotype switching mechanism that allows individual cells to switch between these different cellular states with different environmental sensitivities. Here, we perform a theoretical study based on an exact solution for the case of a periodic variation of the environment to address how phenotype switching emerges and under what conditions switching is or is not beneficial for long-time growth. Specifically we report a bifurcation through which a fitness maximum and minimum emerge above a threshold in the duration of exposure to the antibiotic. Only above this threshold, the optimal phenotype switching rates are adjusted to the time scales of the environment, as emphasized by previous theoretical studies, while below the threshold a non-switching population is fitter than a switching one. The bifurcation can be of different type, depending on how the phenotype switching rates are allowed to vary. If the switching rates for both directions of the switch are coupled, the transition is discontinuous and results in evolutionary hysteresis, which we confirm with a stochastic simulation. If the switching rates vary individually, a continuous transition is obtained and no hysteresis is found. We discuss how both scenarios can be linked to changes in the underlying molecular networks.

  2. Natural Variation of Model Mutant Phenotypes in Ciona intestinalis

    PubMed Central

    Brown, Euan R.; Leccia, Nicola I.; Squarzoni, Paola; Tarallo, Raffaella; Alfano, Christian; Caputi, Luigi; D'Ambrosio, Palmira; Daniele, Paola; D'Aniello, Enrico; D'Aniello, Salvatore; Maiella, Sylvie; Miraglia, Valentina; Russo, Monia Teresa; Sorrenti, Gerarda; Branno, Margherita; Cariello, Lucio; Cirino, Paola; Locascio, Annamaria; Spagnuolo, Antonietta; Zanetti, Laura; Ristoratore, Filomena

    2008-01-01

    Background The study of ascidians (Chordata, Tunicata) has made a considerable contribution to our understanding of the origin and evolution of basal chordates. To provide further information to support forward genetics in Ciona intestinalis, we used a combination of natural variation and neutral population genetics as an approach for the systematic identification of new mutations. In addition to the significance of developmental variation for phenotype-driven studies, this approach can encompass important implications in evolutionary and population biology. Methodology/Principal Findings Here, we report a preliminary survey for naturally occurring mutations in three geographically interconnected populations of C. intestinalis. The influence of historical, geographical and environmental factors on the distribution of abnormal phenotypes was assessed by means of 12 microsatellites. We identified 37 possible mutant loci with stereotyped defects in embryonic development that segregate in a way typical of recessive alleles. Local populations were found to differ in genetic organization and frequency distribution of phenotypic classes. Conclusions/Significance Natural genetic polymorphism of C. intestinalis constitutes a valuable source of phenotypes for studying embryonic development in ascidians. Correlating genetic structure and the occurrence of abnormal phenotypes is a crucial focus for understanding the selective forces that shape natural finite populations, and may provide insights of great importance into the evolutionary mechanisms that generate animal diversity. PMID:18523552

  3. Epigenetic reversion of breast carcinoma phenotype is accompaniedby DNA sequestration

    SciTech Connect

    Sandal, Tone; Valyi-Nagy, Klara; Spencer, Virginia A.; Folberg,Robert; Bissell, Mina J.; Maniotis, Andrew J.

    2006-07-19

    The importance of microenvironment and context in regulation of tissue-specific genes is finally well established. DNA exposure to, or sequestration from, nucleases can be used to detect differences in higher order chromatin structure in intact cells without disturbing cellular or tissue architecture. To investigate the relationship between chromatin organization and tumor phenotype, we utilized an established 3-D assay where normal and malignant human breast cells can be easily distinguished by the morphology of the structures they make (acinus-like vs tumor-like, respectively). We show that these phenotypes can be distinguished also by sensitivity to AluI digestion where the malignant cells are resistant to digestion relative to non-malignant cells. Reversion of the T4-2 breast cancer cells by either cAMP analogs, or a phospatidylinositol 3-kinase (P13K) inhibitor not only reverted the phenotype, but also the chromatin sensitivity to AluI. By using different cAMP-analogs, we show that the cAMP-induced phenotypic reversion, polarization, and shift in DNA organization act through a cAMP-dependent-protein-kinase A-coupled signaling pathway. Importantly, inhibitory antibody to fibronectin also reverted the malignant phenotype, polarized the acini, and changed chromatin sequestration. These experiments show not only that modifying the tumor microenvironment can alter the organization of tumor cells but also that architecture of the tissues and the global chromatin organization are coupled and yet highly plastic.

  4. Effect of cryopreservation protocols on the phenotypic stability of yeast.

    PubMed

    Gujjari, Pushpa; Muldrow, Tamara; Zhou, Jianlong Jim

    2010-01-01

    Eight cryopreservation protocols were assessed for their effects on the viability and phenotypic stability of the yeast Saccharomyces cerevisiae during a five-year study. It is found that viability and phenotypic features have remained largely unchanged when the yeast was preserved in glycerol, dimethyl sulphoxide, or sucrose at -80 degrees C or in liquid nitrogen. When sorbitol was used as a cryoprotectant, yeast cells frozen and stored at -80 degrees C manifested great decreases in viability after six months in storage and concomitantly large fluctuations in the rate of the trpl auxotrophic reversion. This phenotypic reversion was stable passage after passage. Such a degree of phenotypic fluctuations, however, was not observed for yeast cells preserved in the same sorbitol solution that went through a controlled freezing program and were subsequently stored in liquid nitrogen. These results indicate that some combinations of cryoprotective agent, freezing program, and storage temperature disturb biomaterials more profoundly during cryopreservation and imply a genetic basis of this phenotypic change. PMID:20919455

  5. Refining mimicry: phenotypic variation tracks the local optimum.

    PubMed

    Mérot, Claire; Le Poul, Yann; Théry, Marc; Joron, Mathieu

    2016-07-01

    Müllerian mimicry between chemically defended preys is a textbook example of natural selection favouring phenotypic convergence onto a shared warning signal. Studies of mimicry have concentrated on deciphering the ecological and genetic underpinnings of dramatic switches in mimicry association, producing a well-known mosaic distribution of mimicry patterns across geography. However, little is known about the accuracy of resemblance between natural comimics when the local phenotypic optimum varies. In this study, using analyses of wing shape, pattern and hue, we quantify multimodal phenotypic similarity between butterfly comimics sharing the so-called postman pattern in different localities with varying species composition. We show that subtle but consistent variation between populations of the localized species, Heliconius timareta thelxinoe, enhance resemblance to the abundant comimics which drive the mimicry in each locality. Those results suggest that rarer comimics track the changes in the phenotypic optimum caused by gradual changes in the composition of the mimicry community, providing insights into the process by which intraspecific diversity of mimetic pattern may arise. Furthermore, our results suggest a multimodal evolution of similarity, with coordinated convergence in different features of the phenotype such as wing outline, pattern and hue. Finally, multilocus genotyping allows estimating local hybridization rates between H. timareta and comimic H. melpomene in different populations, raising the hypothesis that mimicry refinement between closely related comimics may be enhanced by adaptive introgression at loci modifying the accuracy of resemblance. PMID:27003742

  6. Secondary contact seeds phenotypic novelty in cichlid fishes.

    PubMed

    Nichols, Paul; Genner, Martin J; van Oosterhout, Cock; Smith, Alan; Parsons, Paul; Sungani, Harold; Swanstrom, Jennifer; Joyce, Domino A

    2015-01-01

    Theory proposes that genomic admixture between formerly reproductively isolated populations can generate phenotypic novelty for selection to act upon. Secondary contact may therefore be a significant promoter of phenotypic novelty that allows species to overcome environmental challenges and adapt to novel environments, including during adaptive radiation. To date, this has largely been considered from the perspective of interspecific hybridization at contact zones. However, it is also possible that this process occurs more commonly between natural populations of a single species, and thus its importance in adaptive evolution may have been underestimated. In this study, we tested the consequences of genomic introgression during apparent secondary contact between phenotypically similar lineages of the riverine cichlid fish Astatotilapia calliptera. We provide population genetic evidence of a secondary contact zone in the wild, and then demonstrate using mate-choice experiments that both lineages can reproduce together successfully in laboratory conditions. Finally, we show that genomically admixed individuals display extreme phenotypes not observed in the parental lineages. Collectively, the evidence shows that secondary contact can drive the evolution of phenotypic novelty, suggesting that pulses of secondary contact may repeatedly seed genetic novelty, which when coupled with ecological opportunity could promote rapid adaptive evolution in natural circumstances. PMID:25392475

  7. Cellular phenotype database: a repository for systems microscopy data

    PubMed Central

    Kirsanova, Catherine; Brazma, Alvis; Rustici, Gabriella; Sarkans, Ugis

    2015-01-01

    Motivation: The Cellular Phenotype Database (CPD) is a repository for data derived from high-throughput systems microscopy studies. The aims of this resource are: (i) to provide easy access to cellular phenotype and molecular localization data for the broader research community; (ii) to facilitate integration of independent phenotypic studies by means of data aggregation techniques, including use of an ontology and (iii) to facilitate development of analytical methods in this field. Results: In this article we present CPD, its data structure and user interface, propose a minimal set of information describing RNA interference experiments, and suggest a generic schema for management and aggregation of outputs from phenotypic or molecular localization experiments. The database has a flexible structure for management of data from heterogeneous sources of systems microscopy experimental outputs generated by a variety of protocols and technologies and can be queried by gene, reagent, gene attribute, study keywords, phenotype or ontology terms. Availability and implementation: CPD is developed as part of the Systems Microscopy Network of Excellence and is accessible at http://www.ebi.ac.uk/fg/sym. Contact: jes@ebi.ac.uk or ugis@ebi.ac.uk Supplementary information: Supplementary data are available at Bioinformatics online. PMID:25861964

  8. Towards recommendations for metadata and data handling in plant phenotyping.

    PubMed

    Krajewski, Paweł; Chen, Dijun; Ćwiek, Hanna; van Dijk, Aalt D J; Fiorani, Fabio; Kersey, Paul; Klukas, Christian; Lange, Matthias; Markiewicz, Augustyn; Nap, Jan Peter; van Oeveren, Jan; Pommier, Cyril; Scholz, Uwe; van Schriek, Marco; Usadel, Björn; Weise, Stephan

    2015-09-01

    Recent methodological developments in plant phenotyping, as well as the growing importance of its applications in plant science and breeding, are resulting in a fast accumulation of multidimensional data. There is great potential for expediting both discovery and application if these data are made publicly available for analysis. However, collection and storage of phenotypic observations is not yet sufficiently governed by standards that would ensure interoperability among data providers and precisely link specific phenotypes and associated genomic sequence information. This lack of standards is mainly a result of a large variability of phenotyping protocols, the multitude of phenotypic traits that are measured, and the dependence of these traits on the environment. This paper discusses the current situation of standardization in the area of phenomics, points out the problems and shortages, and presents the areas that would benefit from improvement in this field. In addition, the foundations of the work that could revise the situation are proposed, and practical solutions developed by the authors are introduced. PMID:26044092

  9. Echocardiographic diagnosis of the different phenotypes of hypertrophic cardiomyopathy.

    PubMed

    Parato, Vito Maurizio; Antoncecchi, Valeria; Sozzi, Fabiola; Marazia, Stefania; Zito, Annapaola; Maiello, Maria; Palmiero, Pasquale

    2016-01-01

    Hypertrophic Cardiomyopathy (HCM) is an inherited cardiovascular disorder of great genetic heterogeneity and has a prevalence of 0.1 - 0.2 % in the general population. Several hundred mutations in more than 27 genes, most of which encode sarcomeric structures, are associated with the HCM phenotype. Then, HCM is an extremely heterogeneous disease and several phenotypes have been described over the years. Originally only two phenotypes were considered, a more common, obstructive type (HOCM, 70 %) and a less common, non-obstructive type (HNCM, 30 %) (Maron BJ, et al. Am J Cardiol 48:418 -28, 1981). Wigle et al. (Circ 92:1680-92, 1995) considered three types of functional phenotypes: subaortic obstruction, midventricular obstruction and cavity obliteration. A leader american working group suggested that HCM should be defined genetically and not morphologically (Maron BJ, et al. Circ 113:1807-16, 2006). The European Society of Cardiology Working Group on Myocardial and Pericardial Diseases recommended otherwise a morphological classification (Elliott P, et al. Eur Heart J 29:270-6, 2008). Echocardiography is still the principal tool for the diagnosis, prognosis and clinical management of HCM. It is well known that the echocardiographic picture may have a clinical and prognostic impact. For this reason, in this article, we summarize the state of the art regarding the echocardiographic pattern of the HCM phenotypes and its impact on clinical course and prognosis. PMID:27519172

  10. Secondary contact seeds phenotypic novelty in cichlid fishes

    PubMed Central

    Nichols, Paul; Genner, Martin J.; van Oosterhout, Cock; Smith, Alan; Parsons, Paul; Sungani, Harold; Swanstrom, Jennifer; Joyce, Domino A.

    2015-01-01

    Theory proposes that genomic admixture between formerly reproductively isolated populations can generate phenotypic novelty for selection to act upon. Secondary contact may therefore be a significant promoter of phenotypic novelty that allows species to overcome environmental challenges and adapt to novel environments, including during adaptive radiation. To date, this has largely been considered from the perspective of interspecific hybridization at contact zones. However, it is also possible that this process occurs more commonly between natural populations of a single species, and thus its importance in adaptive evolution may have been underestimated. In this study, we tested the consequences of genomic introgression during apparent secondary contact between phenotypically similar lineages of the riverine cichlid fish Astatotilapia calliptera. We provide population genetic evidence of a secondary contact zone in the wild, and then demonstrate using mate-choice experiments that both lineages can reproduce together successfully in laboratory conditions. Finally, we show that genomically admixed individuals display extreme phenotypes not observed in the parental lineages. Collectively, the evidence shows that secondary contact can drive the evolution of phenotypic novelty, suggesting that pulses of secondary contact may repeatedly seed genetic novelty, which when coupled with ecological opportunity could promote rapid adaptive evolution in natural circumstances. PMID:25392475

  11. Novel phenotypes of Escherichia coli tat mutants revealed by global gene expression and phenotypic analysis.

    PubMed

    Ize, Bérengère; Porcelli, Ida; Lucchini, Sacha; Hinton, Jay C; Berks, Ben C; Palmer, Tracy

    2004-11-12

    The Tat protein export system serves to export folded proteins harboring an N-terminal twin arginine signal peptide across the cytoplasmic membrane. In this study, we have used gene expression profiling of Escherichia coli supported by phenotypic analysis to investigate how cells respond to a defect in the Tat pathway. Previous work has demonstrated that strains mutated in genes encoding essential Tat pathway components are defective in the integrity of their cell envelope because of the mislocalization of two amidases involved in cell wall metabolism (Ize, B., Stanley, N. R., Buchanan, G., and Palmer, T. (2003) Mol. Microbiol. 48, 1183-1193). To distinguish between genes that are differentially expressed specifically because of the cell envelope defect and those that result from other effects of the tatC deletion, we also analyzed two different transposon mutants of the DeltatatC strain that have their outer membrane integrity restored. Approximately 50% of the genes that were differentially expressed in the tatC mutant are linked to the envelope defect, with the products of many of these genes involved in self-defense or protection mechanisms, including the production of exopolysaccharide. Among the changes that were not explicitly linked to envelope integrity, we characterized a role for the Tat system in iron acquisition and copper homeostasis. Finally, we have demonstrated that overproduction of the Tat substrate SufI saturates the Tat translocon and produces effects on global gene expression that are similar to those resulting from the DeltatatC mutation. PMID:15347649

  12. Root Traits and Phenotyping Strategies for Plant Improvement.

    PubMed

    Paez-Garcia, Ana; Motes, Christy M; Scheible, Wolf-Rüdiger; Chen, Rujin; Blancaflor, Elison B; Monteros, Maria J

    2015-01-01

    Roots are crucial for nutrient and water acquisition and can be targeted to enhance plant productivity under a broad range of growing conditions. A current challenge for plant breeding is the limited ability to phenotype and select for desirable root characteristics due to their underground location. Plant breeding efforts aimed at modifying root traits can result in novel, more stress-tolerant crops and increased yield by enhancing the capacity of the plant for soil exploration and, thus, water and nutrient acquisition. Available approaches for root phenotyping in laboratory, greenhouse and field encompass simple agar plates to labor-intensive root digging (i.e., shovelomics) and soil boring methods, the construction of underground root observation stations and sophisticated computer-assisted root imaging. Here, we summarize root architectural traits relevant to crop productivity, survey root phenotyping strategies and describe their advantages, limitations and practical value for crop and forage breeding programs. PMID:27135332

  13. Phenotyping for drought tolerance of crops in the genomics era

    PubMed Central

    Tuberosa, Roberto

    2012-01-01

    Improving crops yield under water-limited conditions is the most daunting challenge faced by breeders. To this end, accurate, relevant phenotyping plays an increasingly pivotal role for the selection of drought-resilient genotypes and, more in general, for a meaningful dissection of the quantitative genetic landscape that underscores the adaptive response of crops to drought. A major and universally recognized obstacle to a more effective translation of the results produced by drought-related studies into improved cultivars is the difficulty in properly phenotyping in a high-throughput fashion in order to identify the quantitative trait loci that govern yield and related traits across different water regimes. This review provides basic principles and a broad set of references useful for the management of phenotyping practices for the study and genetic dissection of drought tolerance and, ultimately, for the release of drought-tolerant cultivars. PMID:23049510

  14. Breath tests to phenotype drug disposition in oncology.

    PubMed

    Opdam, Frans L; Modak, Anil S; Gelderblom, Hans; Guchelaar, Henk-Jan

    2013-11-01

    Breath tests (BTs) have been investigated as diagnostic tools to phenotype drug disposition in cancer patients in the pursuit to individualize drug treatment. The choice of the right phenotype probe is crucial and depends on the metabolic pathway of the anticancer agent of interest. BTs using orally or intravenously administered selective non-radioactive (13)C-labeled probes to non-invasively evaluate dihydropyrimidine dehydrogenase, cytochrome P450 (CYP) 3A4, and CYP2D6 enzyme activity have been published. Clinically, a (13)C-dextromethorphan BT to predict endoxifen levels in breast cancer patients and a (13)C-uracil BT to predict fluoropyrimidine toxicity in colorectal cancer patients are most promising. However, the clinical benefit and cost effectiveness of these phenotype BTs need to be determined in order to make the transition from an experimental setting to clinical practice as companion diagnostic tests. PMID:23868281

  15. Systematic discovery of nonobvious human disease models through orthologous phenotypes.

    PubMed

    McGary, Kriston L; Park, Tae Joo; Woods, John O; Cha, Hye Ji; Wallingford, John B; Marcotte, Edward M

    2010-04-01

    Biologists have long used model organisms to study human diseases, particularly when the model bears a close resemblance to the disease. We present a method that quantitatively and systematically identifies nonobvious equivalences between mutant phenotypes in different species, based on overlapping sets of orthologous genes from human, mouse, yeast, worm, and plant (212,542 gene-phenotype associations). These orthologous phenotypes, or phenologs, predict unique genes associated with diseases. Our method suggests a yeast model for angiogenesis defects, a worm model for breast cancer, mouse models of autism, and a plant model for the neural crest defects associated with Waardenburg syndrome, among others. Using these models, we show that SOX13 regulates angiogenesis, and that SEC23IP is a likely Waardenburg gene. Phenologs reveal functionally coherent, evolutionarily conserved gene networks-many predating the plant-animal divergence-capable of identifying candidate disease genes. PMID:20308572

  16. Mapping genes with longitudinal phenotypes via Bayesian posterior probabilities.

    PubMed

    Musolf, Anthony; Nato, Alejandro Q; Londono, Douglas; Zhou, Lisheng; Matise, Tara C; Gordon, Derek

    2014-01-01

    Most association studies focus on disease risk, with less attention paid to disease progression or severity. These phenotypes require longitudinal data. This paper presents a new method for analyzing longitudinal data to map genes in both population-based and family-based studies. Using simulated systolic blood pressure measurements obtained from Genetic Analysis Workshop 18, we cluster the phenotype data into trajectory subgroups. We then use the Bayesian posterior probability of being in the high subgroup as a quantitative trait in an association analysis with genotype data. This method maintains high power (>80%) in locating genes known to affect the simulated phenotype for most specified significance levels (α). We believe that this method can be useful to aid in the discovery of genes that affect severity or progression of disease. PMID:25519410

  17. Multikernel linear mixed models for complex phenotype prediction.

    PubMed

    Weissbrod, Omer; Geiger, Dan; Rosset, Saharon

    2016-07-01

    Linear mixed models (LMMs) and their extensions have recently become the method of choice in phenotype prediction for complex traits. However, LMM use to date has typically been limited by assuming simple genetic architectures. Here, we present multikernel linear mixed model (MKLMM), a predictive modeling framework that extends the standard LMM using multiple-kernel machine learning approaches. MKLMM can model genetic interactions and is particularly suitable for modeling complex local interactions between nearby variants. We additionally present MKLMM-Adapt, which automatically infers interaction types across multiple genomic regions. In an analysis of eight case-control data sets from the Wellcome Trust Case Control Consortium and more than a hundred mouse phenotypes, MKLMM-Adapt consistently outperforms competing methods in phenotype prediction. MKLMM is as computationally efficient as standard LMMs and does not require storage of genotypes, thus achieving state-of-the-art predictive power without compromising computational feasibility or genomic privacy. PMID:27302636

  18. Root Traits and Phenotyping Strategies for Plant Improvement

    PubMed Central

    Paez-Garcia, Ana; Motes, Christy M.; Scheible, Wolf-Rüdiger; Chen, Rujin; Blancaflor, Elison B.; Monteros, Maria J.

    2015-01-01

    Roots are crucial for nutrient and water acquisition and can be targeted to enhance plant productivity under a broad range of growing conditions. A current challenge for plant breeding is the limited ability to phenotype and select for desirable root characteristics due to their underground location. Plant breeding efforts aimed at modifying root traits can result in novel, more stress-tolerant crops and increased yield by enhancing the capacity of the plant for soil exploration and, thus, water and nutrient acquisition. Available approaches for root phenotyping in laboratory, greenhouse and field encompass simple agar plates to labor-intensive root digging (i.e., shovelomics) and soil boring methods, the construction of underground root observation stations and sophisticated computer-assisted root imaging. Here, we summarize root architectural traits relevant to crop productivity, survey root phenotyping strategies and describe their advantages, limitations and practical value for crop and forage breeding programs. PMID:27135332

  19. NCBI's Database of Genotypes and Phenotypes: dbGaP.

    PubMed

    Tryka, Kimberly A; Hao, Luning; Sturcke, Anne; Jin, Yumi; Wang, Zhen Y; Ziyabari, Lora; Lee, Moira; Popova, Natalia; Sharopova, Nataliya; Kimura, Masato; Feolo, Michael

    2014-01-01

    The Database of Genotypes and Phenotypes (dbGap, http://www.ncbi.nlm.nih.gov/gap) is a National Institutes of Health-sponsored repository charged to archive, curate and distribute information produced by studies investigating the interaction of genotype and phenotype. Information in dbGaP is organized as a hierarchical structure and includes the accessioned objects, phenotypes (as variables and datasets), various molecular assay data (SNP and Expression Array data, Sequence and Epigenomic marks), analyses and documents. Publicly accessible metadata about submitted studies, summary level data, and documents related to studies can be accessed freely on the dbGaP website. Individual-level data are accessible via Controlled Access application to scientists across the globe. PMID:24297256

  20. Criteria, prevalence, and phenotypes of polycystic ovary syndrome.

    PubMed

    Lizneva, Daria; Suturina, Larisa; Walker, Walidah; Brakta, Soumia; Gavrilova-Jordan, Larisa; Azziz, Ricardo

    2016-07-01

    Polycystic ovary syndrome (PCOS) is a highly prevalent disorder effecting reproductive-aged women worldwide. This article addresses the evolution of the criteria used to diagnosis PCOS; reviews recent advances in the phenotypic approach, specifically in the context of the extended Rotterdam criteria; discusses limitations of the current criteria used to diagnosis, particularly when studying adolescents and women in the peri- and postmenopause; and describes significant strides made in understanding the epidemiology of PCOS. This review recognizes that although there is a high prevalence of PCOS, there is increased variability when using Rotterdam 2003 criteria, owing to limitations in population sampling and approaches used to define PCOS phenotypes. Last, we discuss the distribution of PCOS phenotypes, their morbidity, and the role that referral bias plays in the epidemiology of this syndrome. PMID:27233760

  1. Phenotype of asthma-chronic obstructive pulmonary disease overlap syndrome

    PubMed Central

    2015-01-01

    Many patients with asthma or chronic obstructive pulmonary disease (COPD) have overlapping characteristics of both diseases. By spirometric definition, patients with both fixed airflow obstruction (AO) and bronchodilator reversibility or fixed AO and bronchial hyperresponsiveness can be considered to have asthma-COPD overlap syndrome (ACOS). However, patients regarded to have ACOS by spirometric criteria alone are heterogeneous and can be classified by phenotype. Eosinophilic inflammation, a history of allergic disease, and smoke exposure are important components in the classification of ACOS. Each phenotype has a different underlying pathophysiology, set of characteristics, and prognosis. Medical treatment for ACOS should be tailored according to phenotype. A narrower definition of ACOS that includes both spirometric and clinical criteria is needed. PMID:26161009

  2. Phenotypic characterization of Zimbabwean isolates of Pasteurella multocida.

    PubMed

    Mohan, K; Sadza, M; Madsen, M; Hill, F W; Pawandiwa, A

    1994-02-01

    The phenotypic characteristics of 60 Zimbabwean isolates of Pasteurella multocida sensu stricto, from disease syndromes in different host species were studied. A number of representative strains were also serotyped. Consistent results were obtained in the tests for; catalase, oxidase, urease, indole, acid in glucose, inositol, salicin and sucrose. There was no obvious relationship between serotype, host or disease and the pattern of utilization of certain substrates by an isolate. This has been discussed in the context of recent proposals to reclassify Pasteurella and P. multocida on genotypic and phenotypic studies. It is suggested that notwithstanding the relevance of genetic studies in circumscribing P. multocida, the phenotype and disease significance of the taxon should not be ignored. A case of bronchitis in a dog which was simultaneously colonized by three different strains of Pasteurella is described. Also septicaemic pasteurellosis in a Nile crocodile (Crocodylus niloticus) is reported and for the first time prevalence of various serotypes in pasteurellosis of animals in Zimbabwe. PMID:8160349

  3. The phenotypic legacy of admixture between modern humans and Neandertals.

    PubMed

    Simonti, Corinne N; Vernot, Benjamin; Bastarache, Lisa; Bottinger, Erwin; Carrell, David S; Chisholm, Rex L; Crosslin, David R; Hebbring, Scott J; Jarvik, Gail P; Kullo, Iftikhar J; Li, Rongling; Pathak, Jyotishman; Ritchie, Marylyn D; Roden, Dan M; Verma, Shefali S; Tromp, Gerard; Prato, Jeffrey D; Bush, William S; Akey, Joshua M; Denny, Joshua C; Capra, John A

    2016-02-12

    Many modern human genomes retain DNA inherited from interbreeding with archaic hominins, such as Neandertals, yet the influence of this admixture on human traits is largely unknown. We analyzed the contribution of common Neandertal variants to over 1000 electronic health record (EHR)-derived phenotypes in ~28,000 adults of European ancestry. We discovered and replicated associations of Neandertal alleles with neurological, psychiatric, immunological, and dermatological phenotypes. Neandertal alleles together explained a significant fraction of the variation in risk for depression and skin lesions resulting from sun exposure (actinic keratosis), and individual Neandertal alleles were significantly associated with specific human phenotypes, including hypercoagulation and tobacco use. Our results establish that archaic admixture influences disease risk in modern humans, provide hypotheses about the effects of hundreds of Neandertal haplotypes, and demonstrate the utility of EHR data in evolutionary analyses. PMID:26912863

  4. Evolutionary adaptation of phenotypic plasticity in a synthetic microbial system

    NASA Astrophysics Data System (ADS)

    Tans, Sander

    2010-03-01

    While phenotypic plasticity -the capability to respond to the environment- is vital to organisms, tests of its adaptation have remained indecisive because constraints and selection in variable environments are unknown and entangled. We show that one can determine the phenotype-fitness landscape that specifies selection on plasticity, by uncoupling the environmental cue and stress in a genetically engineered microbial system. Evolutionary trajectories revealed genetic constraints in a regulatory protein, which imposed cross-environment trade-offs that favored specialization. However, depending on the synchronicity and amplitude of the applied cue and stress variations, adaptation could break constraints, resolve trade-offs, and evolve optimal phenotypes that exhibit qualitatively altered (inverse) responses to the cue. Our results provide a first step to explain the adaptive origins of complex behavior in heterogeneous environments.

  5. The Genomic and Phenotypic Diversity of Schizosaccharomyces pombe

    PubMed Central

    Jeffares, Daniel C.; Rallis, Charalampos; Rieux, Adrien; Speed, Doug; Převorovský, Martin; Mourier, Tobias; Marsellach, Francesc X.; Iqbal, Zamin; Lau, Winston; Cheng, Tammy M.K.; Pracana, Rodrigo; Mülleder, Michael; Lawson, Jonathan L.D.; Chessel, Anatole; Bala, Sendu; Hellenthal, Garrett; O’Fallon, Brendan; Keane, Thomas; Simpson, Jared T.; Bischof, Leanne; Tomiczek, Bartlomiej; Bitton, Danny A.; Sideri, Theodora; Codlin, Sandra; Hellberg, Josephine E.E.U.; van Trigt, Laurent; Jeffery, Linda; Li, Juan-Juan; Atkinson, Sophie; Thodberg, Malte; Febrer, Melanie; McLay, Kirsten; Drou, Nizar; Brown, William; Hayles, Jacqueline; Carazo Salas, Rafael E.; Ralser, Markus; Maniatis, Nikolas; Balding, David J.; Balloux, Francois; Durbin, Richard; Bähler, Jürg

    2015-01-01

    Natural variation within species reveals aspects of genome evolution and function. The fission yeast Schizosaccharomyces pombe is an important model for eukaryotic biology, but researchers typically use one standard laboratory strain. To extend the utility of this model, we surveyed the genomic and phenotypic variation in 161 natural isolates. We sequenced the genomes of all strains, revealing moderate genetic diversity (π = 3 ×10−3) and weak global population structure. We estimate that dispersal of S. pombe began within human antiquity (~340 BCE), and ancestors of these strains reached the Americas at ~1623 CE. We quantified 74 traits, revealing substantial heritable phenotypic diversity. We conducted 223 genome-wide association studies, with 89 traits showing at least one association. The most significant variant for each trait explained 22% of variance on average, with indels having higher effects than SNPs. This analysis presents a rich resource to examine genotype-phenotype relationships in a tractable model. PMID:25665008

  6. Bridging the Gap between Genotype and Phenotype via Network Approaches

    PubMed Central

    Kim, Yoo-Ah; Przytycka, Teresa M.

    2013-01-01

    In the last few years we have witnessed tremendous progress in detecting associations between genetic variations and complex traits. While genome-wide association studies have been able to discover genomic regions that may influence many common human diseases, these discoveries created an urgent need for methods that extend the knowledge of genotype-phenotype relationships to the level of the molecular mechanisms behind them. To address this emerging need, computational approaches increasingly utilize a pathway-centric perspective. These new methods often utilize known or predicted interactions between genes and/or gene products. In this review, we survey recently developed network based methods that attempt to bridge the genotype-phenotype gap. We note that although these methods help narrow the gap between genotype and phenotype relationships, these approaches alone cannot provide the precise details of underlying mechanisms and current research is still far from closing the gap. PMID:23755063

  7. Effect of Surface Modification and Macrophage Phenotype on Particle Internalization

    SciTech Connect

    Wang, Daniel; Phan, Ngoc; Isely, Christopher; Bruene, Lucas; Bratlie, Kaitlin M

    2014-11-10

    Material properties play a key role in the cellular internalization of polymeric particles. In the present study, we have investigated the effects of material characteristics such as water contact angle, zeta potential, melting temperature, and alternative activation of complement on particle internalization for pro-inflammatory, pro-angiogenic, and naïve macrophages by using biopolymers (~600 nm), functionalized with 13 different molecules. Understanding how material parameters influence particle internalization for different macrophage phenotypes is important for targeted delivery to specific cell populations. Here, we demonstrate that material parameters affect the alternative pathway of complement activation as well as particle internalization for different macrophage phenotypes. Here, we show that the quantitative structure–activity relationship method (QSAR) previously used to predict physiochemical properties of materials can be applied to targeting different macrophage phenotypes. These findings demonstrated that targeted drug delivery to macrophages could be achieved by exploiting material parameters.

  8. Phenotypic Bias and Ethnic Identity in Filipino Americans.

    PubMed

    Kiang, Lisa; Takeuchi, David T

    2009-06-01

    OBJECTIVE: Links between phenotypes (skin tone, physical features) and a range of outcomes (income, physical health, psychological distress) were examined. Ethnic identity was examined as a protective moderator of phenotypic bias. METHOD: Data were from a community sample of 2,092 Filipino adults in San Francisco and Honolulu. RESULTS: After controlling for age, nativity, marital status, and education, darker skin was associated with lower income and lower physical health for females and males. For females, more ethnic features were associated with lower income. For males, darker skin was related to lower psychological distress. One interaction was found such that females with more ethnic features exhibited lower distress; however, ethnic identity moderated distress levels of those with less ethnic features. CONCLUSIONS: Phenotypic bias appears prevalent in Filipino Americans though specific effects vary by gender and skin color versus physical features. Discussion centers on the social importance of appearance and potential strengths gained from ethnic identification. PMID:20107617

  9. Phenotypic Bias and Ethnic Identity in Filipino Americans*

    PubMed Central

    Kiang, Lisa; Takeuchi, David T.

    2009-01-01

    Objective Links between phenotypes (skin tone, physical features) and a range of outcomes (income, physical health, psychological distress) were examined. Ethnic identity was examined as a protective moderator of phenotypic bias. Method Data were from a community sample of 2,092 Filipino adults in San Francisco and Honolulu. Results After controlling for age, nativity, marital status, and education, darker skin was associated with lower income and lower physical health for females and males. For females, more ethnic features were associated with lower income. For males, darker skin was related to lower psychological distress. One interaction was found such that females with more ethnic features exhibited lower distress; however, ethnic identity moderated distress levels of those with less ethnic features. Conclusions Phenotypic bias appears prevalent in Filipino Americans though specific effects vary by gender and skin color versus physical features. Discussion centers on the social importance of appearance and potential strengths gained from ethnic identification. PMID:20107617

  10. The phenotypic legacy of admixture between modern humans and Neanderthals

    PubMed Central

    Simonti, Corinne N.; Vernot, Benjamin; Bastarache, Lisa; Bottinger, Erwin; Carrell, David S.; Chisholm, Rex L.; Crosslin, David R.; Hebbring, Scott J.; Jarvik, Gail P.; Kullo, Iftikhar J.; Li, Rongling; Pathak, Jyotishman; Ritchie, Marylyn D.; Roden, Dan M.; Verma, Shefali S.; Tromp, Gerard; Prato, Jeffrey D.; Bush, William S.; Akey, Joshua M.; Denny, Joshua C.; Capra, John A.

    2016-01-01

    Many modern human genomes retain DNA inherited from interbreeding with archaic hominins, such as Neanderthals, yet the influence of this admixture on human traits is largely unknown. We analyzed the contribution of common Neanderthal variants to over 1,000 electronic health record (EHR)-derived phenotypes in ~28,000 adults of European ancestry. We discovered and replicated associations of Neanderthal alleles with neurological, psychiatric, immunological, and dermatological phenotypes. Neanderthal alleles together explain a significant fraction of the variation in risk for depression and skin lesions resulting from sun exposure (actinic keratosis), and individual Neanderthal alleles are significantly associated with specific human phenotypes, including hypercoagulation and tobacco use. Our results establish that archaic admixture influences disease risk in modern humans, provide hypotheses about the effects of hundreds of Neanderthal haplotypes and demonstrate the utility of EHR data in evolutionary analyses. PMID:26912863

  11. Structural Modeling Insights into Human VKORC1 Phenotypes

    PubMed Central

    Czogalla, Katrin J.; Watzka, Matthias; Oldenburg, Johannes

    2015-01-01

    Vitamin K 2,3-epoxide reductase complex subunit 1 (VKORC1) catalyses the reduction of vitamin K and its 2,3-epoxide essential to sustain γ-carboxylation of vitamin K-dependent proteins. Two different phenotypes are associated with mutations in human VKORC1. The majority of mutations cause resistance to 4-hydroxycoumarin- and indandione-based vitamin K antagonists (VKA) used in the prevention and therapy of thromboembolism. Patients with these mutations require greater doses of VKA for stable anticoagulation than patients without mutations. The second phenotype, a very rare autosomal-recessive bleeding disorder caused by combined deficiency of vitamin K dependent clotting factors type 2 (VKCFD2) arises from a homozygous Arg98Trp mutation. The bleeding phenotype can be corrected by vitamin K administration. Here, we summarize published experimental data and in silico modeling results in order to rationalize the mechanisms of VKA resistance and VKCFD2. PMID:26287237

  12. Phenotype of asthma-chronic obstructive pulmonary disease overlap syndrome.

    PubMed

    Rhee, Chin Kook

    2015-07-01

    Many patients with asthma or chronic obstructive pulmonary disease (COPD) have overlapping characteristics of both diseases. By spirometric definition, patients with both fixed airflow obstruction (AO) and bronchodilator reversibility or fixed AO and bronchial hyperresponsiveness can be considered to have asthma-COPD overlap syndrome (ACOS). However, patients regarded to have ACOS by spirometric criteria alone are heterogeneous and can be classified by phenotype. Eosinophilic inflammation, a history of allergic disease, and smoke exposure are important components in the classification of ACOS. Each phenotype has a different underlying pathophysiology, set of characteristics, and prognosis. Medical treatment for ACOS should be tailored according to phenotype. A narrower definition of ACOS that includes both spirometric and clinical criteria is needed. PMID:26161009

  13. X-Linked Dilated Cardiomyopathy: A Cardiospecific Phenotype of Dystrophinopathy

    PubMed Central

    Nakamura, Akinori

    2015-01-01

    X-linked dilated cardiomyopathy (XLDCM) is a distinct phenotype of dystrophinopathy characterized by preferential cardiac involvement without any overt skeletal myopathy. XLDCM is caused by mutations of the Duchenne muscular dystrophy (DMD) gene and results in lethal heart failure in individuals between 10 and 20 years. Patients with Becker muscular dystrophy, an allelic disorder, have a milder phenotype of skeletal muscle involvement compared to Duchenne muscular dystrophy (DMD) and sometimes present with dilated cardiomyopathy. The precise relationship between mutations in the DMD gene and cardiomyopathy remain unclear. However, some hypothetical mechanisms are being considered to be associated with the presence of some several dystrophin isoforms, certain reported mutations, and an unknown dystrophin-related pathophysiological mechanism. Recent therapy for Duchenne muscular dystrophy, the severe dystrophinopathy phenotype, appears promising, but the presence of XLDCM highlights the importance of focusing on cardiomyopathy while elucidating the pathomechanism and developing treatment. PMID:26066469

  14. Accuracy of phenotyping children with autism based on parent report: what specifically do we gain phenotyping "rapidly"?

    PubMed

    Warren, Zachary; Vehorn, Alison; Dohrmann, Elizabeth; Nicholson, Amy; Sutcliffe, James S; Veenstra-Vanderweele, Jeremy

    2012-02-01

    Autism spectrum disorder (ASD) is considered among the most heritable of all neurodevelopmental and psychiatric disorders, but identification of etiologically significant genetic markers and risk variants has been hampered by a lack of sufficiently large samples. Rapid phenotyping procedures, where self-report measures are used instead of extensive clinical assessment, have been proposed as methods for amassing large genetic databases due to their hypothesized time-efficiency and affordability. We assessed the diagnostic accuracy of potential rapid phenotyping procedures using the Social Communication Questionnaire and the Social Responsiveness Scale in a sample of 333 children who also received extensive phenotypic assessments. While the rapid phenotyping measures were able to accurately identify a large number of children with ASD, they also frequently failed to differentiate children with ASD from children with other complex neurobehavioral profiles. These data support the continued need of expert clinical validation in combination with rapid phenotyping procedures in order to accurately amass large-scale genetic collections of children with ASD. PMID:21972233

  15. Nucleus Morphometry in Cultured Epithelial Cells Correlates with Phenotype.

    PubMed

    Khan, Ayyad Z; Utheim, Tor P; Jackson, Catherine J; Reppe, Sjur; Lyberg, Torstein; Eidet, Jon R

    2016-06-01

    Phenotype of cultured ocular epithelial transplants has been shown to affect clinical success rates following transplantation to the cornea. The purpose of this study was to evaluate the relationship between cell nucleus morphometry and phenotype in three types of cultured epithelial cells. This study provides knowledge for the development of a non-invasive method of determining the phenotype of cultured epithelium before transplantation. Cultured human conjunctival epithelial cells (HCjE), human epidermal keratinocytes (HEK), and human retinal pigment epithelial cells (HRPE) were analyzed by quantitative immunofluorescence. Assessments of nucleus morphometry and nucleus-to-cytoplasm ratio (N/C ratio) were performed using ImageJ. Spearman's correlation coefficient was employed for statistical analysis. Levels of the proliferation marker PCNA in HCjE, HEK, and HRPE correlated positively with nuclear area. Nuclear area correlated significantly with levels of the undifferentiated cell marker ABCG2 in HCjE. Bmi1 levels, but not p63α levels, correlated significantly with nuclear area in HEK. The N/C ratio did not correlate significantly with any of the immunomarkers in HCjE (ABCG2, CK7, and PCNA) and HRPE (PCNA). In HEK, however, the N/C ratio was negatively correlated with levels of the undifferentiated cell marker CK14 and positively correlated with Bmi1 expression. The size of the nuclear area correlated positively with proliferation markers in all three epithelia. Morphometric indicators of phenotype in cultured epithelia can be identified using ImageJ. Conversely, the N/C ratio did not show a uniform relationship with phenotype in HCjE, HEK, or HRPE. N/C ratio therefore, may not be a useful morphometric marker for in vitro assessment of phenotype in these three epithelia. PMID:27329312

  16. Towards an informative mutant phenotype for every bacterial gene

    DOE PAGESBeta

    Deutschbauer, Adam; Price, Morgan N.; Wetmore, Kelly M.; Tarjan, Daniel R.; Xu, Zhuchen; Shao, Wenjen; Leon, Dacia; Arkin, Adam P.; Skerker, Jeffrey M.

    2014-08-11

    Mutant phenotypes provide strong clues to the functions of the underlying genes and could allow annotation of the millions of sequenced yet uncharacterized bacterial genes. However, it is not known how many genes have a phenotype under laboratory conditions, how many phenotypes are biologically interpretable for predicting gene function, and what experimental conditions are optimal to maximize the number of genes with a phenotype. To address these issues, we measured the mutant fitness of 1,586 genes of the ethanol-producing bacterium Zymomonas mobilis ZM4 across 492 diverse experiments and found statistically significant phenotypes for 89% of all assayed genes. Thus, inmore » Z. mobilis, most genes have a functional consequence under laboratory conditions. We demonstrate that 41% of Z. mobilis genes have both a strong phenotype and a similar fitness pattern (cofitness) to another gene, and are therefore good candidates for functional annotation using mutant fitness. Among 502 poorly characterized Z. mobilis genes, we identified a significant cofitness relationship for 174. For 57 of these genes without a specific functional annotation, we found additional evidence to support the biological significance of these gene-gene associations, and in 33 instances, we were able to predict specific physiological or biochemical roles for the poorly characterized genes. Last, we identified a set of 79 diverse mutant fitness experiments in Z. mobilis that are nearly as biologically informative as the entire set of 492 experiments. Therefore, our work provides a blueprint for the functional annotation of diverse bacteria using mutant fitness.« less

  17. Towards an informative mutant phenotype for every bacterial gene

    SciTech Connect

    Deutschbauer, Adam; Price, Morgan N.; Wetmore, Kelly M.; Tarjan, Daniel R.; Xu, Zhuchen; Shao, Wenjen; Leon, Dacia; Arkin, Adam P.; Skerker, Jeffrey M.

    2014-08-11

    Mutant phenotypes provide strong clues to the functions of the underlying genes and could allow annotation of the millions of sequenced yet uncharacterized bacterial genes. However, it is not known how many genes have a phenotype under laboratory conditions, how many phenotypes are biologically interpretable for predicting gene function, and what experimental conditions are optimal to maximize the number of genes with a phenotype. To address these issues, we measured the mutant fitness of 1,586 genes of the ethanol-producing bacterium Zymomonas mobilis ZM4 across 492 diverse experiments and found statistically significant phenotypes for 89% of all assayed genes. Thus, in Z. mobilis, most genes have a functional consequence under laboratory conditions. We demonstrate that 41% of Z. mobilis genes have both a strong phenotype and a similar fitness pattern (cofitness) to another gene, and are therefore good candidates for functional annotation using mutant fitness. Among 502 poorly characterized Z. mobilis genes, we identified a significant cofitness relationship for 174. For 57 of these genes without a specific functional annotation, we found additional evidence to support the biological significance of these gene-gene associations, and in 33 instances, we were able to predict specific physiological or biochemical roles for the poorly characterized genes. Last, we identified a set of 79 diverse mutant fitness experiments in Z. mobilis that are nearly as biologically informative as the entire set of 492 experiments. Therefore, our work provides a blueprint for the functional annotation of diverse bacteria using mutant fitness.

  18. Genotypic richness predicts phenotypic variation in an endangered clonal plant.

    PubMed

    Evans, Suzanna M; Sinclair, Elizabeth A; Poore, Alistair G B; Bain, Keryn F; Vergés, Adriana

    2016-01-01

    Declines in genetic diversity within a species can affect the stability and functioning of populations. The conservation of genetic diversity is thus a priority, especially for threatened or endangered species. The importance of genetic variation, however, is dependent on the degree to which it translates into phenotypic variation for traits that affect individual performance and ecological processes. This is especially important for predominantly clonal species, as no single clone is likely to maximise all aspects of performance. Here we show that intraspecific genotypic diversity as measured using microsatellites is a strong predictor of phenotypic variation in morphological traits and shoot productivity of the threatened, predominantly clonal seagrass Posidonia australis, on the east coast of Australia. Biomass and surface area variation was most strongly predicted by genotypic richness, while variation in leaf chemistry (phenolics and nitrogen) was unrelated to genotypic richness. Genotypic richness did not predict tissue loss to herbivores or epiphyte load, however we did find that increased herbivore damage was positively correlated with allelic richness. Although there was no clear relationship between higher primary productivity and genotypic richness, variation in shoot productivity within a meadow was significantly greater in more genotypically diverse meadows. The proportion of phenotypic variation explained by environmental conditions varied among different genotypes, and there was generally no variation in phenotypic traits among genotypes present in the same meadows. Our results show that genotypic richness as measured through the use of presumably neutral DNA markers does covary with phenotypic variation in functionally relevant traits such as leaf morphology and shoot productivity. The remarkably long lifespan of individual Posidonia plants suggests that plasticity within genotypes has played an important role in the longevity of the species

  19. Genotypic richness predicts phenotypic variation in an endangered clonal plant

    PubMed Central

    Sinclair, Elizabeth A.; Poore, Alistair G.B.; Bain, Keryn F.; Vergés, Adriana

    2016-01-01

    Declines in genetic diversity within a species can affect the stability and functioning of populations. The conservation of genetic diversity is thus a priority, especially for threatened or endangered species. The importance of genetic variation, however, is dependent on the degree to which it translates into phenotypic variation for traits that affect individual performance and ecological processes. This is especially important for predominantly clonal species, as no single clone is likely to maximise all aspects of performance. Here we show that intraspecific genotypic diversity as measured using microsatellites is a strong predictor of phenotypic variation in morphological traits and shoot productivity of the threatened, predominantly clonal seagrass Posidonia australis, on the east coast of Australia. Biomass and surface area variation was most strongly predicted by genotypic richness, while variation in leaf chemistry (phenolics and nitrogen) was unrelated to genotypic richness. Genotypic richness did not predict tissue loss to herbivores or epiphyte load, however we did find that increased herbivore damage was positively correlated with allelic richness. Although there was no clear relationship between higher primary productivity and genotypic richness, variation in shoot productivity within a meadow was significantly greater in more genotypically diverse meadows. The proportion of phenotypic variation explained by environmental conditions varied among different genotypes, and there was generally no variation in phenotypic traits among genotypes present in the same meadows. Our results show that genotypic richness as measured through the use of presumably neutral DNA markers does covary with phenotypic variation in functionally relevant traits such as leaf morphology and shoot productivity. The remarkably long lifespan of individual Posidonia plants suggests that plasticity within genotypes has played an important role in the longevity of the species

  20. RNA Directed Modulation of Phenotypic Plasticity in Human Cells

    PubMed Central

    Burdach, Jon; Morris, Kevin V.

    2016-01-01

    Natural selective processes have been known to drive phenotypic plasticity, which is the emergence of different phenotypes from one genome following environmental stimulation. Long non-coding RNAs (lncRNAs) have been observed to modulate transcriptional and epigenetic states of genes in human cells. We surmised that lncRNAs are governors of phenotypic plasticity and drive natural selective processes through epigenetic modulation of gene expression. Using heat shocked human cells as a model we find several differentially expressed transcripts with the top candidates being lncRNAs derived from retro-elements. One particular retro-element derived transcripts, Retro-EIF2S2, was found to be abundantly over-expressed in heat shocked cells. Over-expression of Retro-EIF2S2 significantly enhanced cell viability and modulated a predisposition for an adherent cellular phenotype upon heat shock. Mechanistically, we find that this retro-element derived transcript interacts directly with a network of proteins including 40S ribosomal protein S30 (FAU), Eukaryotic translation initiation factor 5A (EIF5A), and Ubiquitin-60S ribosomal protein L40 (UBA52) to affect protein modulated cell adhesion pathways. We find one motif in Retro-EIF2S2 that exhibits binding to FAU and modulates phenotypic cell transitions from adherent to suspension states. The observations presented here suggest that retroviral derived transcripts actively modulate phenotypic plasticity in human cells in response to environmental selective pressures and suggest that natural selection may play out through the action of retro-elements in human cells. PMID:27082860

  1. GBM heterogeneity characterization by radiomic analysis of phenotype anatomical planes

    NASA Astrophysics Data System (ADS)

    Chaddad, Ahmad; Desrosiers, Christian; Toews, Matthew

    2016-03-01

    Glioblastoma multiforme (GBM) is the most common malignant primary tumor of the central nervous system, characterized among other traits by rapid metastatis. Three tissue phenotypes closely associated with GBMs, namely, necrosis (N), contrast enhancement (CE), and edema/invasion (E), exhibit characteristic patterns of texture heterogeneity in magnetic resonance images (MRI). In this study, we propose a novel model to characterize GBM tissue phenotypes using gray level co-occurrence matrices (GLCM) in three anatomical planes. The GLCM encodes local image patches in terms of informative, orientation-invariant texture descriptors, which are used here to sub-classify GBM tissue phenotypes. Experiments demonstrate the model on MRI data of 41 GBM patients, obtained from the cancer genome atlas (TCGA). Intensity-based automatic image registration is applied to align corresponding pairs of fixed T1˗weighted (T1˗WI) post-contrast and fluid attenuated inversion recovery (FLAIR) images. GBM tissue regions are then segmented using the 3D Slicer tool. Texture features are computed from 12 quantifier functions operating on GLCM descriptors, that are generated from MRI intensities within segmented GBM tissue regions. Various classifier models are used to evaluate the effectiveness of texture features for discriminating between GBM phenotypes. Results based on T1-WI scans showed a phenotype classification accuracy of over 88.14%, a sensitivity of 85.37% and a specificity of 96.1%, using the linear discriminant analysis (LDA) classifier. This model has the potential to provide important characteristics of tumors, which can be used for the sub-classification of GBM phenotypes.

  2. Limestone: high-throughput candidate phenotype generation via tensor factorization.

    PubMed

    Ho, Joyce C; Ghosh, Joydeep; Steinhubl, Steve R; Stewart, Walter F; Denny, Joshua C; Malin, Bradley A; Sun, Jimeng

    2014-12-01

    The rapidly increasing availability of electronic health records (EHRs) from multiple heterogeneous sources has spearheaded the adoption of data-driven approaches for improved clinical research, decision making, prognosis, and patient management. Unfortunately, EHR data do not always directly and reliably map to medical concepts that clinical researchers need or use. Some recent studies have focused on EHR-derived phenotyping, which aims at mapping the EHR data to specific medical concepts; however, most of these approaches require labor intensive supervision from experienced clinical professionals. Furthermore, existing approaches are often disease-centric and specialized to the idiosyncrasies of the information technology and/or business practices of a single healthcare organization. In this paper, we propose Limestone, a nonnegative tensor factorization method to derive phenotype candidates with virtually no human supervision. Limestone represents the data source interactions naturally using tensors (a generalization of matrices). In particular, we investigate the interaction of diagnoses and medications among patients. The resulting tensor factors are reported as phenotype candidates that automatically reveal patient clusters on specific diagnoses and medications. Using the proposed method, multiple phenotypes can be identified simultaneously from data. We demonstrate the capability of Limestone on a cohort of 31,815 patient records from the Geisinger Health System. The dataset spans 7years of longitudinal patient records and was initially constructed for a heart failure onset prediction study. Our experiments demonstrate the robustness, stability, and the conciseness of Limestone-derived phenotypes. Our results show that using only 40 phenotypes, we can outperform the original 640 features (169 diagnosis categories and 471 medication types) to achieve an area under the receiver operator characteristic curve (AUC) of 0.720 (95% CI 0.715 to 0.725). Moreover, in

  3. Genotypic richness and phenotypic dissimilarity enhance population performance.

    PubMed

    Ellers, Jacintha; Rog, Stefanie; Braam, Ciska; Berg, Matty P

    2011-08-01

    Increases in biodiversity can result from an increase in species richness, as well as from a higher genetic diversity within species. Intraspecific genetic diversity, measured as the number of genotypes, can enhance plant primary productivity and have cascading effects at higher trophic levels, such as an increase in herbivore and predator richness. The positive effects of genotypic mixtures are not only determined by additive effects, but also by interactions among genotypes, such as facilitation or inhibition. However, so far there has been no effort to predict the extent of such effects. In this study, we address the question of whether the magnitude of the effect of genotype number on population performance can be explained by the extent of dissimilarity in key traits among genotypes in a mixture. We examine the relative contribution of genotype number and phenotypic dissimilarity among genotypes to population performance of the soil arthropod, Orchesella cincta. Nearly homogeneous genotypes were created from inbred isofemale lines. Phenotypic dissimilarity among genotypes was assessed in terms of three life-history traits that are associated with population growth rate, i.e., egg size, egg development time, and juvenile growth rate. A microcosm experiment with genotype mixtures consisting of one, two, four, and eight genotypes, showed that genotypic richness strongly increased population size and biomass production and was associated with greater net diversity effects. Most importantly, there was a positive log-linear relationship between phenotypic dissimilarity in a mixture and the net diversity effects for juvenile population size and total biomass. In other words, the degree of phenotypic dissimilarity among genotypes determined the magnitude of the genotypic richness effect, although this relationship leveled off at higher values of phenotypic dissimilarity. Although the exact mechanisms responsible for these effects are currently unknown, similar

  4. The role of phenotypic plasticity in driving genetic evolution.

    PubMed Central

    Price, Trevor D; Qvarnström, Anna; Irwin, Darren E

    2003-01-01

    Models of population divergence and speciation are often based on the assumption that differences between populations are due to genetic factors, and that phenotypic change is due to natural selection. It is equally plausible that some of the differences among populations are due to phenotypic plasticity. We use the metaphor of the adaptive landscape to review the role of phenotypic plasticity in driving genetic evolution. Moderate levels of phenotypic plasticity are optimal in permitting population survival in a new environment and in bringing populations into the realm of attraction of an adaptive peak. High levels of plasticity may increase the probability of population persistence but reduce the likelihood of genetic change, because the plastic response itself places the population close to a peak. Moderate levels of plasticity arise whenever multiple traits, some of which are plastic and others not, form a composite trait involved in the adaptive response. For example, altered behaviours may drive selection on morphology and physiology. Because there is likely to be a considerable element of chance in which behaviours become established, behavioural change followed by morphological and physiological evolution may be a potent force in driving evolution in novel directions. We assess the role of phenotypic plasticity in stimulating evolution by considering two examples from birds: (i) the evolution of red and yellow plumage coloration due to carotenoid consumption; and (ii) the evolution of foraging behaviours on islands. Phenotypic plasticity is widespread in nature and may speed up, slow down, or have little effect on evolutionary change. Moderate levels of plasticity may often facilitate genetic evolution but careful analyses of individual cases are needed to ascertain whether plasticity has been essential or merely incidental to population differentiation. PMID:12965006

  5. Weak Epistasis Generally Stabilizes Phenotypes in a Mouse Intercross

    PubMed Central

    Tyler, Anna L.; Donahue, Leah Rae; Churchill, Gary A.; Carter, Gregory W.

    2016-01-01

    The extent and strength of epistasis is commonly unresolved in genetic studies, and observed epistasis is often difficult to interpret in terms of biological consequences or overall genetic architecture. We investigated the prevalence and consequences of epistasis by analyzing four body composition phenotypes—body weight, body fat percentage, femoral density, and femoral circumference—in a large F2 intercross of B6-lit/lit and C3.B6-lit/lit mice. We used Combined Analysis of Pleiotropy and Epistasis (CAPE) to examine interactions for the four phenotypes simultaneously, which revealed an extensive directed network of genetic loci interacting with each other, circulating IGF1, and sex to influence these phenotypes. The majority of epistatic interactions had small effects relative to additive effects of individual loci, and tended to stabilize phenotypes towards the mean of the population rather than extremes. Interactive effects of two alleles inherited from one parental strain commonly resulted in phenotypes closer to the population mean than the additive effects from the two loci, and often much closer to the mean than either single-locus model. Alternatively, combinations of alleles inherited from different parent strains contribute to more extreme phenotypes not observed in either parental strain. This class of phenotype-stabilizing interactions has effects that are close to additive and are thus difficult to detect except in very large intercrosses. Nevertheless, we found these interactions to be useful in generating hypotheses for functional relationships between genetic loci. Our findings suggest that while epistasis is often weak and unlikely to account for a large proportion of heritable variance, even small-effect genetic interactions can facilitate hypotheses of underlying biology in well-powered studies. PMID:26828925

  6. RNA Directed Modulation of Phenotypic Plasticity in Human Cells.

    PubMed

    Trakman, Laura; Hewson, Chris; Burdach, Jon; Morris, Kevin V

    2016-01-01

    Natural selective processes have been known to drive phenotypic plasticity, which is the emergence of different phenotypes from one genome following environmental stimulation. Long non-coding RNAs (lncRNAs) have been observed to modulate transcriptional and epigenetic states of genes in human cells. We surmised that lncRNAs are governors of phenotypic plasticity and drive natural selective processes through epigenetic modulation of gene expression. Using heat shocked human cells as a model we find several differentially expressed transcripts with the top candidates being lncRNAs derived from retro-elements. One particular retro-element derived transcripts, Retro-EIF2S2, was found to be abundantly over-expressed in heat shocked cells. Over-expression of Retro-EIF2S2 significantly enhanced cell viability and modulated a predisposition for an adherent cellular phenotype upon heat shock. Mechanistically, we find that this retro-element derived transcript interacts directly with a network of proteins including 40S ribosomal protein S30 (FAU), Eukaryotic translation initiation factor 5A (EIF5A), and Ubiquitin-60S ribosomal protein L40 (UBA52) to affect protein modulated cell adhesion pathways. We find one motif in Retro-EIF2S2 that exhibits binding to FAU and modulates phenotypic cell transitions from adherent to suspension states. The observations presented here suggest that retroviral derived transcripts actively modulate phenotypic plasticity in human cells in response to environmental selective pressures and suggest that natural selection may play out through the action of retro-elements in human cells. PMID:27082860

  7. Structural Phenotyping of Stem Cell-Derived Cardiomyocytes

    PubMed Central

    Pasqualini, Francesco Silvio; Sheehy, Sean Paul; Agarwal, Ashutosh; Aratyn-Schaus, Yvonne; Parker, Kevin Kit

    2015-01-01

    Summary Structural phenotyping based on classical image feature detection has been adopted to elucidate the molecular mechanisms behind genetically or pharmacologically induced changes in cell morphology. Here, we developed a set of 11 metrics to capture the increasing sarcomere organization that occurs intracellularly during striated muscle cell development. To test our metrics, we analyzed the localization of the contractile protein α-actinin in a variety of primary and stem-cell derived cardiomyocytes. Further, we combined these metrics with data mining algorithms to unbiasedly score the phenotypic maturity of human-induced pluripotent stem cell-derived cardiomyocytes. PMID:25733020

  8. A new childhood asthma phenotype: obese with early menarche.

    PubMed

    Castro-Rodriguez, Jose A

    2016-03-01

    Three concomitant phenomena occur in the later years of childhood: increases in the incidence of asthma, obesity and early menarche. This article is an overview of the current epidemiologic, basic, genetic and epigenetic evidence about this relationship. As a consequence we propose that obese girls who have an early menarche (≤ 11 years of age) constitute a new asthma phenotype in childhood. Future studies need to be carried out in order to find the best control and treatment of this new asthma phenotype. PMID:26644272

  9. Phenotype pharmacology of lower urinary tract α1-adrenoceptors

    PubMed Central

    Nishimune, A; Yoshiki, H; Uwada, J; Anisuzzaman, ASM; Umada, H; Muramatsu, I

    2012-01-01

    α1-Adrenoceptors are involved in numerous physiological functions, including micturition. However, the pharmacological profile of the α1-adrenoceptor subtypes remains controversial. Here, we review the literature regarding α1-adrenoceptors in the lower urinary tract from the standpoint of α1L phenotype pharmacology. Among three α1-adrenoceptor subtypes (α1A, α1B and α1D), α1a-adrenoceptor mRNA is the most abundantly transcribed in the prostate, urethra and bladder neck of many species, including humans. In prostate homogenates or membrane preparations, α1A-adrenoceptors with high affinity for prazosin have been detected as radioligand binding sites. Functional α1-adrenoceptors in the prostate, urethra and bladder neck have low affinity for prazosin, suggesting the presence of an atypical α1-adrenoceptor phenotype (designated as α1L). The α1L-adrenoceptor occurs as a distinct binding entity from the α1A-adrenoceptor in intact segments of variety of tissues including prostate. Both the α1L- and α1A-adrenoceptors are specifically absent from Adra1A (α1a) gene-knockout mice. Transfection of α1a-adrenoceptor cDNA predominantly expresses α1A-phenotype in several cultured cell lines. However, in CHO cells, such transfection expresses α1L- and α1A-phenotypes. Under intact cell conditions, the α1L-phenotype is predominant when co-expressed with the receptor interacting protein, CRELD1α. In summary, recent pharmacological studies reveal that two distinct α1-adrenoceptor phenotypes (α1A and α1L) originate from a single Adra1A (α1a-adrenoceptor) gene, but adrenergic contractions in the lower urinary tract are predominantly mediated via the α1L-adrenoceptor. From the standpoint of phenotype pharmacology, it is likely that phenotype-based subtypes such as the α1L-adrenoceptor will become new targets for drug development and pharmacotherapy. LINKED ARTICLE This article is commented on by Ventura, pp. 1223–1225 of this issue. To view this commentary

  10. Searching For Valid Psychiatric Phenotypes: Discrete Latent Variable Models

    PubMed Central

    Leoutsakos, Jeannie-Marie S.; Zandi, Peter P.; Bandeen-Roche, Karen; Lyketsos, Constantine G.

    2010-01-01

    Introduction A primary challenge in psychiatric genetics is the lack of a completely validated system of classification for mental disorders. Appropriate statistical methods are needed to empirically derive more homogenous disorder subtypes. Methods Using the framework of Robins & Guze’s (1970) five phases, latent variable models to derive and validate diagnostic groups are described. A process of iterative validation is proposed through which refined phenotypes would facilitate research on genetics, pathogenesis, and treatment, which would in turn aid further refinement of disorder definitions. Conclusions Latent variable methods are useful tools for defining and validating psychiatric phenotypes. Further methodological research should address sample size issues and application to iterative validation. PMID:20187060

  11. Online Phenotype Discovery in High-Content RNAi Screens using Gap Statistics

    NASA Astrophysics Data System (ADS)

    Yin, Zheng; Zhou, Xiaobo; Bakal, Chris; Li, Fuhai; Sun, Youxian; Perrimon, Norbert; Wong, Stephen T. C.

    2007-11-01

    Discovering and identifying novel phenotypes from images inputting online is a major challenge in high-content RNA interference (RNAi) screens. Discovered phenotypes should be visually distinct from existing ones and make biological sense. An online phenotype discovery method featuring adaptive phenotype modeling and iterative cluster merging using gap statistics is proposed. The method works well on discovering new phenotypes adaptively when applied to both of synthetic data sets and RNAi high content screen (HCS) images with ground truth labels.

  12. Adult Phenotypes in Angelman- and Rett-Like Syndromes

    PubMed Central

    Willemsen, M.H.; Rensen, J.H.M.; van Schrojenstein-Lantman de Valk, H.M.J.; Hamel, B.C.J.; Kleefstra, T.

    2012-01-01

    Background Angelman- and Rett-like syndromes share a range of clinical characteristics, including intellectual disability (ID) with or without regression, epilepsy, infantile encephalopathy, postnatal microcephaly, features of autism spectrum disorder, and variable other neurological symptoms. The phenotypic spectrum generally has been well studied in children; however, evolution of the phenotypic spectrum into adulthood has been documented less extensively. To obtain more insight into natural course and prognosis of these syndromes with respect to developmental, medical, and socio-behavioral outcomes, we studied the phenotypes of 9 adult patients who were recently diagnosed with 6 different Angelman- and Rett-like syndromes. Methods All these patients were ascertained during an ongoing cohort study involving a systematic clinical genetic diagnostic evaluation of over 250, mainly adult patients with ID of unknown etiology. Results We describe the evolution of the phenotype in adults with EHMT1, TCF4, MECP2, CDKL5, and SCN1A mutations and 22qter deletions and also provide an overview of previously published adult cases with similar diagnoses. Conclusion These data are highly valuable in adequate management and follow-up of patients with Angelman- and Rett-like syndromes and accurate counseling of their family members. Furthermore, they will contribute to recognition of these syndromes in previously undiagnosed adult patients. PMID:22670143

  13. Language Phenotypes and Intervention Planning: Bridging Research and Practice

    ERIC Educational Resources Information Center

    Fidler, Deborah J.; Philofsky, Amy; Hepburn, Susan L.

    2007-01-01

    This paper focuses on the communication and language phenotypes associated with three genetic disorders: Down syndrome, Williams syndrome, and fragile X syndrome. It is argued that there is empirical evidence that these disorders predispose children to specific profiles of strength and weakness in some areas of speech, language, and communication,…

  14. Fragile X mutation and FG syndrome-like phenotype

    SciTech Connect

    Piussan, C.; Mathieu, M.; Berquin, P.

    1996-08-09

    We present data on 4 mentally retarded brothers, 2 of whom were dizygotic twins with congenital hypotonia, constipation, head size disproportionately large for length or height, and a combination of minor anomalies suggestive of FG syndrome. These brothers have a mentally retarded full sister with similar minor anomalies and an older half-brother with the Martin-Bell syndrome. The mother is mentally retarded; 4 of 7 individuals are positive for fragile X, but all have a CGG expansion ranging from 0.2-2 to 4 kb. Although the phenotype is not completely typical of the FG syndrome and the coincidence of the FMR1 mutation and segregation of the MCA/MR phenotype are highly unlikely, the FMR1 mutation may affect morphogenesis more extensively and differently than the Martin-Bell syndrome does to effect an FG syndrome-like phenotype in certain families. This phenotype does not appear to be a contiguous gene syndrome, but an effect of the FMR1 mutation on an adjacent gene must be considered. 18 refs., 4 figs.

  15. Phenotypic data collection and management using barcodes, MSExcel and MSAccess

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A “Rice Diversity Panel” composed of 409 purified Oryza sativa accessions originating from 79 countries was developed in order to conduct an association mapping study. The methods used to collect and manage the phenotypic data on plant morphology, seed morphology, grain quality, and selected agrono...

  16. Sirolimus modulates HIVAN phenotype through inhibition of epithelial mesenchymal transition

    PubMed Central

    Yadav, Anju; Kumar, Dileep; Salhan, Divya; Rattanavich, Rungwasee; Maheshwari, Subani; Adabala, Madhuri; Ding, Guohua; Singhal, Pravin C.

    2012-01-01

    HIV-associated nephropathy (HIVAN) is characterized by proliferative phenotype in the form of collapsing glomerulopathy and microcystic dilatation of tubules. Recently, epithelial mesenchymal transition (EMT) of renal cells has been demonstrated to contribute to the pathogenesis of proliferative HIVAN phenotype. We hypothesized that sirolimus would modulate HIVAN phenotype by attenuating renal cell EMT. In the present study, we evaluated the effect of sirolimus on the development of renal cell EMT as well as on display of HIVAN phenotype in a mouse model of HIVAN (Tg26). Tg26 mice receiving normal saline (TgNS) showed enhanced proliferation of both glomerular and tubular cells when compared to control mice-receiving normal saline (CNS); on the other hand, Tg26 mice receiving sirolimus (TgS) showed attenuated renal cell proliferation when compared with TgNS. TgNS also showed increased number of α-SMA-, vimentin-, and FSP1- positive cells (glomerular as well as tubular) when compared with CNS; however, TgS showed reduced number of SMA, vimentin, and FSP1 +ve renal cells when compared to TgNS. Interestingly, sirolimus preserved renal epithelial cell expression of E-cadherin in TgS. Since sirolimus attenuated renal cell ZEB expression (a repressor of E-cadherin transcription), it appears that sirolimus may be attenuating renal cell EMT by preserving epithelial cell E-cadherin expression. PMID:22579465

  17. Phenotypic Characterization of a Diversity Panel of Tomato

    Technology Transfer Automated Retrieval System (TEKTRAN)

    At the USDA, ARS Plant Genetic Resources Unit (PGRU) we have phenotypically characterized more than 2,000 accessions of tomato (Solanum lycopersicum L.) for which data are publically available on the National Plant Germplasm System (NPGS) Germplasm Resources Information Network (GRIN) (http://www.ar...

  18. Jacalin-Activated Macrophages Exhibit an Antitumor Phenotype

    PubMed Central

    Danella Polli, Cláudia; Pereira Ruas, Luciana; Chain Veronez, Luciana; Herrero Geraldino, Thais; Rossetto de Morais, Fabiana; Roque-Barreira, Maria Cristina; Pereira-da-Silva, Gabriela

    2016-01-01

    Tumor-associated macrophages (TAMs) have an ambiguous and complex role in the carcinogenic process, since these cells can be polarized into different phenotypes (proinflammatory, antitumor cells or anti-inflammatory, protumor cells) by the tumor microenvironment. Given that the interactions between tumor cells and TAMs involve several players, a better understanding of the function and regulation of TAMs is crucial to interfere with their differentiation in attempts to skew TAM polarization into cells with a proinflammatory antitumor phenotype. In this study, we investigated the modulation of macrophage tumoricidal activities by the lectin jacalin. Jacalin bound to macrophage surface and induced the expression and/or release of mainly proinflammatory cytokines via NF-κB signaling, as well as increased iNOS mRNA expression, suggesting that the lectin polarizes macrophages toward the antitumor phenotype. Therefore, tumoricidal activities of jacalin-stimulated macrophages were evaluated. High rates of tumor cell (human colon, HT-29, and breast, MCF-7, cells) apoptosis were observed upon incubation with supernatants from jacalin-stimulated macrophages. Taken together, these results indicate that jacalin, by exerting a proinflammatory activity, can direct macrophages to an antitumor phenotype. Deep knowledge of the regulation of TAM functions is essential for the development of innovative anticancer strategies. PMID:27119077

  19. Phenotypic Variation and FMRP Levels in Fragile X

    ERIC Educational Resources Information Center

    Loesch, Danuta Z.; Huggins, Richard M.; Hagerman, Randi J.

    2004-01-01

    Data on the relationships between cognitive and physical phenotypes, and a deficit of fragile X mental retardation 1 (FMR1) gene-specific protein product, FMRP, are presented and discussed in context with earlier findings. The previously unpublished results obtained, using standard procedures of regression and correlations, showed highly…

  20. Phenotypic complexity and local variations in neutral degree.

    PubMed

    Lehre, Per Kristian; Haddow, Pauline C

    2007-02-01

    Neutrality is important in natural, molecular and artificial evolution. This work studies how local neutral degree varies over the genospace in a simple class of Lindenmayer-systems, and investigates whether this variation relates to Lempel-Ziv complexity of the phenotype. PMID:17188803

  1. Evolutionary escape on complex genotype-phenotype networks.

    PubMed

    Ibáñez-Marcelo, Esther; Alarcón, Tomás

    2016-04-01

    We study the problem of evolutionary escape that is the process whereby a population under sudden changes in the selective pressures acting upon it try to evade extinction by evolving from previously well-adapted phenotypes to those that are favoured by the new selective pressure. We perform a comparative analysis between results obtained by modelling genotype space as a regular hypercube (H-graphs), which is the scenario considered in previous work on the subject, to those corresponding to a complex genotype-phenotype network (B-graphs). In order to analyse the properties of the escape process on both these graphs, we apply a general theory based on multi-type branching processes to compute the evolutionary dynamics and probability of escape. We show that the distribution of distances between phenotypes in B-graphs exhibits a much larger degree of heterogeneity than in H-graphs. This property, one of the main structural differences between both types of graphs, causes heterogeneous behaviour in all results associated to the escape problem. We further show that, due to the heterogeneity characterising escape on B-graphs, escape probability can be underestimated by assuming a regular hypercube genotype network, even if we compare phenotypes at the same distance in H-graphs. Similarly, it appears that the complex structure of B-graphs slows down the rate of escape. PMID:26802479

  2. Beef cattle metabiomes and their relationships with economically important phenotypes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The selection and optimization of economically important phenotypes, i.e. feed efficiency, in cattle has long been an effort devoted to host genetics, management, and diet. Feed costs remain the largest variable cost in beef production, and consequently, the improvement of feed efficiency is of sig...

  3. The hordeum toolbox - the barley CAP genotype and phenotype resource

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The use of DNA markers in public sector plant breeding is now the norm. Such markers are common across breeding programs and this commonality enables and enhances collaboration. Thus, large collaborative research projects that measure several phenotypes across multiple environments coupled with the ...

  4. Method for restoration of normal phenotype in cancer cells

    DOEpatents

    Bissell, Mina J.; Weaver, Valerie M.

    2000-01-01

    A method for reversing expression of malignant phenotype in cancer cells is described. The method comprises applying .beta..sub.1 integrin function-blocking antibody to the cells. The method can be used to assess the progress of cancer therapy. Human breast epithelial cells were shown to be particularly responsive.

  5. PHOCOS: inferring multi-feature phenotypic crosstalk networks

    PubMed Central

    Deng, Yue; Altschuler, Steven J.; Wu, Lani F.

    2016-01-01

    Motivation: Quantification of cellular changes to perturbations can provide a powerful approach to infer crosstalk among molecular components in biological networks. Existing crosstalk inference methods conduct network-structure learning based on a single phenotypic feature (e.g. abundance) of a biomarker. These approaches are insufficient for analyzing perturbation data that can contain information about multiple features (e.g. abundance, activity or localization) of each biomarker. Results: We propose a computational framework for inferring phenotypic crosstalk (PHOCOS) that is suitable for high-content microscopy or other modalities that capture multiple phenotypes per biomarker. PHOCOS uses a robust graph-learning paradigm to predict direct effects from potential indirect effects and identify errors owing to noise or missing links. The result is a multi-feature, sparse network that parsimoniously captures direct and strong interactions across phenotypic attributes of multiple biomarkers. We use simulated and biological data to demonstrate the ability of PHOCOS to recover multi-attribute crosstalk networks from cellular perturbation assays. Availability and implementation: PHOCOS is available in open source at https://github.com/AltschulerWu-Lab/PHOCOS Contact: steven.altschuler@ucsf.edu or lani.wu@ucsf.edu PMID:27307643

  6. ELECTRORETINOGRAPHIC FEATURES OF THE RETINOPATHY, GLOBE ENLARGED (RGE) CHICK PHENOTYPE.

    EPA Science Inventory

    A manuscript examines the retinal changes in an avian model of inherited loss of vision. Avian models of eye diseases that affect humans have previously been identified. Characterizing the phenotype of the rge strain is a necessary step in determining whether the loss of vision...

  7. Phenotypic Involvement in Females with the FMR1 Gene Mutation.

    ERIC Educational Resources Information Center

    Riddle, J. E.; Cheema, A.; Sobesky, W. E.; Gardner, S. C.; Taylor, A. K.; Pennington, B. F.; Hagerman, R. J.

    1998-01-01

    A study investigated phenotypic effects seen in 114 females with premutation and 41 females (ages 18-58) with full Fragile X mental retardation gene mutation. Those with the full mutation had a greater incidence of hand-flapping, eye contact problems, special education help for reading and math, and grade retention. (Author/CR)

  8. Genomic Evaluations with Many More Genotypes and Phenotypes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Reliabilities of genomic evaluations increase when more genotypes are matched to more phenotypes. Options to expand genomic evaluation include genotyping more animals or markers; combining data sets across breed and geographical borders; using low cost, less dense marker subsets to obtain genotypes ...

  9. Phenotypes and genotypes in epilepsy with febrile seizures plus.

    PubMed

    Ito, M; Yamakawa, K; Sugawara, T; Hirose, S; Fukuma, G; Kaneko, S

    2006-08-01

    In the last several years, mutations of sodium channel genes, SCN1A, SCN2A, and SCN1B, and GABA(A) receptor gene, GABRG2 were identified as causes of some febrile seizures related epilepsies. In 19 unrelated Japanese families whose probands had febrile seizures plus or epilepsy following febrile seizures plus, we identified 2 missense mutations of SCN1A to be responsible for the seizure phenotypes in two FS+ families and another mutation of SCN2A in one family. The combined frequency of SCN1A, SCN2A, SCN1B, SCN2B, and GABRG2 mutations in Japanese patients with FS+ was 15.8%. One family, which had R188W mutation in SCN2A, showed digenic inheritance, and another modifier gene was thought to take part in the seizure phenotype. The phenotypes of probands were FS+ in 5, FS+ and partial epilepsy in 10, FS+ and generalized epilepsy in 3, and FS+ and unclassified epilepsy in 1. We proposed the term epilepsy with febrile seizures plus (EFS+), because autosomal-dominant inheritance in EFS+ might be rare, and most of EFS+ display a complex pattern of inheritance, even when it appears to be an autosomal-dominant inheritance. There is a possibility of simultaneous involvement of multiple genes for seizure phenotypes. PMID:16884893

  10. Maternal Vitamin D Levels and the Autism Phenotype among Offspring

    ERIC Educational Resources Information Center

    Whitehouse, Andrew J. O.; Holt, Barbara J.; Serralha, Michael; Holt, Patrick G.; Hart, Prue H.; Kusel, Merci M. H.

    2013-01-01

    We tested whether maternal vitamin D insufficiency during pregnancy is related to the autism phenotype. Serum 25(OH)-vitamin D concentrations of 929 women were measured at 18 weeks' pregnancy. The mothers of the three children with a clinical diagnosis of autism spectrum disorder had 25(OH)-vitamin D concentrations above the population mean.…

  11. Genomic Evaluations With Many More Genotypes And Phenotypes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Reliabilities of genomic evaluations increase when more genotypes are matched to more phenotypes. Options to expand genomic evaluation include genotyping more animals or markers; combining data sets across breed and geographical borders; using low cost, less dense marker subsets to obtain genotypes ...

  12. Standardized phenotyping: advantages to horticulture, introduction to the workshop

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This article introduces a workshop on standardized phenotyping and the advantages it provides for horticultural crops. The workshop was held at the 2009 American Society for Horticultural Science Annual Conference in St. Louis, MO, and was organized by the Genetics and Germplasm Working Group. The o...

  13. Association Between Serum Osteocalcin and Markers of Metabolic Phenotype

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Osteocalcin has been recently reported to contribute to the regulation of glucose tolerance and insulin secretion and sensitivity in experimental animals; however, the data in humans are sparse. To examine the association between serum osteocalcin concentration and markers of dysmetabolic phenotype...

  14. Myelin alters the inflammatory phenotype of macrophages by activating PPARs

    PubMed Central

    2013-01-01

    Background Foamy macrophages, containing myelin degradation products, are abundantly found in active multiple sclerosis (MS) lesions. Recent studies have described an altered phenotype of macrophages after myelin internalization. However, mechanisms by which myelin affects the phenotype of macrophages and how this phenotype influences lesion progression remain unclear. Results We demonstrate that myelin as well as phosphatidylserine (PS), a phospholipid found in myelin, reduce nitric oxide production by macrophages through activation of peroxisome proliferator-activated receptor β/δ (PPARβ/δ). Furthermore, uptake of PS by macrophages, after intravenous injection of PS-containing liposomes (PSLs), suppresses the production of inflammatory mediators and ameliorates experimental autoimmune encephalomyelitis (EAE), an animal model of MS. The protective effect of PSLs in EAE animals is associated with a reduced immune cell infiltration into the central nervous system and decreased splenic cognate antigen specific proliferation. Interestingly, PPARβ/δ is activated in foamy macrophages in active MS lesions, indicating that myelin also activates PPARβ/δ in macrophages in the human brain. Conclusion Our data show that myelin modulates the phenotype of macrophages by PPAR activation, which may subsequently dampen MS lesion progression. Moreover, our results suggest that myelin-derived PS mediates PPARβ/δ activation in macrophages after myelin uptake. The immunoregulatory impact of naturally-occurring myelin lipids may hold promise for future MS therapeutics. PMID:24252308

  15. High-Throughput Quantification of Phenotype Heterogeneity Using Statistical Features

    PubMed Central

    Chaddad, Ahmad; Tanougast, Camel

    2015-01-01

    Statistical features are widely used in radiology for tumor heterogeneity assessment using magnetic resonance (MR) imaging technique. In this paper, feature selection based on decision tree is examined to determine the relevant subset of glioblastoma (GBM) phenotypes in the statistical domain. To discriminate between active tumor (vAT) and edema/invasion (vE) phenotype, we selected the significant features using analysis of variance (ANOVA) with p value < 0.01. Then, we implemented the decision tree to define the optimal subset features of phenotype classifier. Naïve Bayes (NB), support vector machine (SVM), and decision tree (DT) classifier were considered to evaluate the performance of the feature based scheme in terms of its capability to discriminate vAT from vE. Whole nine features were statistically significant to classify the vAT from vE with p value < 0.01. Feature selection based on decision tree showed the best performance by the comparative study using full feature set. The feature selected showed that the two features Kurtosis and Skewness achieved a highest range value of 58.33–75.00% accuracy classifier and 73.88–92.50% AUC. This study demonstrated the ability of statistical features to provide a quantitative, individualized measurement of glioblastoma patient and assess the phenotype progression. PMID:26640485

  16. Meningocele in a Congolese Female with Beckwith-Wiedemann Phenotype

    PubMed Central

    Mbuyi-Musanzayi, Sébastien; Lubala Kasole, Toni; Lumaka, Aimé; Kayembe Kitenge, Tony; Kabamba Ngombe, Leon; Kalenga Muenze, Prosper; Lukusa Tshilobo, Prosper; Tshilombo Katombe, François; Banza Lubaba Nkulu, Célestin; Devriendt, Koenraad

    2014-01-01

    Beckwith-Wiedemann syndrome (BWS) is a rare congenital syndrome characterized by an overgrowth, macroglossia, exomphalos, and predisposition to embryonal tumors. Central nervous abnormalities associated with BWS are rare. We describe a one-day-old Congolese female who presented meningocele associated with BWS phenotype. PMID:25610673

  17. Nonspecific phenotype of Noonan syndrome diagnosed by whole exome sequencing

    PubMed Central

    Coromilas, Alexandra; Wynn, Julia; Haverfield, Eden; Chung, Wendy K

    2015-01-01

    Key Clinical Message Noonan syndrome is a genetically heterogeneous condition primarily due to missense mutations in PTPN11. Prenatal diagnosis is typically made in a fetus with increased nuchal translucency and normal karyotype. We demonstrate the ability of whole exome sequencing to make prenatal diagnoses that would not have been made from phenotype alone. PMID:25914815

  18. Diet-induced phenotypic plasticity in European eel (Anguilla anguilla).

    PubMed

    De Meyer, Jens; Christiaens, Joachim; Adriaens, Dominique

    2016-02-01

    Two phenotypes are present within the European eel population: broad-heads and narrow-heads. The expression of these phenotypes has been linked to several factors, such as diet and differential growth. The exact factors causing this dimorphism, however, are still unknown. In this study, we performed a feeding experiment on glass eels from the moment they start to feed. Eels were either fed a hard diet, which required biting and spinning behavior, or a soft diet, which required suction feeding. We found that the hard feeders develop a broader head and a larger adductor mandibulae region than eels that were fed a soft diet, implying that the hard feeders are capable of larger bite forces. Next to this, soft feeders develop a sharper and narrower head, which could reduce hydrodynamic drag, allowing more rapid strikes towards their prey. Both phenotypes were found in a control group, which were given a combination of both diets. These phenotypes were, however, not as extreme as the hard or the soft feeding group, indicating that some specimens are more likely to consume hard prey and others soft prey, but that they do not selectively eat one of both diets. In conclusion, we found that diet is a major factor influencing head shape in European eel and this ability to specialize in feeding on hard or soft prey could decrease intra-specific competition in European eel populations. PMID:26847560

  19. The genomic and phenotypic diversity of Schizosaccharomyces pombe.

    PubMed

    Jeffares, Daniel C; Rallis, Charalampos; Rieux, Adrien; Speed, Doug; Převorovský, Martin; Mourier, Tobias; Marsellach, Francesc X; Iqbal, Zamin; Lau, Winston; Cheng, Tammy M K; Pracana, Rodrigo; Mülleder, Michael; Lawson, Jonathan L D; Chessel, Anatole; Bala, Sendu; Hellenthal, Garrett; O'Fallon, Brendan; Keane, Thomas; Simpson, Jared T; Bischof, Leanne; Tomiczek, Bartlomiej; Bitton, Danny A; Sideri, Theodora; Codlin, Sandra; Hellberg, Josephine E E U; van Trigt, Laurent; Jeffery, Linda; Li, Juan-Juan; Atkinson, Sophie; Thodberg, Malte; Febrer, Melanie; McLay, Kirsten; Drou, Nizar; Brown, William; Hayles, Jacqueline; Carazo Salas, Rafael E; Ralser, Markus; Maniatis, Nikolas; Balding, David J; Balloux, Francois; Durbin, Richard; Bähler, Jürg

    2015-03-01

    Natural variation within species reveals aspects of genome evolution and function. The fission yeast Schizosaccharomyces pombe is an important model for eukaryotic biology, but researchers typically use one standard laboratory strain. To extend the usefulness of this model, we surveyed the genomic and phenotypic variation in 161 natural isolates. We sequenced the genomes of all strains, finding moderate genetic diversity (π = 3 × 10(-3) substitutions/site) and weak global population structure. We estimate that dispersal of S. pombe began during human antiquity (∼340 BCE), and ancestors of these strains reached the Americas at ∼1623 CE. We quantified 74 traits, finding substantial heritable phenotypic diversity. We conducted 223 genome-wide association studies, with 89 traits showing at least one association. The most significant variant for each trait explained 22% of the phenotypic variance on average, with indels having larger effects than SNPs. This analysis represents a rich resource to examine genotype-phenotype relationships in a tractable model. PMID:25665008

  20. Genetic mechanisms involved in the phenotype of Down syndrome.

    PubMed

    Patterson, David

    2007-01-01

    Down syndrome (DS) is the most common genetic cause of significant intellectual disability in the human population, occurring in roughly 1 in 700 live births. The ultimate cause of DS is trisomy of all or part of the set of genes located on chromosome 21. How this trisomy leads to the phenotype of DS is unclear. The completion of the DNA sequencing and annotation of the long arm of chromosome 21 was a critical step towards understanding the genetics of the phenotype. However, annotation of the chromosome continues and the functions of many genes on chromosome 21 remain uncertain. Recent findings about the structure of the human genome and of chromosome 21, in particular, and studies on mechanisms of gene regulation indicate that various genetic mechanisms may be contributors to the phenotype of DS and to the variability of the phenotype. These include variability of gene expression, the activity of transcription factors both encoded on chromosome 21 and encoded elsewhere in the genome, copy number polymorphisms, the function of conserved nongenic regions, microRNA activities, RNA editing, and perhaps DNA methylation. In this manuscript, we describe current knowledge about these genetic complexities and their likely importance in the context of DS. We identify gaps in current knowledge and suggest priorities to fill these gaps. PMID:17910086

  1. Model Invariance across Genders of the Broad Autism Phenotype Questionnaire

    ERIC Educational Resources Information Center

    Broderick, Neill; Wade, Jordan L.; Meyer, J. Patrick; Hull, Michael; Reeve, Ronald E.

    2015-01-01

    ASD is one of the most heritable neuropsychiatric disorders, though comprehensive genetic liability remains elusive. To facilitate genetic research, researchers employ the concept of the broad autism phenotype (BAP), a milder presentation of traits in undiagnosed relatives. Research suggests that the BAP Questionnaire (BAPQ) demonstrates…

  2. The Cognitive and Behavioural Phenotype of Roifman Syndrome

    ERIC Educational Resources Information Center

    de Vries, P. J.; McCartney, D. L.; McCartney, E.; Woolf, D.; Wozencroft, D.

    2006-01-01

    Background: Roifman syndrome (OMIM 300258) is a multi-system disorder with a physical phenotype that includes B-cell immunodeficiency, intra-uterine and postnatal growth retardation, spondyloepiphyseal dysplasia, retinal dystrophy and characteristic facial dysmorphism. So far, six cases, all boys, have been reported in the literature. Roifman…

  3. Inference on biological mechanisms using an integrated phenotype prediction model.

    PubMed

    Enomoto, Yumi; Ushijima, Masaru; Miyata, Satoshi; Matsuura, Masaaki; Ohtaki, Megu

    2008-03-01

    We propose a methodology for constructing an integrated phenotype prediction model that accounts for multiple pathways regulating a targeted phenotype. The method uses multiple prediction models, each expressing a particular pattern of gene-to-gene interrelationship, such as epistasis. We also propose a methodology using Gene Ontology annotations to infer a biological mechanism from the integrated phenotype prediction model. To construct the integrated models, we employed multiple logistic regression models using a two-step learning approach to examine a number of patterns of gene-to-gene interrelationships. We first selected individual prediction models with acceptable goodness of fit, and then combined the models. The resulting integrated model predicts phenotype as a logical sum of predicted results from the individual models. We used published microarray data on neuroblastoma from Ohira et al (2005) for illustration, constructing an integrated model to predict prognosis and infer the biological mechanisms controlling prognosis. Although the resulting integrated model comprised a small number of genes compared to a previously reported analysis of these data, the model demonstrated excellent performance, with an error rate of 0.12 in a validation analysis. Gene Ontology analysis suggested that prognosis of patients with neuroblastoma may be influenced by biological processes such as cell growth, G-protein signaling, phosphoinositide-mediated signaling, alcohol metabolism, glycolysis, neurophysiological processes, and catecholamine catabolism. PMID:18578362

  4. The Broad Autism Phenotype. Findings from an Epidemiological Survey

    ERIC Educational Resources Information Center

    Micali, N.; Chakrabarti, S.; Fombonne, E.

    2004-01-01

    This study aimed to determine if relatives of children with autism and less severe pervasive developmental disorders (PDDs) have higher rates of various components of the broad autistic phenotype. Psychiatric and medical disorders were investigated. Parents of children with PDDs were selected from an epidemiological survey and compared with…

  5. Functionalities of expressed messenger RNAs revealed from mutant phenotypes.

    PubMed

    Liao, Ben-Yang; Weng, Meng-Pin

    2016-07-01

    Total messenger RNAs mRNAs that are produced from a given gene under a certain set of conditions include both functional and nonfunctional transcripts. The high prevalence of nonfunctional mRNAs that have been detected in cells has raised questions regarding the functional implications of mRNA expression patterns and divergences. Phenotypes that result from the mutagenesis of protein-coding genes have provided the most straightforward descriptions of gene functions, and such data obtained from model organisms have facilitated investigations of the functionalities of expressed mRNAs. Mutant phenotype data from mouse tissues have revealed various attributes of functional mRNAs, including tissue-specificity, strength of expression, and evolutionary conservation. In addition, the role that mRNA expression evolution plays in driving morphological evolution has been revealed from studies designed to exploit morphological and physiological phenotypes of mouse mutants. Investigations into yeast essential genes (defined by an absence of colony growth after gene deletion) have further described gene regulatory strategies that reduce protein expression noise by mediating the rates of transcription and translation. In addition to the functional significance of expressed mRNAs as described in the abovementioned findings, the functionalities of other type of RNAs (i.e., noncoding RNAs) remain to be characterized with systematic mutations and phenotyping of the DNA regions that encode these RNA molecules. WIREs RNA 2016, 7:416-427. doi: 10.1002/wrna.1329 For further resources related to this article, please visit the WIREs website. PMID:26748449

  6. Jacalin-Activated Macrophages Exhibit an Antitumor Phenotype.

    PubMed

    Danella Polli, Cláudia; Pereira Ruas, Luciana; Chain Veronez, Luciana; Herrero Geraldino, Thais; Rossetto de Morais, Fabiana; Roque-Barreira, Maria Cristina; Pereira-da-Silva, Gabriela

    2016-01-01

    Tumor-associated macrophages (TAMs) have an ambiguous and complex role in the carcinogenic process, since these cells can be polarized into different phenotypes (proinflammatory, antitumor cells or anti-inflammatory, protumor cells) by the tumor microenvironment. Given that the interactions between tumor cells and TAMs involve several players, a better understanding of the function and regulation of TAMs is crucial to interfere with their differentiation in attempts to skew TAM polarization into cells with a proinflammatory antitumor phenotype. In this study, we investigated the modulation of macrophage tumoricidal activities by the lectin jacalin. Jacalin bound to macrophage surface and induced the expression and/or release of mainly proinflammatory cytokines via NF-κB signaling, as well as increased iNOS mRNA expression, suggesting that the lectin polarizes macrophages toward the antitumor phenotype. Therefore, tumoricidal activities of jacalin-stimulated macrophages were evaluated. High rates of tumor cell (human colon, HT-29, and breast, MCF-7, cells) apoptosis were observed upon incubation with supernatants from jacalin-stimulated macrophages. Taken together, these results indicate that jacalin, by exerting a proinflammatory activity, can direct macrophages to an antitumor phenotype. Deep knowledge of the regulation of TAM functions is essential for the development of innovative anticancer strategies. PMID:27119077

  7. Inherited PTEN mutations and the prediction of phenotype.

    PubMed

    Leslie, Nicholas R; Longy, Michel

    2016-04-01

    PTEN has been heavily studied due to its role as a tumour suppressor and as a core inhibitory component of the phosphoinositide 3-kinase (PI3K) signalling network. It is a broadly expressed phosphatase which displays complexity and diversity in both its functions and regulation and accordingly, in the laboratory numerous classes of functionally distinct mutations have been generated. Inherited loss of function mutations in the PTEN gene were originally identified in sufferers of Cowden disease, but later shown to associate with more diverse human pathologies, mostly relating to cell and tissue overgrowth, leading to the use of the broader term, PTEN Hamartoma Tumour Syndrome. Recent phenotypic analysis of clinical cohorts of PTEN mutation carriers, combined with laboratory studies of the consequences of these mutations implies that stable catalytically inactive PTEN mutants may lead to the most severe phenotypes, and conversely, that mutants retaining partial function associate more frequently with a milder phenotype, with autism spectrum disorder often being diagnosed. Future work will be needed to confirm and to refine these genotype-phenotype relationships and convert this developing knowledge into improved patient management and potentially treatment with emerging drugs which target the PI3K pathway. PMID:26827793

  8. The physical basis of how prion conformations determine strain phenotypes

    NASA Astrophysics Data System (ADS)

    Tanaka, Motomasa; Collins, Sean R.; Toyama, Brandon H.; Weissman, Jonathan S.

    2006-08-01

    A principle that has emerged from studies of protein aggregation is that proteins typically can misfold into a range of different aggregated forms. Moreover, the phenotypic and pathological consequences of protein aggregation depend critically on the specific misfolded form. A striking example of this is the prion strain phenomenon, in which prion particles composed of the same protein cause distinct heritable states. Accumulating evidence from yeast prions such as [PSI+] and mammalian prions argues that differences in the prion conformation underlie prion strain variants. Nonetheless, it remains poorly understood why changes in the conformation of misfolded proteins alter their physiological effects. Here we present and experimentally validate an analytical model describing how [PSI+] strain phenotypes arise from the dynamic interaction among the effects of prion dilution, competition for a limited pool of soluble protein, and conformation-dependent differences in prion growth and division rates. Analysis of three distinct prion conformations of yeast Sup35 (the [PSI+] protein determinant) and their in vivo phenotypes reveals that the Sup35 amyloid causing the strongest phenotype surprisingly shows the slowest growth. This slow growth, however, is more than compensated for by an increased brittleness that promotes prion division. The propensity of aggregates to undergo breakage, thereby generating new seeds, probably represents a key determinant of their physiological impact for both infectious (prion) and non-infectious amyloids.

  9. Phenotypic differences among three clonal lineages of Phytophthora ramorum

    Technology Transfer Automated Retrieval System (TEKTRAN)

    There are three major clonal lineages of Phytophthora ramorum present in North America and Europe named NA1, NA2, and EU1. Twenty-three isolates representing all three lineages were evaluated for phenotype including (i) aggressiveness on detached Rhododendron leaves and (ii) growth rate at minimum, ...

  10. Use of microdose phenotyping to individualise dosing of patients.

    PubMed

    Hohmann, Nicolas; Haefeli, Walter E; Mikus, Gerd

    2015-09-01

    Administering the right amount of the right drug at the right time is a key mission of clinical medicine. This comprises dose adaptation according to a patient's intrinsic and extrinsic factors influencing drug disposition. Several biomarkers are available for dose adaptation; still, prediction of individual drug disposition may be improved. Phenotyping is the quantification of drug metabolism with probe substrates specific to drug-metabolising enzymes. This allows measurement of baseline metabolism and changes after modulation of drug metabolism. This article explores the concept of phenotyping using pharmacologically ineffective microdoses of probe substrates to obtain information on drug metabolism. Several probe drugs such as midazolam for cytochrome P450 3A have already been used, but validation of other microdosed probe drugs, analytical procedures and drug formulations still face some challenges that have to be overcome. Since microdosed probe drugs have no risk of adverse drug reactions or interference with therapy, more widespread use is possible. This allows drug-drug interaction data to be safely obtained during first-in-man studies, enhancing the clinical safety of human healthy volunteers and patients in clinical trials, and, most importantly, allows determination of the drug-metabolising phenotype in severely ill patients. With harmless probe drugs at hand quantifying drug metabolism and adapting the dose accordingly, a phenotyping-based dosing strategy could become reality, offering the possibility of individualised drug therapy with reduced adverse effects and fewer therapeutic failures. PMID:25925712

  11. Phenotyping and genotyping RIL populations of peanut for marker development

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Phenotyping of structured populations, along with molecular genotyping, is needed for marker development in peanut. This research is essential for making the peanut genome sequence useful to breeders because it will make the connection between genes, gene markers, genetic maps, and agronomic traits...

  12. Cognitive Flexibility in Phenotypes of Pediatric Bipolar Disorder

    ERIC Educational Resources Information Center

    Dickstein, Daniel P.; Nelson, Eric E.; McClure, Erin B.; Grimley, Mary E.; Knopf, Lisa; Brotman, Melissa A.; Rich, Brendan A.; Pine, Daniel S.; Leibenluft, Ellen

    2007-01-01

    Objective: Clinicians and researchers debate whether children with chronic, nonepisodic irritability should receive the diagnosis of bipolar disorder (BD). To address this debate, we evaluated cognitive flexibility, or the ability to adapt to changing contingencies, in three groups of children: narrow-phenotype BD (NP-BD; full-duration manic…

  13. Genotypic and phenotypic detection of efflux pump in Rhodococcus equi

    PubMed Central

    Gressler, Letícia Trevisan; de Vargas, Agueda Castagna; da Costa, Mateus Matiuzzi; Pötter, Luciana; da Silveira, Bibiana Petri; Sangioni, Luis Antônio; de Avila Botton, Sônia

    2014-01-01

    The req_39680 gene, associated to a putative efflux system, was detected in 60% (54/90) of R. equi isolates by PCR. The phenotypic expression of efflux mechanism was verified in 20% of the isolates using ethidium bromide. For the first time, the expression of efflux mechanism was demonstrated in R. equi. PMID:25242956

  14. Macrophage Phenotype and Function in Different Stages of Atherosclerosis.

    PubMed

    Tabas, Ira; Bornfeldt, Karin E

    2016-02-19

    The remarkable plasticity and plethora of biological functions performed by macrophages have enticed scientists to study these cells in relation to atherosclerosis for >50 years, and major discoveries continue to be made today. It is now understood that macrophages play important roles in all stages of atherosclerosis, from initiation of lesions and lesion expansion, to necrosis leading to rupture and the clinical manifestations of atherosclerosis, to resolution and regression of atherosclerotic lesions. Lesional macrophages are derived primarily from blood monocytes, although recent research has shown that lesional macrophage-like cells can also be derived from smooth muscle cells. Lesional macrophages take on different phenotypes depending on their environment and which intracellular signaling pathways are activated. Rather than a few distinct populations of macrophages, the phenotype of the lesional macrophage is more complex and likely changes during the different phases of atherosclerosis and with the extent of lipid and cholesterol loading, activation by a plethora of receptors, and metabolic state of the cells. These different phenotypes allow the macrophage to engulf lipids, dead cells, and other substances perceived as danger signals; efflux cholesterol to high-density lipoprotein; proliferate and migrate; undergo apoptosis and death; and secrete a large number of inflammatory and proresolving molecules. This review article, part of the Compendium on Atherosclerosis, discusses recent advances in our understanding of lesional macrophage phenotype and function in different stages of atherosclerosis. With the increasing understanding of the roles of lesional macrophages, new research areas and treatment strategies are beginning to emerge. PMID:26892964

  15. Genetic Mechanisms Involved in the Phenotype of Down Syndrome

    ERIC Educational Resources Information Center

    Patterson, David

    2007-01-01

    Down syndrome (DS) is the most common genetic cause of significant intellectual disability in the human population, occurring in roughly 1 in 700 live births. The ultimate cause of DS is trisomy of all or part of the set of genes located on chromosome 21. How this trisomy leads to the phenotype of DS is unclear. The completion of the DNA…

  16. Elastase Deficiency Phenotype of Pseudomonas aeruginosa Canine Otitis Externa Isolates

    PubMed Central

    Petermann, Shana R.; Doetkott, Curt; Rust, Lynn

    2001-01-01

    Pseudomonas aeruginosa veterinary isolates were assayed for elastase and total matrix protease activity. The elastase activity of canine ear isolates was much less than that of strain PAO1 and that of all other veterinary isolates (P < 0.0001). The results indicate that canine ear isolates have a distinct elastase phenotype. PMID:11329471

  17. Skeletal muscle calcineurin: influence of phenotype adaptation and atrophy

    NASA Technical Reports Server (NTRS)

    Spangenburg, E. E.; Williams, J. H.; Roy, R. R.; Talmadge, R. J.; Spangenberg, E. E. (Principal Investigator)

    2001-01-01

    Calcineurin (CaN) has been implicated as a signaling molecule that can transduce physiological stimuli (e.g., contractile activity) into molecular signals that initiate slow-fiber phenotypic gene expression and muscle growth. To determine the influence of muscle phenotype and atrophy on CaN levels in muscle, the levels of soluble CaN in rat muscles of varying phenotype, as assessed by myosin heavy chain (MHC)-isoform proportions, were determined by Western blotting. CaN levels were significantly greater in the plantaris muscle containing predominantly fast (IIx and IIb) MHC isoforms, compared with the soleus (predominantly type I MHC) or vastus intermedius (VI, contains all 4 adult MHC isoforms). Three months after a complete spinal cord transection (ST), the CaN levels in the VI muscle were significantly reduced, despite a significant increase in fast MHC isoforms. Surprisingly, the levels of CaN in the VI were highly correlated with muscle mass but not MHC isoform proportions in ST and control rats. These data demonstrate that CaN levels in skeletal muscle are highly correlated to muscle mass and that the normal relationship with phenotype is lost after ST.

  18. Psychiatric and Cognitive Phenotype of Childhood Myotonic Dystrophy Type 1

    ERIC Educational Resources Information Center

    Douniol, Marie; Jacquette, Aurelia; Cohen, David; Bodeau, Nicolas; Rachidi, Linda; Angeard, Nathalie; Cuisset, Jean-Marie; Vallee, Louis; Eymard, Bruno; Plaza, Monique; Heron, Delphine; Guile, Jean-Marc

    2012-01-01

    Aim: To investigate the psychiatric and cognitive phenotype in young individuals with the childhood form of myotonic dystrophy type 1 (DM1). Method: Twenty-eight individuals (15 females, 13 males) with childhood DM1 (mean age 17y, SD 4.6, range 7-24y) were assessed using standardized instruments and cognitive testing of general intelligence,…

  19. Modeling nuisance variables for phenotypic evaluation of bull fertility

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This research determined which (available) nuisance variables should be included in a model for phenotypic evaluation of US service sire conception rate (CR), based on DHI data. Models were compared by splitting data into records for estimation (n=3,613,907) and set-aside data (n=2,025,884), computi...

  20. Identifying neurobiological phenotypes associated with alcohol use disorder severity.

    PubMed

    Claus, Eric D; Ewing, Sarah W Feldstein; Filbey, Francesca M; Sabbineni, Amithrupa; Hutchison, Kent E

    2011-09-01

    Although numerous studies provide general support for the importance of genetic factors in the risk for alcohol use disorders (AUDs), candidate gene and genome-wide studies have yet to identify a set of genetic variations that explain a significant portion of the variance in AUDs. One reason is that alcohol-related phenotypes used in genetic studies are typically based on highly heterogeneous diagnostic categories. Therefore, identifying neurobiological phenotypes related to neuroadaptations that drive the development of AUDs is critical for the future success of genetic and epigenetic studies. One such neurobiological phenotype is the degree to which exposure to alcohol taste cues recruits the basal ganglia, prefrontal cortex, and motor areas, all of which have been shown to have a critical role in addictive behaviors in animal studies. To that end, this study was designed to examine whether cue-elicited responses of these structures are associated with AUD severity in a large sample (n=326) using voxelwise and functional connectivity measures. Results suggested that alcohol cues significantly activated dorsal striatum, insula/orbitofrontal cortex, anterior cingulate cortex, and ventral tegmental area. AUD severity was moderately correlated with regions involved in incentive salience such as the nucleus accumbens and amygdala, and stronger relationships with precuneus, insula, and dorsal striatum. The findings indicate that AUDs are related to neuroadaptations in these regions and that these measures may represent important neurobiological phenotypes for subsequent genetic studies. PMID:21677649

  1. A novel clinical tool to classify facioscapulohumeral muscular dystrophy phenotypes.

    PubMed

    Ricci, Giulia; Ruggiero, Lucia; Vercelli, Liliana; Sera, Francesco; Nikolic, Ana; Govi, Monica; Mele, Fabiano; Daolio, Jessica; Angelini, Corrado; Antonini, Giovanni; Berardinelli, Angela; Bucci, Elisabetta; Cao, Michelangelo; D'Amico, Maria Chiara; D'Angelo, Grazia; Di Muzio, Antonio; Filosto, Massimiliano; Maggi, Lorenzo; Moggio, Maurizio; Mongini, Tiziana; Morandi, Lucia; Pegoraro, Elena; Rodolico, Carmelo; Santoro, Lucio; Siciliano, Gabriele; Tomelleri, Giuliano; Villa, Luisa; Tupler, Rossella

    2016-06-01

    Based on the 7-year experience of the Italian Clinical Network for FSHD, we revised the FSHD clinical form to describe, in a harmonized manner, the phenotypic spectrum observed in FSHD. The new Comprehensive Clinical Evaluation Form (CCEF) defines various clinical categories by the combination of different features. The inter-rater reproducibility of the CCEF was assessed between two examiners using kappa statistics by evaluating 56 subjects carrying the molecular marker used for FSHD diagnosis. The CCEF classifies: (1) subjects presenting facial and scapular girdle muscle weakness typical of FSHD (category A, subcategories A1-A3), (2) subjects with muscle weakness limited to scapular girdle or facial muscles (category B subcategories B1, B2), (3) asymptomatic/healthy subjects (category C, subcategories C1, C2), (4) subjects with myopathic phenotype presenting clinical features not consistent with FSHD canonical phenotype (D, subcategories D1, D2). The inter-rater reliability study showed an excellent concordance of the final four CCEF categories with a κ equal to 0.90; 95 % CI (0.71; 0.97). Absolute agreement was observed for categories C and D, an excellent agreement for categories A [κ = 0.88; 95 % CI (0.75; 1.00)], and a good agreement for categories B [κ = 0.79; 95 % CI (0.57; 1.00)]. The CCEF supports the harmonized phenotypic classification of patients and families. The categories outlined by the CCEF may assist diagnosis, genetic counseling and natural history studies. Furthermore, the CCEF categories could support selection of patients in randomized clinical trials. This precise categorization might also promote the search of genetic factor(s) contributing to the phenotypic spectrum of disease. PMID:27126453

  2. Cytochrome P450 reaction-phenotyping: an industrial perspective.

    PubMed

    Zhang, Hongjian; Davis, Carl D; Sinz, Michael W; Rodrigues, A David

    2007-10-01

    It is now widely accepted that the fraction of the dose metabolized by a given drug-metabolizing enzyme is one of the major factors governing the magnitude of a drug interaction and the impact of a polymorphism on (total) drug clearance. Therefore, most pharmaceutical companies determine the enzymes involved in the metabolism of a new chemical entity (NCE) in vitro, in conjunction with human data on absorption, distribution, metabolism and excretion. This so called reaction-phenotyping, or isozyme-mapping, usually involves the use of multiple reagents (e.g., recombinant proteins, liver subcellular fractions, enzyme-selective chemical inhibitors and antibodies). For the human CYPs, reagents are readily available and in vitro reaction-phenotyping data are now routinely included in most regulatory documents. Ideally, the various metabolites have been definitively identified, incubation conditions have afforded robust kinetic analyses, and well characterized (high quality) reagents and human tissues have been employed. It is also important that the various in vitro data are consistent (e.g., scaled turnover with recombinant CYP proteins, CYP inhibition and correlation data with human liver microsomes) and enable an integrated in vitro CYP reaction-phenotype. Results of the in vitro CYP reaction-phenotyping are integrated with clinical data (e.g., human radiolabel and drug interaction studies) and a complete package is then submitted for regulatory review. If the NCE receives market approval, information on key routes of clearance and their associated potential for drug-drug interactions are included in the product label. The present review focuses on in vitro CYP reaction-phenotyping and the integration of data. Relatively simple strategies enabling the design and prioritization of follow up clinical studies are also discussed. PMID:17916054

  3. Phenotype profile of a genetic mouse model for Muenke syndrome

    PubMed Central

    Koyama, Eiki; Agochukwu, Nneamaka B.; Bartlett, Scott P.; Muenke, Maximilian

    2014-01-01

    Purpose The Muenke syndrome mutation (FGFR3P250R), which was discovered 15 years ago, represents the single most common craniosynostosis mutation. Muenke syndrome is characterized by coronal suture synostosis, mid-face hypoplasia, subtle limb anomalies, and hearing loss. However, the spectrum of clinical presentation continues to expand. To better understand the pathophysiology of the Muenke syndrome, we present collective findings from several recent studies that have characterized a genetically equivalent mouse model for Muenke syndrome (FgfR3P244R) and compare them with human phenotypes. Conclusions FgfR3P244R mutant mice show premature fusion of facial sutures, premaxillary and/or zygomatic sutures, but rarely the coronal suture. The mice also lack the typical limb phenotype. On the other hand, the mutant mice display maxillary retrusion in association with a shortening of the anterior cranial base and a premature closure of intersphenoidal and spheno-occipital synchondroses, resembling human midface hypoplasia. In addition, sensorineural hearing loss is detected in all FgfR3P244R mutant mice as in the majority of Muenke syndrome patients. It is caused by a defect in the mechanism of cell fate determination in the organ of Corti. The mice also express phenotypes that have not been previously described in humans, such as reduced cortical bone thickness, hypoplastic trabecular bone, and defective temporomandibular joint structure. Therefore, the FgfR3P244R mouse provides an excellent opportunity to study disease mechanisms of some classical phenotypes of Muenke syndrome and to test novel therapeutic strategies. The mouse model can also be further explored to discover previously unreported yet potentially significant phenotypes of Muenke syndrome. PMID:22872265

  4. Phenotypic Characteristics of Vancomycin-Non-Susceptible Staphylococcus aureus

    PubMed Central

    Sirichoat, Auttawit; Wongthong, Sujintana; Kanyota, Ratdawan; Tavichakorntrakool, Ratree; Chanawong, Aroonwadee; Welbat, Jariya Umka; Lulitanond, Aroonlug

    2016-01-01

    Background: Staphylococcus aureus, with reduced vancomycin susceptibility, is probably under the regulation of several genes and various express phenotypes. Objectives: This study aimed to investigate the phenotypic differences between vancomycin-susceptible S. aureus (VSSA), vancomycin-intermediate S. aureus (VISA), and heterogeneous VISA (hVISA) isolates. Materials and Methods: A total of 130 methicillin-resistant S. aureus (MRSA) isolates were studied, including 49 VSSA, 28 hVISA, and 5 VISA isolates from blood cultures and 48 isolates (two VSSA, six hVISA, and 40 VISA) derived in vitro (laboratory-induced/sub-passaged). Their phenotypes were examined using a coagulase tube test, colony spreading on soft agar, and urease activity. The SCCmec and agr typing were performed using multiplex PCR. Results: Most of the MRSA isolates were SCCmec III-agr I (84.5%), followed by SCCmec II-agr II (11.8%). The average plasma coagulation time of vancomycin-non-susceptible isolates was longer than that of the susceptible isolates (12 vs. 2.6 hours). Four hVISA (P = 0.023) and nine VISA (P < 0.001) isolates yielded a negative coagulase test after 24-hour incubation. The percentage of VSSA isolates showing non-spreading colonies (accessory gene regulator (agr) dysfunction) was significantly lower than in the VISA group (P = 0.013), but no significant difference was found between VSSA and hVISA. The VISA group showed higher urease activity than that of the VSSA and hVISA groups (P = 0.002). Conclusions: There were diverse phenotypic changes among vancomycin-non-susceptible S. aureus isolates. This may be due to the variety of related regulatory systems. The diversity of phenotypic expression may result in its misidentification in routine laboratory checks. PMID:27099678

  5. Identifying phenotypic signatures of neuropsychiatric disorders from electronic medical records

    PubMed Central

    Lyalina, Svetlana; Percha, Bethany; LePendu, Paea; Iyer, Srinivasan V; Altman, Russ B; Shah, Nigam H

    2013-01-01

    Objective Mental illness is the leading cause of disability in the USA, but boundaries between different mental illnesses are notoriously difficult to define. Electronic medical records (EMRs) have recently emerged as a powerful new source of information for defining the phenotypic signatures of specific diseases. We investigated how EMR-based text mining and statistical analysis could elucidate the phenotypic boundaries of three important neuropsychiatric illnesses—autism, bipolar disorder, and schizophrenia. Methods We analyzed the medical records of over 7000 patients at two facilities using an automated text-processing pipeline to annotate the clinical notes with Unified Medical Language System codes and then searching for enriched codes, and associations among codes, that were representative of the three disorders. We used dimensionality-reduction techniques on individual patient records to understand individual-level phenotypic variation within each disorder, as well as the degree of overlap among disorders. Results We demonstrate that automated EMR mining can be used to extract relevant drugs and phenotypes associated with neuropsychiatric disorders and characteristic patterns of associations among them. Patient-level analyses suggest a clear separation between autism and the other disorders, while revealing significant overlap between schizophrenia and bipolar disorder. They also enable localization of individual patients within the phenotypic ‘landscape’ of each disorder. Conclusions Because EMRs reflect the realities of patient care rather than idealized conceptualizations of disease states, we argue that automated EMR mining can help define the boundaries between different mental illnesses, facilitate cohort building for clinical and genomic studies, and reveal how clear expert-defined disease boundaries are in practice. PMID:23956017

  6. The puzzle of immune phenotypes of childhood asthma.

    PubMed

    Landgraf-Rauf, Katja; Anselm, Bettina; Schaub, Bianca

    2016-12-01

    Asthma represents the most common chronic childhood disease worldwide. Whereas preschool children present with wheezing triggered by different factors (multitrigger and viral wheeze), clinical asthma manifestation in school children has previously been classified as allergic and non-allergic asthma. For both, the underlying immunological mechanisms are not yet understood in depth in children. Treatment is still prescribed regardless of underlying mechanisms, and children are not always treated successfully. This review summarizes recent key findings on the complex mechanisms of the development and manifestation of childhood asthma. Whereas traditional classification of childhood asthma is primarily based on clinical symptoms like wheezing and atopy, novel approaches to specify asthma phenotypes are under way and face challenges such as including the stability of phenotypes over time and transition into adulthood. Epidemiological studies enclose more information on the patient's disease history and environmental influences. Latest studies define endotypes based on molecular and cellular mechanisms, for example defining risk and protective single nucleotide polymorphisms (SNPs) and new immune phenotypes, showing promising results. Also, regulatory T cells and recently discovered T helper cell subtypes such as Th9 and Th17 cells were shown to be important for the development of asthma. Innate lymphoid cells (ILC) could play a critical role in asthma patients as they produce different cytokines associated with asthma. Epigenetic findings showed different acetylation and methylation patterns for children with allergic and non-allergic asthma. On a posttranscriptional level, miRNAs are regulating factors identified to differ between asthma patients and healthy controls and also indicate differences within asthma phenotypes. Metabolomics is another exciting chapter important for endotyping asthmatic children. Despite the development of new biomarkers and the discovery of

  7. Differentiating Asthma Phenotypes in Young Adults through Polyclonal Cytokine Profiles

    PubMed Central

    Zoratti, Edward; Havstad, Suzanne; Wegienka, Ganesa; Nicholas, Charlotte; Bobbitt, Kevin R.; Woodcroft, Kimberley J.; Ownby, Dennis R.; Johnson, Christine Cole

    2014-01-01

    Background Recent research has emphasized the need to better discriminate asthma phenotypes and consider underlying mechanistic endotypes in epidemiological and clinical studies. While allergic asthma and non-allergic asthma are frequently combined into one disease category in observational research and clinical trials, few studies have investigated the extent to which these two separate phenotypes are associated with distinct cytokine immunological profiles in a representative young adult population. Objective To investigate the cytokine production-based endotypes underlying the clinical phenotypes of allergic and non-allergic asthma among a population-based birth cohort evaluated as young adults. Methods Subjects included 18–21 year-old members (n=540) of a suburban Detroit birth cohort study, the Childhood Allergy Study. PMA-stimulated whole blood IL4, IL5, IL10, IL12, IL13, IL17A, IL17F, IL22 and IFNγ secretory responses were analyzed for associations comparing participants with allergic versus non-allergic asthma phenotypes to those without asthma. Results Th2-polarized responses, measured as higher mean IL5 and IL13 secretion and lower ratios of IFNγ and IL12 to three Th2 cytokines IL4, IL5, or IL13, were observed only in allergic asthmatics. Non-allergic asthma was associated with Th1-polarized responses including higher adjusted IFNγ secretion compared to both allergic asthmatics and surprisingly, to those without asthma [OR=2.5 (1.2–5.1), p<0.01]. Conclusions As expected, young adults with a history of an allergic asthma phenotype exhibit a Th2-polarized cytokine response after polyclonal stimulation. However, Th1-polarization was observed in subjects with a history of non-allergic asthma. Allergic and non-allergic asthma are associated with etiologically distinct immune endotypes underscoring the importance of discriminating these endotypes in research analyses and clinical management. PMID:24801891

  8. Alteration of fibroblast phenotype by asbestos-induced autoantibodies.

    PubMed

    Pfau, Jean C; Li, Sheng'ai; Holland, Sara; Sentissi, Jami J

    2011-06-01

    Pulmonary fibrosis is a relentlessly progressive disease for which the etiology can be idiopathic or associated with environmental or occupational exposures. There is not a clear explanation for the chronic and progressive nature of the disease, leaving treatment and prevention options limited. However, there is increasing evidence of an autoimmune component, since fibrotic diseases are often accompanied by production of autoantibodies. Because exposure to silicates such as silica and asbestos can lead to both autoantibodies and pulmonary/pleural fibrosis, these exposures provide an excellent tool for examining the relationship between these outcomes. This study explored the possibility that autoantibodies induced by asbestos exposure in mice would affect fibroblast phenotype. L929 fibroblasts and primary lung fibroblasts were treated with serum IgG from asbestos- or saline-treated mice, and tested for binding using cell-based ELISA, and for phenotypic changes using immunofluorescence, laser scanning cytometry and Sirius Red collagen assay. Autoantibodies in the serum of C57Bl/6 mice exposed to asbestos (but not sera from untreated mice) bound to mouse fibroblasts. The autoantibodies induced differentiation to a myofibroblast phenotype, as demonstrated by increased expression of smooth muscle α-actin (SMA), which was lost when the serum was cleared of IgG. Cells treated with purified IgG of exposed mice produced excess collagen. Using ELISA, we tested serum antibody binding to DNA topoisomerase (Topo) I, vimentin, TGFβ-R, and PDGF-Rα. Antibodies to DNA Topo I and to PDGF-Rα were detected, both of which have been shown by others to be able to affect fibroblast phenotype. The anti-fibroblast antibodies (AFA) also induced STAT-1 activation, implicating the PDGF-R pathway as part of the response to AFA binding. These data support the hypothesis that asbestos induces AFA that modify fibroblast phenotype, and suggest a mechanism whereby autoantibodies may mediate

  9. Phenotypic variation and genotype-phenotype discordance in canine cone-rod dystrophy with an RPGRIP1 mutation

    PubMed Central

    Kato, Kumiko; Aguirre-Hernández, Jesús; Tokuriki, Tsuyoshi; Morimoto, Kyohei; Busse, Claudia; Barnett, Keith; Holmes, Nigel; Ogawa, Hiroyuki; Sasaki, Nobuo; Mellersh, Cathryn S.; Sargan, David R.

    2009-01-01

    Purpose Previously, a 44 bp insertion in exon 2 of retinitis pigmentosa GTPase interacting protein 1 (RPGRIP1) was identified as the cause of cone-rod dystrophy 1 (cord1), a recessive form of progressive retinal atrophy (PRA) in the Miniature Longhaired Dachshund (MLHD), a dog model for Leber congenital amaurosis. The cord1 locus was mapped using MLHDs from an inbred colony with a homogeneous early onset disease phenotype. In this paper, the MLHD pet population was studied to investigate phenotypic variation and genotype-phenotype correlation. Further, the cord1 locus was fine-mapped using PRA cases from the MLHD pet population to narrow the critical region. Other dog breeds were also screened for the RGPRIP1 insertion. Methods This study examined phenotypic variation in an MLHD pet population that included 59 sporadic PRA cases and 18 members of an extended family with shared environment and having six PRA cases. Ophthalmologic evaluations included behavioral abnormalities, responses to menace and light, fundoscopy, and electroretinography (ERG). The RPGRIP1 insertion was screened for in all cases and 200 apparently normal control MLHDs and in 510 dogs from 66 other breed. To fine-map the cord1 locus in the MLHD, 74 PRA cases and 86 controls aged 4 years or more were genotyped for 24 polymorphic markers within the previously mapped cord1 critical region of 14.15 Mb. Results Among sporadic PRA cases from the MLHD pet population, the age of onset varied from 4 months to 15 years old; MLHDs from the extended family also showed variable onset and rate of progression. Screening for the insertion in RPGRIP1 identified substantial genotype-phenotype discordance: 16% of controls were homozygous for the insertion (RPGRIP1−/−), while 20% of PRA cases were not homozygous for it. Four other breeds were identified to carry the insertion including English Springer Spaniels and Beagles with insertion homozygotes. The former breed included both controls and PRA cases, yet in

  10. Phenotypic and genetic characterization of a novel phenotype in pigs characterized by juvenile hairlessness and age dependent emphysema

    PubMed Central

    Bruun, Camilla S; Jørgensen, Claus B; Bay, Lene; Cirera, Susanna; Jensen, Henrik E; Leifsson, Páll S; Nielsen, Jens; Christensen, Knud; Fredholm, Merete

    2008-01-01

    Background A pig phenotype characterized by juvenile hairlessness, thin skin and age dependent lung emphysema has been discovered in a Danish pig herd. The trait shows autosomal co-dominant inheritance with all three genotypes distinguishable. Since the phenotype shows resemblance to the integrin β6 -/- knockout phenotype seen in mice, the two genes encoding the two subunits of integrin αvβ6, i.e. ITGB6 and ITGAV, were considered candidate genes for this trait. Results The mutated pig phenotype is characterized by hairlessness until puberty, thin skin with few hair follicles and absence of musculi arrectores pili, and at puberty or later localized areas of emphysema are seen in the lungs. Comparative mapping predicted that the porcine ITGB6 andITGAV orthologs map to SSC15. In an experimental family (n = 113), showing segregation of the trait, the candidate region was confirmed by linkage analysis with four microsatellite markers. Mapping of the porcine ITGB6 and ITGAV in the IMpRH radiation hybrid panel confirmed the comparative mapping information. Sequencing of the ITGB6 and ITGAV coding sequences from affected and normal pigs revealed no evidence of a causative mutation, but alternative splicing of the ITGB6 pre-mRNA was detected. For both ITGB6 and ITGAV quantitative PCR revealed no significant difference in the expression levels in normal and affected animals. In a western blot, ITGB6 was detected in lung protein samples of all three genotypes. This result was supported by flow cytometric analyses which showed comparable reactions of kidney cells from affected and normal pigs with an integrin αvβ6 monoclonal antibody. Also, immunohistochemical staining of lung tissue with an integrin β6 antibody showed immunoreaction in both normal and affected pigs. Conclusion A phenotype resembling the integrin β6 -/- knockout phenotype seen in mice has been characterized in the pig. The candidate region on SSC15 has been confirmed by linkage analysis but molecular

  11. Phenotypic variation of erythrocyte linker histone H1.c in a pheasant (Phasianus colchicus L.) population.

    PubMed

    Kowalski, Andrzej; Pa Yga, Jan; Górnicka-Michalska, Ewa; Bernacki, Zenon; Adamski, Marek

    2010-07-01

    Our goal was to characterize a phenotypic variation of the pheasant erythrocyte linker histone subtype H1.c. By using two-dimensional polyacrylamide gel electrophoresis three histone H1.c phenotypes were identified. The differently migrating allelic variants H1.c1 and H1.c2 formed either two homozygous phenotypes, c1 and c2, or a single heterozygous phenotype, c1c2. In the pheasant population screened, birds with phenotype c2 were the most common (frequency 0.761) while individuals with phenotype c1 were rare (frequency 0.043). PMID:21637419

  12. Effects of a lifestyle modification trial among phenotypically obese metabolically normal and phenotypically obese metabolically abnormal adolescents in comparison with phenotypically normal metabolically obese adolescents.

    PubMed

    Kelishadi, Roya; Hashemipour, Mahin; Sarrafzadegan, Nizal; Mohammadifard, Noushin; Alikhasy, Hasan; Beizaei, Maryam; Sajjadi, Firouzeh; Poursafa, Parinaz; Amin, Zahra; Ghatreh-Samani, Shohreh; Khavarian, Noushin; Siadat, Zahra Dana

    2010-07-01

    This study aimed to assess the effects of a 2-month lifestyle modification trial on cardio-metabolic abnormalities and C-reactive protein (CRP) among obese adolescents with metabolic syndrome [phenotypically obese metabolically abnormal (POMA)] and obese adolescents without a cardio-metabolic disorder [phenotypically obese metabolically normal (POMN)], as well as in normal-weight adolescents with at least one cardio-metabolic disorder [phenotypically normal metabolically obese (PNMO)]. The study comprised 360 adolescents assigned in three groups of equal number of POMN, POMA and PNMO. They were enrolled in a trial consisting of aerobic activity classes, diet and behaviour modification, and were recalled after 6 months. Overall, 94.7% of participants completed the 2-month trial, and 87.3% of them returned after 6 months. The mean CRP was not significantly different between the POMA and PNMO groups, but was higher than in the POMN group. After the trial, body mass index (BMI) and waist circumference (WC) decreased in obese participants, and the mean body fat mass decreased in all groups. At 2 months, the mean total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG) and CRP decreased in the POMA and PNMO groups. After 2 and 6 months, the decrease in mean TC, LDL-C, TG, CRP and systolic blood pressure was greater in the POMA than in the POMN group. The magnitude of decrease in CRP correlated with that of BMI, WC, fat mass, TG, TC and LDL-C. Lifestyle modification programmes for primordial/primary prevention of chronic diseases would be beneficial at the population level and should not be limited to obese children. PMID:20929499

  13. Interethnic variation of CYP2C19 alleles, 'predicted' phenotypes and 'measured' metabolic phenotypes across world populations.

    PubMed

    Fricke-Galindo, I; Céspedes-Garro, C; Rodrigues-Soares, F; Naranjo, M E G; Delgado, Á; de Andrés, F; López-López, M; Peñas-Lledó, E; LLerena, A

    2016-04-01

    The present study evaluates the worldwide frequency distribution of CYP2C19 alleles and CYP2C19 metabolic phenotypes ('predicted' from genotypes and 'measured' with a probe drug) among healthy volunteers from different ethnic groups and geographic regions, as well as the relationship between the 'predicted' and 'measured' CYP2C19 metabolic phenotypes. A total of 52 181 healthy volunteers were studied within 138 selected original research papers. CYP2C19*17 was 42- and 24-fold more frequent in Mediterranean-South Europeans and Middle Easterns than in East Asians (P<0.001, in both cases). Contrarily, CYP2C19*2 and CYP2C19*3 alleles were more frequent in East Asians (30.26% and 6.89%, respectively), and even a twofold higher frequency of these alleles was found in Native populations from Oceania (61.30% and 14.42%, respectively; P<0.001, in all cases), which may be a consequence of genetic drift process in the Pacific Islands. Regarding CYP2C19 metabolic phenotype, poor metabolizers (PMs) were more frequent among Asians than in Europeans, contrarily to the phenomenon reported for CYP2D6. A correlation has been found between the frequencies of CYP2C19 poor metabolism 'predicted' from CYP2C19 genotypes (gPMs) and the poor metabolic phenotype 'measured' with a probe drug (mPMs) when subjects are either classified by ethnicity (r=0.94, P<0.001) or geographic region (r=0.99, P=0.002). Nevertheless, further research is needed in African and Asian populations, which are under-represented, and additional CYP2C19 variants and the 'measured' phenotype should be studied. PMID:26503820

  14. Partial phenotyping in voluntary blood donors of Gujarat State

    PubMed Central

    Gajjar, Maitrey; Patel, Tarak; Bhatnagar, Nidhi; Patel, Kruti; Shah, Mamta; Prajapati, Amit

    2016-01-01

    Introduction: Partial phenotyping of voluntary blood donors has vital role in transfusion practice, population genetic study and in resolving legal issues. The Rh blood group is one of the most complex and highly immunogenic blood group known in humans. The Kell system, discovered in 1946, is the third most potent system at triggering hemolytic transfusion reactions and consists of 25 highly immunogenic antigens. Knowledge of Rh & Kell phenotypes in given population is relevant for better planning and management of blood bank; the main goal is to find compatible blood for patients needing multiple blood transfusions. The aim of this study was to evaluate the frequency of Rh & Kell phenotype of voluntary donors in Gujarat state. Materials and Methods: The present study was conducted by taking 5670 samples from random voluntary blood donors coming in blood donation camp. Written consent was taken for donor phenotyping. The antigen typing of donors was performed by Qwalys-3(manufacturer: Diagast) by using electromagnetic technology on Duolys plates. Results: Out of 5670 donors, the most common Rh antigen observed in the study population was e (99.07%) followed by D (95.40%), C (88.77%), c (55.89%) and E (17.88%). The frequency of the Kell antigen (K) was 1.78 %. Discussion: The antigen frequencies among blood donors from Gujarat were compared with those published for other Indian populations. The frequency of D antigen in our study (95.4%) and north Indian donors (93.6) was significantly higher than in the Caucasians (85%) and lower than in the Chinese (99%). The frequencies of C, c and E antigens were dissimilar to other ethnic groups while the ‘e’ antigen was present in high frequency in our study as also in the other ethnic groups. Kell antigen (K) was found in only 101 (1.78 %) donors out of 5670. Frequency of Kell antigen in Caucasian and Black populations is 9% & 2% respectively. The most common Kell phenotype was K-k+, not just in Indians (96.5%) but also

  15. Reporting phenotypes in mouse models when considering body size as a potential confounder.

    PubMed

    Oellrich, Anika; Meehan, Terrence F; Parkinson, Helen; Sarntivijai, Sirarat; White, Jacqueline K; Karp, Natasha A

    2016-01-01

    Genotype-phenotype studies aim to identify causative relationships between genes and phenotypes. The International Mouse Phenotyping Consortium is a high throughput phenotyping program whose goal is to collect phenotype data for a knockout mouse strain of every protein coding gene. The scale of the project requires an automatic analysis pipeline to detect abnormal phenotypes, and disseminate the resulting gene-phenotype annotation data into public resources. A body weight phenotype is a common result of knockout studies. As body weight correlates with many other biological traits, this challenges the interpretation of related gene-phenotype associations. Co-correlation can lead to gene-phenotype associations that are potentially misleading. Here we use statistical modelling to account for body weight as a potential confounder to assess the impact. We find that there is a considerable impact on previously established gene-phenotype associations due to an increase in sensitivity as well as the confounding effect. We investigated the existing ontologies to represent this phenotypic information and we explored ways to ontologically represent the results of the influence of confounders on gene-phenotype associations. With the scale of data being disseminated within the high throughput programs and the range of downstream studies that utilise these data, it is critical to consider how we improve the quality of the disseminated data and provide a robust ontological representation. PMID:26865945

  16. Atypical phenotype in two patients with LAMA2 mutations.

    PubMed

    Marques, Joana; Duarte, Sofia T; Costa, Sónia; Jacinto, Sandra; Oliveira, Jorge; Oliveira, Márcia E; Santos, Rosário; Bronze-da-Rocha, Elsa; Silvestre, Ana Rita; Calado, Eulália; Evangelista, Teresinha

    2014-05-01

    Congenital muscular dystrophy type 1A is caused by mutations in the LAMA2 gene, which encodes the α2-chain of laminin. We report two patients with partial laminin-α2 deficiency and atypical phenotypes, one with almost exclusive central nervous system involvement (cognitive impairment and refractory epilepsy) and the second with marked cardiac dysfunction, rigid spine syndrome and limb-girdle weakness. Patients underwent clinical, histopathological, imaging and genetic studies. Both cases have two heterozygous LAMA2 variants sharing a potentially pathogenic missense mutation c.2461A>C (p.Thr821Pro) located in exon 18. Brain MRI was instrumental for the diagnosis, since muscular examination and motor achievements were normal in the first patient and there was a severe cardiac involvement in the second. The clinical phenotype of the patients is markedly different which could in part be explained by the different combination of mutations types (two missense versus a missense and a truncating mutation). PMID:24534542

  17. The significance of macrophage phenotype in cancer and biomaterials

    SciTech Connect

    Bygd, Hannah C.; Forsmark, Kiva D.; Bratlie, Kaitlin M.

    2014-11-25

    Macrophages have long been known to exhibit heterogeneous and plastic phenotypes. They show functional diversity with roles in homeostasis, tissue repair, immunity and disease. There exists a spectrum of macrophage phenotypes with varied effector functions, molecular determinants, cytokine and chemokine profiles, as well as receptor expression. In tumor microenvironments, the subset of macrophages known as tumor-associated macrophages generates byproducts that enhance tumor growth and angiogenesis, making them attractive targets for anti-cancer therapeutics. With respect to wound healing and the foreign body response, there is a necessity for balance between pro-inflammatory, wound healing, and regulatory macrophages in order to achieve successful implantation of a scaffold for tissue engineering. In this review, we discuss the multitude of ways macrophages are known to be important in cancer therapies and implanted biomaterials.

  18. Rh Immunoprophylaxis for Women With a Serologic Weak D Phenotype.

    PubMed

    Virk, Mrigender; Sandler, S Gerald

    2015-01-01

    It is standard practice for pregnant RhD-negative women who have not already formed anti-D to receive antepartum Rh immunoprophylaxis and, if they deliver an RhD-positive neonate, to receive postpartum Rh immunoprophylaxis. An estimated 0.6% to 1.0% of white women have red blood cells that express a serologic weak D phenotype. Of these women, approximately 80% will have a weak D type 1, 2, or 3 that could be managed safely as RhD-positive. Surveys of laboratory practice reveal a lack of standards for interpreting the RhD type for women with a serologic weak D and for determining their need for Rh immunoprophylaxis. RhD genotyping is recommended to determine the molecular basis of serologic weak D phenotypes in pregnant women as a basis for determining their candidacy for Rh immunoprophylaxis. PMID:26199257

  19. Behavioral and Neuroanatomical Phenotypes in Mouse Models of Autism.

    PubMed

    Ellegood, Jacob; Crawley, Jacqueline N

    2015-07-01

    In order to understand the consequences of the mutation on behavioral and biological phenotypes relevant to autism, mutations in many of the risk genes for autism spectrum disorder have been experimentally generated in mice. Here, we summarize behavioral outcomes and neuroanatomical abnormalities, with a focus on high-resolution magnetic resonance imaging of postmortem mouse brains. Results are described from multiple mouse models of autism spectrum disorder and comorbid syndromes, including the 15q11-13, 16p11.2, 22q11.2, Cntnap2, Engrailed2, Fragile X, Integrinβ3, MET, Neurexin1a, Neuroligin3, Reelin, Rett, Shank3, Slc6a4, tuberous sclerosis, and Williams syndrome models, and inbred strains with strong autism-relevant behavioral phenotypes, including BTBR and BALB. Concomitant behavioral and neuroanatomical abnormalities can strengthen the interpretation of results from a mouse model, and may elevate the usefulness of the model system for therapeutic discovery. PMID:26036957

  20. Improved human disease candidate gene prioritization using mouse phenotype

    PubMed Central

    Chen, Jing; Xu, Huan; Aronow, Bruce J; Jegga, Anil G

    2007-01-01

    Background The majority of common diseases are multi-factorial and modified by genetically and mechanistically complex polygenic interactions and environmental factors. High-throughput genome-wide studies like linkage analysis and gene expression profiling, tend to be most useful for classification and characterization but do not provide sufficient information to identify or prioritize specific disease causal genes. Results Extending on an earlier hypothesis that the majority of genes that impact or cause disease share membership in any of several functional relationships we, for the first time, show the utility of mouse phenotype data in human disease gene prioritization. We study the effect of different data integration methods, and based on the validation studies, we show that our approach, ToppGene , outperforms two of the existing candidate gene prioritization methods, SUSPECTS and ENDEAVOUR. Conclusion The incorporation of phenotype information for mouse orthologs of human genes greatly improves the human disease candidate gene analysis and prioritization. PMID:17939863

  1. Paralytic ileus in MELAS with phenotypic features of MNGIE.

    PubMed

    Chang, Tung-Ming; Chi, Ching-Shiang; Tsai, Chi-Ren; Lee, Hsiu-Fen; Li, Mu-Chun

    2004-11-01

    This report describes a child having the syndrome of overlapping phenotypic features of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE). Mitochondrial DNA analysis revealed a point mutation at position A3243G, whereas activity of thymidine phosphorylase and its corresponding gene analysis were normal. The most striking feature of this case was paralysis of one segment of the terminal ileum observed on laparotomy. The electron microscopic findings of the resected ileum and colon by limited right hemicolectomy disclosed accumulation of numerous enlarged mitochondria with ill-defined cristae which were similar to mitochondria reported in three previous MELAS cases and one MNGIE case with intestinal dysmotility. We emphasize that the MELAS and MNGIE phenotypes overlapped in this case and that the mechanism of acute ileus in MELAS was associated with functional paralysis of the intestine. PMID:15519124

  2. Loss of gene function and evolution of human phenotypes

    PubMed Central

    Oh, Hye Ji; Choi, Dongjin; Goh, Chul Jun; Hahn, Yoonsoo

    2015-01-01

    Humans have acquired many distinct evolutionary traits after the human-chimpanzee divergence. These phenotypes have resulted from genetic changes that occurred in the human genome and were retained by natural selection. Comparative primate genome analyses reveal that loss-of-function mutations are common in the human genome. Some of these gene inactivation events were revealed to be associated with the emergence of advantageous phenotypes and were therefore positively selected and fixed in modern humans (the “less-ismore” hypothesis). Representative cases of human gene inactivation and their functional implications are presented in this review. Functional studies of additional inactive genes will provide insight into the molecular mechanisms underlying acquisition of various human-specific traits. [BMB Reports 2015; 48(7): 373-379] PMID:25887751

  3. Jagged 1 Rescues the Duchenne Muscular Dystrophy Phenotype.

    PubMed

    Vieira, Natassia M; Elvers, Ingegerd; Alexander, Matthew S; Moreira, Yuri B; Eran, Alal; Gomes, Juliana P; Marshall, Jamie L; Karlsson, Elinor K; Verjovski-Almeida, Sergio; Lindblad-Toh, Kerstin; Kunkel, Louis M; Zatz, Mayana

    2015-11-19

    Duchenne muscular dystrophy (DMD), caused by mutations at the dystrophin gene, is the most common form of muscular dystrophy. There is no cure for DMD and current therapeutic approaches to restore dystrophin expression are only partially effective. The absence of dystrophin in muscle results in dysregulation of signaling pathways, which could be targets for disease therapy and drug discovery. Previously, we identified two exceptional Golden Retriever muscular dystrophy (GRMD) dogs that are mildly affected, have functional muscle, and normal lifespan despite the complete absence of dystrophin. Now, our data on linkage, whole-genome sequencing, and transcriptome analyses of these dogs compared to severely affected GRMD and control animals reveals that increased expression of Jagged1 gene, a known regulator of the Notch signaling pathway, is a hallmark of the mild phenotype. Functional analyses demonstrate that Jagged1 overexpression ameliorates the dystrophic phenotype, suggesting that Jagged1 may represent a target for DMD therapy in a dystrophin-independent manner. PAPERCLIP. PMID:26582133

  4. A side effect resource to capture phenotypic effects of drugs

    PubMed Central

    Kuhn, Michael; Campillos, Monica; Letunic, Ivica; Jensen, Lars Juhl; Bork, Peer

    2010-01-01

    The molecular understanding of phenotypes caused by drugs in humans is essential for elucidating mechanisms of action and for developing personalized medicines. Side effects of drugs (also known as adverse drug reactions) are an important source of human phenotypic information, but so far research on this topic has been hampered by insufficient accessibility of data. Consequently, we have developed a public, computer-readable side effect resource (SIDER) that connects 888 drugs to 1450 side effect terms. It contains information on frequency in patients for one-third of the drug–side effect pairs. For 199 drugs, the side effect frequency of placebo administration could also be extracted. We illustrate the potential of SIDER with a number of analyses. The resource is freely available for academic research at http://sideeffects.embl.de. PMID:20087340

  5. Variable phenotypes are associated with PMP22 missense mutations.

    PubMed

    Russo, M; Laurá, M; Polke, J M; Davis, M B; Blake, J; Brandner, S; Hughes, R A C; Houlden, H; Bennett, D L H; Lunn, M P T; Reilly, M M

    2011-02-01

    Charcot-Marie-Tooth disease (CMT) is the commonest hereditary neuropathy encompassing a large group of clinically and genetically heterogeneous disorders. The commonest form of CMT, CMT1A, is usually caused by a 1.4 megabase duplication of chromosome 17 containing the PMP22 gene. Mutations of PMP22 are a less common cause of CMT. We describe clinical, electrophysiological and molecular findings of 10 patients carrying PMP22 missense mutations. The phenotype varied from mild hereditary neuropathy with liability to pressure palsies (HNPP) to severe CMT1. We identified six different point mutations, including two novel mutations. Three families were also found to harbour a Thr118Met mutation. Although PMP22 point mutations are not common, our findings highlight the importance of sequencing the PMP22 gene in patients with variable CMT phenotypes and also confirm that the PMP22 Thr118Met mutation is associated with a neuropathy albeit with reduced penetrance. PMID:21194947

  6. Phenotypic characterization of rare interstitial deletion of chromosome 4

    PubMed Central

    Ismail, Samira; Helmy, Nivine A.; Mahmoud, Wael M.; El-Ruby, Mona O.

    2012-01-01

    Interstitial deletion of the long arm of chromosome 4 is rare. Patients with interstitial deletion of the long arm of chromosome 4 differ from those with terminal deletions. Phenotypes may be variable, depending upon the specific length and location of the deleted portion. Here, we report on a boy exhibiting most of the congenital malformations encountered in terminal 4q syndrome. The conventional karyotyping and Fluorescence in-situ hybridization revealed a de novo interstitial del (4)(q31q32). The current report is a further document highlighting that deletion of segment q31 could be contributing to the expression of most of the phenotype of 4q deletion syndrome. Using array comparative genome hybridization methodology is recommended for investigating further cases with similar segmental interstitial deletions to support and delineate findings and to define genes implicated in the pathogenesis of the disorder.

  7. Sequential phenotypic constraints on social information use in wild baboons.

    PubMed

    Carter, Alecia J; Torrents Ticó, Miquel; Cowlishaw, Guy

    2016-01-01

    Social information allows the rapid dissemination of novel information among individuals. However, an individual's ability to use information is likely to be dependent on phenotypic constraints operating at three successive steps: acquisition, application, and exploitation. We tested this novel framework by quantifying the sequential process of social information use with experimental food patches in wild baboons (Papio ursinus). We identified phenotypic constraints at each step of the information use sequence: peripheral individuals in the proximity network were less likely to acquire and apply social information, while subordinate females were less likely to exploit it successfully. Social bonds and personality also played a limiting role along the sequence. As a result of these constraints, the average individual only acquired and exploited social information on. PMID:27067236

  8. Two new molecular bases for the Dombrock null phenotype.

    PubMed

    Rios, Maria; Storry, Jill R; Hue-Roye, Kim; Chung, Amy; Reid, Marion E

    2002-06-01

    Red blood cells (RBCs) with the Do(null) phenotype lack all antigens in the Dombrock blood group system, i.e. Do(a), Do(b), Gy(a), Hy and Jo(a). Sequence analysis of DNA from one proband with the Do(null) phenotype revealed a single nucleotide mutation of t to c in the donor splice site of DO (IVS1 + 2t > c), with outsplicing of exon 2. Analysis of a second proband revealed a homozygous nonsense mutation 442 C > T in exon 2 predicting a premature stop codon (Gln148 Stop). The molecular bases described in these two probands provide an explanation for the lack of Do glycoprotein on their RBCs. PMID:12028057

  9. X-Linked Retinoschisis: Phenotypic Variability in a Chinese Family

    PubMed Central

    Xiao, Yangyan; Liu, Xiao; Tang, Luosheng; Wang, Xia; Coursy, Terry; Guo, Xiaojian; Li, Zhuo

    2016-01-01

    X-linked juvenile retinoschisis (XLRS), a leading cause of juvenile macular degeneration, is characterized by a spoke-wheel pattern in the macular region of the retina and splitting of the neurosensory retina. Our study is to describe the clinical characteristics of a four generations of this family (a total of 18 members)with X-linked retinoschisis (XLRS) and detected a novel mutations of c.3G > A (p.M1?) in the initiation codon of the RS1 gene. by direct sequencing.Identification of this mutation in this family provides evidence about potential genetic or environmental factors on its phenotypic variance, as patients presented with different phenotypes regardless of having the same mutation. Importantly, OCT has proven vital for XLRS diagnosis in children. PMID:26823236

  10. The significance of macrophage phenotype in cancer and biomaterials

    DOE PAGESBeta

    Bygd, Hannah C.; Forsmark, Kiva D.; Bratlie, Kaitlin M.

    2014-11-25

    Macrophages have long been known to exhibit heterogeneous and plastic phenotypes. They show functional diversity with roles in homeostasis, tissue repair, immunity and disease. There exists a spectrum of macrophage phenotypes with varied effector functions, molecular determinants, cytokine and chemokine profiles, as well as receptor expression. In tumor microenvironments, the subset of macrophages known as tumor-associated macrophages generates byproducts that enhance tumor growth and angiogenesis, making them attractive targets for anti-cancer therapeutics. With respect to wound healing and the foreign body response, there is a necessity for balance between pro-inflammatory, wound healing, and regulatory macrophages in order to achieve successfulmore » implantation of a scaffold for tissue engineering. In this review, we discuss the multitude of ways macrophages are known to be important in cancer therapies and implanted biomaterials.« less

  11. Phenotypic characteristics for discrimination between advanced genotypes of Brachiaria ruziziensis.

    PubMed

    Rezende, B A; Ribeiro, C B; Teixeira, D H L; Gonçalves, F M A; Souza Sobrinho, F

    2016-01-01

    The aim of this study was to use multivariate methods and Pearson and partial correlations to disregard phenotypic characteristics that contribute little to differentiation between Brachiaria ruziziensis genotypes. Eighty-one genotypes of B. ruziziensis were assessed in completely randomized blocks with three replications. Ten phenotypic characteristics were assessed: plant height, leaf length, leaf width, sheath length, length of the flower stem, length of the inflorescence axis, number of racemes per inflorescence, length of the basal raceme, number of spikelets per basal raceme, and width of the rachis. The best traits for differentiation between genotypes were determined by assessing relative contribution to diversity, canonical variables, as well as Pearson and partial correlations. Four canonical variables were found to account for 57% of the overall variation, while plant height, sheath length, and number of racemes per inflorescence were considered traits that could potentially be disregarded in future assessments. PMID:27051034

  12. Oestrogen receptor: a stable phenotype in breast cancer.

    PubMed Central

    Robertson, J. F.

    1996-01-01

    Oestrogen receptor (ER) expression in breast cancer is regarded as a phenotype that may change during the natural history of the disease or during endocrine therapy. It has been suggested that in up to 70% of tumours that show acquired resistance the mechanism may be changed in ER status from positive to negative. This paper proposes an alternative hypothesis that ER expression in a stable phenotype in breast cancer. The paper reviews the literature on ER expression during the natural history of breast cancer in patients and also presents data on the effect of endocrine therapy on ER expression. If the alternative hypothesis is true it has important implications for treatment from chemoprevention to acquired endocrine resistance in advanced disease. Equally, if the hypothesis is true, attempts to develop laboratory models of endocrine resistance where ER-positive tumours become ER negative need to be re-evaluated. PMID:8554983

  13. UAV-based high-throughput phenotyping in legume crops

    NASA Astrophysics Data System (ADS)

    Sankaran, Sindhuja; Khot, Lav R.; Quirós, Juan; Vandemark, George J.; McGee, Rebecca J.

    2016-05-01

    In plant breeding, one of the biggest obstacles in genetic improvement is the lack of proven rapid methods for measuring plant responses in field conditions. Therefore, the major objective of this research was to evaluate the feasibility of utilizing high-throughput remote sensing technology for rapid measurement of phenotyping traits in legume crops. The plant responses of several chickpea and peas varieties to the environment were assessed with an unmanned aerial vehicle (UAV) integrated with multispectral imaging sensors. Our preliminary assessment showed that the vegetation indices are strongly correlated (p<0.05) with seed yield of legume crops. Results endorse the potential of UAS-based sensing technology to rapidly measure those phenotyping traits.

  14. Bacterial phenotype variants in group B streptococcal toxic shock syndrome.

    PubMed

    Sendi, Parham; Johansson, Linda; Dahesh, Samira; Van-Sorge, Nina M; Darenberg, Jessica; Norgren, Mari; Sjölin, Jan; Nizet, Victor; Norrby-Teglund, Anna

    2009-02-01

    We conducted genetic and functional analyses of isolates from a patient with group B streptococcal (GBS) necrotizing fasciitis and toxic shock syndrome. Tissue cultures simultaneously showed colonies with high hemolysis (HH) and low hemolysis (LH). Conversely, the HH and LH variants exhibited low capsule (LC) and high capsule (HC) expression, respectively. Molecular analysis demonstrated that the 2 GBS variants were of the same clonal origin. Genetic analysis found a 3-bp deletion in the covR gene of the HH/LC variant. Functionally, this isolate was associated with an increased growth rate in vitro and with higher interleukin-8 induction. However, in whole blood, opsonophagocytic and intracellular killing assays, the LH/HC phenotype demonstrated higher resistance to host phagocytic killing. In a murine model, LH/HC resulted in higher levels of bacteremia and increased host mortality rate. These findings demonstrate differences in GBS isolates of the same clonal origin but varying phenotypes. PMID:19193266

  15. Methods of integrating data to uncover genotype-phenotype interactions.

    PubMed

    Ritchie, Marylyn D; Holzinger, Emily R; Li, Ruowang; Pendergrass, Sarah A; Kim, Dokyoon

    2015-02-01

    Recent technological advances have expanded the breadth of available omic data, from whole-genome sequencing data, to extensive transcriptomic, methylomic and metabolomic data. A key goal of analyses of these data is the identification of effective models that predict phenotypic traits and outcomes, elucidating important biomarkers and generating important insights into the genetic underpinnings of the heritability of complex traits. There is still a need for powerful and advanced analysis strategies to fully harness the utility of these comprehensive high-throughput data, identifying true associations and reducing the number of false associations. In this Review, we explore the emerging approaches for data integration - including meta-dimensional and multi-staged analyses - which aim to deepen our understanding of the role of genetics and genomics in complex outcomes. With the use and further development of these approaches, an improved understanding of the relationship between genomic variation and human phenotypes may be revealed. PMID:25582081

  16. Allergic and nonallergic asthma in children: are they distinct phenotypes?

    PubMed

    Mahdaviani, Seyed Alireza; Mohajerani, Seyed Amir; Fakhri, Mohammad; Ebrahimi, Mazaher; Bashardoost, Bahram; Razavi, Seyed Jafar; Toolabi, Masoumeh; Tajik, Ali; Khalilzadeh, Soheila; Masjedi, Mohamad Reza

    2014-10-01

    The aim of current study is to describe clinical similarities and differences between atopic and non-atopic asthma in children. In a cross-sectional study, 95 asthmatic children (75 allergics and 20 nonallergics) were included in the study. Demographic, clinical, and familial history were compared between two groups. There was no significant differences between variables like sex, age of onset (p=0.75), severity (p=0.70), and family history among the two groups (p=0.42). Patients with allergic asthma were significantly older than those with non- allergic asthma (11.28 ± 3.19 and 9.75 ± 2.35 years, respectively, p=0.02). The controversy lingers over the presence of a completely distinct phenotype of non-atopic asthma in children. Our study suggested that phenotypes of allergic and non-allergic asthma in children were not entirely distinct. PMID:25150079

  17. A review of standardized metabolic phenotyping of animal models.

    PubMed

    Rozman, Jan; Klingenspor, Martin; Hrabě de Angelis, Martin

    2014-10-01

    Metabolic phenotyping of genetically modified animals aims to detect new candidate genes and related metabolic pathways that result in dysfunctional energy balance regulation and predispose for diseases such as obesity or type 2 diabetes mellitus. In this review, we provide a comprehensive overview on the technologies available to monitor energy flux (food uptake, bomb calorimetry of feces and food, and indirect calorimetry) and body composition (qNMR, DXA, and MRI) in animal models for human diseases with a special focus on phenotyping methods established in genetically engineered mice. We use an energy flux model to illustrate the principles of energy allocation, describe methodological aspects how to monitor energy balance, and introduce strategies for data analysis and presentation. PMID:25199945

  18. Metabolic and Cardiovascular Implications of a Metabolically Healthy Obesity Phenotype

    PubMed Central

    Seo, Mi Hae

    2014-01-01

    Metabolically healthy obesity (MHO) is a new concept in which an individual may exhibit an obese phenotype in the absence of any metabolic abnormalities. There are a number of definitions of MHO that utilize a variety of components. The findings of clinical and basic studies indicate that subjects with MHO do not exhibit an increased mortality, an increased risk of cardiovascular disease, or an increased risk of type 2 diabetes mellitus, as compared to normal-weight controls. Although these findings imply that metabolic health is a more important factor than obesity, several studies have shown that subjects with MHO have a similar risk of metabolic or cardiovascular diseases as those with metabolically unhealthy obesity. Thus, there is still debate regarding not only the implications of the MHO phenotype but its very existence. Accordingly, future studies should focus on developing a unified definition of MHO and distinguishing subjects who will be at a high risk for metabolic and cardiovascular diseases. PMID:25559571

  19. Mature phenotype in Hemerocallis plantlets fortuitously generated in vitro

    NASA Technical Reports Server (NTRS)

    Fitter, M. S.; Krikorian, A. D.

    1985-01-01

    Daylily plantlets generated on semi-solid media from morphogenetically competent cells or morphogenetically competent cells regenerated from protoplasts can give rise in aseptic culture to plantlets with a mature phenotype. The individual leaves of these plantlets open to the extreme base so that no encircling leaf sheath is present. This permits the overlapping bases and leaves to assume an open fan-like arrangement. The occurrence of fans correlates with exceptionally tightly sealed culture vessels and experiments to date suggest a gaseous component is associated with this change of growth form. It has not been possible to fix the mature growth mode, however, and new leaf growth assumes the more normal juvenile phenotype when the gaseous environment is altered by admitting or exposure to room air.

  20. A phenotypic null hypothesis for the genetics of personality.

    PubMed

    Turkheimer, Eric; Pettersson, Erik; Horn, Erin E

    2014-01-01

    We review the genetically informed literature on the genetics of personality. Over the past century, quantitative genetic studies, using identical and fraternal twins, have demonstrated that differences in human personality are substantially heritable. We focus on more contemporary questions to which that basic observation has led. We examine whether differences in the heritability of personality are replicable across different traits, samples, and studies; how the heritability of personality relates to its reliability; and how behavior genetics can be employed in studies of validity, and we discuss the stability of personality in genetic and environmental variance. The appropriate null hypothesis in behavior genetics is not that genetic or environmental influence on personality is zero. Instead, we offer a phenotypic null hypothesis, which states that genetic variance is not an independent mechanism of individual differences in personality but rather a reflection of processes that are best conceptualized at the phenotypic level. PMID:24050184

  1. Genotype-Phenotype Interactions In Pediatric Obstructive Sleep Apnea

    PubMed Central

    Kheirandish-Gozal, Leila; Gozal, David

    2013-01-01

    Pediatric sleep disordered breathing (PSDB) is not only a very frequent condition affecting 2–4% of all children, but is also associated with an increased risk for a variety of manifestations underlying end-organ injury and dysfunction that impose both immediate and potentially long-term morbidities and corresponding inherent elevations in healthcare costs. One of the major problems with the creation of valid algorithms aiming to stratify diagnostic and treatment prioritization lies in our current inability to predict and identify those children who are most at-risk for PSDB-induced adverse consequences. Thus, improved our understanding of the mechanisms governing phenotype variance in PSDB is essential. Here, we examine some of the potential underpinnings of phenotypic variability in PSDB, and further propose a conceptual framework aimed at facilitating the process of advancing knowledge in this frequent disorder. PMID:23563156

  2. 3-Dimensional Imaging Modalities for Phenotyping Genetically Engineered Mice

    PubMed Central

    Powell, K. A.; Wilson, D.

    2013-01-01

    A variety of 3-dimensional (3D) digital imaging modalities are available for whole-body assessment of genetically engineered mice: magnetic resonance microscopy (MRM), X-ray microcomputed tomography (microCT), optical projection tomography (OPT), episcopic and cryoimaging, and ultrasound biomicroscopy (UBM). Embryo and adult mouse phenotyping can be accomplished at microscopy or near microscopy spatial resolutions using these modalities. MRM and microCT are particularly well-suited for evaluating structural information at the organ level, whereas episcopic and OPT imaging provide structural and functional information from molecular fluorescence imaging at the cellular level. UBM can be used to monitor embryonic development longitudinally in utero. Specimens are not significantly altered during preparation, and structures can be viewed in their native orientations. Technologies for rapid automated data acquisition and high-throughput phenotyping have been developed and continually improve as this exciting field evolves. PMID:22146851

  3. Endocrine Flexibility: Optimizing Phenotypes in a Dynamic World?

    PubMed

    Taff, Conor C; Vitousek, Maren N

    2016-06-01

    Responding appropriately to changing conditions is crucial in dynamic environments. Individual variation in the flexibility of physiological mediators of phenotype may influence the capacity to mount an integrated response to unpredictable changes in social or ecological context. We propose here a conceptual framework of rapid endocrine flexibility that integrates ecological endocrinology with theoretical and empirical studies of phenotypic plasticity and behavioral syndromes. We highlight the need for research addressing variation in the scope and speed of flexibility, and provide suggestions for future studies of these potentially evolving traits. Elucidating the causes and consequences of variation in endocrine flexibility may have important implications for the evolution of behavior, and for predicting the response of individuals and populations to rapidly changing environments. PMID:27055729

  4. The significance of macrophage phenotype in cancer and biomaterials.

    PubMed

    Bygd, Hannah C; Forsmark, Kiva D; Bratlie, Kaitlin M

    2014-12-01

    Macrophages have long been known to exhibit heterogeneous and plastic phenotypes. They show functional diversity with roles in homeostasis, tissue repair, immunity and disease. There exists a spectrum of macrophage phenotypes with varied effector functions, molecular determinants, cytokine and chemokine profiles, as well as receptor expression. In tumor microenvironments, the subset of macrophages known as tumor-associated macrophages generates byproducts that enhance tumor growth and angiogenesis, making them attractive targets for anti-cancer therapeutics. With respect to wound healing and the foreign body response, there is a necessity for balance between pro-inflammatory, wound healing, and regulatory macrophages in order to achieve successful implantation of a scaffold for tissue engineering. In this review, we discuss the multitude of ways macrophages are known to be important in cancer therapies and implanted biomaterials. PMID:26932379

  5. Unique phenotype in a patient with CHARGE syndrome

    PubMed Central

    2011-01-01

    CHARGE is a phenotypically heterogeneous autosomal dominant disorder recognized as a cohesive syndrome since the identification of CHD7 as a genetic etiology. Classic features include: Coloboma, Heart defects, Atresia choanae, Retarded growth and development, Genitourinary abnormalities, and Ear anomalies and/or deafness. With greater accessibility to genetic analysis, a wider spectrum of features are emerging, and overlap with disorders such as DiGeorge syndrome, Kallmann syndrome, and Hypoparathyroidism Sensorineural Deafness and Renal Disease syndrome, is increasingly evident. We present a patient with a unique manifestation of CHARGE syndrome, including primary hypoparathyroidism and a limb anomaly; to our knowledge, he is also the first CHARGE subject reported with bilateral multicystic dysplastic kidneys. Furthermore, with structural modeling and murine expression studies, we characterize a putative CHD7 G744S missense mutation. Our report continues to expand the CHARGE phenotype and highlights that stringent fulfillment of conventional criteria should not strictly guide genetic analysis. PMID:21995344

  6. Animal Models of Cystic Fibrosis Pathology: Phenotypic Parallels and Divergences.

    PubMed

    Lavelle, Gillian M; White, Michelle M; Browne, Niall; McElvaney, Noel G; Reeves, Emer P

    2016-01-01

    Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The resultant characteristic ion transport defect results in decreased mucociliary clearance, bacterial colonisation, and chronic neutrophil-dominated inflammation. Much knowledge surrounding the pathophysiology of the disease has been gained through the generation of animal models, despite inherent limitations in each. The failure of certain mouse models to recapitulate the phenotypic manifestations of human disease has initiated the generation of larger animals in which to study CF, including the pig and the ferret. This review will summarise the basic phenotypes of three animal models and describe the contributions of such animal studies to our current understanding of CF. PMID:27340661

  7. Phenotypic bistability in Escherichia coli's central carbon metabolism

    PubMed Central

    Kotte, Oliver; Volkmer, Benjamin; Radzikowski, Jakub L; Heinemann, Matthias

    2014-01-01

    Fluctuations in intracellular molecule abundance can lead to distinct, coexisting phenotypes in isogenic populations. Although metabolism continuously adapts to unpredictable environmental changes, and although bistability was found in certain substrate-uptake pathways, central carbon metabolism is thought to operate deterministically. Here, we combine experiment and theory to demonstrate that a clonal Escherichia coli population splits into two stochastically generated phenotypic subpopulations after glucose-gluconeogenic substrate shifts. Most cells refrain from growth, entering a dormant persister state that manifests as a lag phase in the population growth curve. The subpopulation-generating mechanism resides at the metabolic core, overarches the metabolic and transcriptional networks, and only allows the growth of cells initially achieving sufficiently high gluconeogenic flux. Thus, central metabolism does not ensure the gluconeogenic growth of individual cells, but uses a population-level adaptation resulting in responsive diversification upon nutrient changes. PMID:24987115

  8. Genetic Factors in Systemic Lupus Erythematosus: Contribution to Disease Phenotype

    PubMed Central

    Ceccarelli, Fulvia; Perricone, Carlo; Borgiani, Paola; Ciccacci, Cinzia; Rufini, Sara; Cipriano, Enrica; Alessandri, Cristiano; Spinelli, Francesca Romana; Sili Scavalli, Antonio; Novelli, Giuseppe; Valesini, Guido; Conti, Fabrizio

    2015-01-01

    Genetic factors exert an important role in determining Systemic Lupus Erythematosus (SLE) susceptibility, interplaying with environmental factors. Several genetic studies in various SLE populations have identified numerous susceptibility loci. From a clinical point of view, SLE is characterized by a great heterogeneity in terms of clinical and laboratory manifestations. As widely demonstrated, specific laboratory features are associated with clinical disease subset, with different severity degree. Similarly, in the last years, an association between specific phenotypes and genetic variants has been identified, allowing the possibility to elucidate different mechanisms and pathways accountable for disease manifestations. However, except for Lupus Nephritis (LN), no studies have been designed to identify the genetic variants associated with the development of different phenotypes. In this review, we will report data currently known about this specific association. PMID:26798662

  9. Lysophosphatidylcholine perpetuates macrophage polarization toward classically activated phenotype in inflammation.

    PubMed

    Qin, Xiaofei; Qiu, Chunguang; Zhao, Luosha

    2014-01-01

    Pro-inflammatory macrophages are involved in vascular inflammation and serve as the major effector cells in the pathophysiology of atherosclerosis. Phosphatidylcholine (PC) is a major phospholipid moiety affixed to oxidized low-density lipoprotein (oxLDL) and thought to play important roles in the development of atherosclerosis. In this study we described that a bioactive lipid derivative, lysophosphatidylcholine (lysoPC), generated from hydrolysis of the PC moiety of oxidized LDL, promoted and stabilized a strong M1 phenotype in macrophage polarization. Another derivative, 9-hydroxyoctadecadienoic acid (9-HODE), did not show the similar biological function. Blockade of G protein coupled receptor, G2A, which mediates the signal transduction of lysoPC, diminished the effects of lysoPC on the macrophage polarization toward M1 phenotype. The results provide insights into the new mechanism on how oxidized LDL participates in tissue inflammation in atherosclerosis. PMID:24841857

  10. Characterizing visible and invisible cell wall mutant phenotypes.

    PubMed

    Carpita, Nicholas C; McCann, Maureen C

    2015-07-01

    About 10% of a plant's genome is devoted to generating the protein machinery to synthesize, remodel, and deconstruct the cell wall. High-throughput genome sequencing technologies have enabled a reasonably complete inventory of wall-related genes that can be assembled into families of common evolutionary origin. Assigning function to each gene family member has been aided immensely by identification of mutants with visible phenotypes or by chemical and spectroscopic analysis of mutants with 'invisible' phenotypes of modified cell wall composition and architecture that do not otherwise affect plant growth or development. This review connects the inference of gene function on the basis of deviation from the wild type in genetic functional analyses to insights provided by modern analytical techniques that have brought us ever closer to elucidating the sequence structures of the major polysaccharide components of the plant cell wall. PMID:25873661

  11. Visualization of Growth Curve Data from Phenotype MicroarrayExperiments

    SciTech Connect

    Jacobsen, Janet S.; Joyner, Dominique C.; Borglin, Sharon E.; Hazen, Terry C.; Arkin, Adam P.; Bethel, E. Wes

    2007-04-19

    Phenotype microarrays provide a technology to simultaneouslysurvey the response of an organism to nearly 2,000 substrates, includingcarbon, nitrogen and potassium sources; varying pH; varying saltconcentrations; and antibiotics. In order to more quickly and easily viewand compare the large number of growth curves produced by phenotypemicroarray experiments, we have developed software to produce and displaycolor images, each of which corresponds to a set of 96 growth curves.Using color images to represent growth curves data has proven to be avaluable way to assess experiment quality, compare replicates, facilitatecomparison of the responses of different organisms, and identifysignificant phenotypes. The color images are linked to traditional plotsof growth versus time, as well as to information about the experiment,organism, and substrate. In order to share and view information and dataproject-wide, all information, plots, and data are accessible using onlya Web browser.

  12. Analysis of Constituents for Phenotyping Drought Tolerance in Crop Improvement

    PubMed Central

    Setter, Tim L.

    2012-01-01

    Investigators now have a wide range of analytical tools to use in measuring metabolites, proteins and transcripts in plant tissues. These tools have the potential to assist genetic studies that seek to phenotype genetic lines for heritable traits that contribute to drought tolerance. To be useful for crop breeding, hundreds or thousands of genetic lines must be assessed. This review considers the utility of assaying certain constituents with roles in drought tolerance for phenotyping genotypes. Abscisic acid (ABA), organic and inorganic osmolytes, compatible solutes, and late embryogenesis abundant proteins, are considered. Confounding effects that require appropriate tissue and timing specificity, and the need for high-throughput and analytical cost efficiency are discussed. With future advances in analytical methods and the value of analyzing constituents that provide information on the underlying mechanisms of drought tolerance, these approaches are expected to contribute to development crops with improved drought tolerance. PMID:22675308

  13. Understanding the Anatomy of Dystonia: Determinants of Penetrance and Phenotype

    PubMed Central

    Lerner, Renata P; Niethammer, Martin; Eidelberg, David

    2013-01-01

    The dystonias comprise a group of syndromes characterized by prolonged involuntary muscle contractions resulting in repetitive movements and abnormal postures. Primary dystonia has been associated with over 14 different genotypes, most of which follow an autosomal dominant inheritance pattern with reduced penetrance. Independent of etiology, the disease is characterized by extensive variability in disease phenotype and clinical severity. Recent neuroimaging studies investigating this phenomenon in manifesting and non-manifesting genetic carriers of dystonia have discovered microstructural integrity differences in the cerebello-thalamo-cortical tract in both groups related to disease penetrance. Further study suggests these differences to be specific to subrolandic white matter regions somatotopically related to clinical phenotype. Clinical severity was correlated to the degree of microstructural change. These findings suggest a mechanism for the penetrance and clinical variability observed in dystonia and may represent a novel therapeutic target for patients with refractory limb symptoms. PMID:24114145

  14. Genotype-phenotype associations and human eye color.

    PubMed

    White, Désirée; Rabago-Smith, Montserrat

    2011-01-01

    Although eye color is usually modeled as a simple, Mendelian trait, further research and observation has indicated that eye color does not follow the classical paths of inheritance. Eye color phenotypes demonstrate both epistasis and incomplete dominance. Although there are about 16 different genes responsible for eye color, it is mostly attributed to two adjacent genes on chromosome 15, hect domain and RCC1-like domain-containing protein 2 (HERC2) and ocular albinism (that is, oculocutaneous albinism II (OCA2)). An intron in HERC2 contains the promoter region for OCA2, affecting its expression. Therefore, single-nucleotide polymorphisms in either of these two genes have a large role in the eye color of an individual. Furthermore, with all genetic expression, aberration also occurs. Some individuals may express two phenotypes--one in each eye--or a complete lack of pigmentation, ocular albinism. In addition, the evolutionary and population roles of the different expressions are significant. PMID:20944644

  15. Gaucher Disease: The Metabolic Defect, Pathophysiology, Phenotypes And Natural History

    PubMed Central

    Baris, Hagit N.; Cohen, Ian J.; Mistry, Pramod K.

    2015-01-01

    Gaucher disease (GD), a prototype lysosomal storage disorder, results from inherited deficiency of lysosomal glucocerebrosidase due to biallelic mutations in GBA. The result is widespread accumulation of macrophages engorged with predominantly lysosomal glucocerebroside. A complex multisystem phenotype arises involving the liver, spleen, bone marrow and occasionally the lungs in type 1 Gaucher disease; in neuronopathic fulminant type 2 and chronic type 3 disease there is in addition progressive neurodegenerative disease. Manifestations of Gaucher disease type 1 (GD1) include hepatosplenomegaly, cytopenia, a complex pattern of bone involvement with avascular osteonecrosis (AVN), osteoporosis, fractures and lytic lesions. Enzyme replacement therapy became the standard of care in 1991, and this has transformed the natural history of GD1. This article reviews the clinical phenotypes of GD, diagnosis, pathophysiology and its natural history. A subsequent chapter discusses the treatment options. PMID:25345088

  16. Phenotypic effects of membrane protein overexpression in Saccharomyces cerevisiae

    NASA Astrophysics Data System (ADS)

    Melén, Karin; Blomberg, Anders; von Heijne, Gunnar

    2006-07-01

    Large-scale protein overexpression phenotype screens provide an important complement to the more common gene knockout screens. Here, we have targeted the so far poorly understood Saccharomyces cerevisiae membrane proteome and report growth phenotypes for a strain collection overexpressing 600 C-terminally tagged integral membrane proteins grown both under normal and three different stress conditions. Although overexpression of most membrane proteins reduce the growth rate in synthetic defined medium, we identify a large number of proteins that, when overexpressed, confer specific resistance to various stress conditions. Our data suggest that regulation of glycosylphosphatidylinositol anchor biosynthesis and the Na+/K+ homeostasis system constitute major downstream targets of the yeast PKA/RAS pathway and point to a possible connection between the early secretory pathway and the cells' response to oxidative stress. We also have quantified the expression levels for >550 membrane proteins, facilitating the choice of well expressing proteins for future functional and structural studies. caffeine | paraquat | salt tolerance | yeast

  17. Phenotypic Evolution in Fossil Species: Pattern and Process

    NASA Astrophysics Data System (ADS)

    Hunt, Gene; Rabosky, Daniel L.

    2014-05-01

    Since Darwin, scientists have looked to the fossil record with the hope of using it to document how the phenotypes of species change over substantial periods of time. How best to interpret this record has been controversial, but empirical and methodological advances have resolved at least two issues about pattern: (a) directional transformations are seldom sustained over geological timescales, and (b) net rates of morphological change in fossil species are usually quite slow. Considerable uncertainty remains, however, about the processes responsible for these patterns, but most fruitful explanations use the framework of adaptive landscapes to consider the role of natural selection and other processes. An additional, unresolved issue is the claim that most phenotypic change is associated with speciation. A variety of methods, using data from both fossil and extant species, have supported such a link, at least in some clades and traits, but its prevalence and underlying mechanism remain unresolved.

  18. Mesenchymal stem cell subpopulations: phenotype, property and therapeutic potential.

    PubMed

    Mo, Miaohua; Wang, Shan; Zhou, Ying; Li, Hong; Wu, Yaojiong

    2016-09-01

    Mesenchymal stem cells (MSC) are capable of differentiating into cells of multiple cell lineages and have potent paracrine effects. Due to their easy preparation and low immunogenicity, MSC have emerged as an extremely promising therapeutic agent in regenerative medicine for diverse diseases. However, MSC are heterogeneous with respect to phenotype and function in current isolation and cultivation regimes, which often lead to incomparable experimental results. In addition, there may be specific stem cell subpopulations with definite differentiation capacity toward certain lineages in addition to stem cells with multi-differentiation potential. Recent studies have identified several subsets of MSC which exhibit distinct features and biological activities, and enhanced therapeutic potentials for certain diseases. In this review, we give an overview of these subsets for their phenotypic, biological and functional properties. PMID:27141940

  19. Transcriptomic Analysis of Phenotypic Changes in Birch (Betula platyphylla) Autotetraploids

    PubMed Central

    Mu, Huai-Zhi; Liu, Zi-Jia; Lin, Lin; Li, Hui-Yu; Jiang, Jing; Liu, Gui-Feng

    2012-01-01

    Plant breeders have focused much attention on polyploid trees because of their importance to forestry. To evaluate the impact of intraspecies genome duplication on the transcriptome, a series of Betula platyphylla autotetraploids and diploids were generated from four full-sib families. The phenotypes and transcriptomes of these autotetraploid individuals were compared with those of diploid trees. Autotetraploids were generally superior in breast-height diameter, volume, leaf, fruit and stoma and were generally inferior in height compared to diploids. Transcriptome data revealed numerous changes in gene expression attributable to autotetraploidization, which resulted in the upregulation of 7052 unigenes and the downregulation of 3658 unigenes. Pathway analysis revealed that the biosynthesis and signal transduction of indoleacetate (IAA) and ethylene were altered after genome duplication, which may have contributed to phenotypic changes. These results shed light on variations in birch autotetraploidization and help identify important genes for the genetic engineering of birch trees. PMID:23202935

  20. Phenotype Recognition for RNAi Screening by Random Projection Forest

    NASA Astrophysics Data System (ADS)

    Zhang, Bailing

    2011-06-01

    High-content screening is important in drug discovery. The use of images of living cells as the basic unit for molecule discovery can aid the identification of small compounds altering cellular phenotypes. As such, efficient computational methods are required for the rate limiting task of cellular phenotype identification. In this paper we first investigate the effectiveness of a feature description approach by combining Haralick texture analysis with Curvelet transform and then propose a new ensemble approach for classification. The ensemble contains a set of base classifiers which are trained using random projection (RP) of original features onto higher-dimensional spaces. With Classification and Regression Tree (CART) as the base classifier, it has been empirically demonstrated that the proposed Random Projection Forest ensemble gives better classification results than those achieved by the Boosting, Bagging and Rotation Forest algorithms, offering a classification rate ˜88% with smallest standard deviation, which compares sharply with the published result of 82%.

  1. Integrating Evolutionary Game Theory into Mechanistic Genotype-Phenotype Mapping.

    PubMed

    Zhu, Xuli; Jiang, Libo; Ye, Meixia; Sun, Lidan; Gragnoli, Claudia; Wu, Rongling

    2016-05-01

    Natural selection has shaped the evolution of organisms toward optimizing their structural and functional design. However, how this universal principle can enhance genotype-phenotype mapping of quantitative traits has remained unexplored. Here we show that the integration of this principle and functional mapping through evolutionary game theory gains new insight into the genetic architecture of complex traits. By viewing phenotype formation as an evolutionary system, we formulate mathematical equations to model the ecological mechanisms that drive the interaction and coordination of its constituent components toward population dynamics and stability. Functional mapping provides a procedure for estimating the genetic parameters that specify the dynamic relationship of competition and cooperation and predicting how genes mediate the evolution of this relationship during trait formation. PMID:27017185

  2. Architectural phenotypes in the transparent testa mutants of Arabidopsis thaliana

    PubMed Central

    Buer, Charles S.; Djordjevic, Michael A.

    2009-01-01

    Flavonoids are low molecular weight secondary plant metabolites with a myriad of functions. As flavonoids affect auxin transport (an important growth-controlling hormone) and are biologically active in eukaryotes, flavonoid mutants were expected to have undescribed architectural phenotypes. The Arabidopsis thaliana transparent testa (tt) mutants are compromised in the enzymatic steps or transcriptional regulators affecting flavonoid synthesis. tt mutant seedlings were grown on hard-slanted agar (a stress condition), under varying light conditions, and in soil to examine the resulting growth patterns. These tt mutants revealed a wide variety of architectural phenotypes in root and aerial tissues. Mutants with increased inflorescences, siliques, and lateral root density or reduced stature are traits that could affect plant yield or performance under certain environmental conditions. The regulatory genes affected in architectural traits may provide useful molecular targets for examination in other plants. PMID:19129166

  3. Mouse genetic and phenotypic resources for human genetics

    PubMed Central

    Schofield, Paul N.; Hoehndorf, Robert; Gkoutos, Georgios V.

    2012-01-01

    The use of model organisms to provide information on gene function has proved to be a powerful approach to our understanding of both human disease and fundamental mammalian biology. Large-scale community projects using mice, based on forward and reverse genetics, and now the pan-genomic phenotyping efforts of the International Mouse Phenotyping Consortium (IMPC), are generating resources on an unprecedented scale which will be extremely valuable to human genetics and medicine. We discuss the nature and availability of data, mice and ES cells from these large-scale programmes, the use of these resources to help prioritise and validate candidate genes in human genetic association studies, and how they can improve our understanding of the underlying pathobiology of human disease. PMID:22422677

  4. Animal Models of Cystic Fibrosis Pathology: Phenotypic Parallels and Divergences

    PubMed Central

    McElvaney, Noel G.

    2016-01-01

    Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The resultant characteristic ion transport defect results in decreased mucociliary clearance, bacterial colonisation, and chronic neutrophil-dominated inflammation. Much knowledge surrounding the pathophysiology of the disease has been gained through the generation of animal models, despite inherent limitations in each. The failure of certain mouse models to recapitulate the phenotypic manifestations of human disease has initiated the generation of larger animals in which to study CF, including the pig and the ferret. This review will summarise the basic phenotypes of three animal models and describe the contributions of such animal studies to our current understanding of CF. PMID:27340661

  5. Witnessing Phenotypic and Molecular Evolution in the Fruit Fly.

    PubMed

    Heil, Caiti S S; Hunter, Mika J; Noor, Juliet Kf; Miglia, Kathleen; Manzano-Winkler, Brenda; McDermott, Shannon R; Noor, Mohamed Af

    2012-12-01

    This multi-day exercise is designed for a college Genetics and Evolution laboratory to demonstrate concepts of inheritance and phenotypic and molecular evolution using a live model organism, Drosophila simulans. Students set up an experimental fruit fly population consisting of ten white eyed flies and one red eyed fly. Having red eyes is advantageous compared to having white eyes, allowing students to track the spread of this advantageous trait over several generations. Ultimately, the students perform PCR and gel electrophoresis at two neutral markers, one located in close proximity to the eye-color locus, and one located at the other end of the chromosome. Students observe that most flies have red eyes, and these red-eyed flies have lost variation at the near marker, but maintained variation at the far marker, hence observing a "selective sweep" and the "hitchhiking" of a nearby neutral variant. Students literally observe phenotypic and molecular evolution in their classroom! PMID:23459154

  6. An Effective Method to Identify Heritable Components from Multivariate Phenotypes.

    PubMed

    Sun, Jiangwen; Kranzler, Henry R; Bi, Jinbo

    2015-01-01

    Multivariate phenotypes may be characterized collectively by a variety of low level traits, such as in the diagnosis of a disease that relies on multiple disease indicators. Such multivariate phenotypes are often used in genetic association studies. If highly heritable components of a multivariate phenotype can be identified, it can maximize the likelihood of finding genetic associations. Existing methods for phenotype refinement perform unsupervised cluster analysis on low-level traits and hence do not assess heritability. Existing heritable component analytics either cannot utilize general pedigrees or have to estimate the entire covariance matrix of low-level traits from limited samples, which leads to inaccurate estimates and is often computationally prohibitive. It is also difficult for these methods to exclude fixed effects from other covariates such as age, sex and race, in order to identify truly heritable components. We propose to search for a combination of low-level traits and directly maximize the heritability of this combined trait. A quadratic optimization problem is thus derived where the objective function is formulated by decomposing the traditional maximum likelihood method for estimating the heritability of a quantitative trait. The proposed approach can generate linearly-combined traits of high heritability that has been corrected for the fixed effects of covariates. The effectiveness of the proposed approach is demonstrated in simulations and by a case study of cocaine dependence. Our approach was computationally efficient and derived traits of higher heritability than those by other methods. Additional association analysis with the derived cocaine-use trait identified genetic markers that were replicated in an independent sample, further confirming the utility and advantage of the proposed approach. PMID:26658140

  7. HMG Nuclear Proteins: Linking Chromatin Structure to Cellular Phenotype

    PubMed Central

    Reeves, Raymond

    2009-01-01

    I. Summary Although the three families of mammalian HMG proteins (HMGA, HMGB and HMGN) participate in many of the same nuclear processes, each family plays its own unique role in modulating chromatin structure and regulating genomic function. This review focuses on the similarities and differences in the mechanisms by which the different HMG families impact chromatin structure and influence cellular phenotype. The biological implications of having three architectural transcription factor families with complementary, but partially overlapping, nuclear functions are discussed. PMID:19748605

  8. Operationalizing Frailty Using the Frailty Phenotype and Deficit Accumulation Approaches

    PubMed Central

    Theoua, Olga; Walstonb, Jeremy; Rockwooda, Kenneth

    2016-01-01

    In both demographic and clinical studies, frailty is understood as a multidimensional state of increased vulnerability compared with the status of others of the same age. Of the many theoretical definitions of frailty, two are commonly employed: the physical frailty/phenotypic approach and the deficit accumulation approach. The purpose of this chapter is to discuss how frailty is conceptualized and operationalized based on these two approaches. PMID:26301980

  9. [Partial trisomy of chromosome 15 with new phenotypic manifestations].

    PubMed

    Mar González, J; Llaurado Robles, R A; Cabrera Rivas, T; Lantigua Cruz, A; Rodríguez Verdecia, B

    1994-01-01

    A patient with a 15 partial trisomy and a 4 target chromosome in 100% of metaphases is presented. Phenotypic manifestations not previously described were observed such as macrocephally, long face, low implantation of ears, narrow forehead, epicanthal fold, copious eyebrows and synophrys, short nasolabial distance, convergent strabismus, delayed bucal eruption, long neck, hypertrophy of thenar and hypothenar bulging and articular hypermobility. The eyeground was degeneratively myopic. This case makes more extensive the variety of clinical manifestations of this disease. PMID:7997134

  10. The Broader Autism Phenotype in Simplex and Multiplex Families

    ERIC Educational Resources Information Center

    Gerdts, Jennifer A.; Bernier, Raphael; Dawson, Geraldine; Estes, Annette

    2013-01-01

    Mothers, fathers, and siblings from 87 multiplex (M-mothers, M-fathers, and M-siblings) and 41 simplex (S-mothers, S-fathers, and S-siblings) Autism spectrum disorder families were assessed using the Broader Phenotype Autism Symptom Scale. S-mothers, S-fathers, and S-siblings showed more social interest and were more expressive in their use of…

  11. Child with Sotos phenotype and a 5:15 translocation

    SciTech Connect

    Maround, C.; Schmerler, S.; Hutcheon, R.G.

    1994-04-15

    The authors report on a 4-year-old girl with Sotos phenotype and a de novo balanced translocation between the long arms of chromosome 5 and chromosome 15 [46,XX,t(5,15)(q35;q22)]. They suggest a relationship between genetic material at 5q35 or 15q22 and the expression of an autosomal dominant gene. 18 refs., 2 figs.

  12. Empirically derived phenotypic subgroups – qualitative and quantitative trait analyses

    PubMed Central

    Wilcox, Marsha A; Wyszynski, Diego F; Panhuysen, Carolien I; Ma, Qianli; Yip, Agustin; Farrell, John; Farrer, Lindsay A

    2003-01-01

    Background The Framingham Heart Study has contributed a great deal to advances in medicine. Most of the phenotypes investigated have been univariate traits (quantitative or qualitative). The aims of this study are to derive multivariate traits by identifying homogeneous groups of people and assigning both qualitative and quantitative trait scores; to assess the heritability of the derived traits; and to conduct both qualitative and quantitative linkage analysis on one of the heritable traits. Methods Multiple correspondence analysis, a nonparametric analogue of principal components analysis, was used for data reduction. Two-stage clustering, using both k-means and agglomerative hierarchical clustering, was used to cluster individuals based upon axes (factor) scores obtained from the data reduction. Probability of cluster membership was calculated using binary logistic regression. Heritability was calculated using SOLAR, which was also used for the quantitative trait analysis. GENEHUNTER-PLUS was used for the qualitative trait analysis. Results We found four phenotypically distinct groups. Membership in the smallest group was heritable (38%, p < 1 × 10-6) and had characteristics consistent with atherogenic dyslipidemia. We found both qualitative and quantitative LOD scores above 3 on chromosomes 11 and 14 (11q13, 14q23, 14q31). There were two Kong & Cox LOD scores above 1.0 on chromosome 6 (6p21) and chromosome 11 (11q23). Conclusion This approach may be useful for the identification of genetic heterogeneity in complex phenotypes by clarifying the phenotype definition prior to linkage analysis. Some of our findings are in regions linked to elements of atherogenic dyslipidemia and related diagnoses, some may be novel, or may be false positives. PMID:14975083

  13. Novel strategies to enforce an epithelial phenotype in mesenchymal cells.

    PubMed

    Dragoi, Ana-Maria; Swiss, Rachel; Gao, Beile; Agaisse, Hervé

    2014-07-15

    E-cadherin downregulation in cancer cells is associated with epithelial-to-mesenchymal transition (EMT) and metastatic prowess, but the underlying mechanisms are incompletely characterized. In this study, we probed E-cadherin expression at the plasma membrane as a functional assay to identify genes involved in E-cadherin downregulation. The assay was based on the E-cadherin-dependent invasion properties of the intracellular pathogen Listeria monocytogenes. On the basis of a functional readout, automated microscopy and computer-assisted image analysis were used to screen siRNAs targeting 7,000 human genes. The validity of the screen was supported by its definition of several known regulators of E-cadherin expression, including ZEB1, HDAC1, and MMP14. We identified three new regulators (FLASH, CASP7, and PCGF1), the silencing of which was sufficient to restore high levels of E-cadherin transcription. In addition, we identified two new regulators (FBXL5 and CAV2), the silencing of which was sufficient to increase E-cadherin expression at a posttranscriptional level. FLASH silencing regulated the expression of E-cadherin and other ZEB1-dependent genes, through posttranscriptional regulation of ZEB1, but it also regulated the expression of numerous ZEB1-independent genes with functions predicted to contribute to a restoration of the epithelial phenotype. Finally, we also report the identification of siRNA duplexes that potently restored the epithelial phenotype by mimicking the activity of known and putative microRNAs. Our findings suggest new ways to enforce epithelial phenotypes as a general strategy to treat cancer by blocking invasive and metastatic phenotypes associated with EMT. PMID:24845104

  14. Novel strategies to enforce an epithelial phenotype in mesenchymal cells

    PubMed Central

    Dragoi, Ana-Maria; Swiss, Rachel; Gao, Beile; Agaisse, Hervé

    2014-01-01

    E-cadherin downregulation in cancer cells is associated with epithelial-to-mesenchymal transition (EMT) and metastatic prowess, but the underlying mechanisms are incompletely characterized. In this study, we probed E-cadherin expression at the plasma membrane as a functional assay to identify genes involved in E-cadherin downregulation. The assay was based on the E-cadherin-dependent invasion properties of the intracellular pathogen Listeria monocytogenes. On the basis of a functional readout, automated microscopy and computer-assisted image analysis were used to screen siRNAs targeting 7,000 human genes. The validity of the screen was supported by its definion of several known regulators of E-cadherin expression, including ZEB1, HDAC1 and MMP14. We identified three new regulators (FLASH, CASP7 and PCGF1), the silencing of which was sufficient to restore high levels of E-cadherin transcription. Additionally, we identified two new regulators (FBXL5 and CAV2), the silencing of which was sufficient to increase E-cadherin expression at a post-transcriptional level. FLASH silencing regulated the expression of E-cadherin and other ZEB1-dependent genes, through post-transcriptional regulation of ZEB1, but it also regulated the expression of numerous ZEB1-independent genes with functions predicted to contribute to a restoration of the epithelial phenotype. Finally, we also report the identification of siRNA duplexes that potently restored the epithelial phenotype by mimicking the activity of known and putative microRNAs. Our findings suggest new ways to enforce epithelial phenotypes as a general strategy to treat cancer by blocking invasive and metastatic phenotypes associated with EMT. PMID:24845104

  15. Correlating phenotype and genotype in autism spectrum disorder research.

    PubMed

    McMurry, Andrew; Cervone, Maria; Polumbo, Gregory; McCray, Alexa T

    2008-01-01

    Genotype-phenotype association studies often require investigators to collaborate across institutions and research disciplines. However, the relevant data are often inaccessible, heterogeneous, and difficult to correlate. Our query aggregator allows an investigator to compose a query, broadcast it to Autism Consortium databases and aggregate the query results in near-real-time. This collaborative infrastructure enables integrative investigations across disciplines, institutions and modalities, and may drive new hypotheses for the genetic basis of disease. PMID:18998837

  16. Genotype/Phenotype Correlations in Tuberous Sclerosis Complex.

    PubMed

    Curatolo, Paolo; Moavero, Romina; Roberto, Denis; Graziola, Federica

    2015-12-01

    Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by the development of widespread hamartomatous lesions in various organs, including brain, skin, kidneys, heart, and eyes. Central nervous system is almost invariably involved, with up to 85% of patients presenting with epilepsy, and at least half of patients having intellectual disability or other neuropsychiatric disorders including autism spectrum disorder. TSC is caused by the mutation in one of the 2 genes TSC1, at 9q34, and TSC2, at 16p13.3. They respectively encode for hamartin and tuberin, which form an intracellular complex inhibiting the mammalian target of rapamycin. Mammalian target of rapamycin overactivation following the genetic defect determines the cell growth and proliferation responsible for TSC-related lesions, as well as the alterations in neuronal excitability and synaptogenesis leading to epilepsy and neuropsychiatric disorders. A causative mutation for the disorder is identified in about 85% of patients with a clinical diagnosis of TSC. Mosaicism and technology limits likely explain most of the no mutation identified cases. This review confirms that patients with TSC2 mutations considered as a group usually present a more severe phenotype, characterized by higher number of tubers, earlier age at seizure onset and higher prevalence of intellectual disability. However, the clinical phenotype of the disease presents a high variability, thus making the prediction of the phenotype on an individual basis still challenging. The increasing application of new molecular techniques to subjects with TSC has the potential to significantly reduce the rate of patients with no mutation demonstrated and to identify an increasing higher number of mutations. This would hopefully allow a better characterization of higher risk mutations, which might help clinicians to plan individualized surveillance plans. Furthermore, the increasing availability of disease registries to collect

  17. Coronary Intraplaque Hemorrhage Evokes a Novel Atheroprotective Macrophage Phenotype

    PubMed Central

    Boyle, Joseph J.; Harrington, Heather A.; Piper, Emma; Elderfield, Kay; Stark, Jaroslav; Landis, Robert C.; Haskard, Dorian O.

    2009-01-01

    Intraplaque hemorrhage accelerates atherosclerosis via oxidant stress and contributes to lesion development and destabilization. Normally, macrophages scavenge hemoglobin-haptoglobin (HbHp) complexes via CD163, and this process provokes the secretion of the anti-inflammatory atheroprotective cytokine interleukin (IL)-10. We therefore tested the hypothesis that HbHp complexes may drive monocyte differentiation to an atheroprotective phenotype. Examination of the macrophage phenotype in hemorrhaged atherosclerotic plaques revealed a novel hemorrhage-associated macrophage population (HA-mac), defined by high levels of CD163, but low levels of human leukocyte antigen-DR. HA-mac contained more iron, a pro-oxidant catalyst, but paradoxically had less oxidative injury, measured by 8-oxo-guanosine content. Differentiating monocytes with HbHp complexes reproduced the CD163high human leukocyte antigen-DRlow HA-mac phenotype in vitro. These in vitro HA-mac cells cleared Hb more quickly, and consistently showed less hydrogen peroxide release, highly reactive oxygen species and oxidant stress, and increased survival. Differentiation to HA-mac was prevented by neutralizing IL-10 antibodies, indicating that IL-10 mediates an autocrine feedback mechanism in this system. Nonlinear dynamic modeling showed that an IL-10/CD163-positive feedback loop drove a discrete HA-mac lineage. Simulations further indicated an all-or-none switch to HA-mac at threshold levels of HbHp, and this conversion was experimentally verified. These data demonstrate the creation of a novel atheroprotective (HA-mac) macrophage subpopulation in response to intraplaque hemorrhage and raise the possibility that therapeutically reproducing this macrophage phenotype may be cardio-protective in cases of atherosclerosis. PMID:19234137

  18. An Effective Method to Identify Heritable Components from Multivariate Phenotypes

    PubMed Central

    Sun, Jiangwen; Kranzler, Henry R.; Bi, Jinbo

    2015-01-01

    Multivariate phenotypes may be characterized collectively by a variety of low level traits, such as in the diagnosis of a disease that relies on multiple disease indicators. Such multivariate phenotypes are often used in genetic association studies. If highly heritable components of a multivariate phenotype can be identified, it can maximize the likelihood of finding genetic associations. Existing methods for phenotype refinement perform unsupervised cluster analysis on low-level traits and hence do not assess heritability. Existing heritable component analytics either cannot utilize general pedigrees or have to estimate the entire covariance matrix of low-level traits from limited samples, which leads to inaccurate estimates and is often computationally prohibitive. It is also difficult for these methods to exclude fixed effects from other covariates such as age, sex and race, in order to identify truly heritable components. We propose to search for a combination of low-level traits and directly maximize the heritability of this combined trait. A quadratic optimization problem is thus derived where the objective function is formulated by decomposing the traditional maximum likelihood method for estimating the heritability of a quantitative trait. The proposed approach can generate linearly-combined traits of high heritability that has been corrected for the fixed effects of covariates. The effectiveness of the proposed approach is demonstrated in simulations and by a case study of cocaine dependence. Our approach was computationally efficient and derived traits of higher heritability than those by other methods. Additional association analysis with the derived cocaine-use trait identified genetic markers that were replicated in an independent sample, further confirming the utility and advantage of the proposed approach. PMID:26658140

  19. Crab-mediated phenotypic changes in Spartina densiflora Brong.

    NASA Astrophysics Data System (ADS)

    Bortolus, Alejandro; Laterra, Pedro; Iribarne, Oscar

    2004-01-01

    Although plant phenotypic plasticity has been historically studied as an important adaptive strategy to overcome herbivory and environmental heterogeneity, there are several aspects of its ecological importance that remain controversial. The burrowing crab Chasmagnathus granulata eats Spartina densiflora, and also causes several geomorphologic changes that indirectly affect Spartina growth. Here we evaluate if this crab affects the sexual reproductive effort of S. densiflora by mediating changes in plant phenotypic plasticity (i.e., shape of leaves and spikes) while affecting aboveground production, and if these effects interact with disturbance intensity. We conducted local and regional surveys and two-year field experiments manipulating the density of crabs in a mature Spartina marsh where we clipped at ground level different 1×1 m marsh areas to create and compare crab's effect on young (plants growing after the clipping) and mature (unclipped) Spartina stands. Our results suggest that crabs mediate the phenotypic plasticity of sexual reproductive structures of Spartina. Crabs induced an increase in seed production (up to 721%) and seed viability, potentially favoring Spartina dispersal and colonization of distant sites. This effect appears to be maximal when combined with the experimental clipping disturbance. Crabs also exerted a strong effect on clipped plants by increasing the number of standing dead stems and decreasing the photosynthetic area and leaf production. These effects disappear in about two years if no other disturbance occurs. An a posteriori regional field survey agreed with our experimental results corroborating the prediction that plants in old undisturbed marshes have lower sexual reproductive effort than plants in highly disturbed marshes populated by burrowing-herbivore crabs. All these phenotypic changes have important taxonomic and macro-ecological implications that should not be ignored in discussions of applied ecology and

  20. Human Cancers Express a Mutator Phenotype: Hypothesis, Origin, and Consequences

    PubMed Central

    Loeb, Lawrence A.

    2016-01-01

    The mutator phenotype hypothesis was postulated more than 40 years ago. It was based on the multiple enzymatic steps required to precisely replicate the 6 billion bases in the human genome each time a normal cell divides. A reduction in this accuracy during tumor progression could be responsible for the striking heterogeneity of malignant cells within a tumor and for the rapidity by which cancers become resistant to therapy. PMID:27197248